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From “Publish or Perish” to “Patent and Prosper”

2006; Elsevier BV; Volume: 281; Issue: 11 Linguagem: Inglês

10.1074/jbc.x600002200

1083-351X

H. K. Schachman,

Health and Medical Research Impacts

After spending more than 55 years doing research and 45 years teaching a graduate course in physical biochemistry with the last 5 years spent attempting to teach ethics in a required course on Responsible Conduct of Research, I had wondered about what to write in response to Herb Tabor's kind invitation and urging to submit an article on “Reflections.” Tempting as it is to write about my love affairs with the ultracentrifuge, tobacco mosaic virus, nucleic acids, ribosomes, and a host of proteins including aspartate transcarbamoylase in particular (1Schachman H.K. Still looking for the ivory tower.Annu. Rev. Biochem. 2000; 69: 1-29Crossref PubMed Scopus (4) Google Scholar), I decided instead to look back at the way science was done at the start of my career and how our research environment and academia, in particular, have changed in the past half-century. In doing so, I offer apologies at the outset. This account cannot be construed as “history.” Instead it offers personal recollections, biases, impressions, and evaluations, frequently without documentation. Indeed many of the papers and historical records that I would cite are not readily available. Regrettably from my point of view, Stanley Hall, my home on the Berkeley Campus for 50 years, was demolished several years ago to be replaced by a much larger laboratory, and this Reflections is being written in a temporary office. The following pages present my views on various topics such as how careers in science have changed, how federal funding of research in universities was initiated, and how politics interfered with the funding process. In addition, the peer review system is discussed along with the plight of dissatisfied applicants. Finally, I present my impression of the impact of federal funding on universities, the controversy over indirect costs, the burden of government regulations, the enduring struggle over fraud in science, and the major changes in the culture of academia and the commercialization of universities stemming from the Bayh-Dole Act. On many of these controversial issues I was personally involved both in advocating and opposing policies under consideration by government agencies. As President of the American Society of Biological Chemists (ASBC), now the American Society for Biochemistry and Molecular Biology (ASBMB), and later as President of the Federation of American Societies for Experimental Biology (FASEB) and Chair of the Public Affairs Committee of ASBMB, I traveled extensively to Bethesda and, in concert with other concerned biomedical researchers, helped to formulate positions that we hoped represented the working scientist's point of view. Moreover, I had the privilege of serving for 6 years as an advisor to the Director of the National Institutes of Health (NIH), Harold Varmus, and as its Ombudsman in the Basic Sciences. This part-time activity involved extensive visits to more than 45 universities and medical schools where I learned a great deal about the conduct of biomedical research and the problems encountered by investigators. To some extent, therefore, this Reflections, although not about my research, is indeed a personal memoir. Although a significant amount of material presented below is critical of government agencies and policies, university administrators, and actions of fellow scientists, I wish to emphasize that the triumphs of biochemistry in the past 60 years are almost impossible to encompass. Although biochemistry formerly was concentrated in medical schools and a few schools of agriculture, now university campuses throughout the country have thriving departments. Moreover biochemistry is “invading” chemistry and physics departments as well as engineering schools. Leadership in research is now in the hands of innumerable creative young people who have fallen in love with biochemistry and are largely responsible for the startling discoveries of the past half-century. The training of these scientists and the support of their research resulted from the magnificent contributions of those great institutions, NIH and the National Science Foundation (NSF). Conducting scientific research today is dramatically different from what I and others of my age experienced, and the pace of discovery is much more rapid. Superb commercial instruments for numerous techniques are now available. In addition, innumerable reagents biochemists formerly prepared in their laboratories can now be purchased, thereby freeing investigators to perform imaginative experiments. New journals, numbering in the thousands, are available for publication of the findings. Who could have imagined that the Journal of Biological Chemistry (JBC), which in 1945 had an Editorial Board of 12 members and published 365 articles comprising about 3600 pages, would 60 years later have 650 biochemists on the Editorial Board leading to the publication of about 5000 articles comprising 43,000 pages? And today's JBC pages are much larger than those in the 1950s. How did this come about? What factors led to such dramatic growth? How did little Biochemistry morph into Molecular Biology and Cell Biology, Big Science, and Big Business? How did academia change from “Publish or Perish” to “Patent and Prosper?” What may we expect for the next 60 years? As a newly minted Instructor in Biochemistry at Berkeley in 1948 just after receiving my Ph.D., I was acutely aware of the unpredictability and hazards of an academic career. My training as an undergraduate