An Administrative History of the National Cancer Institute’s

An Administrative History of the National Cancer Institute’s

Postby admin » Sun Dec 13, 2015 2:05 am

An Administrative History of the National Cancer Institute’s Viruses and Cancer Programs, 1950-1972
by Carl G. Baker, M.D

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To my wife, CATHY

Table of Contents

• Acknowledgements
• Preface
• Introduction
• Chapter 1: Background and Initiation of Viral Oncology Activities
• Chapter 2: Cancer Research Philosophy, Systems Research Planning, and Reorganization of the National Cancer Institute
• Chapter 3: Implementation and Early Program Outputs
• Chapter 4. Correction of Problems (Fine Tuning of Program Operations) and Further Expansion of Program Outputs
• Chapter 5. Politics and Science Interactions
• Chapter 6. Completion of Systems Planning for Implementation of the New Cancer Act
• Epilogue
• Reading List

The cell-free transmission of methylcholanthrene-induced lymphomas and development of murine leukemia viral antibody suggested that unmasking of latent leukemia virus might represent an indigenous actuating cause of the leukemia. Dr. Miller, based on experience gained from study of mass-immunization with polio-vaccine containing SV-40, suggested four steps that would greatly simplify follow-up studies:

1. to maintain samples of vaccine lots frozen in storage;

2. for manufacturers to keep records identifying persons experimentally immunized, with notation of the vaccine lot used;

3. for physicians to note on their records the lot numbers of (at least) newly approved vaccines for general use; and

4. for similar permanent immunization records to be kept by the mother for each of her children....

-- An Administrative History of the National Cancer Institute's Viruses and Cancer Programs, 1950-1972, by Carl G. Baker, M.D.
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Re: An Administrative History of the National Cancer Institu

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Acknowledgements

The National Institutes of Health (NIH) staff have been a constant source of information, wisdom, trust, and inspiration. Integrity and high standards have always been expected at all levels, from the top, at the level of the Director, on down. During my tenure at NIH, my fellow staff members in the National Cancer Institute were outstanding. The senior staff included Gordon Zubrod, Palmer Saunders, Nat Berlin, Dick Rauscher, Cal Baldwin, Lou Carrese, Jim Kieley, and Bud Morrison. Earlier, Ken Endicott, NCI Director, and Bob Learmouth, NCI Executive Officer, provided leadership and wisdom. There were many outstanding scientists on the staff; several were leaders in cancer research and were past Presidents of the American Association for Cancer Research. The staff of the Research Contracts Branch and the Grants personnel generously provided the mechanism to fund the research and also ensured proper accounting. The secretaries, laboratory technicians, and animal caretakers also had a sense of responsibility and worked to try to help solve the problems of cancer. I have tried to highlight all of these wonderful characteristics in this book.

In writing this book, Dr. Victoria Harden, NIH Historian, offered encouragement and helpful advice on many matters. Editorial guidance from Dr. Nancy Berlage was of essential help. Dr. Robert Stevenson, formerly NCI staff member and former Director of the American Type Culture Collection, has been of great help in charting the course of this book, and he also interviewed several of those who were knowledgeable of the viral oncology activities. Warm support from my family is gratefully acknowledged. My wife Cathy provided great help and encouragement.
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Re: An Administrative History of the National Cancer Institu

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Preface

Although the major advances of the science aspects of viral oncology are recorded in various histories, the science-administrative aspects and the managerial decisions behind the program developments have not been well set forth. This book discusses these elements in relation to the Viruses and Cancer Programs of the National Cancer Institute during the period, 1953-1972. The staff members who conduct the science-administrative efforts that lay behind the science have rarely received recognition of their contributions. Moreover, with the widespread use of advisory groups, the record makes it appear that the Federal Government staff has not been able to conduct the work without the advice of committees composed of non-Government individuals. Most of the time, however, the staff has formulated the program proposals, new guidelines and policies, after which advice was obtained. To be sure, many groups of outstanding experts can provide helpful advice in specialized areas. However, in broader areas (such as determining the value of various components in cancer research as a whole) those who work full-time on the total picture of cancer research may well have a better grasp of the subject than a committee that deals with the subject at three-day meetings held three times a year.

In addition, this book illustrates how the NCI Viruses and Cancer Programs added to the foundations of molecular biology and biotechnology and provided techniques, resources, and concepts important for research on AIDS. They funded, through contracts, production of developmental research resources that were otherwise not available. Currently, many of these resources and techniques, which are now available commercially, are outgrowths of the contract funding of these NCI R&D contracts.

This history of the NIH viral oncology program describes the activities of senior NCI staff and gives an accounting of scientific and administrative events; it shows the interweaving the two components. I have provided an account of key management decisions and actions for the period, 1953-1972. I have also described Congressional actions in relation to the National Cancer Act of 1971 and the various aspects of planning that went into it.

Prior to 1960 the NCI viral oncology extra-mural efforts were funded by grants for individual projects. During the period 1959-1960 efforts were made to begin to define the scientific problems and the resources needed. Staff also developed various options for managing the new viral oncology activities. The Viruses and Cancer Panel of the National Advisory Cancer Council (NACC)was formed and scientific-technical committees were appointed. As a whole, the internal NCI viral oncology efforts were enlarged.

From 1960 to 1966 there was a change in the NCI philosophy of cancer research from emphasis on project support of individual investigators (grants) to complementing the grants funding with broad multi-discipline, integrated programmatic efforts. This also encompassed a greater focus on defining goals and objectives. In order to do this, systems planning—-under the name “the Convergence Technique”--was utilized as a means of giving proposed program operations more central direction. In addition, NCI staff and NACC committees were reorganized to reflect the new philosophy. Contracts, integrated into the systems plan, became the major tool for implementing the program. Quality controls were instituted to ensure that contamination from interfering bacterial or viral presence in tissue cultures, and other deficiencies were corrected. After these changes, the Program picked up its pace in terms of accomplishments. Important research results were achieved on a regular basis, scientific information was exchanged between scholars, and there was increased availability of defined standardized resources. While the extensive annual reviews of the Program before the Scientific Directorate and the NACC required the NCI staff to generate large—even excessive—amounts of documentation, they nonetheless signaled that NCI was committed to making the viral oncology programs a success.
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Re: An Administrative History of the National Cancer Institu

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Introduction

The National Cancer Institute (NCI) Viruses and Cancer programs laid the groundwork for the development of molecular biology and biotechnology. The Special Virus Leukemia Program, and later the Special Virus Cancer Program, was especially significant. In 1982, Nobel Laureate James Watson, who was a member of the National Advisory Cancer Board, told Vincent DeVita, former Director of the NCI, “Given the still prevalent unfair public misconception that the NCI Tumor Virus Program was a failure, and the strong possibility (fact?) that most if not all of viral oncogenes have their human counterparts, the time is more than ripe for NCI to point out how well the public purse has, in fact, been used.” (NCI Monograph 64, May, 1984, page 1).

The NCI viral oncology programs provided the basis for the discovery of AIDS and supplied concepts, techniques, and tools for subsequent research on AIDS. In the January 18, 1999, issue of The Scientist, NCI geneticist Stephen J. O’Brien was quoted: ”The development of our sophistication in virology and immunology, and the relationship between genetics, virology, and cancer, all came out of this infusion of money in the virus-cancer program; it did empower us ... to recognize that [AIDS] was a virus -- and how it worked.” Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases, added: “Now that AIDS has really opened up whole new fields of research, there is cross-fertilizing back to cancer. But what we know about AIDS really emanated from a lot of creative people many years ago investigating the relationship between viral genes, cellular genes, and cancer transformation.” The NCI viral oncology program produced a new set of research tools necessary to further development of the field.

This document sets forth the programmatic history of the Viruses and Cancer Programs of the National Cancer Institute 1950-1972. Although the history of the scientific aspects of the viruses and cancer area has been well documented, the associated administrative aspects have not been well documented. This latter aspect includes the history of the development of the required quality resources: tissue culture cell lines; virus preparations; antibodies; special animals and animal model systems; hazard containing facilities; banks of human tissues and sera and other resources; low temperature storing equipment; and special instrumentation. Today most of these resources are commercially available, but in the early years of the Programs they were not available in the quantities needed, and many of the materials were of insufficient quality.

These programs in the early years, when the focus was on the scientific and technical matters, were illustrative of the cooperative relationship between NCI expert scientific and administrative staff and advisors outside the Government. They jointly analyzed the main problems to solve, set forth the strategic directions to go, identified the resources required, and outlined the administrative structures needed to implement the expanded effort. While the relationship was excellent at first, it deteriorated to some extent over the years as outside advisors became more heavily oriented to political factors, especially those resulting from appointments made to the National Advisory Cancer Council (NACC). The NCI staff was mostly responsible for implementing the administrative program; this included the review of project proposals, evaluation of program development, making actual decisions about the program and the approval of projects, the development of budget, and defending the program higher levels in the Executive Branch and the Congress. Some of the pioneering efforts in systems planning of biomedical research programs derived from the search for better ways to develop the budget, which included the Viruses and Cancer Programs. Individual outside advisors made some important implementation steps. With respect to advice, it is often better to have advice from an individual who is very knowledgeable than from a committee that usually must compromise to reach a conclusion. The Foreign Minister of Israel recently said, “Compromise is failure.” The January 2003 issue of Reader’s Digest quoted British Prime Minister Margaret Thacher as saying: “Consensus is the negation of leadership.” Also, to advise is easier than to implement.
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Re: An Administrative History of the National Cancer Institu

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Part 1 of 2

Chapter 1: Background and Initiation of Viral Oncology Activities

Little interest in viral oncology research was shown before 1953 when Ludwik Gross demonstrated that cell-free extracts of mouse leukemic tissues contained one or more viruses that caused cancer in animals. This finding led to the possibility that viruses caused human leukemia and perhaps other human tumors and that vaccines capable of preventing such cancers could be produced. Several other animal virus-caused tumors were soon identified; these results strengthened the possible significance for man.

These dramatic discoveries changed the views of cancer investigators from no interest to excitement in cancer virology research; the number of investigators interested in cancer virology began to increase. By 1958 the accumulated research findings led the Director, National Cancer Institute (NCI), and Nobel Laureate Wendell Stanley at their testimony before the Congressional Appropriation Committees to emphasize progress in cancer virology and to seek additional funds for this work. The Congress subsequently called for vigorous stimulation of research and training efforts in the study of the possible viral origin of human cancer. To emphasize the importance of this research, the Congress appropriated an additional $1 million for added viral oncology efforts. The NCI science-administrators decided these funds would be spent as research and training grants.

The National Advisory Cancer Council (NACC) recommended that long-term support be given to outstanding investigators, some of whom were active in poliomyelitis research. The Virology and Rickettsiology Study Section (V&R SS) concurred and invited grant proposals in four categories: 1) basic research on viruses and animal hosts, utilizing tissue cultures, electron microscopy (EM), and model systems with reference to man; 2) training; 3) distribution of living host and viral materials, and 4) expansion of the research grant mechanism to support large-scale inter-disciplinary explorations over a long period of time.

The NCI, with endorsement of the NACC, established an expert Panel on Viruses and Cancer to provide advice to the Council and staff, working with the V&R SS. At the request of NCI, The V&R SS agreed to an expedited review of grant proposals. to speed up the initiation of new cancer virology research.

After NCI expanded the virology grants program, the next task was to define the aim and scope of the effort, the primary scientific problems, and the resources required; the focus would be on the search for human tumor-causing viruses. The aim of the effort was to determine if any human tumors were viral induced and, if so, whether they could be prevented with vaccines. The scientific problems at this stage primarily dealt with techniques for isolating, identifying and classifying viruses from tumors and studying the effects of viruses on animals and cells, including tumor causation. A variety of resources would need to be produced to conduct the scientific investigations.

Tissue culture techniques are major tools in virology research, and NCI brought together in mid-1959 experts in the growth, characterization, and preservation of animal cells. However, before the tissue culture techniques could be profitably used in human virus research, several problems needed to be worked out. Because individual investigators had carried out their research largely independently, tissue culture cell lines developed with little coordination between these efforts. The cell lines needed to be standardized. In addition, other problems plagued researchers who used tissue culture systems, such as lack of standardization of tissue culture growth media, mislabeling of cell lines, contaminations with bacteria or viruses, and improper storage.

The experts developed a plan to address the most pressing problems: standardizing the tissue culture methods and cell lines; organizing a central tissue bank, and ensuring proper coordination and quality control. The Viruses and Cancer Panel, appointed earlier, delineated several immediate objectives for a more direct attack rather than the usual more general, long-term support of the basic research projects approach.

Over the course of several meetings, the staff and advisors refined and prioritized the list of other scientific problems that needed to be tackled. By the early 1960s, interest in cancer virology had increased dramatically. The integration of the scientific aspects and the resources into one program had its beginning at this time.

Although research advances were progressing rapidly, research tools needed to be made more reliable. By 1961, the staff and their advisors had developed a charter of very broadened scope for creating an enlarged program. Research advances were progressing rapidly. In addition, research concepts and approaches, techniques and methods, new resources, and data and knowledge gained from animal studies were being vigorously applied to the search for human tumor viruses. Problems with the quality control over resources still plagued the viral oncology efforts, but these problems would largely be solved over the next few years.

Early Cancer Work

Very little interest was shown in viruses and cancer research prior to 1953. In 1911 Peyton Rous produced sarcomas in chickens with cell-free extracts of the tumors and demonstrated that a virus was the causative agent. In the 1930’s a few additional viral-induced tumors were identified in rabbits (Rous and Beard; Shope), mammary tumor in mice (Bittner and Andervont), and kidney tumors in the frog (Lucké). The study of viruses and cancer was not even considered as part of cancer research in the 1938 report of the committee appointed by Surgeon General Parran to advise on the research to be funded by the newly established National Cancer Institute(Report: Fundamental Cancer Research, Public Health Reports, 53: 2121-2130, 1938). Members of the Committee were: S. Bayne-Jones; R. G. Harrison; C.C. Little; J. Northop; and J.B. Murphy, Chairman. Despite the unpopularity of work in the field, Joe Beard, Ray Bryan and Ben Burmester, and Rous himself, continued research on the Rous sarcoma agent.

Virus Causation of Leukemia

A dramatic change occurred (akin to the concept of the “paradigm change” of the historian Thomas Kuhn) in 1953 when the work of Ludwik Gross was confirmed by other investigators (Thomas S. Kuhn, The Structure of Scientific Revolutions, Chicago: University of Chicago Press, 1970). He produced leukemia in mice with cell-free extracts containing a virus. Soon after this (1953-1957), other leukemia producing viruses were found in mice by A. Graffi and by Charlotte Friend, and Sarah Stewart and Bernice Eddy isolated from mice a polyoma virus that produced twenty-three different tumor types in hamsters. Following this work Frank Rauscher isolated another leukemia virus, Henry Kaplan found another leukemia virus from irradiated mice, and John Moloney isolated a sarcoma virus from a sarcoma and later another leukemia virus. These research findings produced great excitement among cancer investigators as the results from the laboratory with animals suggested the possibility that some human tumors were caused by viruses and might be prevented with vaccines. The field quickly became very complicated with the finding that some of the viruses required “helper” viruses for them to produce their effects. Moreover, many of the animal systems and tissue culture cell lines were contaminated or even mislabeled.

1958

In the spring of 1958, NCI Director Rod Heller gave special emphasis in his testimony on recent developments in viruses and cancer research before the Appropriations Committees of Congress. He reported that several animal cancers had been induced by injection of cell-free extracts from leukemic tissues and tumors. These extracts had been filtered to remove all particles the size of bacteria or larger. Viruses were shown to be involved in the induction of the cancers. He also reported that the notion that viruses could cause cancer in man was of growing acceptance among cancer investigators. Nobel Laureate Wendell Stanley, who was a member of the National Advisory Cancer Council (NACC) and later a member of the NCI Board of Scientific Councilors (for NCI Intramural Research Programs), also testified before Congressional Appropriations Committees in favor of a larger budget than the one proposed by the Administration. He called for expanded research in viruses and cancer work and presented scientific evidence supporting the call for the expansion. Based on these presentations, in part, the Congress called for vigorous effort to stimulate research and training efforts in the study of the possible viral origin of human cancers. The aim of the effort was an expansive one: to search for viruses causing human cancers and their prevention. To the regular appropriation for the NCI of $27.814 million, the Congress appropriated an additional $1 million for added viruses and cancer efforts.

One of the earliest symposia that covered work on viruses and cancer was “Perspectives in Virology,” held in February 1958. The Program Committee consisted of Joe Beard, René Dubos, Bob Huebner, Morris Pollard, Richard Shope, and James Steele. There were 117 attendees (Perspectives in Virology, edited by Morris Pollard, John Wiley & Sons, Inc., 1959).

At the June 16, 1958, meeting of the National Advisory Cancer Council, the Council recommended long-term support (up to ten years in some cases) for outstanding investigators, with emphasis on the individual rather than on a submitted detailed project proposal. Grant support for viruses and cancer research was about $698,000 in fiscal year 1958 and $2,000,000 in 1959(about half the increase resulted from the special activities of the NCI Program on viruses and cancer).

The Virology and Rickettsiology Study Section (V & R SS), the regular NIH Study Section that reviewed grant proposals in the area of virology, sponsored a meeting on September 16, 1958, on “The Role of Viruses in Relation to Human Malignancies.” Fifteen expert investigators were invited to the meeting. They were: Joe Beard; Ray Bryan; John Enders; Charles Evans (Chairman); Hilary Koprowski; Salvatore Luria; Dan Moore; Alfred Prince; Stanfield Rogers; Harry Rubin; Albert Sabin; Jonas Salk; Richard Shope; and Jerry Syverton. Harvey Scudder, Executive Secretary, V & R SS, and Robert Backus, NCI, provided staff support from the National Institutes of Health (NIH). The group discussed expanding the research through technological, educational and institutional means. The members focused on four major categories:

1) basic research on viruses and animal hosts, utilizing tissue culture, electron microscopy, and model systems with reference to man;

2) greater emphasis on training;

3) improvement of the sources and distribution of living host and viral materials; and

4) expansion of the research grant mechanism beyond the current project concept to support large-scale inter-disciplinary explorations over a long period of time (Internal document, September 1958).

On September 18 the V & R SS itself endorsed the conclusions reached at the September 16 meeting and the statement from the June 16, 1958, NACC meeting that long-term support of investigators would be required.

The NACC Panel on Viruses and Cancer

At the November 1958 NACC meeting, the NCI established, with Council endorsement, a Panel on Viruses and Cancer with Council member Stanhope Bayne-Jones as Chairman. Robert Backus of the staff of the NCI Grants and Fellowships Branch was appointed Executive Secretary. The Panel, consisting of experts in virology and in cancer, was formed to provide advice to the Council and the NCI staff. Its function was to supply broad policy guidance, survey the field of viruses and cancer, identify areas needing greater emphasis, consider training needs, and give counsel on program needs and means of accomplishing goals. In performing these functions, the Panel would work closely with the V & R SS.

NCI science-administrators decided to use most of the $1 million special appropriation for grants to individuals. For the first time in the viruses and cancer area, NCI made a portion of the funds available for contracts should it become necessary to provide a mechanism for supplying tissue culture stem cells and human tumor tissues to investigators throughout the country. Administrators decided not to use contracts at that time for support of research work. Industrial organizations instead could apply for grants. During the initial stages, responsibility for the conduct of the Program was given to Carl G. Baker who recently had become the NCI Assistant Director after nearly two and a half years as Assistant to Dr. Joe Smadel, Associate Director for Intramural Research, NIH. This NCI assignment involved coordination of the various viruses and cancer activities, and close cooperation would be maintained with Ralph Meader, Chief of the Grants and Fellowships Branch and his staff, and with Harvey Scudder, Executive Secretary, V & R SS.

Following extensive discussions, the NCI asked the V & R SS to follow a precedent set on a few other occasions when Congress had earmarked funds for specific diseases. The Study Section was asked to nominate individuals for whom area grants might be recommended for long-term support. These grants were to be based on the individual rather than on a submitted detailed project description. To speed the process and allow new research to begin at once, letters of intent (to be followed by full grant proposals) were invited from outstanding investigators in the field. At the suggestion of the Study Section Chairman, Dr. John Dingle, staff of the NCI, along with Study Section members and its Executive Secretary, telephoned many investigators in the virology and cancer fields. Dr. Smadel, who knew most of the virologists who had worked in poliomyelitis research, telephoned them to invite their participation in the accelerated program.

1959

At a January 5, 1959 meeting, the V & R SS, in response to a request from NCI to expedite review of grant proposals, moved to speed up the process and help create a new accelerated program of research on the relation between human cancers and viruses. The Study Section circulated a statement to the scientific community on four areas that the Study Section would be interested in receiving grant applications. The statement read as follows:

RESEARCH ON THE RELATION 0F VIRUSES TO CANCER

The Study Section has been informed of the desire to establish a special mechanism for allocating funds with the intent of expediting research on the problem of the relation of viruses to cancer with special consideration of human malignancies. After thorough consideration, the Study Section expresses unanimous approval of the principle of all possible support of this field and wishes to make the following suggestions with respect to the procedure for implementing the program: 1) that funds allocated for this purpose be employed for the support of long term programs designed for the systematic approach to the direct study of viruses in cancer with special emphasis on human malignancies as rapidly as the development of knowledge and methods permit; 2) these funds shall be made available to any investigator judged to be competent to work in the field; 3) that the funds may be regarded as support for area research described in terms of general direction of approach; and 4) that the applications be processed by the Study Section and that a Subcommittee be appointed by the Chairman of the Study Section to expedite implementation of the special program (Minutes of V&RSS, January 1959).

At this meeting twelve “letters of intent” were discussed. The study section had accepted these abbreviated proposals for research, as a way to speed up the bureaucratic process. Six proposals (totaling $325,442 for fiscal year 1959) were recommended for approval, and six others (totaling $613,941) were deferred until additional information could be obtained. At another meeting on February 21 the Study Section met in special session to review twenty more applications totaling $1.332 million (first year only). With recommendations from the Study Section, the NACC at its March 2-4, 1959, meeting recommended approval of nineteen proposals for a total of more than $1 million (Minutes of the V&RSS Meetings).

