Varmus Research Articles

Thinking out of the box: Harold Varmus

Thinking out of the box: Harold Varmus

Reactions to the Hwang Scandal

Reactions to the Hwang Scandal

Harold Varmus Provides Vision While Venting at ASCO Meeting

Harold Varmus Provides Vision While Venting at ASCO Meeting

Africa focus raises malaria funds

A new series of grants bolsters efforts to develop new approaches to counter major diseases of poorer countries, writes Nigel Williams A new series of grants bolsters efforts to develop new approaches to counter major diseases of poorer countries, writes Nigel Williams People concerned that malaria is not receiving enough attention from researchers and funding bodies as they seek to bolster aid to Africa (Current Biology, 15, R477-478) got a boost last month with the announcement of $440 million in grants from the Bill and Melinda Gates Foundation to develop new strategies to fight the disease along with other major human health problems in poorer countries The foundation, whose multibillionaire founder knows something about invention, last month revealed the winners of the Grand Challenges in global health, which it launched in 2003 to identify the major obstacles to improving health and find ways to overcome them. Among the 43 projects to receive funding are several aiming to produce vaccines that do not require refrigeration. There is also a plan to genetically engineer mosquitoes that die before they are mature enough to pass on dengue fever. There are ideas for vaccinating children without using needles, which can cause infections if they are not sterile, and schemes for growing crops full of vitamins often absent from the diets of the poorest children. The enthusiasm in the research proposals was enormous, said the Gates Foundation. “We were amazed by the response,” said Harold Varmus, chair of the international scientific board that guides the Grand Challenges project. “Clearly, there’s tremendous untapped potential among the world’s scientists to address diseases of the developing world.” The 14 challenges were chosen from more than 1,000 suggestions from scientists and health experts around the world. They included: improving vaccines so that needles, refrigeration and multiple doses would not be required; developing new ways to stop insects transmitting diseases such as malaria; finding ways to treat latent infection such as tuberculosis which has not yet manifested itself in symptoms; and finding ways to fight the resistance that bacteria develop to drugs. Developments in tackling diseases tend to help the rich world. Global health experts talk of the “10:90 gap”, in which only 10 per cent of spending on health research and development addresses the needs of the 90 per cent of the world’s population which is the poorest and least healthy. “Unfortunately, the scientific efforts at creating modern medicines have often ignored the diseases mostly experienced by half to two-thirds of the world that live in developing countries.” said Richard Klausner, executive director of the global health program of the foundation. With the recent summit in Scotland of the G8 group of the wealthiest nations committing to doubling aid to Africa by 2010 together with a plan of debt relief for the poorest countries, there is growing hope that the burden of malaria, the biggest killer of children under five on the continent, and that of other diseases, will come under renewed and invigorated attack.

Manhattan Showered With Stem Cell Gifts

Philanthropists are pouring money into three New York City biomedical institutions to support stem cell research. The latest gift comes from the Starr Foundation, which is dividing $50 million over 3 years among Rockefeller University, Memorial Sloan-Kettering Cancer Center, and Weill Medical College of Cornell University. Last year Weill received $15 million from the Houston, Texas-based Ansary Foundation to establish a center for stem cell therapeutics, and earlier this month Mount Sinai School of Medicine took in $10 million from donors for its own stem cell institute ( Science , 13 May, p. [937][1]). The Starr Foundation was established by Cornelius Vander Starr, founder of the financial and insurance companies called American International Group Inc. Its Tri-Institutional Stem Cell Initiative will focus on a wide range of stem cell projects, involving cells from embryos, adult tissues, and cancerous tumors, says Sloan-Kettering President Harold Varmus. He says the gift is already influencing recruitments at Sloan-Kettering, and he hopes it might lessen the possible lure of California's $3 billion in public funding. “We don't want people leaving or young people to ignore the fact that we have a lot of support for this research in New York,” he says. Weill Dean Antonio Gotto hopes some of the funds will allow researchers at its large fertility clinic to produce new stem cell lines from cloned human embryos. [1]: /lookup/doi/10.1126/science.308.5724.937b