in chemical engineering at MIT followed by graduate school in physical chemistry at Princeton provided me with little knowledge of biochemistry, and there I was, by good luck, on the faculty of a biochemistry department. Accordingly, by auditing various courses, I slowly became familiar with metabolic pathways leading me to describe the auspicious position of Instructor as a “Hypothetical Unstable Intermediate.” Today, virtually no one is appointed as an Instructor. On the contrary, most individuals enter academia in science as Assistant Professors or even Associate Professors. Such appointments are made after they have spent several years, and often too many years, as postdoctoral fellows. It is now commonplace for young investigators to have two, or even three, different postdoctoral stints. As a consequence, researchers in the biomedical sciences do not become independent investigators until a significantly older age than was the case 40–60 years ago. Appointments to faculty positions at an older age coupled with the termination of mandatory retirement have resulted in numerous reports bemoaning the aging of the research community. I can recall joking 30 years ago that consideration of promotion of a biochemistry faculty member to tenure no longer involved reading their papers. The inability to comprehend the contents of the burgeoning literature resulted, according to folklore, in the practice of “weighing” the papers and, at a later time, of “counting” them. Finally, a rebellion occurred over the “quickies,” and academic departments began considering content again. However in the past 10 years, it appears that more consideration is focused on where an article was published rather than on what was published. Fortunately, leading academics responsible for this “need” to publish in Cell, Nature, Science, or the Proceedings of the National Academy of Sciences (PNAS) are now realizing that they have become captives of their own creation; papers in those journals are essential for winning prizes and for promotion of younger faculty members to tenure. Although there is still considerable “hype” by Editors of these prestigious journals in order to attract papers, resentment is now growing in the academic community about this emphasis on where to publish. Whether this change in the culture of academia will have an impact on young investigators and their decisions as to where to send their “hot” papers remains to be seen. In that regard, it is relevant to ask whether the almost limitless proliferation of journals will ever end. Professional societies justify publishing new specialized journals based on the growth of science, and private companies have found science reporting a profitable venture. From the perspective of today it is difficult for those whose careers began in the 1940s to recall how research was done before federal funds became commonplace. The birth of the NSF in 1950 was the outcome of the remarkable report (2Bush V. Science—the endless frontier.A Report to the President on a Program for Postwar Scientific Research. U. S. Government Printing Office, Washington, D. C.1945Crossref Google Scholar) by Vannevar Bush to the President of the United States on July 5, 1945. That insightful and visionary report, entitled “Science—The Endless Frontier,” should be required reading today for Members of the United States House of Representatives and the Senate as they are perilously close to reducing the budget of NIH for next year. The report of only 40 pages, plus the more detailed appendices by various subcommittees, has only 6 parts (or chapters). Individual sections are devoted to research aimed at understanding and eliminating disease, the benefits to public welfare from scientific research, the need for training future generations of scientists, the importance of openness in science and the “freedom of inquiry,” and finally the establishment of a government agency to foster and fund scientific research in universities. Basic scientific research and training in this country today stem directly from the Bush report, an outgrowth of his experience as head of the Office of Scientific Research and Development (OSRD) in supervising civilian scientific activities during World War II. The recognition of the invaluable contributions to the war effort made by the scientific community led to extensive deliberation of the potential role of government in the support of science in peacetime. Not only is the NSF the direct beneficiary as spelled out magnificently in the section termed “The Means to the End” but also, to a substantial extent, that “great invention,” NIH, from which most biochemists receive research support, owes its largesse to the spirit of the Bush Report in the part entitled “The War Against Disease.” However it should be noted that 5 years elapsed between the submission of the Bush Report and the establishment of the NSF. During that interval of debate and political bickering over the governance of the proposed agency (3Lomask M. A Minor Miracle: an Informal History of the National Science Foundation. National Science Foundation, Washington, D. C.1975Google Scholar), the medical community, many of whose members were not enthusiastic about biomedical research being centered in the new foundation, devoted efforts to steer more government funds to the Public Health Service and thereby to NIH. That activity led to the astonishing increase in NIH funding for extramural research from less than 1 million dollars in 1946 to about 4 million in 1947 (4Allen E.M. Early years of research grants.NIH Alumni Association Newsletter. 