NCI Tissue Culture Consultants Meeting

One of the major tools in virology research is in vitro cultivation of cells and of viruses. The effects of viruses on cells can be studied with profit in such systems. However, because investigators had generally worked largely independently, the tissue culture cell lines had been developed with little coordination or standardization. Thus, cell line names were not always accurately applied, cultures could be contaminated with viruses or bacteria, and the cell lines might not be properly characterized and stored. The staff of the NCI asked seventeen consultants to come to the NIH May 15-16, 1959, to discuss the need for, and possible technical problems involved in, coordinating the characterization activities of investigators working with cytological materials. These consultants were selected for their competence in various aspects of cell growth, characterization and preservation. At the meeting, the consultants generally agreed that coordination was rapidly becoming necessary: an overwhelming amount of information had been accumulated, but the data was nearly impossible to correlate because researchers had used varying methods and nonstandardized resources. They agreed that a tissue culture bank should be organized around contributions that would be made available to investigators who were participating in the program. This Consultants Conference was Chaired by Council member Dr. Charles Evans, University of Washington. Dr. Jerome Syverton, University of Minnesota, presented an opening statement on the “Characterization, Preservation and Supply of Tissue Culture Cell Lines.” Most of the members of the Viruses and Cancer Panel attended the meeting. The Panel met the day after the Conference and concluded that a clear need existed for a coordinated cell-characterization program and that a program should be given sufficient impetus and administrative guidance and support to assure the success of a self-sustaining program. A second Conference of the expert consultants was called for to determine how best to undertake a cooperative effort for initiating and sustaining a mammalian cell bank with insurance of quality control (Minutes of the Virus and Cancel Panel, May 1959).

The Second NCI Tissue Culture Consultants Meeting

The second Conference of the expert consultants was held June 3, 1959. A plan developed for the creation of one or more centralized tissue bank facilities and a number of participating ancillary laboratories. Provision should be made for a long-term, low-temperature preservation of valuable materials characterized for future reference and for regularly scheduled cultivation for distribution as starter cultures. It would be expected that investigators utilizing banked materials would provide detailed data and contribute information that would add to the characterization of the registered and/or reposited materials. Such a facility could serve to accelerate the pace of productive biological research by minimizing the duplication of effort and by integrating pertinent information on a cumulative scale. Two of the participants, Drs. Cy Stulberg and Lou Coriell, voluntarily submitted detailed applications to organize centralized laboratory facilities for the coordinated characterization and banking operations. Nearly all of the participants in the meeting volunteered services within their individual areas of competence in a cooperative program (Minutes of the Second Meeting of the Expert Tissue Culture Consultants, June 1959).

The First Meeting of the Viruses and Cancer Panel

The first meeting of the Viruses and Cancer Panel was held February 11, 1959. The Panelists focused on the best way to uncover the relationship between viruses and cancer. The members focused on several immediate objectives for a more direct attack, rather than broad, general long-term basic research projects. They delineated the following objectives:

1) that opportunities for better communication among investigators in various disciplines should be made available.

2) that arrangements be made for anticipated source material needs including: a) a registry of tumor-viruses and specific antisera; b) registration and retention of tissue cell lines to be available to investigators; and c) encouragement through grants if possible, or contracts if necessary, of research specifically directed to characterization and stabilization of tissue culture cell lines (the staff was requested to explore with The American

Type Culture Collection the extent of undertaking these items by the Collection with funding by grant or contract).

3) that available primate animal resources be determined for studies of inter-species transmission of viral agents from human sources.

4) that the needs for technical personnel and professional investigators for the present and future be reviewed.

5) that consideration be given to meeting certain specialized service needs such as immune sera preparation, instrument development, electron microscopy, etc. (February 1959, Minutes of the V&C Panel).

The recommendations were sent to the NACC.

The Second Meeting of the Viruses and Cancer Panel

The second meeting of the Viruses and Cancer Panel was held June 31, 1959. At this meeting members decided to recommend to the NCI and the NACC specific proposals to implement a coordinated cell characterization program. They felt that the Panel should not engage in any direct effort to “organize” a program of the magnitude and complexity envisioned at the first meeting. They also thought that NCI should form a “Cell Culture Collection Coordinating Committee.” The committee was to be made up of individuals particularly sensitive to the problems and needs of the Program. The NCI Director appointed Dr. Syverton Chairman of the Committee. The applications of Drs. Stulberg and Coriell and of Dr. Clark from the American Type Culture Collection were reviewed by the Pathology Study Section and subsequently assigned to the NIH Division of Research Grants for review. Favorable recommendations were made by the Pathology Study Section. An application from Dr. Clark for a matching funds facilities grant was recommended by the Health Research Facilities Council at $90,278. This Council was fully informed of the programming interests of the Viruses and Cancer Panel and the NCI staff. Robert Coghill (Special Assistant for Industrial Relations to the NCI Director and to the Head of the Cancer Chemotherapy National Service Center) and Carl G. Baker (NCI Assistant Director) assisted Dr. Clark in finding the matching funds required by the facilities grant. This grant allowed the move of the extensive invaluable collection of bacterial strains, fungi, virus preparations, and cell lines from a modified frame house fire hazard to a modern brick structure designed to meet functional requirements (Minutes of the Second Meeting of the V&C Panel, June 1959).

1960

By 1960 the interest in cancer virology had increased dramatically as evidenced by the support given by public institutions such as Congress and private public health organizations such as the American Cancer Society. At the Appropriation Hearings for fiscal year 1960 the Congress again expressed strong interest in viruses and cancer work. Funds appropriated for additional cancer research increased more than 30% for 1960 over 1959 to $37 million. For viruses and cancer research there were 108 grants totaling $3.6 million. For viruses and cancer training the amount of funding was $847,565. Another indication of the growing interest in cancer virology was the sponsorship by the American Cancer Society of a major symposium on “The Possible Role of Viruses in Cancer” held November 19-21, 1959. The meeting was organized by a committee of Richard Shope (Chairman), Joe Beard, Hilary Koprowski, Ted Puck, and Peyton Rous. Twenty-nine scientists were invited to attend (Cancer Research, 20, 669-830(1960)).

A New NCI Director

On July 1, 1960, NCI Director Rod Heller became Director of the Memorial Sloan-Kettering Cancer Center in New York City. Ken Endicott, who had been Chief of the NCI Cancer Chemotherapy National Service Center and then NIH Associate Director for Training and earlier, succeeded Rod Heller as NCI Director. Bo Mider, NCI Scientific Director, succeeded Joe Smadel as NIH Deputy Director for Laboratories and Clinics. On September 13, 1960, Ken Endicott made the following appointments: Ralph Meader, Associate Director for Grants and Training; Mike Shimkin, Associate Director for Field Studies; Stu Sessoms, Associate Director for Chemotherapy (and Chief, Cancer Chemotherapy National Service Center); Eli Nadel, Assistant Director; Gordon Zubrod, Clinical Director, with responsibility for intramural clinical research; and Carl Baker, Assistant Director, with responsibility for intramural non-clinical research. Dr. Baker was also made NCI Acting Scientific Director and represented the Institute at the NIH Scientific Directors meetings. Dr. Zubrod represented the Institute at the NIH Clinical Directors meetings. Dr. Endicott had experience in the grants philosophy of supporting individual scientists with project grants when he was Executive Secretary of the Pathology Study Section (while also conducting laboratory research on blood cell formation) and later Scientific Director of the NIH Division of Research Grants. When he headed the CCNSC he also gained science-management experience in developing defined multi-discipline programs aimed at solving specific problems (in this case discovering and developing new drugs useful in the treatment of cancer patients). While he strongly endorsed the support of basic research, he also believed the NIH research programs should include directed research target programs aimed at solving important disease problems. He brought this philosophy to the Directorship of the NCI and would proceed to reorganize the NCI to reflect this philosophy. This change was a shift from a largely reactive to an added proactive stance on the part of the management style of the Institute. The NCI Assistant Director, Dr. Baker, later the Associate Director for Program, was in agreement with this philosophy and would give Dr. Endicott strong support in bringing about the change.

The Third Meeting of the NACC Viruses and Cancer Panel

It had become evident by early 1960 that in vitro and whole animal systems as well as viral and antibody preparations were contaminated with various viruses. Characterized and standardized antisera and animal and tissue culture systems had to be developed to ensure sound quality controlled experimental systems comparable from one laboratory to another. The Viruses and Cancer Panel met September 29-30, 1960, and developed an outline for how the program should operate:

“Statement of Current Program Interests”:

1) Use of known tumor viruses in model systems for virus-cancer research, and the search for unknown tumor viruses in man and other animals.

2) Mammalian cell culture characterization, certification, distribution, and long-term preservation through a group of cooperating laboratories.

3) Procurement, certification, and distribution of virological typing reagents for human and experimental animal viruses, with establishment of typing centers.

4) Arrangements to facilitate provision of normal and neoplastic human tissue, including blood, for virus-cancer research, with establishment of collection centers.

5) Development of “defined” animals for laboratory research as characterized by viral experience and genetics (including tumor susceptibility).

6) Inquiry into studies of newborn primates as experimental animals for virus-cancer research, especially with reference to candidate human tumor viruses.

7) Utilization of primates with neoplastic diseases for virus-cancer research, with provision for harvesting primate tumors at whatever age they exist.

8) Encouragement of training in virology and related disciplines, especially as applied to neoplastic diseases.

9) Improvement in communication in the interdisciplinary area of cancer virology.

10) Development of special research equipment considered essential to the advancement of virus-cancer research (Minutes of the Third V&C Panel, September 30, 1960).

The rapidly enlarging activities related to resources needed for the research led to the formation of a new Virology Research Resources Branch (VRRB). The above list of the ten items was drafted by Harvey Scudder who had recently joined the NCI Division of Grants and Training under Dr. Meader and was made Chief of the newly created Virology Research Resources Branch. Robert Stevenson was to join the Branch from his position as Head of the Cell Culture Section at the National Naval Medical Center. The Branch was to have three Sections: Cancer Virology; Cell Culture and Tissue Materials; and Laboratory Animals.

The Viruses and Cancer Panel also passed several resolutions:

1) The Viruses and Cancer Panel should report directly through its Chairman to the Council, rather than to the Research Review Board which is the present arrangement.

2) Contract proposals serving the Viruses and Cancer Program should receive dual review for their scientific need and merit. The Panel unanimously recommends primary review by a competent technical committee and final review by the Panel itself, with communication to the Council. The advisory groups for the primary review might be such technical committees as the Cell Culture Collection Coordinating Committee, the Enterovirus Committee, and the proposed Committee on Laboratory Animals.

3) In addition, the Panel passed the following resolutions concerned with implementation of the new program in viruses and cancer research. The Panel recommended that the National Cancer Institute take the measures to:

a) Liquid nitrogen equipment: Encourage the design and production of liquid nitrogen refrigerator and accessory equipment suitable for individual laboratory use, for the purpose of long term preservation of mammalian cells, tissues, and other biologic reagents, for which satisfactory equipment is not now commercially available; grant or contract mechanism to be used, if necessary, to facilitate this aim.

b) Human material supply: Arrange at one to five hospitals or medical centers for the collection, preservation, and distribution of human tissues, including blood, both neoplastic and normal, properly processed and diagnosed; grant or contract to be used, if necessary, to accomplish this.

c) Committee on Laboratory Animals: Appoint a technical committee, preferably chaired by member of the Panel, to serve as an advisory group on laboratory animals, in order to undertake planning and technical guidance in the general areas of laboratory animal definition, provision, and techniques insofar as their development is considered essential to progress in the virus-cancer field. The Committee should be concerned with the development of facilities for handling virus-defined animals.

d) Typing reagents for mouse viruses: Encourage the development and procurement of typing reagents for mouse viruses, with independent confirmation as needed; grant or contract mechanism to be used, if necessary, to accomplish this.

e) Virology investigations at primate centers or stations: Encourage a cooperative program of viral investigation in the primate centers, which are currently being planned and financed by the National Heart Institute.

f) Primates for virus-cancer studies: Determine what must be done to make available primates of known background, especially new-born primates, for work in the virus-cancer field, and proceed in cooperation with other interested Institutes in achieving this goal.


g) Typing reagents for human viruses: Arrange for the production of adequate quantities of typing reagents (several liters) for any of the human viruses for which the production protocols are fully developed, using contracts or grants, if necessary.

h) Standardization of viral typing reagents: When considered necessary by the Viruses and Cancer Panel, arrange by contract or otherwise for the independent confirmation, standardization, and certification of viral typing reagents (antisera and antigens) produced under contract or otherwise.

i) Virology training: Establish two or more regional summer training centers, on west and east coast areas, for the training of experienced researchers in the virus and cancer field. These centers should represent institutes for advanced study, making provision for lectures, seminars, and laboratory sessions of various types. Some courses in basic techniques of virology and cancer research could be taught yearly, other courses in new techniques or development given as expedient (Minutes of the Third V&C Panel, September 30, 1960).

All these items, which indicated the broad scope of the effort, were essential for carrying out the viral oncology activities, and they would have to be integrated with the research activities into one total program.

At its November 14-16, 1960, meeting, the NACC recommended that the recommendations of the Panel be accepted in principle and that the various facets pointed out be utilized for furtherance of this program as seems appropriate. At that time 153 viruses and cancer projects totaling $5.6 million were supported by NCI grants (NACC Minutes, November 1960).

1961 - Enlarged Scope of Viruses and Cancer Research Programs

The acceptance of these recommendations developed by the NCI staff and advisors thus provided a charter of very broadened scope for development of an enlarged viruses and cancer program. This charter laid out the future general development of the research. The implementation of the new efforts, especially development of resources (largely under contract), required intensive effort by the NCI staff over the next decade. The volume of work required for developing invitations for contracts, evaluating contract proposals along with establishing review committees, justifying decisions on contractor selection, and monitoring contractor performance was extremely heavy. Many of the Federal Government procurement regulations and some auditing rules were not well suited for research. While over the next couple of years many advances were made, such as discoveries of additional animal cancer viruses and identification of various virus particles with the electron microscope, considerable confusion still existed as to identifying characteristics of tissue culture cell lines, virus and antibody preparations, animal test systems, and even animals themselves. Progress was made in the development of portable liquid nitrogen refrigerators for storage and transport of cell lines and tissues and in improving viability success in freezing and thawing specimens. Problems remained, however, for the selection, removal, collection, preservation, and distribution of mature and embryonic tissues. Human tissues were still in short supply. Quantification of viruses was improved through developments in complement fixation and other immunological techniques. A major step forward was the plaque assay developed by Renato Dulbecco, which allowed much better quantitation of virus levels. Production and certification of mouse virus reagents still had many problems (spelled out in detail in a July 27, 1961, memorandum sent by Wally Rowe to members of the program). Extensive efforts to overcome the confusion were made by NCI administrators and investigators, contractors, and grantees. Dr. Robert Huebner sent another comprehensive memoranda to the directors of NIAID and NCI proposing joint research efforts of NIAID (Huebner) and NCI (Shimkin) (“Collaborative Studies of viruses and Cancer as an Inter-Institute (NCI-NIAID) Effort,” February 20, 1961.)

Reorganization of the NCI

On February 27, 1961, Ken Endicott sent forward a memorandum containing an agenda for discussion with the Deputy Director, NIH on NCI reorganization of the “Grey Areas.” They were programs in the Field Investigations and Demonstrations Branch (FIDB), the Biometry Branch, the Cancer Chemotherapy National Service Center (CCNSC), and the Cancer Control Program in the Bureau of State Services (BSS), PHS. In the reorganization:

1) The Chief of CCNSC became Associate Director for Chemotherapy and also assumed responsibility for the virus program.

2) The Associate Director for Field Studies assumed responsibility for the Biometry Branch as well as for three new Branches (Epidemiology, Carcinogenesis Studies, and Diagnostic Research).

3) The FIDB was abolished and its activities were transferred, modified, or abolished, as appropriate.

4) Epidemiology, Diagnostic and Environmental activities of FIDB were moved to the Associate Director for Field Studies.

5) All grant activities of FIDB were transferred to appropriate branches under the Associate Director for Grants and Training. Field Investigation Grants became regular Research Grants. Traineeships and Clinical Training Grants were combined with Research Training Grants.

6) The Cancer Nursing Section would be transferred to BSS.

7) The Uranium Miners Study would be transferred to BSS.

8) NACC review of grants to States and Special Project Grants were discontinued.

The Virology Research Resources Branch, headed by Harvey Scudder, was shifted from the Division of Grants and Training under Dr. Meader to the Division of Chemotherapy under Dr. Sessoms (requested March 1, 1961 and approved by the Director, NIH, April 18, 1961). The main reason for this transfer was that the Chemotherapy staff had extensive experience in managing large projects on resources production funded with contracts. It was anticipated that the VRRB effort would expand in this direction.
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Re: An Administrative History of the National Cancer Institu

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Part 2 of 2

The NCI Policy Group

The reorganization was effected to allow the senior staff to focus on the science aspects and program planning and less on administrative details. The NCI Policy Group was the focal point for bringing about the science-management changes. On May 10, 1961, Dr. Endicott sent a memorandum to the NCI senior staff establishing a NCI Policy Group consisting of Dr. Endicott as Chairman; Mr. Learmouth; and Drs. Baker, Zubrod, Sessoms, Shimkin, Meader, and Sloan. Dr. Baker was to serve as Executive Secretary. The initial paragraph of the memorandum was:

“For some time, there has been a need for the Director to discuss in a systematic fashion with members of the staff who have major program responsibilities, certain aspects of operations and plans of the Institute. The need is especially great in the area of long-range planning and in those aspects of operations that necessitate coordination, and indeed integration, among the major segments of the Institute. The key to successful approaches to these problems lies in: 1) periodic, structured discussions by a small group of senior program leaders, and 2) careful, orderly, systematized selection of agenda items of major import and the appropriate staff work in conjunction with each meeting.”

To begin to make clear what was wanted, specific agenda items had to be formulated and selected. Further in the Memorandum:

“Dr. Baker has suggested that the following topics might be worthy of discussion:

I. NACC activities:

A. Organization and functions of Council Boards and composition of Council, Boards, Panels and technical subcommittees.

B. Council agenda.

C. Periodic reports to the Council, including their timing.

1. Design of the reports to ensure usefulness in overall Institute operating effectiveness and improved communication within NCI and NIH.

D. Extent of Council participation in long-range scientific program planning.

E. Role of Council in the review process in the face of large numbers of regular project grant applications, initiation of new grant programs, and the fact that the decisions on awarding most grants rest predominantly with the Study Sections since the Council rarely changes the Study Sections recommendations (how closely does the collective action on grant applications relate to Institute programmatic interests?).

II. Institute operations.

A. What are the most effective means of coordinating and integrating the activities of different segments of the Institute programs?

1. Participation of intramural scientists in programs of Field Studies, CCNSC and international activities:

a. Epidemiology.

b. Carcinogenesis.

c. Viruses-Cancer.

d. Geographic Pathology.

e. Cancer Diagnosis.

f. Chemotherapy.

2. Programmatic relationships:

a. Epidemiology and epizoology studies in Field Studies, Intramural and Viruses and Cancer programs.

b. Dynamics of the CCNSC programs and their relation to the viruses and tissue culture programs.

c. Carcinogenesis studies in Field Studies and in the Intramural area.

d. Enzymology and immunology studies in the Diagnostic Research Branch and the Intramural Branch.

B. Will work scheduling documents aid in accomplishing better Institute coordination of programs?

C. What should the nature of the Institute be five years from now?

Ten years?

1. What mechanisms should be employed to move toward the long-range goals?

2. What new programs should be instituted?

3. How can modern data processing methods help?

D. What should be the Institute training goals?

1. How large should the training programs be?

2. What types of training programs?

3. How best to move toward the training goals?

E. How should NCI relate to the BSS cancer programs?

1. Should a program of research on cancer patient care and rehabilitation be initiated?

F. How should NCI relate to the Bureau of Environmental Health?

G. How can the NCI weekly report and annual Highlights be improved?

1. The Policy Group can serve as a convenient mechanism for selection of appropriate scientific topics or areas.

H. What international programs should be engaged in by NCI?

I. Should more attention be given to awards for NCI staff?

1. How can the mechanics of award submittal be simplified?

J. Additional broad decisions on the new building.

III. Relationships with NIH:

A. What are the best mechanisms for dealing with the multiple channels for communication (and “semi-authority”) between the Institute and NIH staff?

1. What should NCI do, if anything, about the lack of clarity on the “grey areas” at the NIH level?

2. Should NCI seek to decrease the action channels outside the Director (NIH) -- Director (NCI) route?

a. Should NCI seek organizational changes in the non-Institute part of NIH?

B. What should NCI’s position be on NIH dealing with bigness?

1. Should we seek greater autonomy?

2. Should other types of decentralization be favored?

a. Decentralization of grants and fellowships activities.

b. Establishment of major field stations.

(I) In university settings?

(II) Relatively independent major Branches?

3. What are the alternatives to the continuing proportional expansion of NIH central services?

C. How should NCI programs and plans relate to the NIH farm and other animal activities?” (Internal NCI document, May 10, 1961).

Other suggestions were invited. This action initiated a management tool (the NCI Policy Group) that would form the basis for participation in policy formulations and operational decision-making by the knowledgeable senior staff of the Institute. It also developed into a forum through careful selection of agenda items and associated staff work for considering high priority subjects in cancer and dealing with problems needing attention that arose. Funding considerations and review actions on program plans and on contracts were ongoing functions of the Group.

The NCI Scientific Directorate

Later in 1961 Dr. Endicott further reorganized the Institute to strengthen functions of the NCI Policy Group. The Group was renamed the Scientific Directorate [much later called the Executive Committee]. Dr. Baker was appointed Associate Director for Program with enlarged Executive Secretary directorate staff and functions, plus added coordination and analysis and planning responsibilities. Dr. Zubrod was appointed Associate Director for intramural activities and NCI Scientific Director and was made Chairman of the Scientific Directorate. The Scientific Directorate became the NCI focus for program developments and direction (with final decision-making authority with the NCI Director).

NACC Boards and NCI Boards Advisory to the NCI Director

On May 22, 1961, Ken Endicott requested approval for reorganization of the NCI Advisory Committee Structure (approved by the NIH Director June 7, 1961). Partly, this action to change the NACC committees was taken because the Kennedy Administration wished to decrease conflicts of interest problems. However, Dr. Endicott had discussed with the NACC in closed sessions how the actions of the NACC and its committees might be improved, and the proposed reorganization carried NACC general agreement. The change constituted a shift of emphasis to science-technical oriented units from mostly administrative-mechanics orientation. The memorandum on this reorganization to NCI staff included:

1. All standing subcommittees of the National Advisory Cancer Council (Planning Board, Research Review Board, Training Review Board, Cancer Control Board, and Chemotherapy Review Board) are abolished.

2. Three Boards of the National Cancer Institute advisory to the Director, NCI, on programs that utilize research contracts in combination with direct operations for the three major collaborative research programs in virology, chemotherapy, and field studies were established.