The Human Cancer Genome Project—one more misstep in the war on cancer

Strap yourself in and get ready for some serious ‘more of the same.’ A recent proposal to sequence cancer genomes holds out the promise of personalized cures for each of 50 different cancers. The cost? A mere $12 billion at today’s prices1. This human cancer genome megaproject is the equivalent of 12,500 human genome projects and already has the backing of several prominent scientists. Harold Varmus believes that the project could “completely change how we view cancer”1; Eric Lander argues that “knowing the defects of the cancer cell points you to the Achilles’ heel of tumors”1; and Francis Collins predicts that he “can confidently tell you that something will happen here”1. More pragmatically, Craig Venter points out that “...it’s not clear what answer we’d get; there might be better ways to move cancer research forward”1. In a nutshell, the megaproject aims to catalog all somatic mutations from primary tumors as the basis for designer drugs to cure most cancers. Success is predicated on the assumption that drugs can be targeted to very specific mutated regions of gene products. However, most patients with a localized primary tumor are cured by surgery and local radiation. It is not the primary tumor, but the metastatic spread of a small population of deadly cells that ultimately compromises a normal tissue or organ, that kills in cancer2 (for an excellent popular account, see ref. 3). Are primary tumors therefore the appropriate focus for such a massive project and are their bulk mutational spectra therapeutically useful? The clinical track record Cancer research has consumed hundreds of billions of dollars to date3 and yet the main killers—breast, prostate, lung and colorectal cancer—are essentially as deadly as ever4 (see Fig. 1). Despite the glacial progress in treatment and the advent of ‘molecularly targeted’ therapy, cancer research continues to focus myopically on individual oncogenes, tumor suppressors and repair genes5, with little effort devoted to alternative mechanisms and targets6–8. Although conventional chemotherapeutic agents remain the first-line treatment of choice, newer molecularly targeted therapies are now reaching the market. Thus far, however, these therapies have had very limited success against solid tumors, which after all make up 90% of all cancers. Success has been largely restricted to rare leukemias; for example, imatinib mesylate (Gleevec; Novartis, Basel) has initially proven effective in patients with chronic myelogenous leukemia (CML). Whereas the initial clinical success of imatinib in CML was spectacular, this has not been repeated in most of the succeeding cancer therapies against solid tumors. Gefitinib (Iressa; AstraZeneca, London)-based treatment shrinks tumors in only about 10% of advanced non-small cell lung cancer patients9. A recent study in one very small (35) patient group indicated that trastuzumab (Herceptin; Genentech, S. San Francisco) induces a partial response in only 23% of individuals with advanced HER2/neu-overexpressing breast cancers10; early indications are that bevacizumab (Avastin; Genentech, S. San Francisco) is not much better in colon cancer. All of these agents have serious associated toxicities11–13, most extend patient survival only by a matter of months and there is a variable period of remission before a resistant form of the cancer returns, even in the case of imatinib14. In the light of these findings, the concept of intervening in cancer networks at a single ‘oncoprotein’ or ‘tumor suppressor protein’ George L. Gabor Miklos is at Secure Genetics Pty Limited, 19 Bungan Head Road, Newport Beach, Sydney, New South Wales, Australia 2106. He was an advisor to the Berkeley Drosophila Genome Project and to the human and mouse genome projects at Celera. e-mail: gmiklos@securegenetics.com Figure 1 Glacial progress. National Cancer Institute data of 5 year relative survival for patients with distant metastases of colorectal, lung, breast and prostate cancer. 0 5 10 15 20 25 30 35 40

NIH consulting ban a matter of ethics

After months of deliberation, NIH director Elias A. Zerhouni formally announced on February 1, 2005, that federal scientists would be prohibited from consulting for pharmaceutical, biotechnology, and medical device companies, as well as for any research institute that receives funding from the NIH. The new rules, which are expected to be put into effect quickly, also limit NIH researchers' stock investments in drug and biotech companies to $15,000 and earnings from prizes and honorariums to only $200. The guidelines on consulting and accepting speaking fees were made liberal in the 1990s when former NIH director Harold Varmus was at the helm. Varmus encouraged outside consulting with the goal of recruiting better scientists to the NIH. But this policy drew widespread criticism for presenting researchers with potential conflicts of interest. In some cases, NIH employees accepted exorbitant, and perhaps unethical, consulting fees. The new guidelines have brought about mixed reactions from the research community. Some argue that the rules put federal scientists at a disadvantage compared with their academic colleagues, many of whom engage in outside pursuits to boost their salaries and promote scientific discovery. They also fear this will discourage good scientists from working for the NIH. Supporters of the plan feel that these rules are needed to ensure the public's trust in the NIH and that they will not negatively affect scientific exchange. Of course, NIH collaboration with academia and industry is critical to the advancement of science and for bench-to-bedside translation of research. The impact of the new regulations on NIH recruitment and interaction with external colleagues will be monitored as these guidelines are implemented.

Open access publishing.