1980; 2: 6-8Google Scholar). Ever since, NIH has become the sponsor of most biomedical research and training. The role of NSF in supporting basic biological research is meager by comparison. Whereas there was substantial support for doubling the NIH budget recently, a similar effort to double the NSF budget has not been successful. Indeed Congress and the public have been extremely enthusiastic about increasing funding for research aimed at improving the health of the citizenry. Almost invariably over the past 60 years, the annual increases in NIH funding approved by Congress exceeded those proposed by the President. Some have attributed that to the personal interests of members of Congress in their own health. Whatever the motivation, funding of NIH has increased phenomenally, reaching the present staggering level of about $29 billion. But it should not come as a surprise that the “doubling” policy of funding from 1999 to 2003 was bound to end. The scientific community was hoping for “a soft landing” with increases of 7–9% annually as contrasted to the 15% increase during the doubling period. That soft landing has not materialized, and complaints are now widespread about the inadequacy of annual increases that do not even account for inflation. As can be readily gleaned from this brief history of federal funding, scientists of my generation did not spend much time writing grant applications as they launched their careers. In my first few years as a faculty member, I received funds kindly provided by Wendell Stanley who, as a Nobel Laureate, had grants from various private foundations. The first graduate student in my laboratory was supported by university funds. Several years after initiating my research in Berkeley, I received my first grant. Actually it was a contract, of about $7,000, from the Office of Naval Research (ONR) for research on tobacco mosaic virus and the ultracentrifuge. Administrators at ONR were enthusiastic about basic science and provided enormous freedom to investigators. After a few years, many of the staff at ONR moved to NSF, and I began receiving funding from NSF. That support continued for many years, culminating years later in an annual budget of about $70,000. In the early days of federal support, I had the narrow view that my laboratory was not doing biomedical research, and I didn't apply to NIH even though larger grants were readily available. My NSF grant was adequate for many years. Graduate students in the early 1950s were supported as teaching assistants or research assistants funded by small grants to faculty members or departmental funds. A typical laboratory would have one or two graduate students, a technician, and perhaps one postdoc, a far cry from the research group of today. Although most scientists were ecstatic about the Bush report and the concept of federal funding of research at universities, some expressed reservations; there was considerable apprehension about the possibility of political interference and curtailment of free inquiry. Indeed over the years, there have been periods, such as the 1950s, when NIH grants to individuals were terminated because of their presumed political activities. In 1953, while McCarthyism was rampant, the Federal Bureau of Investigation (FBI) began screening grantees. Based on FBI reports, Oveta Culp Hobby, as Secretary of Health, Education and Welfare (HEW) in the Eisenhower administration, interceded and ordered the cancellation of grants to Linus Pauling and other prominent scientists. Protests were mounted both within NIH and in the extramural community. Some leading administrators at NIH were so appalled about the policy dictated by the Secretary that they suggested to some of the “debarred” investigators that they substitute a colleague's name as the Principal Investigator, in which case the grant would still be funded to the institution. About 4 years elapsed before the policy of screening grantees under the policy initiated by Secretary Hobby was essentially abandoned. During that period, William Consolazio, who headed the section on Molecular Biology at NSF and was one of the pioneers at both ONR and NSF, sent me an urgent request for a prompt review of an application from Pauling for funding his research previously supported by NIH. According to my recollection, I sent Consolazio two responses. One was a detailed review of the proposal along with a summary indicating that the proposed research was ground-breaking and would have a great impact on our understanding of protein structure. In addition, my formal evaluation included, “The principal investigator is a giant in the field of science and is eminently and uniquely qualified to perform the research that is outlined.” That was for the record. The second response was much more personal because I knew Consolazio well and served on his panel. It asked rhetorically, “Who am I to evaluate a research grant application from God?” For anyone interested in physical chemistry and its application to biological problems, Linus Pauling was God! Not only did NSF, through Consolazio's intervention, fund Pauling's grant application, but others who were cut off by NIH also received funds from NSF. There have been other episodes of political interference in the operation of the granting agencies, with the most serious threats occurring during the Nixon administration. Beginning in 1971, for example, the training grant function at NIH was taken away from the Institutes, the number of review committees was reduced drastically, appropriated funds were impounded, and plans to separate the National Cancer Institute from NIH were initiated. Finally, Robert Q. Marston, Director of NIH for 5 years, was summarily fired in 1973 for refusing to cooperate with the Office of Management and Budget (OMB) in cutting basic research programs. At