These Boards and the technical Panels associated with each are as follows:

1. Viruses and Cancer Board

(a) Cancer Virology Panel

(b) Cell Culture Panel

(c) Laboratory Animal Panel

(d) Human Studies Panel

2. Chemotherapy Board

(a) Chemistry Panel

(b) Drug Evaluation Panel

(c) Endocrinology Panel

(d) Clinical Studies Panel

3. Field Studies Board

(a) Biometry-Epidemiology Panel

(b) Carcinogenesis Studies Panel

(c) Diagnostic Research Panel

ROTATION PLAN

1. Boards; Three or four members of the National Advisory Cancer Council will be asked to serve on each Board, one of whom will be asked to serve as Chairman. These Council members will rotate off at the time their Council appointment terminates. The remainder of each Board will consist of the several technical Panel chairman advising that Board and such members-at-large as might be required. The members-at-large will be appointed for one-year terms, renewable indefinitely.

2. Panels: The chairman and members of the Panels will be appointed for one year at a time, renewable indefinitely (Internal NCI document, June 1961).

Dr. Endicott explained in his requesting memorandum that turnover of advisors on a yearly basis (renewable at the option of the Director) rather than on a four-year basis would ensure new talent and better advice. As indicated in a memorandum footnote, at the time there was expectation that NIAID would be given responsibility for diagnostic virus typing reagents program for all of NIH.

Laboratory of Viral Oncology

In February 1961, the NCI had established in its intramural programs the Laboratory of Viral Oncology with Ray Bryan as Chief. This Laboratory was to include such outstanding investigators as Frank Rauscher, Jack Dalton, John Maloney, Sarah Stewart, Mary Fink, Guy de Thé, Bob Manaker, John Bader, Ruth Merwin, Giancarlo Rabotti, Lou Sibal, and Robert Zeigel. Ray Bryan prepared a detailed plan dated July 6, 1961, for expanding studies on human tumor viruses; space and position slots were the greatest shortages. Also projected were requirements of animals for the intramural programs. Gordon Zubrod, in his role as head of clinical activities and his special interest in leukemia, proposed collaborative studies with the Laboratory of Virology staff to learn for example if John Maloney’s findings in mice could be duplicated in human leukemia patients. With electron microscopy, virus particles like those found in mice were seen in some leukemia patients. The status of the viruses and cancer program was reviewed on July 6, 1961, by Ken Endicott with senior staff (Gordon Zubrod; Stu Sessoms; Carl Baker; Margaret Sloan; Bob Learmouth; Walter Magruder; and Ray Bryan). Background information for the review was provided by Dr. Bryan (his July 6 memorandum), and Dr. Zubrod added information on intramural projections and needs (Dr. Zubrod summarized proposals for intramural expansion of viruses and cancer investigations in a July 27 memorandum). Again shortages of space needs and position slots were prominent. Laboratory animals and tissue culture resources would need great expansion. The CCNSC could help with these animal needs by enlarging the outputs from contractors earlier established to increase animal production required for screening in chemotherapy assays. Carl Baker had prepared for review a preliminary program plan for a full-scale NCI program. It was in the form of an organization chart with functional headings suggestive of flow charts of the viruses and cancer activities that would be developed later. Very fruitful collaboration was established between NCI and Bob Huebner’s group in NIAID, which included Wally Rowe and Janet Hartley. A proposal for a field epidemiology study on viruses and cancer in the Hagerstown, Maryland, area as a collaborative effort between the Huebner group and the Epidemiology Branch in NCI Field Studies Division under Bob Miller led to establishment of a base laboratory and animal holding facilities (house-type trailers). This arrangement was temporary; future movement of the activity to the NIH farm at Poolesville would be explored. In addition to joint funding of the collaborative venture, the NCI would provide virus diagnostic reagents for cancer investigations to Bob Huebner and coworkers.

Panels of the NACC Viruses and Cancer Board and Coordination

The NACC Viruses and Cancer Panel was enlarged June 13, 1961, to become the NACC Viruses and Cancer Board with four panels: 1) Virology Panel (Joe Melnick, Chairman; Marvin Harris, Executive Secretary); 2) Cell Culture Panel (William Scherer, Chairman; Robert Stevenson, Executive Secretary); 3) Laboratory Animal Panel (George Poppensiek, Chairman; Robert Holdenried, Executive Secretary); and 4) Human Cancer Panel (Charles Evans, 38

Chairman; Robert Stevenson, Executive Secretary). Priorities and coordination among the Panels needed better definitions. Staff of NCI had some concern that perhaps too many permanent committees were being established. It is difficult to eliminate such committees. Special attention was given in the Director’s Office to coordination of the various viruses and cancer activities funded with contract, grant, and intramural monies. The central focal point was Dr. Baker who worked closely with NACC members and other advisors, Panel members and Executive Secretaries, senior program leaders, and, at times, grantees and contractors. The Executive Secretary position of the NCI Scientific Directorate provided other important coordinating functions.

Virus Typing Reagents

Virus typing agents had been produced under National Foundation for Infantile Paralysis auspices for the poliomyelitis effort by Herb Wenner and the Kansas University Endowment Association. Supplies of these reagents, consisting mostly of those for enteroviruses and adenoviruses, and the focus of programs to develop reference and diagnostic reagents for virology, were moved to the jurisdiction of the NIAID. The NIH movement of these reagents to NIAID without consultation with Dr. Bayne-Jones, who was head of the Viruses and Cancer Panel of the NACC, led to his resignation from the NACC. On July 1, 1960, NCI awarded a contract to the Association to produce virus typing reagents for the viruses and cancer program of NCI. NCI would maintain development for programs in cancer virology for the time being, though consideration was being considered to place all NIH virus activities under the jurisdiction of NIAID. Ken Endicott proposed that a NIH Division of Research Resources be established to provide essential research resources and that a Viral Diagnostic Reagents Program be a part of the Division. Such a Division was later established, but the expansion of tumor viruses reagents was developed by NCI.

Review of VRRB Program Philosophy

On August 15, 1961, Dr. Endicott notified NCI staff of the transfer of the Virology Research Resources Branch (Harvey Scudder as Branch Chief) from Dr. Meader (Grants and Training) to Dr. Sessoms (now NCI Associate Director for Collaborative Research). In a communication in early November 1961 to Dr. Scudder, Dr. Endicott expressed a growing concern that the NCI viruses and cancer effort was fragmented and diffuse. He expected some difficulties in communication because of rapid growth and subdivision of effort. However, he came away from the meeting of the Viruses and Cancer Board with a feeling that the viruses and cancer efforts were not as clearly organized and on course as they should be. Though there were many examples of superb staff work, they seemed to be somewhat off target and fell short in leading to concrete action. Dr. Endicott was also concerned over the apparent lack of communication between the VRRB staff and those in other parts of the Institute who were working on essentially the same problems. There appeared to be a difficulty of communication between Ken Endicott and Harvey Scudder and a difference in philosophy as to the administration of the VRRB Program. Dr. Scudder saw the Branch Program as an enabling activity to provide grantee scientists resources needed for their research. Reagents produced under the Program would be available upon request. Dr. Endicott saw the Branch Program as producing resources based on a defined need of the various resources. The Program should be a planned effort that integrated the various scientific, managerial, and resources components into a unified entity. Dr. Endicott wanted a clear spelling out of what the VRRB was trying to do and how it was proposed to accomplish the tasks. A meeting was held to review the status of the Program, and Dr. Endicott, perhaps partly because of the discussions at the NIH level on the centralization of viruses reagents programs in NIAID, asked Dr. Scudder how long it would take to close down the VRRB Program. Dr. Sessoms sent forward on January 8, 1962, to the Director’s Office Dr. Scudder’s F.Y. 1963 professional judgement budget for VRRB requesting $7.417 million for contracts, an increase of $3.507 million. The F.Y. 1963 apportionment figure for VRRB contracts was $6.150 million.

1962 - Cancer Facilities Construction Needs

In January 1962, Dr. Endicott responded to Dr. Shannon’s request to the Institute Directors for construction needs in their respective areas. The response referred to a two-year old sample survey of ten cancer research institutes made by Dr. Heller. Reported building plans for 1960-1965 totaled $29 million of which over half were for immediate needs (land costs and space for research beds and non-research clinical laboratories were not included). In F.Y. 1961 NCI received 33 applications for $23,982,816; the NACC recommended 15 applications for $11,506,581. The $10 million appropriated in 1961 and 1962 met immediate needs. Dr. Endicott expressed dissatisfaction with respect to disease categorical research and on the separation of funds for operations, manpower and facilities unrelated to cancer and other diseases. Although construction needs are tied to program requirements in NASA, DOD, and AEC, in PHS, funding for facilities for the most part had not been related to cancer research. Advisors to the NIH Health Research Facilities Branch had shown no special interest in furthering cancer research. Moreover, only the wealthiest cancer research institutes could meet the 50:50 matching requirement. Dr. Endicott proposed that NIH seek legislation similar to that of NASA, DOD, and AEC that would make construction funds directly related to program needs. The viruses and cancer activities did indeed require additional construction and renovation funds.

American Type Culture Collection Committee

An advisory committee to the American Type Culture Collection (ATCC) had been meeting for over a year. In preparation for the seventh meeting on April 15, 1962, a Policy Statement had been developed. The ATCC would serve as a repository for cell lines certified by the Cell Collection Coordinating Committee (CCCC or the C-4 Committee). Certification would be based on criteria developed by the Committee: history or genealogy; sterility; morphology; media and growth factors; species specification; viral susceptibility; and specific characteristics. Quality controls were to be based on the certification criteria. Nomenclature and sample handling were spelled out in the Policy Statement. The members of the Committee were: W. Scherer, Chairman; H. Morgan; T. Hsu; D. King; H. Meryman; K. Sanford; John Shannon; C. Stulberg; and R. Stevenson, Executive Secretary. The Policy Statement was approved. Dr. Stevenson reported that the sample handling guidelines were suitable for government regulations regarding shipment in the U.S. Storage and shipments with the liquid-nitrogen refrigerators and freezing and thawing instructions were working well. Consideration was given to a contract proposal from Melpar, Inc. for establishing standards and analyzing samples from other contractors and grantees for components of chemically defined cell culture media.

The Chemically Defined Tissue Culture Media Committee

On May 11, 1962, a meeting was held by another committee concerned with tissue culture: the Chemically Defined Media Committee, a group constituted at the request of the CCCC to make suggestions for more thoroughly characterizing and improving cell culture media. Members of this group were J. Morgan; W. Swim; C. Weymouth; V. Perry; T. McCoy; D. Pace; H. Eagle; D. Merchant; R. Parker; R. Holmes; R. Hull; R. Pumper; K. McCarty; C. Rappaport; and R. Stevenson, Executive Secretary, CCCC. The Melpar proposal, which called for producing five 2000 liter lots of media (standardized with advice of the Committee based on data) was discussed. The participants each discussed their experiences, including problems with purity of chemicals, e.g., allo-isoleucine contaminating leucine. Dr. Eagle was skeptical that group effort could be as good as the same number of individuals working individually, a view he still held in 1971 with respect to planning for implementation of the National Cancer Act of 1971. A second meeting was called for the fall of 1962.

In May 1962 Lou Carrese joined Carl Baker to enhance the systems analysis and planning efforts in the Director’s Office. Dr. Baker had been seeking better ways to develop and present budget priorities and documents, and he had found that systems developments in other agencies offered possible improvement. In addition, systems networks were good for considering program priorities. Lou Carrese, who had a master’s degree in industrial psychology, had experience in Department of Defense contract work in smaller companies where he had had to integrate various functions. A productive collaboration developed that led to expanded planning efforts in cancer research.

NCI Staff Planing Conference

In mid-June, 1962 a two-day Planning Conference attended by the NCI senior staff was held at Airlie House Conference Center, Warrenton, Virginia. In attendance were: Ken Endicott; Bob Learmouth; Ralph Meader; Mike Shimkin; Gordon Zubrod; Stu Sessoms; Nat Berlin; and Carl Baker. Review of the science and management aspects of all programs of the NCI was made. Philosophic bases, current status and future projections for the different NCI program areas were discussed. The general conclusion was that NCI needed to spell out more clearly what problems should be selected for emphasis and what should be done to try to solve the selected problems. Resource requirements should be defined. The NCI Scientific Directorate should make the selections and decide on the courses of action. Underlying the Scientific Directorate considerations should be planning documents prepared by a secretariat in the Office of the Associate Director for Program. Programs for Viruses and Cancer, Carcinogenesis, and Cancer Diagnosis should be structured to function along the lines of the CCNSC. These units, along with Biometry and Epidemiology, would constitute the Collaborative Research of NCI. It was evident that internal shortages in positions and space were limiting program development. As had been demonstrated by the CCNSC effort, contracts increased the ability to expand research in cancer. More investigators could be engaged and added resources could be brought to bear on solving problems. Different scientific disciplines could be integrated into defined efforts, and resources could be more precisely defined and applied to specific problems. Another example of engaging scientists outside NCI was collaboration with Bob Huebner and his group in NIAID by transfer of some NCI funds and positions [Mike Shimkin’s comment about the Huebner collaboration was, “Give Huebner the funds and let him go”]. It was agreed the program planning did not mean telling investigators what experiments they should do. At the program and Institute levels, leadership by NCI staff should be shown and the scientific community should be kept informed of developments and the rationale behind them. The Institute should continue to work closely with the NACC. It was perceived that there was a need to move away from details of individual projects and to move to broader program reviews. The workload on Council members was becoming unmanageable. Program reviews by the NACC would require better documentation.

VRRB F.Y. 1963 Program Proposal

On August 2, 1962, a memorandum to the Director, NCI, over the signature of Randall Thompson, Acting Chief of the VRRB, set forth Branch Program Recommendations for F. Y. 1963. Proposed were 19 projects in 7 areas: 1) Modification of resistance of experimental animals to tumor viruses; 2) Selection of reference strains of tumor viruses; 3) Serological survey of laboratory workers; 4) Comparative susceptibility of types and species of animals to tumor viruses; 5) Search for tumor-associated viruses in animal tissues; 6) Search for tumor-associated viruses in human tumors; and 7) Establish a Cell and Organ Culture Task Force. Because much was already being done in other places, less emphasis would be given to: a) Large scale attempts to isolate viruses from human tumor specimens; b) Extensive serological surveys of human and animal populations; and c) study of immune mechanisms associated with human cancer. The need for integrating various contract efforts was noted; one example was the testing by Microbiological Associates of germ-free animals produced by Carworth Farms. Special emphasis would be given to leukemia with close collaboration with the Leukemia Task Force under the Chairmanship of Gordon Zubrod. VRRB would fund some of the Task Force costs generated by supplying of human tissue specimens and possibly by studies of anti-viral chemotherapy. Projected funding for viruses and cancer research for F.Y. 1963 was $6.457 million for grants and $6.150 million for contracts. The need to relate more closely to other viruses and cancer efforts by others was recognized and would become clearer after the NCI reorganization was completed.


On August 16, 1962, Dr. Endicott responded to the August 2 memorandum from the Acting Chief, VRRB. After review of the Program proposals, Dr. Endicott considered the document to be an excellent review and a comprehensive survey of possibilities. However, with limited resources available, everything could not be done. Hence, priorities would need to be established. For this, advice would be sought from the Viruses and Cancer Task Force which would be convened a short time later. No contracts would be transferred from VRRB to the new NIH Division of Research Facilities. No personnel would be taken from VRRB except Dr. Thompson would move to CCNSC where he could work on virus chemotherapy, an area of special interest to Dr. Thompson.

Collaboration with Dr. Huebner’s Group in NIAID

Dr. Robert Huebner was very well known as an outstanding productive investigator. Not so well known was his ability to construct excellent incisive memoranda on laboratory and organizational operations. They were concise, but comprehensive, placing the subject in a broad background perspective. The problem was clearly stated, and the effort aimed at solving the problem was outlined. Resources required for the proposed program were also spelled out. One such memorandum was his August 22, 1962, one entitled “The Oncogenic Virus Program in the Laboratory of Infectious Diseases” [in NIAID]. It was addressed to the Directors, NIAID and NCI. Drs. Huebner, Rowe, and Hartley of the LID had decided to devote their efforts to the viruses and cancer field. The earlier work of the LID was briefly summarized to show that the LID had unusual capabilities to contribute to this field. In the laboratory, focus had been on characterizing the biological properties of tumor viruses and adapting conventional viral techniques for use in defining their natural behavior. In the field, the approach was similar to that in previous studies of rickettsial diseases (rickettsialpox and Q-fever), Coxsackie diseases (herpangina and pleurodynia), and respiratory virus diseases (due to adenoviruses, para-influenzas, R.S., Eton Agent, etc.). In addition to direct searches for tumor viruses, Dr. Huebner and coworkers (with aid of Microbiological Associates contracts) were able to conduct serological procedures for 120 human and animal viruses, including the well known oncogenic viruses (adenoviruses type 12 and 18; bovine, rabbit, and canine papillomas; polyoma; and SV40). Also available for pilot sero-epidemiological surveys of cancer patients were group and specific antigens for all known myxoviruses, poxviruses, adenoviruses, reoviruses, salivary gland viruses, enteroviruses, and others. The prime obstacle again was shortage of space and positions. NCI had provided to the LID some contract funds and 10 positions (and possibly 4 more for the coming year), but space needs could be met only partially with contracting with commercial organizations. Dr. Huebner, in his memorandum, had proposed a new building to meet the space problem. Nearly five years would pass before it was possible to transfer Dr. Huebner to NCI. Space then had to be taken from other NCI activities.

Additional Resources for Dr. Huebner’s Viruses and Cancer Program

As a follow-up on Dr. Huebner’s memorandum of August 22, a meeting was held on September 5, 1962, of NCI senior staff (K. Endicott; C. Baker; M. Shimkin; R. Bryan; P. Kotin; and R. Stevenson) with Bob Huebner. To carry out the expanded viruses and cancer efforts projected for the future, expansion of resources was required (in addition to space and positions): 1) animal production, including large animals; 2) long-term animal holding; 3) virus identification services; 4) histopathology services (central services and special technologies); 5) electron microscopy; and 6) training. Grants or intramural programs could not meet these needs.

The use of contracts offered solution to the problems. The group discussed possible contractors who might be able to help: Microbiological Associates; Pfizer; Bionetics; Hazleton Laboratories; Walkersvile; Flow Laboratories; Melpar; AEC-Union Carbide; Fort Detrick; Pennsylvania State University; University of Pennsylvania; University of Tennessee-Oak Ridge National laboratories; and Michigan State University. Some of the CCNSC contracts could be modified to help in meeting VRRB needs. A new building was not required. Indeed, a single building would invite cross-contamination. Rather, 10-15 trailers (about 100 square feet) separated from each other would allow Dr. Huebner to begin expansion of high priority work. Dr. Bryan would develop data on the projected needs.
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Re: An Administrative History of the National Cancer Institu

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Part 1 of 2

Chapter 2: Cancer Research Philosophy, Systems Research Planning, and Reorganization of the National Cancer Institute

The primary device used by the National Institutes of Health (NIH) for funding biomedical research during the period under discussion was a research grant made to an individual investigator. Two groups reviewed the grant proposal: first, a Study Section for excellence in a scientific discipline (such as biochemistry or immunology); and second, a Council for relevance to a disease (such as cancer or diabetes). The Council usually concurred in the recommendation of the Study Section. Recommendations for approval were given priority scores, and grants were paid down the ordered list of scores until the funds were exhausted. The National Cancer Institute (NCI), since Congress established it in 1937, continues to fund much of cancer research by this mechanism.

Dr. Kenneth Endicott, who was appointed Director of NCI in 1960, believed that many problems in cancer research required broader, multi-discipline efforts and that better planning of such efforts was needed. He took steps to complement the philosophy of the grants approach supporting projects with defined problem-solving research programs. Contracts were used to fund much of the new work since some central control was necessary to ensure coordination to achieve the integration of parts into a program systems whole. The NCI Office of the Director reviewed the state-of-the-art of systems planning and made modifications to accommodate the research aspects, developing the ”Convergence Technique.” The staff began development of an overall systems plan for the NCI.

The Director also began a reorganization of the Institute and the NACC to reflect the change in research program philosophy. It proved to be difficult and took six years to fully complete (though planning and reorganization are on-going and are never final). Within the Institute the reorganization was effected with a series of management memoranda detailing general guidelines, responsibilities, structural changes and lines of authority, and requirements for reviews of programs and contracts. With respect to the NACC, difficulties were encountered with some Council members in gaining acceptance of the new research program philosophy and in reaching agreement on what and how much information the NCI should provide to the Council.

NCI Review of Program Plans and Contracts - Standing Committees

To improve the functions of NCI and ensure sound quality of contracts, in a September 10, 1962 memorandum (drafted by Carl Baker) Dr. Endicott informed the NCI staff of the abolishing of all panels and boards consisting of outside consultants in accordance with President Kennedy’s concerns about conflicts of interest (see above). Instead, Review of contracts would be done by internal committees. Dr. Endicott suggested that two standing committees be established to review program plans and provide preliminary review of contracts: (1) the Committee on Etiology and Prevention; and (2) the Committee on Diagnosis and Treatment. According to his plane, the final review of program plans and contracts would rest with a staff group of senior NCI program leaders under the chairmanship of Dr. Endicott. Two advisory groups corresponding to the two committees would be established from the NACC, and a large roster of additional outside consultants would be established and maintained. The memorandum continues:

Through this mechanism we intend to provide sound review of contracts within a framework of well thought-out, broad program plans, with appropriate attention to their interrelatedness, importance and significance to the mission of the National Cancer Institute.

In addition to providing: a) broad, long-range support in wide segments of biomedical sciences through the grants mechanism and b) broad support for certain types of research effort requiring a more coordinated effort through the contracts mechanism, we need a mechanism to ensure not only the support for, but forceful and rapid execution of research programs focused on specific problems of high priority and importance, urgently in need of solution.

To provide this latter mechanism, I am establishing Task Forces (only two initially) which will be constituted of scientists from both within the Institute and in outside research organizations who are particularly suited to work together and execute the research aimed at solutions of particular problems, both because of their particular interest, knowledge, skill and motivation and their ability to utilize effectively the types of resources required. Task Forces are expected to concentrate efforts and resources on the problems selected, within a plan formulated by them that calls for a termination of the Task Forces within a finite period of time, most usually not longer than about three to five years. It is important, therefore, that the Task Forces develop their objectives in a concrete manner with a sense of exerting concentrated effort on specific, important and urgent problems, solutions to which are expected within a relatively short period of time. To work with the Task Forces will be a Secretariat consisting of additional Institute Staff, and to assist the group will be contract monies available if needed and justified, in addition to resources already available for operations of the Task Force members. In some respects the Task Forces will operate in a manner similar to that followed by the World War II Commissions of the Armed Forces Epidemiological Boards.