An Open Access Publishing Conference was convened in Atlanta, Georgia, on January 7, 2004, by the libraries of the Centers for Disease Control and Prevention (CDC) and Emory University. Open Access is an emerging publishing model for peer-reviewed scientific research in which authors and their publishers grant free access to their work as long as the authors are acknowledged and the publisher ensures that the work is made freely available in a digital archive (1). conference brought together key stakeholders including scientists, researchers, publishers, and librarians and included approximately 240 participants with 80 offsite registrants connecting through the simultaneous Web cast. The keynote address, The Coming Revolution in the Publication of Scientific Papers, delivered by Harold Varmus, emphasized that 1) in today's Internet era, the traditional Gutenberg print publishing model is outdated; 2) electronic publishing has the advantages of lower costs, global distribution, content that can be linked to datasets, improved archiving, and full-text searching; and 3) rigorous peer review is possible in electronic and Open Access formats. Open Access publishing challenges include engaging professional societies in this approach, building sustainable business plans, and changing academic culture so that published works are evaluated for content rather than for the journal label. Open Access publishing is typically financed by author fees along with a combination of philanthropic and advertising support. Examples are the Public Library of Science, Journal of Clinical Investigation, and BioMed Central journals. Recent milestones include the Bethesda Open Access Principles meeting (1), the Wellcome Trust endorsement of Open Access, and support from the Howard Hughes Medical Foundation and a number of leading European scientific societies. A panel of speakers gave stakeholders' perspectives. Sheldon Kotzin reviewed the National Library of Medicine's (NLM) priorities regarding access to, and permanent retention of, the world's biomedical literature. Reflecting growing concerns about high costs of scientific publications, the U.S. Congress recently directed the NLM to report on the impact of rising journal subscription prices relative to access to medical research information and to identify remedies to ensure that taxpayer-funded research remains in the public domain. NLM's Open Access initiative is PubMed Central, a digital archive of freely available life sciences journals. After a slow start, the PubMed Central repository includes 137 journal titles. PubMed Central expects publishers to deposit full contents of each journal issue soon after publication. Supplementary data files are also encouraged. recent addition of a single article from a journal that is not participating in PubMed Central is broadening the definition of this archive. Another Open Access approach was described by John Nickerson, editor of Emory University's Molecular Vision, which has been freely available on the Internet since its first issue in October 1995. A low-cost operation, Molecular Vision is a refereed open access journal that has achieved scientific recognition in its field. Publishing trends affecting libraries were discussed by Linda Watson, University of Virginia Health Sciences Library, and included: 1) journal subscription price increases outpacing library budgets, 2) publishers' bundling of journal subscriptions into large contracts often not well matched with institutional research interests, 3) consolidations in the publishing industry, 4) restrictive licensing terms overriding copyright and fair use practices, 5) long-term archival access to electronic content, and 6) selective deletions of published articles from databases and e-publications. Presenting a scientist's perspective, CDC's Marta Gwinn noted that the scientific community's overarching responsibility is to ensure that research is conducted with integrity and quality and that access to it is fair, maximizes value to users, and protects the public investment and interests. The open access conference generated discussion about the scientific research dissemination process and the need to strengthen the connections between evidence-based research and healthcare action. With high quality, peer-reviewed scientific research becoming freely available on the Internet, possibilities for more rapid advances in scientific knowledge and ultimately improved public health are important. Collaboration between government and academia is necessary to make progress toward open access to scientific research. This conference was supported in part by the National Networks of Libraries of Medicine, Southeastern Atlantic Region. Conference presentations are available from: http://ada.healthsci.emory.edu/openaccess

Varmus wants tighter NIH rules

Varmus wants tighter NIH rules

The fickle food of fame

How to Win the Nobel Prize—An Unexpected Life in Science J. Michael Bishop Harvard University Press, London, UK 320 pages, $18.50 ISBN 0 674 00880 4 ![][1] I first met J. Michael Bishop at a Gordon Conference in the late 1970s, just after Ray Erikson had discovered that Src was a protein kinase, and before Tony Hunter had realized that it transferred phosphate to tyrosine residues. It was an unnerving experience, because although I had had some experience of protein phosphorylation and protein kinases, whereas Mike had little or none, he had read far, wide and deep, and hadn‘t missed a trick. I felt myself to be in the presence of a superior being. I had a similar experience years later with Bishop's colleague Harold Varmus, this time in connection with protein synthesis. Together, Mike and Harold made a formidable team, as was confirmed in 1989 when they were jointly awarded the Nobel Prize for their discovery of the cellular origin of retroviral oncogenes. Years after our first meeting, I found myself serving under Mike on the Scientific Advisory Board of the Research Institute of Molecular Pathology in Vienna. Once, while we were chatting in a room in the Opera House, he recalled his first inkling of his Nobel Prize, which had come in that very room. “Where are you going to be in the second week … [1]: /embed/graphic-1.gif