that time the entire peer review process was in jeopardy. Other less serious assaults on the grant systems at NSF and NIH dealt mainly with appointments to high level positions, such as the Director of the NSF or advisory councils at NIH. Some grant applications have also been rejected because a political official thought that government should not support the type of research described in the proposal. One prominent former senator, William Proxmire, who crusaded against waste in government, periodically ridiculed granting agencies over grants whose titles he didn't like by publishing his list of “Golden Fleece Awards.” His complaints were often unwarranted. These interferences with peer review arose primarily in areas of social or political controversy such as sexual behavior, AIDS, reproduction science, or climate control. However by and large, granting agencies have managed to resist external political pressure, with the exception of the response to priorities in the appropriation process during times of budgetary constraints. Apprehensions expressed in the 1940s that funding of research by government would be swayed or dominated by politics have not materialized. Although actions in the past few years have caused concern about political interference jeopardizing the peer review process and interfering with the freedom of inquiry, the granting agencies have functioned magnificently. The success of the grant programs does not mean that applicants for grants were not complaining. On the contrary, over the past 40 years there have been many periods when the scientific community has been up in arms about the shortage of funds. Young investigators of today almost certainly will conclude that my description of experience on study sections of NSF and NIH in the 1950s and 1960s is apocryphal. As members of an NSF panel, we were obligated to read all of the applications being considered at a specific meeting even though some of them were outside our area of expertise. The reviews at home, in preparation for the meeting in Washington, required several weeks of intense study. Applications receiving ratings in the highest two grades (out of five) were generally funded. Many of the applications did not receive sufficiently high scores to warrant funding, and a significant number were actually disapproved. For me, as a young Assistant Professor, it was a humbling experience, reading superb applications and attending meetings with older panel members who were my heroes in science. I can recall being pleased to see that senior members on the panel were thorough in their review of the proposals as well as generous and fair in their criticisms. After about 4 years my term ended, and I was appointed to an NIH Study Section where I experienced a culture shock. When we were about to record our vote on a particularly bad proposal, one of the more experienced panel members sitting next to me asked how I was going to rate it. My response was, “Disapprove; it is terrible; the investigator will not learn anything interesting, and the research is not worth doing.” To which he responded, “On NIH panels we hardly ever disapprove grant applications.” At that time NIH was growing rapidly with budgets increasing substantially every year, and “disapproval” was devastating to young investigators. NIH staff justified requests for additional funds on the grounds that so many approved applications were unfunded because of insufficient funds. Quickly recognizing the differences in culture and funding between NSF and NIH, I indicated that I would rate the proposal so low (about 3.0) that the research would not be funded. But my colleague at the table quickly informed me that applications with a rating of 3.0 would be funded. Even many of those with a score of 4.0 were funded. In that one meeting, I learned how much easier it was to receive support from NIH than from NSF. That is still true today, but now applicants to NIH are experiencing major difficulties and even first class proposals receiving ratings of 1.5 or better are not being funded. Grievances about poor ratings are many, diverse and contradictory. They include “those young guys on the panel don't even know about my classical work”; “starting scientists don't have a chance because of the prejudiced senior members on the study sections”; or “the reviewers succumb to fashions and you can't get funds for research on prokaryotic enzymes.” During my tenure in the 1990s as NIH Ombudsman in the Basic Sciences, I had the dubious pleasure of sitting in at many sessions of different Study Sections. Like those scientists whose applications did not lead to funding, I can cite shortcomings in the system. There is much too much nitpicking by members of the panels, such as “the magnesium ion concentration is too low.” Also, the summary statement on the “Pink Sheet” is not consistent with the score. Old timers still refer to Pink Summary Sheets; they haven't been pink for some years and are now replaced by electronic messages. Reviewers, in trying to be kind in their write-ups, frequently offer complimentary comments thereby giving applicants an erroneous impression about the real evaluation of the proposal. Scores often are not consistent with the commentary. As a result, applicants submit a slightly revised request that again receives a poor rating. Hence there are too many amended applications. Panels often have too many “ad hoc” members. Some of them, flattered by the opportunity to evaluate the research of others, go to great lengths to demonstrate their erudition by essentially rewriting the proposals. Applications are too long; experimental minutiae are included thereby becoming the focus of nitpicking. Despite these