One of the Task Forces will be the Human Cancer Virus Task Force. This group will be asked to pose specific cardinal questions directed toward examining the possible role of viruses in the etiology of some types of human cancer, to formulate plans suitable for the Task Force operation for obtaining answers to these questions in the earliest possible time, to implement the plans, and to assess periodically progress made under the plan. This will involve:

1. Identification of the specific problems involved in relating viral agents to the etiology of human cancer.

2. Assessment and evaluation of the present efforts directed toward establishing the viral etiology of human cancer.

3. Delineation of feasible approaches which could be used to augment current research and to explore new areas and to establish priorities for their implementation.

4. Determination of factors that are impeding progress along such feasible approaches.

5. Initiation and implementation of programs to overcome obstacles and to speed progress in exploiting to the maximum the most attractive avenues of approach.

Those invited to become members of the Task Force have already made a prior commitment to the study of the human cancer problem and have established programs commanding relevant ideas, trained personnel and appropriate resources(Internal NCI document, September 10, 1962).

This memorandum was a further effort to complement the philosophy of the grants approach supporting projects of individual investigators with multi-discipline, defined problem-solving research programs involving collaborating investigators and large-scale production of needed defined resources.

Dr. Endicott asked Ray Bryan to be Chairman of the Human Cancer Virus Task Force and Bob Stevenson to be Executive Secretary. Initially, it was planned that the membership include R. Huebner; R. Miller; J. Melnick; P. Kotin; J. Grace; and F. Horsfall. Others could be added later. The second Task Force, chaired by Gordon Zubrod, was on Leukemia, mostly on its treatment research. Collaboration between VRRB and the Leukemia Task Force developed effectively.

VRRB Progress Report - September, 1962

The production of high quality resources was as essential as the conduct of sound viral oncology scientific research. On September 17, 1962, the Virology Research Resources Branch, now headed by Bob Stevenson, sent the NCI Director a ten-page report on the activities of the Branch. The report was well prepared and overcame concerns of Dr. Endicott that the Branch program was too diffuse. The section entitled Progress to Date included the following highlights: 1) three tissue banks of characterized cell cultures and a distribution system to supply cell lines to cancer virologists had become operational (a contract for testing for PPLO and other contaminants was initiated); 2) a system for obtaining and supplying characterized human tissues had been developed for two sites (difficult legal and ethical issues had been addressed and dealt with); 3) in addition to the NIAID program on virus antigens and antibodies, NCI, under contract, produced antigens and antisera for six mouse viruses and would expect seven more paired reagents in the next year; these reagents were candidates for certification by the ATCC; 4) as part of the program to produce viral-defined laboratory animals, one commercial breeder had succeeded in production of significant numbers of germ-free mice on a weekly basis; 5) the value of larger animals (goats, marmoset) was being explored for improved production of viral reagents in addition to other systems; 6) VRRB staff brought together information for distribution to investigators on containment of laboratory infections; 7) a contract was let to ensure the availability of “gradacol” membranes, at the time the only way to size virus particles; 8) the Branch made a survey of training needs and initiated joint program efforts with the NCI Training Branch; 9) a program was instituted to search the literature for publications pertinent to cancer virology and make the results available to investigators in the field; this effort included grants and intramural research in addition to VRRB direct activities; and 10) the problem of inadequate facilities for work requiring control of viral infections was expected to grow and would be restrictive of progress unless regulations on renovation and new construction were to be modified.

Items under the heading 1963 Program Plans included the following: 1) the VRRB would become the staff focus for implementing program and administrative decisions that result from the Scientific Directorate and the Human Cancer Virus Task Force activities (implementation would involve an extensive coordinating role); 2) instead of developing program for general provision of virus resources, the VRRB would now have an integrated effort on programs focused on a) detection, isolation, characterization, growth and evaluation of viruses in human tumor tissues, with emphasis on leukemia (collaboration with the Acute Leukemia Task Force); b) determination of the viral experience of human subjects and the possible relationship to human cancer and studies on the ecology of viruses in man and animals (collaboration with Bryan’s and Huebner’s groups and Bob Miller); c) provision of animal virus resources with emphasis on oncogenic viruses; and d) carcinogenesis studies including attempts to clarify interrelationships of viruses, chemicals, and radiation (collaboration with Huebner’s, Kotin’s, and Bryan’s groups and possibly staff of Oak Ridge National Laboratory); 3) VRRB would be heavily involved in contract supported work; it would: a) serve as a means of bringing together at one point in the Institute on a continuous basis cancer viruses information required by the Scientific Directorate and the Human Cancer Task Force to make proper judgements and decisions for integrating and coordinating the various program and administrative decisions; b) make recommendations to these two groups on program implementation; c) provide Project Officers on contracts concerned with animal viruses resources, and on some contracts developed in conjunction with the Task Force; d) suggest new program developments to the Scientific Directorate, including possible programs for new Task Force implementation; e) assist in developing the facilities necessary for implementing the planned program areas, including animal quarters which would prevent viral contamination of the animals and possible hazard to the workers involved; and f) assist in coordinating the virus activities within the NCI, between NCI and NIAID, and between NCI and groups outside NIH. It was anticipated that the work of the Human Cancer Task Force would require the resources that had been developed through the Virology Research Resources Branch programs. The Branch staff would continue to develop, through the contract mechanism, additional resources required for animal virus studies and would serve as Contract Officers on the projects. Projected were collaborations with Drs. Huebner, Kotin, and Miller on epidemiology studies and on carcinogenesis investigations with viruses, chemicals and radiation [these investigations did not become fully developed].

At this time (1962), the Virus Contracts totaled $2,704,992 and the Cancer Virus Grants totaled $ 7,593,000; the Branch staffing was down to 9 positions (of 14 authorized). Space shortages continued as critical, and extensive analysis and planning steps were taken to begin to ease the shortages. Efforts were initiated to develop non-human primate resources. Consideration of holding animals in isolation was begun should isolated viruses prove to be hazardous to humans. Agreement with Oak Ridge National Laboratory was made for NCI funding of Norman Anderson to develop special centrifuge rotors for preparing virus and antibody reagents of higher purity.

The VRRB Progress Report included the following:

Continuing analysis of grant supported research, assisted in part by the analysis by the NCI Grants and Training staff was made. In addition to several grants made in conjunction with the cooperative program on cell culture characterization and certification, a major effort is underway in many laboratories attempting to evaluate the role of viruses in human cancer. The finding of Trentin that human adenovirus-type 12 induces tumors in hamsters (confirmed by Huebner and Rowe along with the demonstration that adenovirus-type 18 also is oncogenic in hamsters) and confirmation of the oncogenic nature of SV-40, further characterization of its properties in tissue culture (e.g., growth of virus and transformation with chromosomal changes in human cells in culture), and delineation of the nature of the PAPOVA viruses (especially by Melnick, Koprowski, and Hilleman) represent important highlights resulting from grant supported research. Production of tumors by combinations of viruses and chemical agents (e.g., lung epidermoid carcinoma induction in mice with influenza virus and an ozonized gasoline fraction) has provided base information for NCI program expansion aimed at clarifying interrelationships among chemicals, viruses, and radiation in their roles in carcinogenesis. Production of Shope papilloma tumors with highly purified nucleic acid by Ito and Evans adds to the growing body of information indicating that bare nucleic acid can produce disease (polyoma, poliomyelitis, phage, etc.). Knowledge of the type of nucleic acid and the intracellular sites of virus production for several oncogenic viruses has now been determined. The studies of Rubin on avian lymphomatosis which showed that chickens carrying the virus from the egg stage did not develop antibodies against the virus (presumably because of immune tolerance) have important implications for approaches to be employed in studying human cancer. These same studies showed that chickens free of virus at birth could become infected when placed in a flock containing chickens with the virus, but that the incidence of disease was six times lower in these chickens than in those which contained the virus in the egg stage. Studies on virus interference phenomena are throwing further light on the problems in need of solution for the detection of viruses in tumor and other tissues, and some leads have been developed in viral chemotherapy (fermentation producers, e.g., statolon, xersin; naturally occurring products, e.g., interferon; synthetic products, e.g., iododeoxyuridine, thiosemicarbazones, etc.)(Internal NCI document, September 10, 1962).

Additional Guidelines for NCI Standing Committees

On October 16 the Associate Director for Program sent a memorandum on “Additional Guidelines for the NCI Standing Committees” to the Chairmen of the Standing Committees (Carcinogenesis and Prevention and Diagnosis and Treatment). It provided information supplemental to Dr. Endicott’s earlier memorandum and its attached functional statements on procedures to be followed for contract reviews by the Committees and the Scientific Directorate. The intent was to provide helpful guidance for initiating the Committee meetings. The Committees were to become operational on November 1, 1962. The memorandum further stated:

The Committees are being asked to do two things;

(a) To review, evaluate, and report on the major developments of cancer research for their respective areas, indicating the major streams of development, the most important developments in broad terms, and scientific areas receiving too little or too much attention. In essence, the Committees are being asked to do the difficult job of distilling from a very large body of information the important broad aspects in cancer research. They are also being asked to review the NCI program activities, again in broad terms, and relate the information gleaned from the review to that obtained from the broad review of cancer research. From this they are being asked to provide advice to the Director on how well current NCI activities are going and where future emphases should be placed. The purpose is to evaluate the broad areas in ways which do not give undue emphasis to any particular discipline or other segment of cancer research, but rather place each in an appropriate over-all perspective; and

(b) with the above evaluation and background, provide advice to the Scientific Directorate on each contract proposal brought before the Committee for preliminary review.

It is obvious that these are difficult assignments to the Committees. Nevertheless, it should be pointed out that the need for this kind of advice for the Director has been exceedingly difficult to obtain in the past, even though most of the Advisory Committees were made up of some of the best scientists. The reason for this lack seems to be derived from: 1) The Committees tended to spend so much time on details of individual proposals that they were unable to deal with the broad subject, and 2) most of the Committees were brought together to advise on rather specific and somewhat narrow aspects of cancer research, rather than to look at the broad aspects of cancer research as a whole. The Council was mainly affected by the former problems and the Study Sections by both. It will take sustained attention to the assignments of the Committees as stated above to prevent these new Standing Committees from evolving the same way as the earlier advisory committees.

Although the Committees will wish to determine for themselves how they are to accomplish the difficult tasks before them, the following suggestions may be of help in putting the Committees into operation. While the major responsibility for the operation of the Committee will fall on the Chairman, a very key individual in making the Committees function well is the Executive Secretary for each Committee. Under guidance of the Chairman, it will fall to the Executive Secretary to see that the agenda for the meetings are properly developed with attention to what is most important for the Committee activities, to see that appropriate information is brought to the Committee membership prior to the meetings, and to follow up on the implementation and coordination required by actions taken by the Committees. The degree of success of the Committee functioning will depend to a great extent on how well the Executive Secretary can carry out these functions.

Initially, the Committees will need to spend considerable effort on reviewing their respective areas of cancer research in the broad framework of the assignment. To do this, it seems likely that segments of these broad areas will need to be reviewed in turn. The Committees were constituted to include individuals who have considerable knowledge of major segments of cancer research, and the Chairmen may wish to make assignments to members within the Diagnosis & Treatment Committee or within the Carcinogenesis & Prevention Committee. In this responsibility for summarizing for the full Committee, broad segments should include the highlights of current cancer research activities plus summarization of the corresponding NCI program activities. Those reporting will depend upon their own knowledge, their familiarity with the scientific literature, and certain materials produced by NCI, such as the Annual Reports. In some cases the Annual Report statements will be adequate; in others, totally inadequate. It will be very important for future Annual Reports to be strengthened in order to assist the Committees and the program operators in meeting their responsibilities. In a number of instances, broad critical reviews may be available which can help summarize important aspects of an area. It is expected that in the future additional sound critical reviews will be sought with actual payment for the writing done by means of the contract mechanism. Committees will probably also wish to invite individuals who are not on the Committees to present summarizations for particular areas to the Committee.

It is anticipated that once each year the Committees will prepare a written report for the Director which will summarize the state of development of cancer research in their respective areas plus proposed new developments, both scientifically and program-wise.

[These standing committees did not carry out their difficult assigned responsibilities. On the other hand, the Human Cancer Virus Task Force did very well in meeting its assignments. Much credit for this success should go to Dr. Stevenson, Executive Secretary of the Task Force, and to Dr. Charles Evans, the Chairman.]

The procedures to be followed in review of contracts are outlined in the material attached to Dr. Endicott’s memorandum. It should be noted that some of the continuation contracts which are proceeding satisfactorily without change (for example, straight animal procurement contracts) will not need to be brought before the Committees every year. This should save some time of the Committees in the contract review process.

It seems desirable for the Committees to have an initial organization meeting prior to the full-scale operations of program and contract reviews. If I can be of assistance in helping to clarify the system outlined by Dr. Endicott’s memorandum and the attached materials I will be glad to do so. If you wish me to attend the organizational meetings of the Committees please let me know (Internal NCI document, October 16, 1962).

Ray Bryan was appointed Chairman of the Carcinogenesis & Prevention Task Force and Gordon Zubrod Chairman of the Diagnosis & Treatment Task Force.

The First Meeting of the Human Cancer Virus Task Force

Also on October 16, 1962, the Associate Director for Program sent a memorandum to members of the Human Cancer Virus Task Force intending to provide information that might be helpful in preparation for the first meeting of the Task Force (October 25, 1962). Dr. Endicott’s letter of invitation was included in the memorandum. Dr. Endicott was unable to attend the meeting and asked Dr. Baker to meet with the Task Force to provide background information, orientation for the group, and clarification of what the National Cancer Institute was asking the Task Force to do. The memorandum continued:

In Dr. Endicott’s invitation of September 10, 1962 [drafted by C. Baker] was the following:

“Task Forces are expected to concentrate efforts and resources on the problems selected, within a plan formulated by them that calls for a termination of the Task Forces within a finite period of time, most usually not longer than about three to five years. It is important, therefore, that the Task Forces develop their objectives in a concrete manner with a sense of exerting concentrated effort on specific, important and urgent problems, solutions to which are expected within a relatively short period of time.” And further, “This group will be asked to pose specific cardinal questions directed toward examining the possible role of viruses in the etiology of some types of human cancer, to formulate plans suitable for the Task Force operation for obtaining answers to these questions in the shortest possible time, to implement the plans, and to assess periodically progress made under the plan. This will involve:

1. Identification of the specific problems involved in relating viral agents to the etiology of human cancer.

2. Assessment and evaluation of the present efforts directed toward establishing the viral etiology of human cancer.

3. Delineation of feasible approaches that could be used to augment current research and to explore new areas and to establish priorities for their implementation.

4. Determination of factors that are impeding progress along such feasible approaches.

5. Initiation and implementation of programs to overcome obstacles and to speed progress in exploiting to the maximum the most attractive avenues of approach.”

The October 16 memorandum continues:

As a means of providing a framework for discussion, of attempting to sharpen the definition of the Task Force activities, and perhaps of stimulating thought prior to the meeting, the following is offered as types of specific problems:

1) Should the general initial objective of the Task Force be: “To identify viruses obtained from human tumor tissues, grow them in tissue culture and in animals, and learn if preparations made from human tumors, inoculated tissue cultures or animals will produce tumors when introduced into different species and strains of animals”? Some other statement of the general objective?

2) What justification and assumptions underlie the Task Force objective?

3) Will the general plan be: Obtain specimens of human tumor tissues of various morphological types (emphasis on acute leukemia) handled by different methods of preservation;

prepare the selected specimens in a variety of ways (with due attention to preventing viral contamination) for inoculation into animals of defined strains and species and into defined tissue culture cell lines grown in defined media; apply various methods of virus identification to the animals and tissue culture materials; and hold inoculated animals sufficiently long to determine if increased tumor incidence occurs in an environment that will prevent contamination of the animals with extraneous viruses?

(a) What types of human tumor tissues should be selected and what criteria of selection should be utilized? (b) What methods of preservation of the tissues should be employed and why? (c) What methods of preparation may be employed for the selected specimens and what orders of priority should be given to the various methods as regards implementation? (d) What strains and species of animals should be selected and by what criteria? (e) Which cell lines and media may be employed and what is the order of priority for implementation? (f) What methods of viral identification should be employed? (g) How long should inoculated animals and tissue culture preparations be observed? (h) To what extent should the environment be controlled to avoid contamination by extraneous viruses?

4) What resources are required for the Task Force that are not now available?

5) Assuming that the laboratories of Task Force members will maintain their independence and autonomy, how can they best work together to insure integrated exchange of materials and information that will allow the Task Force as a group to move toward its objective more effectively than the individual members might do were they not members of the group?

6) How can the Task Force best evaluate periodically the progress made by the group in moving toward the objective?

7) In view of the sizable research effort already under way in attempting to evaluate the possible role of viruses in human cancer, why have results so far been so meager?

We hope by joining together and focusing thought, effort, and resources on this important area of cancer research that we may clarify the role of viruses in human cancer more rapidly than would be done by a less concentrated and cooperative venture. Each of you has already indicated your high interest in this problem by your ongoing research activities. We look forward to discussing with you the best ways to plan and implement the Task Force activities (Internal NCI document, October 16, 1962).

The members appointed to the Task Force were: Ray Bryan, Chairman; Jim Grace (Roswell Park Memorial Institute); Frank Horsfall (Sloan-Kettering Institute); Bob Huebner; Paul Kotin; Joe Melnick (Baylor University School of Medicine); Bob Miller; and Bob Stevenson, Executive Secretary.

In preparation for the first meeting of the Human Cancer Virus Task Force (October 25, 1962), the Associate Director for Program on October 16, 1962, sent a memorandum to members of the Task Force which might give a means of providing a framework for discussion, of attempting to sharpen the definition of the Task Force activities, and perhaps of stimulating thought prior to the meeting. The memorandum offered types of specific problems that the Task Force might need to address:

“1. Should the general initial objective of the Task Force be: ‘To identify viruses obtained from human tumor tissues, grow them in tissue culture and in animals, and learn if preparations made from human tumors, inoculated tissue cultures or animals will produce tumors when introduced into different species and strains of animals’? Some other statement of the general Objective?

2. What justification and assumptions underlie the Task Force objective?

3. Will the general plan be: Obtain specimens of human tumor tissues of various morphological types (emphasis on acute leukemia) handled by different methods of preservation; prepare the selected specimens in a variety of ways (with due attention to preventing viral contamination) for inoculation into animals of defined strains and species and into defined tissue culture cell lines grown in defined media; apply various methods of virus identification to the animals and tissue culture materials; and hold inoculated animals sufficiently long to determine if increased tumor incidence occurs in an environment that will prevent contamination of the animals with extraneous viruses?

(a) What types of human tumor tissues should be selected and what criteria of selection should be utilized? (b) What methods of preservation of the tissues should be employed and why? (c) What methods of preparation may be employed for the selected specimens and what orders of priority should be given to the various methods as regards implementation? (d) What strains and species of animals should be selected and by what criteria? (e) Which cell lines and media may be employed and what is the order of priority for implementation? (f) What methods of viral identification should be employed? (g) How long should inoculated animals and tissue culture preparations be observed? (h) To what extent should the environment be controlled to avoid contamination by extraneous viruses?

4. What resources are required for the Task Force that are not now available?

5. Assuming that the laboratories of the Task Force members will maintain their independence and autonomy, how can they best work together to insure integrated exchange of materials and information that will allow the Task Force as a group to move forward toward its objective more effectively than the individual members might do were they not members of the group?

6. How can the Task Force best evaluate periodically the progress made by the group in moving toward the objective?

7. In view of the sizable research effort already under way in attempting to evaluate the possible role of viruses in human cancer, why have results so far been so meager?

We hope by joining together and focusing thought, effort, and resources on this important area of cancer research that we may clarify the role of viruses in human cancer more rapidly than would be done by a less concentrated and cooperative venture. Each of you has already indicated your high interest in the problem by your ongoing research activities. We look forward to discussing with you the best ways to plan and implement the Task Force activities.

At the first meeting of the Human Cancer Virus Task Force considerable time was spent on clarifying the charge to and the role of the Task Force. Dr. Baker, in Dr. Endicott’s absence, provided additional background and answered questions. In response to Dr. Grace’s question about a planning function of the Task Force, he stated that the Task Force was appointed to be a working group on a cooperative basis. If the group could see any merit in planning approaches, exchanging data and information, and sharing material or resources on a mutual assistance level, then there was a need and justification for a task force. Otherwise, there was no reason for the existence of a task force. Dr. Melnick asked about research facilities. NCI had limited construction authority for the time being; however, in some cases, contracting with commercial firms could provide more space for the viruses and cancer activities. The Task Force might wish to become a recommending body for programs when they did not wish to become involved directly in the work. Examples of cooperative work could include obtaining clinical material from human leukemia patients and screening for virus-like particles, with division of positive specimens among the members of the Task Force.

Dr. Bryan presented an outline of specific problems for Task Force consideration in three broad areas: 1) virus dependent reactions (RNA viruses); 2) viral transformation of cells through induction of quantal type change (DNA viruses); and 3) joint action of ordinarily nononcogenic viruses with other carcinogenic agents in the induction of neoplasia. At Dr. Bryan’s request, each member discussed current work and specific problems in their own laboratories. Dr. Horsfall felt that the Task Force might make a mistake in suggesting that there is a satisfactory systematic approach for discovering things presently unknown. He urged that the Task Force increase the probability of discovery by increasing the dimensions of the effort and suggested that the history of scientific advance is linked to individual effort, a view expressed by Dr. Eagle at the May 11, 1962, meeting on Chemically Defined Tissue Culture Media (and again in 1971 at a meeting of outstanding scientists constituted by the Director, NCI, to discuss plans for the expanded cancer research effort called for by the coming Cancer Act of 1971 - signed by President Nixon on December 23, 1971). Dr. Bryan suggested that increasing the productivity of investigators by freeing them of routine tasks would, in effect, increase the dimensions and the probability of discovery. Screening of specimens to be used in elaborate experiments and holding animals for observation were concrete examples of ways of increasing the individual’s capabilities. Dr. Huebner offered to provide the diagnostic virology service with Dr. Melnick’s help for the other members of the Task Force. Dr. Stevenson reported that six antigens and corresponding antisera had been produced on contract and seven more pairs were to be done in F.Y. 1963. Higher yields and sharper specificity of antibody titers were being met with use of germ-free animals (which did not seem to have antibodies to a number of viruses commonly encountered in the mouse colonies as Dr. Huebner described). Possible topics for the agenda of the second meeting of the Task Force included: 1) Inbred hamsters; 2) Establishment of a serum bank from cancer patients; 3) Facilities (laboratories, animal holding, etc.); 4) Electron microscope screening service; 5) Viral diagnostic service; 6) Histopathology service; and 7) Epidemiological support. Dr. Baker asked how these needs of individuals expressed in their presentations might be tied together to establish priorities of effort so that available staff would not be diluted in their efforts to provide essentials.