The real stakes of virtual publishing: The transformation of E‐Biomed into PubMed central

AbstractIn May 1999, National Institutes of Health (NIH) Director Harold Varmus proposed an electronic repository for biomedical research literature server called “E‐biomed.” E‐biomed reflected the visions of scholarly electronic publishing advocates: It would be fully searchable, be free to readers, and contain full‐text versions of both preprint and postpublication biomedical research articles. However, within 4 months, the E‐biomed proposal was radically transformed: The preprint section was eliminated, delays were instituted between article publication and posting to the archive, and the name was changed to “PubMed Central.” This case study examines the remarkable transformation of the E‐biomed proposal to PubMed Central by analyzing comments about the proposal that were posted to an online E‐biomed forum created by the NIH, and discussions that took place in other face‐to‐face forums where E‐biomed deliberations took place. We find that the transformation of the E‐biomed proposal into PubMed Central was the result of highly visible and highly influential position statements made by scientific societies against the proposal. The literature about scholarly electronic publishing usually emphasizes a binary conflict between (trade) publishers and scholars/scientists. We conclude that: (1) scientific societies and the individual scientists they represent do not always have identical interests in regard to scientific e‐publishing; (2) stakeholder politics and personal interests reign supreme in e‐publishing debates, even in a supposedly status‐free online forum; and (3) multiple communication forums must be considered in examinations of e‐publishing deliberations.

Revolution or evolution?

A shift to an open-access model of publishing would clearly benefit science, but who should pay?

The Genomic revolution: unveiling the unity of life

From the discoveries of Watson Crick to the appearance of Dolly the Sheep, the last fifty years have ushered in a revolution of knowledge in how organisms develop, function, replicate. Scientists are now engaged in an epic task that will catapult the revolution to new heights: the sequencing of the human genome. Consider the scope of such a discovery. How different are we one another? Does race have a scientific meaning? Is there such a thing as a disease gene? What are the potential risks of genetically modified food? Does a clone have a soul? The Human Genome Project will inevitably lead to landmark changes in medicine, agriculture, the study of evolutiona and will ultimately define the course of human history. The Genomic Revolution: Unveiling the Unity of Life takes readers on a fascinating journey through genomicsa from the basic presentation of ideas about heredity through the essential principles of molecular biology, including an exploration of the ethical implications of the genome project for individuals society. Some of the worlda (TM)s leading experts in genomicsa Harold Varmus, Leroy Hood, Daniel Kevles, Craig Venter, to name just a fewa contribute their assessments of the state of current scientific research. Written for anyone wondering why we are the way we are, The Genomic Revolution is a timely important collection that spans the science, the promise, the potential pitfalls of a field moving so quickly that its achievements may alternately delight trouble us, but almost always surprise us.

Still Moving Toward a Paperless Environment

With war in Iraq now in progress, all other concerns seem trivial. Nevertheless, CSHP and its Journal have several significant financial decisions to make in the coming years, and I would like to share with you some of the considerations that will go into these decisions. About 4 years ago, Harold Varmus, then director of the US National Institutes of Health, proposed that “E-biomed” be developed as a single Web site that would accept papers in every area of biomedicine and provide free access to the full text to all readers. 1 This

Prematurity in gene therapy.

Prematurity in gene therapy.