criticisms, I find the Peer Review System remarkable. One of the most common and often repeated complaints is that panel members don't support highly original proposals. Innovative proposals, according to the complainants, are dismissed with the remark: “it won't work.” Based on my experience as an observer at Study Section meetings as Ombudsman, I have no doubt that panel members prematurely and inappropriately conclude that very original proposals won't work. Despite their favorable comments about the excellent “track record” of the investigators, they give low ratings to such applications. But this criticism of the peer review system is not new. About 50 years ago in a talk on a fictitious enzyme “Money Transferase” at the Gordon Conference on Proteins, I showed the enclosed plot of the probability of obtaining a grant versus the originality of the grant request (Fig. 1). Unfortunately, it still has some validity. Many of the complaints about the peer review system are legitimate, but it is astonishing to hear scientists, whose grant applications were not funded, criticize NIH or NSF when the decisions were rendered largely by panels of outside reviewers. My rejoinder to the critics is that the ratings are attributable to the judgments of the panel members on the review committees and “the enemy is us.” Numerous committees have studied the peer review process (5Mandel R. The Division of Research Grants: a Half Century of Peer Review from 1946 to 1996. National Institutes of Health, Bethesda, MD1996Google Scholar), and their recommendations invariably have led to improvements in the system. The Division of Research Grants (DRG), established in 1946, initiated many reforms over the years in response to suggestions from the extramural community, and an important change occurred when that division was converted in 1997 to the Center for Scientific Review (CSR). A major reclassification of Study Sections is now being implemented. Although individual scientists have expressed concern about which Study Section will review their application, this reorganization was necessary because developments in biomedical science over the past 50 years have resulted in radical changes in the way research is conducted. Whether this new classification will reduce the number of times that important areas of scientific research fall between the cracks remains to be seen. Much will depend on the conduct of reviewers, and attempts by NIH staff to overcome bias in rating approaches to science. It should not be a surprise, for example, that a panel comprising many NMR spectroscopists and crystallographers would give high scores to proposals using these techniques. However in the process, scientists using other physical-chemical tools found themselves disadvantaged, and the ratings of their proposals were poor. In my judgment, this type of bias has occurred in the area of biophysical chemistry and in other areas of scientific research. This deficiency is likely to be mitigated as a result of the reorganization. Doubtless complaints about peer review will continue and probably even increase because the demand for more R01s from the growing scientific community far exceeds the available source of funds. That government has delegated to the scientific community the right to design and operate the peer review system is a remarkable achievement and criticism is invaluable. During the 1950s and 1960s, the number of graduate students interested in biochemistry and molecular biology increased tremendously, appointments to the faculty grew rapidly, and new departments were established in many institutions. At Berkeley in the 1960s, we had both a biochemistry department and a virology department that was later converted into a Department of Molecular Biology. Both thrived despite occasional competition for space, faculty positions, graduate students, and university funds. Growth was rampant, influenced in large measure by the increased federal funding for biomedical research. My own laboratory group, including students from both Biochemistry and Molecular Biology, had grown to about 5 graduate students, several undergraduates, 2 postdocs, and 2 technicians. Despite the large increase in the number of postdoctoral fellowships and the establishment of NIH Training Grants, there was a need for additional funding to individual faculty members. Accordingly in 1964, I applied to NIH for funds and received my first, and still continuing, NIH grant entitled “Structure-Interactions of Biological Macromolecules,” which was significantly larger than the existing NSF grant. Other faculty members experienced similar growth, and not surprisingly, space problems became acute. New buildings became the issue in nearly every research-oriented university. Amalgamation of departments ensued shortly thereafter. Here at Berkeley about 15 years ago there was a major reorganization. The Biochemistry and Molecular Biology group of about 25 faculty members was restructured as 1 of 5 divisions in the mega-Department of Molecular and Cell Biology (MCB) comprising about 90 faculty. This reorganization clearly has been advantageous in recruiting faculty and graduate students, and the resulting clout on campus coupled with the size of MCB has led to occasional calls for even more independence and authority. Why not establish a College of Biology? Whether this growth has resulted in a loss of community and collegiality is for others to judge. Moreover, it will be of interest to observe the interactions of the diverse groups in the new, greatly expanded Stanley Hall. Will there be extensive collaboration leading to Big Science, or will there be just more scientists in the enlarged building not talking to one another?