Five Year Projection of Dr. Huebner’s Viruses and Cancer Program

On November 6, 1962, Dr. Huebner, at NCI’s request, submitted to the NCI Director a memorandum setting forth his projected viruses and cancer program and resources needs for a five-year period. He also outlined the links to the Human Cancer Virus Task Force. The memorandum again was a model document that laid out the scientific basis of the program and management needs, as well as ways to develop solutions to key problems. The full package for the Frederick facility totaled for F.Y. 1963 $791,500 (including contracts for management of the Frederick facility; for developmental work; and for tissue cultures, experimental animals, and other serological materials). A contract with Microbiological Associates was let for viruses characterization, identification (or typing), and viral diagnostic services, using complete complement-fixation, cross neutralization and hemagglutination-inhibition tests on various groups of viral diagnostic reagents. About 50 percent of the effort would be developing and applying virus typing techniques and 50 percent on production of satisfactory viral diagnostic reagents. At this time co-carcinogenesis studies were included, though these were never pursued after Dr. Kotin moved to head the Environmental Health Programs in North Carolina. Dr. Huebner’s long-term view (or vision) projected a tripling of personnel (50 professional and 150 technical workers) and provision of 25,000 square feet for tissue culture work and 5000 square feet for pathology plus outside space for animal quarters. He showed prescience in pointing out the likely need for elaborate and expensive facilities to insure safety and protection for those working with and exposed to oncogenic viruses. Attached to the memorandum was a chart of animal tumor viruses indicating: the natural host; other hosts; nucleic acid types; cellular location of viral inclusions; and other features. The viruses were grouped by seven families (the papova group; adenoviruses; the poxvirus group; the “leukemia” group; the avian leukosis group; mammary carcinoma; and frog kidney carcinoma).
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Re: An Administrative History of the National Cancer Institu

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Part 2 of 2

The Second Meeting of the Human Cancer Virus Task Force

The second meeting of the Human Cancer Virus Task Force was held on December 14, 1962. Dr. Robert Miller, Chief, Epidemiology Branch, NCI, discussed epidemiology aspects of the Task Force efforts. Other items on the agenda included: a) Discussion of Task Force Objectives and Methods of Achieving Them; b) Further Consideration of the Seven Operational Problems Identified at the First Meeting: 1. Inbred hamsters and SPF animals; 2. Establishment of a serum bank from cancer patients; 3. Facilities (laboratories, animal holding, etc.); 4. Electron microscope screening service; 5. Viral diagnostic service; 6. Histopathology service; and 7. Epidemiological support); and c) Other Business.

The Chairman had suggested that the members put down their thoughts about the Task Force activities in memoranda for the record. Drs. Bryan, Melnick, and Huebner brought their memoranda to the meeting for discussion. Dr. Melnick suggested three target areas: 1) Acute Leukemia of Childhood; 2) Papovavirus; and 3) Viruses and Antigens Present in Normal Human Tissues and Human Tumors. Dr. Huebner made several points. Standard certified prototype viral seed and monovalent reference typing serums were and should be handled by committee decisions on protocols and through contracts for production. Diagnostic reagents for identification of viruses and for studies of antibody responses relevant to virus isolation and to controlled sero-epidemiological investigations of viral antibody prevalence and incidence in cancer still required much developmental research. The Task Force might find it necessary to accept responsibility for much of the developmental research that needed to be done on diagnostic reagents. Unlike the standard viral reference reagents, these reagents could not be developed and evaluated through formulation of protocols by committees, but must be handled through contracts and grants for developmental research in which the commercial contracting agencies work hand-in-glove with specific government supported research groups in designing and carrying out research protocols. He agreed with other members that the emphasis in research should be placed on acute leukemia. He expected to place higher emphasis on in vitro rather than in vivo methods for demonstration of a human leukemia agent because of the complex viral picture in animals. Germ-free animals might be helpful for the animal inoculation approach. Survey tools designed to define the natural histories of animal leukemia viruses in their natural ecologies can and should be developed and used. The information provided would be invaluable in the design of similar studies of human leukemia, and might even disclose immunological and zoonotic relationships. He pointed out that the most profitable approach to the definition of the causes of acute viral diseases has been the virus in search of disease approach and epidemiological studies of their clinical and pathological behavior. It is a matter of documented fact that most of the newer human viruses were first isolated in situations that gave little indication of their true clinical behavior. The important concept to be derived from this fact is that the role of most of these viruses in natural disease could not even be suspected from the circumstances in which they were first found. This could be true of viruses found in temporal and spacial relationships to human cancer. Regardless of where suspect viruses are found and what they do in the laboratory, machinery must eventually be set up for studies of the natural history of these agents in their human host, and epidemiological studies capable of distinguishing “real” from “spurious” associations.

Other materials related to presentations of VRRB staff at the Task Force meeting were distributed with the Agenda: 1) Materials Produced by VRRB Programs; 2) Development of Embryonating Eggs Free of Known Poultry Microorganisms; 3) Information on Numbers and Kinds of Tumors in Swine; 4) Syrian Golden Hamsters; 5) Production of Virus-Free Mice; 6) Cancer in Subhuman Primates; and 7) Large Germ-Free Animals.

By the end of 1962 the NCI viruses and cancer activities, especially those of the VRRB, were well defined as to philosophy, main objectives, and organizational patterns. The quality-controlled resources needed to move ahead with the research were beginning to be produced in sizable quantities and made available to investigators requiring them. Discussions were held on additional steps that should be taken in the coming years.

Dr. Huebner’s Suggestions on the Conduct of the Activities of the Human Cancer Virus Task Force and Staff

On January 8, 1963 Dr. Huebner wrote another thoughtful and thought-provoking memorandum to the Human Cancer Virus Task Force members and NCI staff on the future activities of the Task Force. He pointed out that the Task Force had spent too much time discussing at length details on equipment and personnel instead of new ideas and approaches. So much time had been spent discussing the use of the electron microscope for screening of leukemia specimens, he thought that other approaches to screening would not be made until the scopes were working in the participating laboratories. This narrow concept was not the view of the staff. He also misconstrued the meaning of “focus down” in staff documents as narrowing the Task Force activities. The meaning intended was to call for prioritizing among the many possible lines of work, since at the time funds would not allow pursuit of every possibility. The staff was not looking to narrow the scope of the Task Force’s area of consideration, but asking the Task Force to make specific priority selections within the very broad scope of possibilities. Also the participating laboratories should each pursue different directions of their research while collaborating on approaches requiring joint efforts. Dr. Huebner discussed the role of staff in helping to carry out the work of the Task Force. At the time he was not aware of how much the staff agreed with his comments on staff activities. The memorandum stated:

When a certain research approach is approved and certain laboratories are designated as the key ones for carrying it out, I suggest that staff be instructed to take over without further discussion of details. It is a staff function to figure out with each research group their particular needs to accomplish task force objectives. I doubt very much that it is the Task Force’s prerogative to act on such matters anyway - except in an advisory fashion after the planning is completed and only if the staff requests review of specific questions and/or information is needed for justifying certain items.

Further:

I suggest that it is the function of the staff to find specific justification for requirements of the Task Force’s program in the recommendations of the Task Force. I suggest further that the proposals for support of each group be worked out separately on the basis of particular needs (they can’t all be the same) to meet Task Force commitments, and that they be circulated by mail and approved as quickly as possible when we get together. We should reserve most of the time available to the Task Force for discussing new approaches, for building new programs, and supporting them as necessary with published and unpublished data.

The final paragraph:

After all, the only justification of this Task Force will be what it accomplishes in the end, and to this end it must spend most of its time and effort on building programs and on achieving program objectives; this, strangely enough, means working. The chief function of staff is to facilitate this end by assuming as much responsibility as possible for administrative details, leaving the investigators to get on with their work. This is also the best way to serve the best interest of the NCI staff, since it will assure maximum opportunities for achieving something worthwhile. In a five- year race against time, the bearings must be greased, not filled with repetitive consideration of gritty details concerning specific justification (Internal NCI document, January 8, 1963).

The Second Meeting of the CCCC

On January 24, 1963, the Second Meeting of the Cell Culture Collection Committee was held in Bethesda. The meeting focused on media problems, including characterization of media and definition of terms (chemically defined media; characterized media; and maintenance media). Composition of defined media currently in use was discussed. Currently available information on reagents was next taken up (current criteria of purity, analytical procedures, and evaluation of current suppliers). Stability and shelf-life of media and their components were discussed, as was the type of storage required. Could media be frozen or lyophilized? What about interaction of components that compromise the media?

Proposed Sero-Epidemiological Survey

On January 24, 1963, Dr. Huebner sent a memorandum to the Chairman of the Human Cancer Virus Task Force entitled “Sero-epidemiological surveys of human cancers for antiviral antibodies”. He proposed establishment of a “Cancer Serum Center” (in three phases) for surveying numbers of serums from patients with representative different types of cancer for antibody reactions to various viruses. Such a Center should prove useful to the Task Force for serological confirmation and epidemiological testing of specific hypotheses deriving out of current efforts to identify human cancer viruses. An overall center could not be established at the time because of inadequacy of facilities, reagents, personnel, or informational storage. However, a beginning could be made with a pilot program in the Laboratory of Infectious Diseases, NIAID, coupled with supply of specimens from Sloan-Kettering Institute added to the leukemia specimens already being received from the Leukemia Task Force activities (Dr. Zubrod) (Phase 1). Phase 2 would be double-blind controlled studies and Phase 3 would be broader investigations in populations with greater varieties of characteristics. Phase 1 would only need advisory and moral support from the Task Force and a modest amount of funds to Sloan-Kettering Institute for a serum and information collection unit. Phases 1 and 2 would require additional resources.

The Third Meeting of the Human Cancer Virus Task Force

The Third Meeting of the Human Cancer Virus Task Force was held on January 25, 1963. Dr. Stevenson, as Executive Secretary of the Task Force and Head of the Virology Research Resources Branch, supplied several documents to the members of the Task Force. In his memorandum accompanying the agenda he requested policy decisions to initiate the collaborative program agreed to by the members at the second meeting because the program would require a variety of resources to be obtained. The memorandum went on:

“The first specific problem is that of obtaining clinical material and making it available for Task Force use. After the Task Force has decided on the policies and procedures for this aspect of the program, details will be worked out with individual groups. Future topics will include selection or identification of needs for test systems such as animals and cell cultures, sera, etc.”

“Whenever possible, the Virology Research Resources Branch will provide the Task Force with the resources or the administrative mechanisms such as contracts which are identified as being necessary to the collaborative program.”

“At this point, your help and participation in planning are necessary and a suggested program for acquisition of clinical material, its identification and distribution is presented along with suggested data needed for definition of the leukemia patient.”

“We have not attempted to do more than outline the basic aspects of the protocol which will require policy decisions. Specific details of individual items can be worked out by the staff scientists of the respective members programs.”

The VRRB also presented a set of questions for the Task Force:

“1. What criteria are to be used for selection of leukemia patients and controls? (See Zubrod’s protocol).

2. What kind of protocol should be established for the selection of various types of human specimens - blood, urine, etc. (These procedures should be standardized).

3. How are specimens to be allocated to laboratories other than source of specimen? What percent is retained? What percent is distributed? What percent is stored for later reference?

4. How to establish minimum size of specimen if it is to be distributed to other laboratories?

5. How many patients are to be examined per year, and how many specimens per patient?”. (Internal NCI document, January 25, 1963).

Other materials were supplied by Dr. Stevenson: a statement of “Proposed Policies for Collection and Distribution of Clinical Specimens”; the Acute Leukemia Task Force “Protocol #2, Cooperative Study in the Chemotherapy of Acute Leukemia”; a report on the current status of “Development of a Nucleus ‘Germ-Free’ Hamster Breeding Colony”; and details of John Moloney’s procedure, “Preparation and storage of human leukemic blood, blood fractions and bone marrow aspirates.” The pioneering work of the Acute Leukemia Task Force in developing defined procedures for collaborative efforts, including those for handling specimens, was of great help for the Human Cancer Virus Task Force. Other items on the agenda included: a Proposal for Sero-Epidemiological Survey of Human Cancers (Dr. Rowe for Dr. Huebner); a status report on Surveillance of SV-40 Inoculated Patients; and an open discussion of Strategic Approaches to Virus-Cancer Targets. “Identification of and Needs for Specific Test Systems to be Obtained under VRRB-Task Force Contracts” was selected for discussion at the next Task Force meeting. Four days after the January 25 meeting Dr. Melnick submitted a contract proposal to implement Task Force efforts by the Baylor group.

Status Report to the Scientific Directorate

On February 5, 1963 Ray Bryan presented a status report on the activities of the Human Cancer Virus Task Force to the NCI Scientific Directorate. A summary statement was distributed to the Directorate members. It follows:

1. Major objective and purpose of the Task Force.

To determine the relationship of viruses to the etiology of human neoplasms.

2. Working concept of the nature of neoplasia.

A general type of cellular and tissue reaction, rather than a single specific disease entity.

3. Categories of virus-host (or host-cell) interactions associated with neoplasms of animals.

I. Virus-dependent reactions in which specific viruses (or related types of viruses) are the direct continuing causes of certain specific neoplastic diseases. Examples: Rous sarcoma; leukemia of fowls; leukemia of mice.

II. Viruses-initiated reactions in which viruses of different types act as biological carcinogens in the production of a variety of autonomous neoplasms of different tissues and in different species, but the virus is not associated with continuation of the neoplastic reaction (at least in a detectable form). Examples: tumors, or in vitro cell transformations, induced by the polyoma and SV-40 viruses and by adenoviruses 12 and 18.

III. Co-carcinogenic reactions in which not only viruses of dependent neoplasia (e.g., Shope papilloma), but also ordinarily non-tumorogenic viruses (e.g., vaccinia, influenza) act together with chemical or other carcinogenic agents to initiate autonomous neoplasms, but neither type of agent is associated with continuation of the reaction (at least in detectable form).

IV. Other reactions (this category to include future types of interaction not now known or recognized).

4. Major problems common to all categories of tumor viruses and interactions.

(1) Detection (identification) of candidate virus.

(2) Propagation of the virus in the laboratory.

(3) Proof of tumorgenicity of the virus.

(4) Establishment of etiological relationship of the virus to human neoplasia.

No human virus of category I has yet been discovered. Initial work in search of agents of this type is therefore confined to the problems of (1) Detection and (2) Propagation. Unless and until these objectives are accomplished there will be no basis for proceeding to problems (3) and (4).

On the other hand, many viruses unassociated with known disease have already been detected and propagated in the laboratory, and may be considered as candidates for tumorgenic agents of category II. The work on these known agents can therefore proceed immediately to problems (3) and (4). The search for new viruses of this category, however, involves problems (1) and (2).

5. Major segments of the over-all human-cancer-virus-problem (i.e., “targets”) embraced by the Task Force to date.

A. Leukemia and lymphomas (including Hodgkins disease).

The comprehensive task has been embraced of determining whether or not viral etiological agents comparable to those that cause leukemia in fowls and mice are associated with human leukemia and lymphomas. The fowl and mouse agents fall in category I of the types of interaction listed under 3 above. The planned actions for implementation of the Task Force study will therefore follow, initially, the avenues of approach that have given success with the animal model systems of category I.

Although virus-like particles resembling those associated with the animal leukemias have been observed in tissue or blood specimens from some leukemia patients (Dmochowski - published; Beard, et al., Dalton, et al., and Melnick, et al. - unpublished), no definite association of the human disease with a viral agent has yet been made. Nor has propagation in the laboratory of a candidate viral agent resembling the animal etiological agents been successfully achieved. The initial actions of the Task Force with respect to leukemia are therefore directed toward the first two major problems listed under 4, i.e., (1) detection and (2) propagation in the laboratory. If a substantial effort fails after a few years to yield positive results on these problems, the negative outcome will not conclusively prove a lack of association of human leukemia with a viral etiological agent, but will call for a reevaluation of the intensive efforts following these particular presently known animal model systems.

The presently available working approaches to problems (1) and (2) that have been developed with animal model systems (category I) may be listed under the same headings as the problems themselves, for the purpose of identifying specific Task Force projects with the objectives toward which they are directed. The following represent the methods and indicator phenomena, or identification criteria, that may be used for detection and propagation of one or more of the animal leukemia viruses. [Approaches under which specific Task Force contract operations are currently being proposed are marked by an asterisk(*)].

(1) Detection

*1. Electron Microscopy

(a) Thin-section; staining with lead and uranium salts.

(b) Negative contrast of film preparations; staining with salts of phosphotungstic acid.

*2. Cellular transformations in tissue culture (CPE has not yet been observed for type I tumor viruses of animals).

3. Viral interference, using known viruses as indicator agents.

*4. Inoculation of newborn or conditioned animals (mice, hamsters, non-human primates, other).

5. (Immunological and serological methods are potentially useful, but will not be applicable to type I agents until reagents become available through successful propagation in the laboratory).

6. Co-carcinogenesis, and enhancement.

(2) Propagation in laboratory

*1. In primary as well as established cell lines in tissue culture (human, other primate, other).

*2. In animals (non-human primates, hamsters, mice, other).

*(a) Conventional.

*(b) Specific pathogen free (SPF).

B. Seroepidemiological and virus isolation studies on cancer cases in general, for the purpose of defining antibody and virus spectra. This will embrace testing for as many as possible of the known viruses as well as a search for new viruses.

*(1) The initial studies will be “pilot” in nature, for the purpose of obtaining leads for laboratory work through association of cancer type with frequency of isolation or identification of viral type. Leukemia cases will be especially emphasized, in keeping with the targeted all-out attack on leukemia.

(2) A broader program envisioning (a) a large serum and specimen bank, (b) various epidemiologically controlled populations, and (c) collaborative epidemiological investigations, has been approved in principle, but further study and program planning will be required to develop this complex undertaking.

6. Proposed operations requiring contract support.

A. Electron microscopic studies.

Studies by Doctors Dalton and Moloney on mouse leukemia led to the development of methods for detection and rough quantitation of virus from the blood of leukemic, or pre-leukemic inoculated mice. Thin section techniques were used initially, but greater speed and efficiency have recently been achieved through the use of negative contrast staining with phosphotungstate.

These methods were applied to the study of human blood specimens and virus-like particles resembling the mouse leukemia virus have been observed in roughly 1/3 of 51 cases of human leukemia (mostly acute lymphocytic, of children).

In comparable independent studies Dr. Melnick and associates have observed virus-like particles in blood of leukemic patients by the negative contrast procedure.

Virus can be isolated from only a small fraction of leukemic mice of strains which develop leukemia spontaneously (e.g., AK, C58); and, like other neoplasms of type I, the quantity of virus recovered from experimentally infected animals is related to infecting dose and rapidity of development of disease. It is therefore logical to expect that human specimens in which particles can be detected by electron microscopy would represent the most favorable cases for further study in attempts to isolate and propagate a human counterpart of the mouse and fowl leukemia viruses.

To provide this selection of donors and to acquire additional information on the frequency of occurrence of virus-like particles in human leukemia cases, the Task Force voted to activate Electron Microscopic Study Centers in the institutions of interested members who were willing to oversee the local operations and contribute to a collaborative program by pooling information and sharing specimens for study.

Dr. Grace’s proposal and one part of Dr. Melnick-s broader proposal are for activation of such electron microscopic study centers.

Dr. Melnick proposes in addition to develop, under contract, a program for the procurement of clinical specimens. Dr. Grace already has contract support for this phase of the operation that was set up previously under the Virus Research Resources Branch (VRRB).

B. Studies Involving Animals

Newborn and conditioned animals will be used in tests for virus detection and proof of tumorgenicity, as well as for propagation of large quantities of virus for further study. For all three of these purposes, the problem exists of finding a suitable (or the most suitable) species. It has not yet been determined whether specific pathogen free (SPF) animals will be better than conventional animals for the first two purposes, but for the third, namely propagation of virus in the absence of extraneous contaminating agents, SPF animals are considered to be essential.

In view of the latter fact, and the possibility that some human tumor viruses might be capable of propagating only in intact animal hosts (as is presently the case for several known animal viruses), the Task Force voted to support developmental research on SPF animals under the VRRB. Hamsters were designated as the first species to be explored for developmental research under contract (Item 2,a, on agenda).

Task Force collaboration on animal testing has been projected along two lines: (a) division of effort in exploring for possible use as test animals, various species not now included in programs already under way in the laboratories of members; and (b) joint use of primate or other large or expensive animal test-systems which cannot practicably be embraced by individual laboratories, i.e., with available resources.

C. Studies Involving Tissue Culture

As with animal test systems, various cell lines of various species (particularly human and other primate) maintained in tissue culture will be used for detection, propagation, and tests for “tumorgenicity” of viruses (tumorgenicity is in quotation marks because in vitro transformation, though suggestive, cannot alone be considered as proof of tumorgenic properties in animals, but requires confirmation in animals).

As with the animal test systems, a division of effort in trying out various cell types and conditions of culture, using common human specimen materials, has been projected, but specific joint undertakings by Task Force members have not yet been developed. Also, certain common needs for resources (e.g., human and other primate embryonic tissues, human serum, defined media, etc.) have been identified, and the VRRB has been asked to consider the feasibility of making these resources available for Task Force purposes (Internal NCI document, February 5, 1963).

This statement concisely summarized to date (1963) the status of the viruses-cancer research effort and the progress made by the VRRB and the Human Cancer Virus Task Force. Projected program efforts were also identified. The collaborative activities undertaken were uncommon outside wartime efforts; these joint efforts involved sharing of materials and information (prior to publication). The developmental research and production of defined resources initiated a growth of production of biomedical resources that later led to a vast array of commercially available materials, indeed to a whole new industry. During this 1963 period the programs funded with contract funds were determined from defined requirements of planned research, and not made simply to provide resources for individual investigator requests. Most virology investigators did not think large amounts of reagents could be made of sufficient quality by commercial organizations under contract. The NCI assured them that the reagents could be tested by the same methods they themselves used and, if they did not meet their requirements, they would not be used (Dr. Baker pointed out that under current practices of producing reagents in small amounts in individual’s laboratories, after testing there was little material left for other studies - much greater amounts were needed for various studies). Most academic investigators objected to Government research monies going for this collaborative research instead of for support of individual’s project research. Since “target research” (or problem-solving research) aimed at attacking cancer involves larger scale, multi-discipline efforts in addition to projects of individual investigators, NCI felt that the Federal Government laws regarding contracts needed modification if it was to carry out its mandate.

Request for Enlarged Contract Authority for NCI

On February 28, 1963, the Director, NCI, sent a memorandum (drafted by Carl Baker and Zelda Schiffman) to the Director, NIH entitled “Applied developmental research and research services -- Need for legislation.” This memorandum presented a brief summary of NCI’s position, the background, the need, and the changes in law NCI would like to see enacted. Contract authority more nearly like other Government agencies, such as NASA, Department of Energy, and Department of Defense, could allow NCI to meet its needs for additional space, positions, and added managerial capability. Despite clear justification of the need for legislative changes, this memorandum disappeared into a bureaucratic morass.