An Unfathomable Tragedy

At 8:48 A. M. on Tuesday, September 11, 2001, American Airlines flight 11, a Boeing 767 en route from Boston to Los Angeles, hit the north tower of the World Trade Center in New York City. This deliberate crash, followed by further jet crashes into the Trade Center's south tower, the Pentagon, and rural Pennsylvania, not only destroyed symbols of U. S. capitalism and military might, but also assaulted the very foundation of America. Thousands of lives, dreams, and families were destroyed in this senseless and utterly incomprehensible carnage. Glued to the television from the moment this terrible story broke, one hoped that this awful movie would end, but unfortunately it was real. What kind of hatred motivates someone to perpetrate such heinous acts? David Kennedy, a Stanford University historian, summed it up: “Amid the din of destruction, nothing was more eerie and unsettling than the silence of our attackers and [their] studied refusal to specify their demands. Whoever our adversaries are, their objectives are not measured in terms of geography, trade, or any of the usual markers of political rivalry. They seek not simply to destroy but to demoralize, not to seize territory, but to sow chaos, not to conquer, but to cripple and corrupt. They are targeting not only lives and property, but also our most fundamental values, including our commitments to personal liberty and to the institutions of an open society.” The thought that many of these terrorists were living among us for years, participating in our ways of life and enjoying our freedoms, sends shivers down the spine. Perhaps we ate in the same restaurant, flew in the same plane, and may even have had conversations lamenting the sorry state of airport security. The nation is angry and the administration is, understandably, preoccupied with the punishment of those who planned, supported, and nurtured these acts. Justice must prevail, but our motive should not be revenge. Terrorists hide among the innocent, and the innocent will suffer from collateral damage. Millions of destitute young men and women in the world are angry at their miserable living conditions. Engulfed in hopelessness, they view the West and our ways of life as the cause of their desperation. These terrible events are a wake-up call for the “haves” of the world not to ignore the plight of the “have-nots.” Wiping out terrorists will not remove the scourge of terrorism. Education has largely conquered ignorance and science has improved the quality of life of all humanity. But we also need to learn tolerance of all faiths and creeds. We must be vigilant against any discrimination and retaliation against innocents who share the faith but not the values of the faceless terrorists. In science, we do not ask about the beliefs of the experimenters. The Nobel Prize Committee did not consider the religion of Ahmed Zewail, an Egyptian, before awarding him the Nobel Prize in Chemistry for his groundbreaking work on real time chemical reactions at the atomic level, or H. Gobind Khorana, born to a Hindu family in India, for deciphering the genetic code, or J. Michael Bishop, the son of a Lutheran country preacher and co-discoverer of oncogenes with Harold Varmus, himself born to Jewish parents. Science is non-denominational and “sans frontiers.” We must keep our faith in human goodness and keep striving to reveal nature's secrets for society's benefit. The best way to show our solidarity with the victims of this tragedy is focus on what we do best—science! Unlike Hamlet, upon being visited by the ghost, we do not want to “wipe away all trivial fond records” from the edifice of memory, because then we will have handed victory to the perpetrators of the horrible crimes of September 11, 2001.

PubMed Central

Many scientific, technical, and medical publishers today are moving from journal publishing to publishing information resources. This move is based on the Internet, where users have access to the benefits that can be offered with electronic publishing. However, a major problem in the publication process is length of time it can take for actual publication as well as the access restrictions that are often set by the publisher. The need for fast and efficient dissemination of research information led Dr. Harold Varmus, Director of the National Institutes of Health, and his colleagues in Spring 1999 to establish PubMed Central, a Web-based repository at NIH, to provide barrier-free access to primary research reports in the life sciences. Based on its natural integration with the existing PubMed retrieval system, PubMed Central serves as a host for scientific publishers, professional societies, and other groups to archive, organize, and distribute at no cost peer-reviewed reports from journals, as well as reports that have been screened but not formally peer-reviewed. This article provides a status report on the PubMed Central project and discusses issues related to the development and implementation of the repository.

New imaging and bioengineering institute at the NIH

The National Institute of Biomedical Imaging and Bioengineering (NIBIB) has opened – the newest of the National Institutes of Health (NIH). Dr Donna J. Dean, who previously served as a senior scientific advisor in the Office of the NIH Director, will be the acting director of the institute. The new institute will support basic research that applies engineering and imaging to disease and biological processes. It will also coordinate with the ongoing research in the other NIH institutes. This move has been criticized by the former NIH director, Harold Varmus, who argues that NIH already has too many institutes and should be restructured into six units for a more efficient operation. AP

The Growing Family of NIH Institutes

Harold Varmus suggests that too many institutes exist at the National Institutes of Health (NIH) and that this problem might be solved by consolidating the institutes and independent centers into six units of about equal size ( Science 's Compass, Policy Forum, “Proliferation of National

Book Review The Molecular Basis of Blood Diseases Third edition. Edited by George Stamatoyannopoulos, Philip W. Majerus, Roger M. Perlmutter, and Harold Varmus. 1028 pp., illustrated. Philadelphia, W.B. Saunders, 2001. $275. 0-7216-7671-5

Book Review The Molecular Basis of Blood Diseases Third edition. Edited by George Stamatoyannopoulos, Philip W. Majerus, Roger M. Perlmutter, and Harold Varmus. 1028 pp., illustrated. Philadelphia, W.B. Saunders, 2001. $275. 0-7216-7671-5