The Fourth Meeting of the Human Cancer Virus Task Force

The Human Cancer Virus Task Force met on March 8, 1963, for its fourth meeting. The agenda for the meeting included : (1) Progress Report by Dr. Stevenson; (2) Discussion of the Papova-Adeno Virus Group by Dr. Melnick; (3) Needs for Animals and Cell Cultures (Nucleus Colonies and Seed Stock); (4) Planning for Sero-Epidemiology Proposals; and (5) Date for General Meeting of the Task Force Members and their Staffs. The last item began what became a vital pattern of the NCI viruses and cancer activities: annual meetings of those participating in the activities at which information was freely exchanged well before the data were published. Dr. Holdenried presented a progress report on the contract with the Baltimore Biological Laboratory for monitoring of cell strains and virus seed stocks for PPLO contamination. One of every four cultures tested (102 specimens) was contaminated. One of every five cultures contained PPLO organisms. Of the 16 laboratories submitting specimens, two-thirds submitted contaminated specimens. Over half the laboratories submitted specimens contaminated with PPLO’s. Before the evaluation of contaminations on a centralized basis for quality controls, including that on some early VRRB contracts, much work was done without knowledge of contaminated reagents. This early contract demonstrated the necessity of quality controls on resource production contracts.

Development of an NCI Overall Program Document

During the first quarter of 1963, the Associate Director for Program and Lou Carrese, after extensive analyses of activities in cancer research and exploring many options of the form that projected research and organizational plans for NCI might take, produced for the Scientific Directorate and the NACC a preliminary overall NCI program document. The options were based, in part, on a classification scheme made up of three aspects: a conceptional formulation of cancer; resources required to meet problems in cancer research; and the organizational components needed to deal with the problems. This effort was a follow-up on the earlier agreed upon need, at higher NCI levels, to move away from detailed review of projects and toward broader program reviews. The conceptual base and the organizational form for setting forth the NCI program was based on a scientific conception on the nature of cancer and the current major thrusts of cancer research. This approach moved away from presenting the NCI efforts in categories such as Intramural Research, Collaborative Research, and Grants and Training, with emphasis on individual project reviews.

An overall NCI Program Review Document was presented to the NACC at its March 1963 meeting. Although various individuals complimented on the effort were made, little substantive comment resulted from these ideas. Perhaps this conceptualization was too broad for the specialized expertise of the individual Council members, or this approach was too new. Other distributions to the NACC were: The NCI Fact Book; Research and Related Programs of the NCI; Research Grants Distribution by Facet; and Graduate Training Grants Distribution by Discipline. On the evening before the NACC meeting, the Council Subcommittee on Carcinogenesis and Prevention met on March 17, 1963. The Subcommittee consisted of: Walter Burdette (Chairman); George Cooper; Paul Gross; John Kidd; Phil Shubik; J. Walter Wilson; and William Payne (Executive Secretary). Dr. Burdette presented an analysis of the functions of the Subcommittee in relation to the NCI advisory groups. Dr. Kotin discussed the present status and future program of the NCI Carcinogenesis Studies Branch. Dr. Shubik spoke of the problems in the field of carcinogenesis and approaches to their solution. Six grant applications were reviewed; three were recommended for disapproval. Viral carcinogenesis was not discussed.
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Re: An Administrative History of the National Cancer Institu

Postby admin » Sun Dec 13, 2015 3:41 am

Chapter 3: Implementation and Early Program Outputs

As reorganization at the National Cancer Institute began to occur the new emphasis on planning began to have an impact, and implementation of efforts toward defined targets began to take place. Added results were beginning to show up in the scientific programs, in early production of resources, and in better coordination of managing the viral oncology activities. The research efforts were concerned largely with methods for finding, identifying, and growing viruses in animal and human tissues. This included the use of electron microscopy (E.M.) for finding various virus particles and of various innovative immunological methods. These findings were correlated with tumor induction in various animal species.

To conduct the research, it was necessary to have large amounts of resources such as antibody-containing sera and other reagents. Several animal species were developed to serve as possible test system hosts for any human tumor viruses that could be isolated, grown and able to produce tumors. These included non-human primates, man’s closest animal relatives. Tissue culture remained a key resource.

Management of the Program continued to move the Institute to greater emphasis on coordinated multi-discipline programmatic research and at the same time more clearly lay out managerial responsibilities and work loads. These modifications will be ongoing for some time in the continuing search for better management.

On May 1, 1963, NCI, in response to a request from Congress, submitted an analysis of the grants, contracts, and intramural research activities for Fiscal Year 1962. Grants totaled $47,607,147 (1746 projects); contracts totaled $27,573,000 (225 contracts); and the intramural programs totaled $14,495,000 (of which $7,185,000 was for reimbursement to NIH for central services). With grants, the largest category was treatment ($15.651 million); for scientific discipline, the largest category was biochemistry ($21.316 million). Virology grants totaled $4.011 million (106 projects). Multidiscipline program project grants totaled $3.567 million (8 projects). With contracts, the CCNSC Program totaled $22.188 million; virus research totaled $2.363 million. Including funds spent on intramural projects, the amounts per Laboratory were nearly equal; however, Pathology, Biochemistry, and Viral Oncology had the largest budgets.

The Fifth Meeting of the Human Cancer Virus Task Force

At this meeting held at the Airlie House Conference Center on May 12-14, 1963, twenty-six investigators from Task Force participating laboratories presented current work underway in their laboratories. The arrangement provided many opportunities for informal interchange of ideas, information, and future possibilities. The informality and common purpose encouraged the reporting of up-to-date activities well before publication. This meeting initiated a series of annual meetings attended by leading investigators in the cancer-viruses field and their staffs. The annual congregations continued for more than a decade and are continued still under the tutelage of Bob Gallo. At the close of the first meeting five informal subcommittees of the Task Force composed of members from the participating laboratories were formed:

PPLO Subcommittee

J. Horoszewicz (Chairman) RPMI

E. de Harven SKI

A. Moore SKI

R. Manaker LVO-NCI

N. Somerson LID-NIAID

K. Smith Baylor U.

R. Holdenried VRRB-NCI

R. Meyer VRRB-NCI

Laboratory Animals Subcommittee

E Mirand (Chairman) RPMI

F. Rapp Baylor U.

C. Friend SKI

W. Rowe LID-NIAID

P. Sarma LID-NIAID

J. Moloney LVO-NCI

R. Holdenried VRRB-NCI

L. Murphy VRRB-NCI

Primates Subcommittee

J. Melnick (Chairman) Baylor U.

C. Southam SKI

H. Coates LID-NIAID

F. Rauscher LVO-NCI

E. Mirand RPMI

R. Holdenried VRRB-NCI

L. Murphy VRRB-NCI

Cell Culture Subcommittee

R. Stevenson (Chairman) VRRB-NCI

S. Stewart LVO-NCI

D. Yohn RPMI

M. Benyesh-Melnick Baylor U.

A. Moore SKI

R Chanock LID-NIAID

R. Meyer VRRB-NCI

Electron Microscope Subcommittee

A. Dalton (Chairman) LVO-NCI

K. Smith Baylor U.

E. de Harven SKI

R. Zeigel LVO-NCI

G. Niwayama RPMI

J. Horoszewicz RPMI

NCI Proposal for Contract Reviews, Program Reviews and Program Planning

On June 21, 1963, the Office of the Associate Director for Program issued for comment a draft of a major document (6 pages plus a 23 page attachment on details): “NCI Proposal for Contract Reviews, Program Reviews and Program Planning.” The document sat forth the philosophy, definitions, operational and organizational guidelines, evaluation and advisory functions, and review of contracts for NCI Programs. The document was accepted as the NCI position and operating policies and practices.

Goals and Objectives of Cancer Research and their Implementation

The Associate Director for Program prepared a 32-page discussion document for the NACC and for the meeting of its Planning Committee on June 22, 1963. The title of the document was “Goals and Objectives of Cancer Research and their Implementation.” In addition to the scientific aspects, the document also covered the NCI organization and management, the program advisory committees, and review of contracts. The Closing Remarks of the document were:

A. The above discussion has presented certain research goals and objectives, analyzed some of the problems involved, made suggestions for expanding research efforts through new devices, and suggested needed changes in legislation and authorities.

B. Pressing problems include:

1. Inducing some of the best investigators to think deeply and seriously about cancer problems and to work on them.

2. Selection of key goals, objectives and important questions needing answers of paramount significance for cancer research.

3. Allocation of resources, which are never unlimited, most effectively to achieve the selected goals and objectives with a minimum expenditure of time and other resources.

4. New legislation as indicated above will be required.

5. These things simply cannot be done without strengthening government staff involved.

6. Who will do the work even if plans, appropriate legislation, and money are available? (Internal NCI document, June 22, 1963).

This document was also discussed at a June 22 meeting of the NCI Scientific Directorate.

Organization and Staffing Changes in the Institute

On June 25, 1963, Dr. Endicott issued a memorandum “Organization and Staffing Changes in the Institute.” Several Institute Associate Director positions were created:

I. The Intramural Research area -- Gordon Zubrod would continue as Director of Intramural Research (and Scientific Director).

A. Associate Director for Laboratory Research - G. Zubrod.

B. Associate Scientific Director for Viral Oncology - R. Bryan.

C. Associate Scientific Director for Experimental Therapeutics - E. Frei.

D. Clinical Director - N. Berlin.

II. The Collaborative Research area -- T. Philip Waalkes would become Associate Director for Collaborative Research.

III. The Field Studies area -- Paul Kotin would become Associate Director for Field Studies.

The Virology Research Resources Branch, with Bob Stevenson as Branch Chief, would be transferred from the Collaborative Research Area to the Field Studies Area. These changes were approved at the NIH and PHS levels. Much of the remainder of 1963 was spent in working out the details of the reorganization of the Institute. Several key memoranda detailing the organizational relationships and procedures for program and contract reviews were issued (by the Institute Director, the Associate Director for Program, and the Chief, Research Contract Operations Branch - this Branch was transferred to the Office of the Director). Extensive Guidelines for review of programs were distributed to members of the Scientific Directorate for action. Since the VRRB had been transferred to the Field Studies Area, contracts for this Area would be reviewed by the Field Studies Task Committee. This group consisted of: Paul Kotin (Associate Director for Field Studies), Chairman; Ian Mitchell (Special Assistant to the Associate Director for Field Studies), Executive Secretary; Bertrand Brill (Chief, Epidemiology Research Branch, PHS Division of Radiological Health); Jerome Cornfield (Biometrics Research Branch, NHI); Walter Heston (Chief, Laboratory of Biology, NCI); Margaret Kelly (Medicine Branch, NCI); Edward Kuff (Laboratory of Biochemistry, NCI); Frank Lundin, Jr. (Head, Special Cancer Studies Section, Epidemiology Branch, NCI); Robert Manaker (Laboratory of Viral Oncology, NCI); Jerry Niswander (Dental Surgeon, Human Genetics Branch, NIDR); Alan Rabson (Pathologic Anatomy Branch, NCI); and Wallace Rowe (Laboratory of Infectious Diseases, NIAID). Review of animal production contracts, however, would be reviewed by the Scientific Directorate, assisted by the Laboratory Animal Committee. This Committee consisted of: Joseph Leiter (Chief, CCNSC, NCI), Chairman; Samuel Poiley (Head, Mammalian Genetics & Animal Production Section, Drug Evaluation Branch, NCI), Executive Secretary; Walter Heston (Chief, Laboratory of Biology, NCI); Robert Holdenreid (Head, Laboratory Animal Section, VRRB, NCI); Michael Klein (Carcinogenesis Studies Branch, NCI); John Murphy (Assistant Administrative Officer, Intramural Research, NCI); and Jane Taylor (Head, Endocrine-Related Tumor Section, Endocrine Evaluation Branch, NCI).

Following discussion at a special meeting of the Scientific Directorate on June 28, 1963, additional discussion was held by the Director, the Director of Intramural Research, and the Associate Director for Program, on the subject of program and contract reviews within NCI. Based on these discussions, the Executive Secretary of the Scientific Directorate sent to the members on July 11, 1963, a memorandum for further discussion at the Directorate meeting of July 15, 1963. Considerable simplification of scope and procedure was effected by elimination of certain features of the June 21, 1963 document. The final document outlining the new contract review procedures, including forms to be used, was sent to staff by the Director, NCI, on September 17, 1963.

Conduct of the Scientific Directorate Meetings

In July 1963 the Chairman of the Scientific Directorate requested suggestions from the members on the conduct of the Directorate meetings. In his role of Executive Secretary of the Directorate, the Associate Director for Program responded to the request on July 12, 1963, with a twelve-page memorandum to the members. Five pages were concerned with the concept of cancer as might be conceived by the members and included a diagram depicting cancer in the individual (conception at other organismic levels was invited). Items in the other seven pages included; 1) The procedural approaches to the conduct of the Directorate meetings; 2) Discussion of drug development approaches; 3) Approach to evaluation of carcinogenesis, especially screening; 4) The use of inbred animals and transplantable tumors versus random-bred animals and autochthonous tumors; 5) Immunology and cancer; implications for future NCI programs; 6) Biochemical genetics and cancer; 7) Experimental embryology; and 8) Endocrinology and cancer.

Early Systems Planning Efforts

It was about this time (September 1963) that the ideas explored on planning by Carl Baker and Lou Carrese over the past year and a half began to crystallize into concrete substance, permitting formulation of planning efforts for the total area of cancer research. In addition to extensive review of the literature on systems planning, this effort included exploration of planning structures, options for goals and objectives statements, and beginning attempts to define the criteria and associated data required to make decisions defined in the plans. Issues on monitoring, accountability and up-dating of plans were also addressed. The areas of viruses and cancer and cancer chemotherapy were examined to test the planning concepts. The concept of the linear array of the steps required in a drug development program was formulated by this stage of planning for chemotherapy (the Leukemia Task Force, Chaired by Gordon Zubrod, had been formed in 1961 and associated with it was enlarged pharmacology research). The NCI was encouraged by the Director of NIH to proceed with this pioneering systems planning effort.

A Contractor-Operated Research Facility

Much of October, November and December was spent by NCI senior staff on developing documentation on establishing a major nearby contractor-managed and contractor-operated research facility responsive to NCI requirements. The concept was briefly discussed with the NACC by the Director, NCI. The need for such a facility grew out of the constraints of shortages of space and positions (in the face of increasing budgets) and the demonstration of effectiveness of such facilities in NASA, Department of Defense, and the Department of Energy. Part of the background included listing planned contract-supported activities, Fiscal Year 1964 (November 12, 1963 memorandum). This listing included activities important for the viruses-cancer area, such as: 1). an estimated $350,000 effort with the Human Cancer Virus Task Force and the VRRB programs for development of viral diagnostic reagents and their packaging and distribution; development of standardized serum and chemically defined tissue culture media made to specifications; additional primate species; and additional human diploid cell strain work for viral transformation, co-carcinogenesis and DNA studies; and 2). an estimated $500,000 for additional ultracentrifuge development with the Oak Ridge National Laboratory (led by Norman Anderson); immunological studies in primates; and murine and human virus studies in germ-free mice. The listing also included potential contractors capable of meeting the complexities of such operations, including not only science and managerial expertise, but also the ability and willingness to take risks. Preliminary discussions with potential contractors were held by Drs. Endicott, Leiter, Coghill, and others. NCI planning called for $200,000 for initiating a contractor-supported activity in the current Fiscal Year. If successful, it might serve as a prototype for similar facilities in other parts of the country. In preparation for discussion of this topic at the January 4, 1964, meeting of the NCI Executive Committee, a 27 page document on the subject (revised based on review at the December 13, 1963, Executive Committee meeting) was distributed on December 31, 1963. The TABLE OF CONTENTS was as follows:

1. INTRODUCTION

1.1 Rationale for the Facility

1.1.1. High Degree of Flexibility

1.1.2. Problem-solving, Multi-discipline Orientation

1.1.3. Interchange between Biomedical and Physical/Engineering Scientists

1.1.4. Proximity to NIH Campus

1.2 Implications to NCI Staff

1.2.1. Program Planning

1.2.2. Liaison and Coordination

1.2.3. Monitoring and Consultation

1.2.4. Overall Management

1.2.5. Summary

2. PROBLEM AREAS AND REQUIREMENTS

NCI REQUIREMENTS AND CANCER RELEVANCE CHART

3. SUMMARY OF INTEGRATED REQUIREMENTS FOR THE TOTAL FACILITY

3.1 NCI Requirements and Facility Capabilities

3.2 Basic Characteristics of the Organization and Staff

Facility

3.3 General Outline of Installations Required

3.3.1. Centrifuge and Other Separation Techniques

3.3.2. Instrumentation

3.3.3. Containment

3.3.4. Pilot Plant Operations

3.3.5. Cell and Organ Preservation

3.3.6. Electron Microscopy

3.4 Fiscal and Contractual Aspects

3.4.1. Real Estate

3.4.2. Physical Plant

3.4.3. General Contractual Arrangement

3.4.4. Subcontracting with Small Business

Concerns

3.4.5. Personnel Covenant

4. TIME SEQUENCE FOR IMPLEMENTATION

4.1 Basic Document

4.2 Immediate Research

4.3 Formal Invitation

4.4 NCI Administrative Control

4.5 Funding (Internal NCI document, December 13, 1963).

Review of NCI Collaborative Research Programs

The senior staff of the NCI met with the Director, NIH, in mid-1964 to review the NCI Collaborative Research Programs. For this review an outline for discussion was prepared by NCI:

I. Definition of types of activities included under this heading in NCI

A. Research programs which provide services and things to the research community

1. VRRB

2. CCNSC (in part)

3. Biometry

4. Instrumentation

5. ADP and Communications

B. Large-scale, interinstitutional, interdisciplinary target research programs with strong industrial research overtones

1. Chemotherapy (in part)

2. Leukemia Virology

3. Chemical Carcinogenesis

4. Diagnostic Research

C. Studies of human and animal populations aimed at discovering the etiology, incidence, and natural history of cancer in man and animals (Generally regarded as a normal function of governmental health agencies)

1. Biometry (in part)

2. Epidemiology

3. Carcinogenesis (in part)

4. Virology (in part)

D. Miscellaneous activities funded with contracts because they do not fit conveniently into grants or “in house” operations

1. Support of research in organizations which do not qualify for grants

2. Procurement of services and things

II. Criteria for evaluating collaborative research of the above categories

A. Different categories require different criteria. For example:

1. Resource programs have merit only if they provide resources to activities of merit. To be internally efficient and effective is no great virtue in itself if the final end served is of dubious value.

2. Large-scale, industrial-type research is essential to solve certain types of problems. It cannot be evaluated by comparing it with fundamental research projects in academic institutions.

3. Study of populations is a respectable area of science which can be evaluated with the same criteria as biochemistry or physics.

4. The miscellaneous category has to be evaluated bit-by-bit and defies generalizations.

B. For purposes of this discussion, let us concentrate on large-scale target research and list important criteria.

1. Is the target worthwhile?

2. Is it technically feasible?

3. Are the resources available?

4. Is the plan adequate?

5. Is the management adequate?

6. How fast should one move?

C. Applying these criteria to the NCI programs which deal with diagnosis, treatment, and prevention of cancer, the targets are obviously worthwhile and feasible (as isolated examples show) and resources can be found (as previous experience proves). Now let us deal with points 4, 5, and 6 with each program.

III. Analysis of Chemotherapy

A. The plan. Inherent in the chemotherapy program is the orthodox linear array common to all drug development programs, but several features are importantly different.

1. A number of diseases are included.

2. Satisfactory laboratory model systems are only now beginning to emerge.

3. Drug cures are only beginning to emerge which permit the development of basic principles.

4. The total kill concept and the need for a total re-planning

B. The management

1. Recent losses of key men

2. Low morale

3. Failure in recruitment

4. Need to use intramural talents

5. Need for better support from OD/NIH and higher echelons

C. How fast should one move?

1. Program has been held practically level for some years by agreement of Shannon and Endicott.

2. Wooldridge Committee and other political pressures to cut back.

3. Technical reasons for pushing ahead at full speed.

IV. Analysis of Carcinogenesis

A. The plan. No over-all plan has ever been set forth. Limited segments have been planned elegantly (i.e., Leukemia-Virus Program). Others more sketchily. Great potential here.

B. The management. Excellent and getting better by leaps and bounds.

C. How fast should one move? Kotin says should go from 10 to 50 million dollars in the next three years.

V. Analysis of Diagnostic Research

A. The plan. Planning is not active. Existing plans developed by Nadel not accepted by Berlin. Program has been progressively cut back for five years.

B. The management. With Nadel’s retirement this summer, there will be little left.

C. How fast should one move? Would suggest that this be quietly dropped as a line item in the budget.

VI. Some thoughts on OD/NIH, Collaborative Research and the Wooldridge Committee

A. Director, NIH, and Surgeon General should give strong support to collaborative and intramural research without waiting for more studies.

B. Collaborative programs should not be reviewed (from the standpoint of scientific substance) except in the context of the over-all program of an institute.

C. Reaffirm plans for an annual total review of program by Council.

D. Establish a committee to advise Director, NIH, on total program of NIH.

E. Insist on adequate program review at the working level including internal and external advisors.

F. Retain power of contractor selection as an executive function.

The Diagnostic Research Program would be discontinued as a line item in the budget (Dr. Berlin to write rationale for discontinuing the Program). The virology program in Ghana would be phased out. Dr. Shannon liked the idea that Drs. Zubrod, Baker, and Schepartz and Mr. Carrese would lay out a systems plan for the Chemotherapy Program. He wished to involve the NACC subcommittees more in the program reviews and would establish review groups: 1) chemotherapy; and 2) carcinogenesis (would not include VRRB, Epidemiology or Biometry). Biometry and Epidemiology is not like other parts of Collaborative Research, but do require contract dollars. In the review, the Chemotherapy Program was considered sound. For Phase III clinical trials the single instrument grant would continue to be used; NCI would continue internal control of Phase I and Phase II trials. The Lymphoma and Breast Cancer Task Forces would continue as Prime Contractors. Staff positions requiring both scientific and managerial skills were not adequately appreciated; Drs. Shannon and Mider would meet with such staff members to reassure them.

1964

Request for Release of Bureau of the Budget Reserve NCI Funds for Funding of the Contractor-Operator Facility
The NCI Scientific Directorate and the NACC reviewed a document (January 4, 1964) justifying the establishment of a major special purpose contractor-operated research facility, along with a request to fund the facility with NCI monies that had been put into reserve by the Bureau of the Budget. The NCI then sent the document forward through the appropriate channels. The Director of NIH and the PHS Surgeon General supported the request. Although this March 6, 1964, memorandum pointed out the need for quick action, the reply to the request received by NCI June 15, 1964, stated that “in the Fiscal Year to use the funds and release of reserves was therefore denied.”

Although sizable contracts with several commercial firms were let, it was not until President Nixon announced on October 18, 1971, the conversion of the Fort Detrick Germ Warfare Facility (at Frederick, Maryland) to a Cancer Research Facility that the large contractor-operated facility envisioned in the above document sent forward by Dr. Shannon on March 6, 1964 could become a reality. Immediately prior to the President’s announcement, Drs. Baker, Rauscher, and Zubrod reviewed the status of cancer and cancer research with the President at the Frederick facility. They emphasized the viruses and cancer research. The announcement of the awarding of a $6.8 million contract to Litton Bionetics, Inc. was made on June 23, 1972. Litton had won the contract through competitive bidding. Several parts of the contract related directly to viruses and cancer research. William Payne was the project officer for NCI; Robert Stevenson, formerly Head of the VRRB, was the General Manager for Litton; and James Nance was President of Litton Bionetics, Inc.

Review of NIH by the Wooldridge Committee

In late 1963 President Kennedy asked Dr. Jerome Wiesner, his Science Advisor and Chief of the Office of Science and Technology, to undertake a study to assess the quality of biomedical research conducted and supported by the National Institutes of Health. Dr. Dean Wooldridge was appointed Chairman of a committee assigned the task. Dr. Shannon and the senior OD, NIH staff met with the Office of Science and Technology staff and key members of the Committee on January 9, 1964, and on June 25, 1964, to provide orientation and to answer questions from the Committee. In March 1964 NIH staff spent a significant amount of time in preparing orientation material for the Committee. The Committee gave special emphasis to issues such as the optimal size of NIH, if the budget of NIH was “too large,” and whether the money appropriated for NIH was well spent, especially for the Collaborative Research programs. It was important to produce this orientation material because several members of the Committee were not knowledgeable in the biomedical sciences. In addition to Dean Wooldridge, other Committee members were: Dr. Wiesner (MIT); General James Doolittle (Space Technical Labs, Inc.); Dr. William Houston (Rice University); Dr. George James (Commissioner of Health, New York City); Dr. William McElroy (Johns Hopkins University); Dr. Carl Moore (Washington University); Dr. Quigg Newton (Commonwealth Fund); Dr. Joseph Platt (Harvey Mudd College); Mr. Gwilym Price (Westinghouse Electric and Manufacturing Group); Dr. Wayne Reitz (University of Florida); Dr. Julius Stratton (MIT); and Thomas Watson, Jr. (IBM). Several of the Chairmen of the eleven supporting Panels were biomedical investigators. Two Panels were concerned with administrative and policy matters. NCI produced 85 pages of material on NCI Collaborative research programs plus materials on 119 NCI contracts and staffing charts. NIH produced 310 pages on Collaborative Research programs in six Institutes and in the Division of General Medical Sciences. Fifteen pages dealt with the NCI viruses and cancer programs. Members of the Committee and the Panels also interviewed about 500 grantee investigators from over 30 major institutions, about 50 NIH investigators, and a number of contractors in the collaborative areas. In the Report to the President in February 1965, the Committee gave a favorable review to the grants area and intramural programs. Questions were raised about the Collaborative Research areas. As was usual, the recommendation from the Committee was that NIH needed more advice from committees that had members from outside Government (i.e., from the academic community). In the case of the CCNSC it was recommended that another committee be established to review in further depth the CCNSC (this recommendation led to the review of CCNSC by the Richardson Committee). [It is of interest that NIH has been reviewed by many committees over the years: the Wolverton Committee, 1958; the Bayne-Jones Committee, 1958; the Bane Committee, 1959; the Jones Committee, 1960; the Barber Committee, 1964; the Wooldridge Committee, 1964; the Committee on Heart Disease, Cancer, and Stroke, 1964-1965; the Rogers Committee, 1966; the Ruina Committee, 1966; the Fountain Committee, 1959-1968; and others, in addition to the various Congressional Committees (e.g., the Elliott and Daddario Committees), including the examinations made annually by the Congressional Appropriations Committees.]

NCI Program Review of Clinical Studies, Collaborative Research

The NCI Scientific Directorate undertook an extensive review of cancer clinical studies at its meetings of April 7, 21, and 28, and May 12, 1964. Dr. Waalkes, Associate Director for Collaborative Research, provided a large amount of documentation for the review. This material had been discussed with the Clinical Studies Panel as part of consideration of the analysis and planning for the CCNSC. The Panel consisted of: I.S. Ravdin (University of Pennsylvania), Chairman; Emil Frei, III (NCI); Albert Segaloff (Alton Ochsner Medical Foundation); Bruce Shnider (Georgetown University); Albert Owens, Jr. (Johns Hopkins University); Anthony Curreri (University of Wisconsin); Jesse Steinfeld (University of Southern California); and Lyndon Lee (Veterans Administration). The meetings focused on improving the activities of five categories of twenty-three cooperative groups and the need for additional pharmacology studies. The five categories were: 1) Hematologic Malignancies; 2) Solid Tumors; 3) Hormone-Dependent Tumors; 4) Surgery Adjuvant Studies; and 5) Radiation Studies. Special efforts were needed in defining protocol requirements and information flows. Some investigators objected to the requirements of uniformity imposed by NCI, but uniformity of definition and information handling was (and is) essential for drug development and for analysis and evaluation of the activities of the groups. In addition to $5,843,000 budgeted for programmed grants, the clinical trials effort included $1,020,816 in supporting contracts plus $1,511,030 in transfer funds to the VA, Walter Reed Army Hospital, and the PHS Division of Hospitals. The clinical trials were financed with programmed grants because the HEW lawyers believed (erroneously, it turned out) that this course would keep the Government free of liability lawsuits.

These materials were presented to the NACC when the Chemotherapy Program was reviewed by the Council in March 1964. The NACC supported the plans for the clinical studies. Some members of the NACC were beginning to raise questions about the use of contracts. The NACC membership in 1964 consisted of: Walter Burdette (University of Utah); Lee Clark (M.D. Anderson Hospital); Philip Cohen (University of Wisconsin); George Cooper (St. Joseph College); Charles Evans (University of Washington); Sidney Farber (Harvard Medical School); Abner McGehee Harvey (Johns Hopkins University; Mary Lasker (Albert and Mary Lasker Foundation); Leo Rigler (Cedars of Lebanon Hospital); and Philippe Shubik (Chicago Medical School). Mary Lasker, supported by Sidney Farber and Leo Rigler, wanted the NACC to have the same approval requirements for contracts as for grants. Other Council members did not agree. Anticipating questions from the Council, NCI sent on May 15, 1964, to the Council a four-page document by the Associate Director for Program setting forth the nature of research contracting, the reasons for its use, and review mechanisms. The document pointed out that the NCI, in order to meet its responsibilities to further cancer research, needed to support and engage in the full spectrum of research, with fundamental or exploratory research at one end of the spectrum and developmental research at the other. For the most part, exploratory research depended upon independent investigators conducting self-generating projects. Developmental research was most often part of a broader scope of multidiscipline R&D efforts integrated into a program consisting of many interrelated parts. Grants were most suited for funding projects and contracts for funding programs. Central control was not preferable for exploratory research (grants). The necessity of integrating the components into a program required central control, especially since the input from one contract was at times dependent on the output of other contracts. Several contracts were production contracts for defined mice and other animals, tissue culture cell lines, media, virus preparations, antibody preparations, information collecting and distribution, and so on. Programs required central planning (but not down at the project level). NCI staff conducted exploratory research on an intramural basis, administered the extensive grants activities, and managed the contract activities. The third area involved program planning and integration of science and management expertise. As an aid for planning, the Associate Director for Program created a comprehensive grid showing various scientific and administrative components making up cancer research and which contrasted with ten organismic levels (radiation; atomic; micromolecular; macromolecular; subcellular; cellular; tissue and organ; multicellular individuals; populations; and societies).

As of November 1963, the dollar distribution of contract monies was:

Chemotherapy $24,650,000

Leukemia Task Force 600,000

Other Leukemia Activities 325,000

Biometry 645,000

Epidemiology 389,000

Carcinogenesis 2,023,000

Viral Resources and Virus Task Force 2,264,000

Other Virus Activities 2,525,000

Diagnostic Research 1,000,000

Reserve for Expenditure Adjustments 500,000

Unallocated or Bureau of Budget Reserve 4,045,000

TOTAL $38,966,000

NACC Meeting of June 22, 1964

The NCI Director made changes in the Intramural Program and in the Grants and Training area 1963-1964 to utilize senior staff more for broad substantive cancer considerations and less for routine issues. He and the NACC agreed that analogous changes were needed in the conduct of the activities of the Council. It was also agreed that the NACC should move away from so much time spent on individual project applications and give more time and attention to cancer program considerations, including planning. To move in this direction, the Associate Director for Program sent to the Council Members a 32-page document entitled “Goals and Objectives of Cancer Research and their Implementation.” This document dated June 22, 1964, was a discussion document specifically for the Planning Committee, NACC. The Associate Director also sent to the Council members the responses received from the NACC members to Dr. Endicott’s request for their “views in writing on the trends, thrusts, deficiencies and so on regarding cancer research over the next decade.” Two responses had been received. The contrast between the two is interesting. One, from Dr. Philip Cohen, was general and dealt with training needs (physical facilities, job opportunities, and funding support for more trained scientists), and greater dollar support for fundamental research (with less emphasis at NIH for categorical research). He warned that the gap was wide between the accumulated knowledge and the application in the clinic. He thought that all basic problems in biology, including those in cancer, were so complex that they would not be solved by merely continuing to spend more money in the same way as in the past. The other response, from Dr. Charles Evans, set forth objectives, mostly in terms of substantive scientific aspects of cancer problems. He first listed obvious objectives: cause, prevention, cures, treatment of incurable cancer, and determination of means whereby popular acceptance can be achieved for procedures that are known to prevent cancer. Next, he set forth some peripheral goals: define consequences that would follow from the controlling of cancer and make plans for use in cancer research and control of the increasing manpower pool resulting from technological advances. Next, he detailed more specific objectives related to the major goals. He also outlined some recommendations on manpower needs for cancer research and cancer control.

These two examples illustrate two very different approaches to the giving of advice. One focuses on the mechanics of funding with emphasis on basic research support. The other attempts to identify substantive scientific aspects of the problem area and project research needs based on the scientific conceptual schemes. They also illustrate very different attitudes where one view sees the problem as the glass being half-empty and the other as half-full. The former is a pessimistic view that says that we do not know enough to do more than generally support individual scientists. The other, with a more optimistic outlook, suggests that analysis of the situation can lead to selected priorities that form the basis for action. The efforts can be aimed at solving defined problems derived from the selections of priorities. More often than not the advice given to NIH is the former.
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Part 1 of 7

Chapter 4. Correction of Problems, Fine Tuning Of Program Operations, and Further Expansion of Program Outputs

By mid-1964 the viral oncology activities were expanding satisfactorily. Earlier problems with the supplies of normal and tumor tissues from humans and animals and as well as those with acquiring, preserving, freezing and thawing, and transporting these tissues were solved. Virus particles seen with E.M. budding off cell membranes of animal tumor tissues were also tantalizingly observed in some human tumor biopsy specimens. With tissue culture cell lines, some problems of labeling and contamination continued until 1966.

Many additional tumor-causing viruses from animals were isolated and classified, but none clearly from man. In the hope that the biological closeness to man of non-human primates would make for sensitive test systems for finding human tumor-causing viruses, many human tumor specimens were administered to these animals, colonies of which had been developed in the resources part of the Program. Moreover, techniques developed with animal viruses for increasing the purity and concentration of virus in the preparations derived from tumor biopsies were applied to those human specimens being injected into the non-human primates. Also, as the purity of the virus preparations produced with the special centrifuges in the Program at Oak Ridge Laboratories increased, analysis could begin to determine the viral DNA (or RNA) structure. Researchers also hoped to learn which parts of the viral DNA (or RNA) were responsible for tumor induction, for virus reproduction, and for other properties.

Participants in the SVCP discovered temperature-sensitive mutants of tumor viruses, another important tool for getting at the structure and sequences of the building blocks of the nucleic acids. Some of these Rous sarcoma virus (RSV) mutants would induce cancer transformation of tissue culture cells grown at 34 degrees C., but would lose that ability if growth was at 41 degrees C. These changes were reversible. The viruses would continue to multiply at either temperature. Further studies indicated that a single gene - called src - was involved in transformation. Thus the stage was set for mapping the region of the src gene (about 2000 nucleotides). The mutants were distributed to appropriate investigators.

The research results from the Program by mid-1964 were sufficient to warrant an NCI request to Congress for a special appropriation to fund a larger program on leukemia. For this new Program, the NCI appropriation contained an additional $10 million.

The NCI, utilizing the “Convergence Technique,” developed a systems plan for the new Special Virus Leukemia Program (SVLP). This plan provided staff and advisors a framework for decision making in the total Program perspective. It also was an aid in modifying the Program as new information was gained from the research and in projecting future activities. Once the laboratory methodologies for animal and human cancer virology were worked out (including availability of sufficient quantities of viral and immunological reagents), studies began to correlate the laboratory data with the data from population groups. These groups were constituted not only of humans and animals with different types of cancer, but also with different epidemiological categories (e.g., different age groups, different environments, contacts with different animals, and different exposures to air pollutants).

Because of the potential danger resulting from isolating and increasing the potency of several virus preparations, NCI had built a special facility for handling hazardous biological materials. [This development improved the U.S. ability to deal later with bioterrorism.] Along with the facility, the Institute developed a teaching program for handling hazardous materials that built on the excellent program of the U.S. Army. This segment of the SVLP developed improved safety measures and created the widely used red symbol warning of dangerous biological materials [Figure 3]. Later NCI developed a contractor-operated facility at Frederick, Maryland.

The number and total dollar amounts for contract-funded activities continued to increase appreciably, and the Institute continued to develop methods for improving the review of contracts and programs to achieve quality control. Numerous memoranda emanated from the NCI Office of the Director and gave detailed guidelines and instructions. These actions, supplemented by the systems plan, ensured coordination of the various components of the Program. At the NACC meetings, extensive information on these programs and contracts were supplied each year.

The Program continued to provide research materials to participants in the Program and to others including grantees. An important example of this was distribution of large amounts of reverse transcriptase, the enzyme that allowed the coded information in RNA viruses to be converted to DNA information. The enzyme also allowed the cloning or making copies of segments of the DNA code and the determination of sequences of building blocks in nucleic acid.

Robert Huebner and George Todaro made a major advance with the publication of their paper on the “Oncogene Theory.” In this theory certain genes (Oncogenes) in the cell nucleus, when turned on, can lead to cancers. Much of the time they are switched off but can be made active by radiation, certain genetic patterns where one gene may influence other genes, some chemical compounds, some hormonal agents, and ageing. The theory, supported by extensive evidence in several fields, concludes that cancer is not an infectious disease, and that cancer susceptibility is passed from one generation to the next by means of the information in the DNA. DNA information could be turned on easily or not depending on the genetic make-up and the lifetime experiences of the organism. Huebner thought that some of the coding in the cell’s DNA came from tumor-causing viruses. Only later, did Bishop and Varmus discover through the application of additional tools (restriction enzyme) that oncogenes do not need to be derived from viruses and are present normally in our chromosomes. In 1972 the total number of publications emanating from the SVCP reached 604 (294 published and 310 in press).

Request for a Special $10,000,000 Appropriation for Acute Leukemia Research

By July 1964 Dr. Endicott had reached the conclusion that the results of research on acute leukemia had advanced to a stage where additional funds should be added for this area of research. Numerous opportunities for further research existed and could be exploited if additional support were given. On July 16, 1964, the Director, NCI, sent to the Director, NIH, a memorandum headed “Need for Funds in Acute Leukemia.” This memorandum, drafted by Ray Bryan, Frank (“Dick”) Rauscher, and Carl Baker, and reviewed by Gordon Zubrod, provided important status summarization and justification for asking for additional funds. Dr. Endicott asked Dr. Shannon for permission to seek additional funds from the Congress for leukemia research in the amount of $10,000,000. Requesting special funds outside the usual budget channels was highly unusual, but the NCI believed it was justified. The memorandum follows:

The pace of research in the causation of leukemia and particularly acute leukemia of childhood and comparable lesions has become very rapid, and through the improved communication lines provided by our two Task Forces, I have been made aware of a number of new observations, as yet unpublished, which when added to the evidence already at hand indicates a clear need for further intensification of this activity. It seems quite probable that a deliberate program can be successful on several critical issues that remain to be resolved to establish on a firm scientific base the viral nature of these leukemias. The objective is particularly important in light of the possibility that an agent may be isolated and that we might be able to prevent this lethal disease.

Much of the most recent work has been made possible by the diversion of funds from other areas to this one, and I feel I cannot make further diversions without serious inroads on other programs that have great importance in themselves. The resources of the National Cancer Institute as represented by the budget presented to the Congress for fiscal year 1965 are inadequate to cope with these emerging problems. I hope that it will be possible to take immediate steps to obtain a special fund with appropriate authorities in order for me to move more aggressively in the pursuit of these exciting leads.

The following is a series of specific findings that have characterized leukemia research in the past few years, most of them new observations of which many are yet to be published.

Facts

1. It is well established that leukemia in both domestic chickens and mice is caused by viruses. Extensive investigations of the disease in both species have established that virus is present and can be demonstrated by both animal tests and electron microscopy not only during clinical disease, but also prior to the onset of clinical symptoms.

Virus particles can be seen with the electron microscope in leukemic cells in the spleen, lymph nodes, bone marrow and other affected organs. What is more important, leukemia virus is produced in much larger amounts by certain cells of the body that, although they “manufacture” large quantities of virus, do not themselves undergo cancerous transformation. The cells which manufacture virus but show no ill effects of it are among those that normally produce large quantities of protein, such as the acinar cells of the pancreas, megakaryocytes of the spleen and bone marrow, and epithelial cells of the mammary glands. It therefore appears that leukemia viruses may parasitize the intracellular protein producing mechanisms of cells.

2. In 1957, Dmochowski reported the presence of virus-like particles in thin sections of lymph nodes taken from human leukemic patients. Beard (unpublished) confirmed this observation, but in only one of about a dozen cases studied.

3. Dalton and Moloney showed that virus was present in the plasma of leukemic mice, and that fractions isolated and concentrated by ultracentrifugation showed typical virus particles when examined by thin section electron microscopy. In collaboration with Porter, Frei and Mitchell they also studied over 50 plasma specimens from children with acute leukemia, and found particles resembling mouse leukemia virus particles in 8 cases.

No such particles were seen in the plasma of 86 normal humans, 36 of which were young children of the same age as the leukemic children.

Other investigators using a less critical electron microscopic method (negative staining) have reported a larger proportion of leukemia in cases showing virus-like particles (Melnick and associates; Burger and associates).

4. Fink and Malmgren succeeded in working out specific immunofluorescence methods which detect the presence of viral antigen in leukemic cells induced with certain mouse leukemia viruses. Application of the method to human leukemia, using plasma fractions shown by electron microscopy to contain virus-like particles for the production of antibodies in rabbits, has revealed a fluorescent antigen in leukemic cells in a high percentage of the human leukemia cases studied. Many of the positive cases also showed a cross reaction with specific antisera against the Rauscher mouse leukemia virus, indicating that common antigens are shared by the Rauscher virus and something (viral antigen?) in some human leukemia cells.

5. Epstein has succeeded in propagating cells from human lymphoma (Burkitt) in tissue culture, which continue to elaborate a membrane-bound virus-like particle. These tissue culture cells give a very strong immunoflourescent reaction with the human antibody reagent of Fink and Malmgren as well as with that of the Rauscher mouse leukemia virus. Mass cultivation of these cells in tissue culture could provide an abundance of virus for further studies, including vaccine development.

6. Epstein inoculated suspensions of fresh lymphoma cells from a case of Burkitt lymphoma into 4 suckling African gray monkeys. Of three that survived two years but have recently come to autopsy, two showed dilation of the marrow cavity and the resulting space filled with malignant lymphoblasts indistinguishable from those of the original Burkitt tumor. It appears that a human lymphoma has been transmitted to a sub-human primate for the first time, probably by a virus present in the inoculated cells. Of 11 monkeys inoculated with Burkitt tumor cells that had been stored at low temperature, 5 are now showing X-ray evidence of bone marrow lesions, similar to the X-ray pictures that had been taken of the two positive monkeys, before they came to autopsy.

More recently, Epstein has reported finding myelosclerotic lesions in bone marrows of several uninoculated primates from London zoos and from an adult colony maintained in Africa. These lesions in “normal” animals apparently are indistinguishable from those which occurred in animals inoculated with Burkitt lymphoma cells. Further control studies, therefore, are obviously necessary to access the significance of Epstein’s preliminary transmission experiment in primates.

7. In NCI contract research conducted in collaboration with the Pfizer Company, a mixed mouse thymus and spleen culture was successfully inoculated with Rauscher mouse leukemia virus. For several months the cell cultures showed no evidence of producing virus, but eventually small amounts (1 or 2 particles per electron microscopic grid) were observed. Subsequently, the culture line began producing large quantities of virus and is now being used for the in vitro production of Rauscher virus.

A mixture of human embryonic thymus and spleen was established in tissue culture by the Pfizer group, and is now being used for the inoculation of human plasma concentrates in which particles are seen with the electron microscope. One such line inoculated several months ago is now showing “1 or 2 particles per grid” when culture fluid is examined under the electron microscope. Since no particles had been seen until recently, and since no such particles have yet been seen in uninoculated control culture fluids, this experiment with a human specimen containing a “candidate” virus appears to be following the same course observed with the mouse leukemia virus. Although not yet successfully established as a virus producing line of practical significance, the results to date strongly indicate that success will be achieved in the propagation of a human leukemia virus.

8. Grace and collaborators (unpublished) have succeeded in propagating human myeloid leukemia cells in tissue culture for many months. The cultures are still in good condition and are releasing virus-like particles into tissue culture fluid. This system is now ready for mass production trials for the recovery of large amounts of the virus-like particles for further study by immunological and biological methods. Small concentrations of the materials have already been inoculated into newborn monkeys.

Leads

1. Studies on 3 “clusters” of leukemia, such as that which occurred in Niles, Illinois are under investigation. One surviving leukemic child of the Niles cluster (now in remission) has been tested on two occasions. Virus-like particles were found in her plasma on both occasions. Her mother and her sister also showed similar particles in their plasmas.

In the Green Bay, Wisconsin area there are now 5 cases of childhood leukemia within an area 1.5 miles in diameter. A sixth case just recently reported lives 11 miles away. Of these 6, 4 have been found to be positive for presence in the plasma of particles resembling mouse leukemia virus particles. The father of one case and the mother and sister of another have likewise shown virus-like particles in their plasmas. No such particles have yet been observed in normal humans unrelated to leukemics.

A third “cluster” in Osage, Iowa is also under study. Of three original cases only one is now alive. Satisfactory tests were not obtained before death of the other two, but three successive tests on the surviving child were positive. The father of this child and the mother of one of the other children were also positive for characteristic virus-like particles in their plasmas.

A local veterinarian volunteered the information that there seemed to be an increasing incidence of lymphosarcoma in a herd of prize Holstein dairy cows in his area. This particular herd has been under close surveillance for about 15 years by the same veterinary group. The families use pasteurized milk from four different local dairies. Three of the first four leukemic children studied were bottle-fed. (Information is not yet available on the other one).

2. Three cases in which leukemia in a child has followed within a short time (2 to 3 months) a bite by a dog has come to our attention. In no case was the dog leukemic. Another case of leukemia in a young man followed shortly after the death of a pet dog with leukemia. There was no history of dog bite in this case.

Of the five cases of leukemia within a 1.5 mile diameter in the Green Bay “cluster”, all families have 1 or more dogs. The dog of one of the leukemic children was clinically ill with “distemper” about 1 month before the child became symptomatic.

Virus-like particles have been observed in the plasma of 3 leukemic dogs studied by Moloney.

3. A series of papers concerned with bovine leukemias was published in Annals of the New York Academy of Sciences, 108:1149-1268,1963. Some identified herds in the United States studied by Dutcher, Coriell and Marshak have experienced multiple cases of lymphosarcoma, or leukemia, during the period of study. The most extreme case is a herd of 50 milk cows in which 20 have died of these lesions since 1956 and most of them since 1960. The course of the disease is characterized by a non-leukemic lymphocytosis followed by frank neoplasia. A pronounced drop in the lymphocytosis precedes the onset of cancer. Examination of leukemic cell cultures and lymph nodes from affected cattle disclose particles similar to those found in mouse leukemias known to be transmitted by viruses. Milk from apparently normal individuals, those demonstrating lymphocytosis or those frankly leukemic contain racket-shaped particles, as demonstrated by negative staining under the electron microscope. Thin section specimens are being prepared.

Other herds have been identified in which leukemias and allied diseases have not been known to occur. Neither their milk nor their tissues have contained any virus-like particles on appropriate examination.

European experience suggests that bovine leukemias can be introduced into a clean herd by transfer of breeding stock from multiple case herds. More than 30,000 head of dairy cattle have been sacrificed in Denmark because of lymphocytosis.

4. Burmester has obtained evidence of antibodies against fowl leukemia virus in the serum of a few human leukemia patients.

5. Rauscher and Fink have observed three cases in which serum from leukemic patients neutralized a mouse leukemic virus.

6. Jarrett and associates have recently reported that leukemia in cats can be transmitted within the species by cell-free preparations. Virus particles similar to mouse leukemia particles were also observed. This indicates that cat leukemia is also caused by a virus.

Kenneth M. Endicott, M.D.

Dr. Endicott was authorized to present at the Appropriations Committee hearings a proposal for an expanded program for cancer virus studies. A $10,000,000 program for these studies was proposed in addition to the regular appropriation request. The projected expenditures of the $10 million, as were transmitted to Herman Downey, the Clerk of the Senate Appropriations Committee, were outlined as in the following memorandum to Dr. Shannon, the Director of NIH from Carl Baker, the Acting Director of NCI, dated August 12, 1964:

Use of $10 Million in Additional Funds.

We have previously indicated to Mr. Downey, in a budget requested through channels, that we would expend $10 million as shown below:

(1) For research, design, mock-up and testing of special rooms, to be placed within existing or leased space to protect persons against dangerous materials $ 1,500,000

(2) For development and production of tissue cultures, viruses, reagents and fluorescent antibodies and other resource requirements 3,800,000

(3) Studies of viruses in animals and their relationship to human cancer 1,500,000

(4) Epidemiology and related field work including limited sampling of blood from a selected group or groups in search for causative agents 1,000,000

(5) Clinical research - strengthening of the existing NCI team, support of two additional teams for intensification of viral and therapeutic research with patients, including maintenance of outpatients, hospital costs and related pharmacology 1,400,000

(6) Special instrumentation and other engineering developments for virus and cell separations 800,000 $10,000,000

In addition, 90 additional positions should be provided for carrying out this enlarged program.

Needless to say, the number of positions authorized was nowhere near the 90 positions requested.

Planning of a New $10 Million Viruses-Cancer-Leukemia Program

After the Appropriations Bill passed, Dr. Endicott said to Dr. Baker and Mr. Carrese, “OK, you guys have been talking about the need for program planning, plan me a $10 million program on viruses and cancer-leukemia.” He appointed the two of them plus Dick Rauscher to form a science/management team operating from his Office to plan, develop, and manage the Program. In September 1964, the three members of the Science/Management Team isolated themselves from other contacts for a three-week period to develop a systems network depicting the Program. The planning was done in phases with each phase resulting in a more complete and refined revision. This approach set forth the Program structure based on the science and the program logic required for moving toward Program objectives. An important addition to the network plans was the defining of key decisions (Decision Points) that must be made periodically to move the Program along. Spelled out for each Decision Point were criteria that had to be met to make the decision and the information inputs required to meet the criteria. [Systems planning for the Cancer Chemotherapy Program later led to the addition of Monitoring Points; these were like Decision Points except that they called for periodic decisions on whether the program structure itself must be changed. The Monitoring Points also required that criteria required for making the decision and the information necessary to meet the criteria be closely defined.] The illustration of the systems network (Figure 4) showed multiple inter-connections among the various parts of the Program with connecting arrows. The network consisted of two arrays or program flows: 1. Human Leukemia Etiology, Prevention and Control; and 2. Production and Quality Control of Candidate Virus(es) and Vaccines.

Systems networks provide the basis for key decisions that must be made for a program to progress operationally, i.e., through various Program phases. As a program evolves, outputs of program efforts (data or materials) move to required sites in the planned program, and flows of information and other resources move across the network. The systems approach was a great improvement over the earlier grid because inter-relationships could be shown, and Program decisions were aided by the systems network. Another advantage is that the network allows reiterative visualization of the total program, and, if changes are made, the effects on other components can be noted more easily. A systems network chart is also a great aid for presenting and communicating complex programs.

The use of a systems network for planning and operating a research program required modification (to accommodate the research aspects) of other systems planning efforts (production and construction programs, e.g., the Polaris Missile Program and CPM - Critical Path Method - for major construction programs). Moreover, time and cost estimates cannot be as precise in research programs, though time is always a critical factor. In this pioneering effort by NCI, the concept of converging program efforts toward target objectives led to labeling the systems effort the “Convergence Technique.” A full presentation of this technique was later published by Lou Carrese and Carl Baker, as “The Convergence Technique. A Method for the Planning and Programming of Research Efforts,” in the April 1967 issue of Management Science (see vol. 13, no. 8, pp. B420-B438).

This planning activity also resulted in three historic documents, all dated September 28, 1964. They projected research efforts based on the current status of research and opportunities to exploit many leads. These documents were sent to the Scientific Directorate for a scheduled review on October 6. They were also sent to the NACC and the NCI Board of Scientific Counselors for the upcoming joint meeting to review the viruses leukemia plans on October 13 and 14. The documents were: 1. “The Special Virus-Cancer-Leukemia Program” (5 pages); 2. “Proposed Operational Plan for the Special Virus-Cancer-Leukemia Program” (3 pages); and 3. A chart titled “Gross Program Divisions, Special Virus-Cancer-Leukemia Program.” The initial Program later became known as The Special Virus Leukemia Program.

The five-page broad Program statement (1) stated:

The Special Virus-Cancer-Leukemia Program

The NCI request for a supplemental appropriation was based on the conviction that there now exists sufficient scientific knowledge and information and technical capability to plan and carry out an intensified, coordinated virus--cancer-leukemia research effort.

The program is being planned along four main lines of effort, all of which are interrelated. Concise preliminary program statements for these four program areas are given below. These broad general statements provide a convenient way to describe the total effort and, more important, serve as the basis on which the next level of more detailed plans can be formulated (see the second attachment).

I. Human Leukemia Etiology and Prevention

This major program area is the performance of integrated research and development efforts directed toward the prime objective -- prevention of human leukemia by production of an effective vaccine for human leukemia and/or other control methods of virology. An essential target in moving toward this objective is the successful growth of large quantities of human leukemia virus in tissue culture for the immunology studies requisite to vaccine development.

Following is the basic structure of the program in this area:

A. Assumption: At least one virus is an indispensable element for the induction of at least one kind of human leukemia, and the virus continues present in the individual.

B. The Main Program Objective: To develop an effective vaccine or other measures for the prevention and control of human leukemia.

C. Major Program Elements

1. The production of large quantities of human leukemia virus (and other oncogenic viruses) necessary for requisite immunologic studies and production of an effective vaccine utilizing required cell lines.

2. The improved detection of specific biological activity of human candidate virus preparations for selection of specimens for additional work-up, for monitoring biohazard work, etc., by enhancing the sensitivity of present laboratory indicator systems and/or the development of new test systems.

3. The provision of greater capacity for screening large numbers of human leukemia for selection of the most favorable patients and materials for virus isolation and propagation studies by the further development and increased production of required reagents and increasing the number of trained personnel.

4. The determination of whether leukemias in certain animals are virus induced, and, if so, to establish their antigenic relationships, the mode of transmission, and attempt to determine the etiologic relationships to human leukemia.

II. Human Leukemia Therapy [developed with Gordon Zubrod]

The second program area is concerned with the intensification and expansion of research to achieve the ultimate therapeutic objective of the complete destruction of all leukemic cells with tolerable (minimal) toxicity for the patient.
Total kill of leukemic cells has been achieved in mice and approximated in a few patients. Slight improvements in therapy may make this feasible in many patients.

Following is presented the basic structure of the program plan in this area in terms of more proximate objectives:

A. Support of the patient by amelioration of drug side effects. For example, if side effects of antileukemic drugs upon bone marrow could be ignored, much larger doses could be tolerated.

1. Platelet replacement for thrombocytopenia.

a. Storage of platelets so that they can be made available to all patients.

b. Simplification of collection techniques in order to adapt them to Red Cross collection system.

c. Mass tissue culture of megakaryocytes.

2. Granulocyte replacement for agranulocytosis.

a. Development of technique for harvesting granulocytes from 2 to 3 blood volumes of normal donor. This will require perfecting the in-line centrifuge.

b. Storage of granulocytes.

c. Mass tissue culture of precursor bone marrow cell.

3. Immunocyte replacement.

Lymphocyte - plasmocyte deficiency occurs as host response to leukemia and antileukemic drugs, and is probably responsible for fungal and viral infections. Have same needs for harvesting, storage and mass culture of these plasmocyte cells and precursors.

B. Prediction from animal studies of better therapeutic ratio of drugs used in patients. It will be recalled that ultimate objective:

Greatest Efficacy

Least Toxicity = Therapeutic Ratio.

1. Prediction of greatest efficacy.

a. Better new drugs. These will flow from present NCI mechanisms but great need for studies on pharmacological disposition in mouse and patient.

b. Better use of current drugs.

(1) More efficacious combinations of current drugs. Studies underway but have little data on prediction systems for drug combinations or pharmacological distribution of several drugs used together.

(2) Better use of current drugs used singly. Need to validate prediction system for best route, schedule, need for maintenance, etc.

2. Prediction of least toxicity.

a. Quantitative: i.e., Prediction of safe dose. The predictive value of animal models is now understood on a dosage basis, but there is a great need to reinterpret and to refine prediction in terms of comparative blood and tissue drug concentrations. Hence need extensive increase in pharmacologic studies of all current and new drugs in animals and man.

b. Qualitative: i.e., Prediction of toxicity to specific organ systems. Same needs as under B.1.

3. Prediction of adjuvant effects of other therapies. It will be recalled that the working hypothesis is that any additional help to patient may make total destruction of leukemic cells systematic. Thus, the destruction of the last few logs of cells might be achieved by adjuvant immunotherapy, or -- if human leukemia is due to a virus -- the production of new leukemic cells might be prevented by viricidal agents.

a. Immunotherapy. Animal studies show that Rauscher leukemia can be altered by passive immununization. Plans should be made to apply this to patients. What should be source of antibodies?

??Hyperimmunization of normal volunteer by killed vaccine.

?? In vitro antibody production.

b. Viral chemotherapy.

(1) Prediction of drugs for destroying leukemia virus.

(2) Prediction of drugs for destroying secondary viral invaders such as cytomegalic inclusion virus.

c. Fungal chemotherapy.

Prediction of drugs for destroying secondary fungal invaders -- Histoplasma, Candida, Aspergilli, etc.

III. Biohazards Control and Containment

The third program area is the performance of urgently needed, coordinated efforts directed toward successful containment and safe handling of oncogenic viruses – a potential biohazard to those conducting oncogenic virus investigations. The experience with animal model systems indicates that the activity of oncogenic viruses is greatly enhanced when produced in quantities and concentrations utilized in advanced study of leukemia. Also, recent developments permitting oncogenic viruses to cross species lines further emphasizes the urgency of this work.

IV. Special Animal Leukemia Ecology Studies

The fourth area is concerned with the nature of animal leukemias and their possible relationships to man. Accumulated evidence from a variety of sources suggests a relationship between the occurrence of leukemia in persons who have associated with domesticated animals and the occurrence of leukemia in these animals. Virus-like particles have been seen in cows’ milk and milk products and in greater numbers from leukemic herds than from non-leukemic herds. Because of the economic, political, social, and, perhaps, health implications of these observations, it is a matter of urgent and serious obligation to clarify the nature of leukemias and associated viruses in several types of domesticated animals, their relationships with each other and with human leukemias, and to attempt determination of the significance of the virus-like particles in milk, including studies on inactivation of viruses contained in milk. The preliminary findings suggesting the exquisite sensitivity of newborn swine to oncogenic viruses from other species should be followed up with dispatch.

In addition to the major lines of program emphasis described above, other supplementary efforts will be conducted. These efforts, although not currently judged to be critical to the achievement of the more specific objectives outlined for the major program areas, are nonetheless important for the potential basic scientific knowledge they may provide (“The Special Virus-Cancer-Leukemia Program,” Associate Director for Program to the Scientific Directorate, the Board of Scientific Counselors and the NACC, September 28, 1964).

The three-page September 28, 1964 document, “Proposed Operational Plan for the Special Virus-Cancer-Leukemia Program” (2) was as follows:

1. Initial Program Planning

A science/management team appointed by the Director, and operating from his Office, has developed a preliminary draft of the overall program plan. The Scientific Directorate and the National Advisory Cancer Council will review this general plan and advise the Director as to its suitability.

2. Detailed Planning Prior to Implementation

For purposes of detailed program development, it is proposed that this special research effort be divided into four major program areas: human leukemia etiology and prevention; human leukemia therapy; biohazards control and containment; and special animal leukemia ecology studies. To pinpoint working responsibility, these four areas, in turn, are divided into eight working groups representing segments of the major program areas: development; testing and monitoring; epidemiology (epizootiology); resources and logistics; production; biohazards control and containment; special animal leukemia ecology studies; and human leukemia therapy (see attached chart). A chairman for each of these working groups will be selected from NCI operating units. The chairmen will invite scientists from NCI, NIH, and outside organizations to participate as a group in the development of detailed plans for their respective program segment.

The working group chairmen (and others as required) will meet with the OD science/management team to correlate and integrate the eight separate detailed plans into one overall program plan. This more detailed plan will also be made available to the Scientific Directorate and the National Advisory Cancer Council.

3. Implementation, Monitoring and Coordination

Following the generation and review of the detailed program plans, each working group will develop individual project proposals comprising their respective program segment. These will be reviewed in the usual manner.

Once the approved projects are implemented, program monitoring and coordination will also be accomplished through the eight working groups. The chairman of each of the groups (or another member appointed by Chairman) will function as a program manager for all projects included within his particular program segment, and will have overall responsibility for monitoring and coordinating these projects regardless of the mechanism of performance. The program segment manager will monitor all projects not only from the standpoint of being generally aware of the progress and status of each project, but he will also be cognizant of problems which may be impeding the expected pace of progress toward project objectives and initiate action necessary to solve these problems. Thus, the program segment manager plays an active role in the assessment and evaluation of performance on each project and initiates action to modify the projects in close coordination with the project directors. Coordination between program segments is accomplished in two ways: through frequent “cross talk” among program segment managers and project directors; and through periodic meetings of the program segment managers with the science/management team. These meetings will take place at least quarterly, and more often if necessary, to meet the requirements of specific situations. Progress and status reports for each program segment will be presented and discussed. The OD Science/management team will integrate these reports into overall program reports and forward copies to the Director, the National Advisory Cancer Council, the Scientific Directorate, and the program segment managers. Each project director will provide a periodic, updated overview of his total program area (Proposed Operational Plan for the Special-Virus-Cancer-Leukemia Program,” the Associate Directorate for Program to the Scientific Directorate, the Board of Scientific Counselors, and the NACC, September 28, 1964).

An organizational diagram was included. The Gross Program Division Chart (3) was a grid chart with the program segments down the left margin and four phases across the top:

Phase 1. Identify unknown virus agents & establish replicating capability in some system.

Phase 2. Produce large quantities of highly purified virus & reagent antibody.

Phase 3. Etiological substantiation & developmental control work: (a) substantiate leukemogenesis in man; (b) vaccine development; (c) development of other control measures.

Phase 4. Planning & execution of field trials & evaluation of control measures.

The grid chart includes additional details under each of the four Phases.

The designated program segment managers (and deputies) were: Development: Ray Bryan (Jack Dalton); Testing and Monitoring: Bob Stevenson (Mary Fink); Epidemiology (Epizootiology): Bob Miller; Production: Bob Manaker; Resources and Logistics: Bob Stevenson; Human Leukemia Therapy: Gordon Zubrod; Special Animal Leukemia Ecology Studies: John Moloney (Bob Holdenreid); Biohazards Control & Containment: Bill Payne (Robert Runkle) (Gross Program Divisions, Special Virus-Cancer-Leukemia Program,” a grid chart organizational diagram from the Associate Director for Program to the Scientific directorate, the Board of Scientific Counselors, and the NACC, September 28, 1964).

The NCI Program Review book sent to the members also contained detailed data on 283 research grants ($13,902,772), 51 contracts ($9,672,019), and 65 intramural research projects (about 4.4 million man years of effort) all related to virology/leukemia research projects. Also sent out was a “Report of Working Conference on Bovine Leukemia” dated September 17, 1964. Invited to this conference were 55 participants; Gordon Zubrod chaired the conference. The Resources and Logistics Section of the Virology Research Resources Branch supplied “A Bibliography and General Reference Guide to the Bovine, Canine and Feline Leukemias”; this was a good example of the bibliographic services that the VRRB provided.

It may be noted that Bob Miller published a paper in the July 2, 1964, issue of the New England Journal of Medicine entitled “Radiation, Chromosomes and Viruses in the Etiology of Leukemia. Evidence from Epidemiologic Research” in which the final paragraph was as follows:

“Some viruses that produce chromosomal abnormalities are oncogenic in laboratory animals. Furthermore, unlike ionizing radiation, viruses may invoke malignant transformations in human tissue culture. Despite these impressive laboratory observations, epidemiologic research, so effective in defining other factors in leukemogenesis, has been unable to reveal convincing evidence of a virus-like spread of leukemia in man.”

With the rapid progress in animal studies, including demonstration of transmission of many animal oncogenic viruses, it may be understandable that insufficient attention was given to Bob Miller’s calling attention to the lack of epidemiologic evidence in human subjects.

Reviews of the Plans for the Special Viruses Leukemia Program

The overall Special Viruses Leukemia Program Plan was presented to the Scientific Directorate on October 6, 1964 (“The Special Virus-Cancer-Leukemia Progra,” and “Proposed Operational Plan for the Special Virus-Cancer-Leukemia Program,” from the Science Management Team to the Scientific Directorate and the NACC, September 28, 1964). Dr. Baker discussed the scientific rationale for the Program and the general administrative and operational aspects and Dr. Rauscher discussed the detailed scientific aspects. Chairmen were selected for the eight segment working groups; the groups would function in a manner similar to existing NCI Program Review as regards review, but would have additional planning responsibilities. Following full discussion, the Plan received Scientific Directorate approval for implementation (pending approval at the joint meeting of the NACC and the Board of Scientific Councilors).

Immediately after the Scientific Directorate meeting, each Chairman was asked to review the total plan (about 160 projects) and tentatively identify those projects that he considered to be within the sphere of his particular research area. He was also asked to identify those that represented combined, coordinated responsibility of several working groups. In addition, potential investigators and their affiliations were noted after each project. A composite list was prepared for presentation at the joint meeting.

At the October 13-14, 1964, joint meeting with the NACC, essentially the same presentation was given before the Scientific Directorate. In addition to Dr. Baker’s and Dr. Rauscher’s presentations, Dr. Emil Frei (representing Dr. Zubrod) gave a special presentation regarding the human leukemia therapy aspects of the Program, and the role to be played by the Acute Leukemia Task Force in the effort. Following brief discussion, the total scientific and operational Plan received unanimous endorsement from the NACC (and the Board of Scientific Counselors) with the recommendation for immediate implementation.

The OD Science/Management Team and the Chairmen of the working groups spent much of the remaining time in 1964 determining the division of responsibilities and assignments of contracts to the particular working groups. Priorities were developed for each set of contracts and contracts proposals. Many meetings were held among and between the Chairmen to resolve problems. Also, firmer requirements for space and personnel were drawn up. It was clear that additional space would be necessary to carry out the Program. When the projected preliminary totals were added up, the dollar amount was over $13 million and the positions totaled 148. Through additional meetings focusing on priorities, the amounts for contracts were brought down to the $7 million amount available for new contracts. Detailed allocations of the total Program funds were made into the main budget categories of contracts, other objects, travel, construction and renovation, space, equipment, payroll, and reserve for contingencies. In November, after approval by the NCI Director, potential members of the working groups were invited to serve on the working groups. Between five and ten outstanding investigators were to make up the membership of each working group. This activity under the rubric of the overall plan ensured participation of investigators within and outside the NCI in not only review of proffered projects, but in the continuing planning of needed new proposals. The first meetings of the working groups were held from mid-December 1964 to early January 1965. The eight working groups totaled 59 in memberships (27 from within NCI and 32 from outside the Institute). The OD Science/Management Team prepared for the new members of the working groups a package providing general information on the Program. The NCI staff, especially the working group Chairmen, responded very well to the sudden large increase in workload and deserve much credit for implementing quickly the new program.
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