In January 2000, Harold Varmus began his tenure as President of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, NY, the oldest and largest cancer center in the world. As he reflected in his autobiography, The Art and Politics of Science, the new job was simpler in some ways than the NIH directorship. MSKCC, a private, non-profit entity, has only two major sections (Memorial Hospital and the Sloan Kettering Institute) and half as many employees as NIH; it is local, not international; the administration is smaller and simpler; and the center is dedicated to researching and treating only one type of disease. His many accomplishments at MSKCC, like those at NIH, included building new facilities; strengthening the intramural research and clinical research programs, increasing budgets, and encouraging collaborations within MSKCC and with other institutions. Varmus also continued to be active in open-access scientific publishing, global health initiatives, advocating for stem cell research, and overseeing his own laboratory's cancer research.

During his first years at MSKCC, Varmus expanded the basic research enterprise, adding programs in computational biology, developmental biology, structural biology, and cancer biology. Many of his later innovations focused on narrowing the gap between laboratory researchers, who study the basic mechanisms of disease and potential therapeutic agents, and clinical investigators, who conduct trials of new therapies with patients. He strengthened the institution's translational research efforts with the Human Oncology and Pathogenesis Program, based at Memorial Hospital, and built stronger collaborations with two neighboring research institutions, Weill-Cornell Medical College and Rockefeller University. In 2000, the three formed the Tri-Institutional Research Program, an education partnership for sharing faculty, facilities, and graduate training resources. Several PhD and MD/PhD programs have developed from this collaboration, including the innovative cancer biology program at MSKCC's Gerstner Sloan Kettering School of Biomedical Sciences, opened in 2006. Reasoning that many medical researchers might want to become knowledgeable about disease and medicine even if they don't want to become physicians, Varmus proposed that MSKCC establish a graduate program that allowed basic science researchers to also get training in clinical oncology.

Varmus also improved the connections between clinical and basic science investigators by creating "centers without walls," virtual centers such as the Geoffrey Beene Cancer Research Center and the Experimental Therapeutics Center, to foster interaction between MSKCC programs. Like any institutional leader trying to expand programs and attract the best staff, Varmus also raised funds and built new physical facilities at MSKCC. The Zuckerman Research Center, opened in 2006, was the largest; he also supported the completion of several construction projects already underway including a new pediatric wing at Memorial Hospital and a new Breast and Imaging Center.

Along with his many administrative activities, Varmus headed his own lab at MSKCC, where investigators continued to explore the molecular mechanisms of oncogenesis. Varmus and his team also began investigating several types of lung cancers which had been dramatically reduced by treatment with the drugs gefitnib and erlotinib. These agents inhibit the signaling protein epidermal growth factor receptor (EGFR) tyrosine kinase. In 2003, as part of his lung cancer work, Varmus organized the Lung Cancer Oncogenome Group, an alliance of oncologists, surgeons, radiologists, pathologists, molecular biologists, and others, to study a range of genetic abnormalities found in that disease. The group's original mission was to screen samples of lung tumors that had responded to the two drugs, looking for mutations in the gene that codes for EGFR. Such mutations produce about ten percent of adenocarcinoma (the most common lung cancer). Subsequent work has identified other mutations involved in the disease, using analysis of tumor samples as well as research with specially engineered mouse models. Varmus and his colleagues also continue to explore the ways in which adenocarcinoma cells develop resistance to tyrosine kinase inhibitors.

Open-access publishing and the evolution of PLoS

Varmus's open-access advocacy, begun during his last year as NIH director, continued to evolve. He and his colleagues had succeeded in setting up an open-access archive of biomedical literature--PubMed Central, hosted at the National Library of Medicine's National Center for Biomedical Information was launched in January 2000. But the new archive was nearly empty. Most science and medicine publishers declined to add their content to PMC, concerned about loss of journal subscription revenue, loss of editorial quality-control, and a possible government monopoly of the scientific literature, among other things. To nudge publishers to participate in the open-access venture, Varmus, together with Patrick Brown of Stanford University, Michael Eisen of the University of California at Berkeley, and others, formed an advocacy group they called the Public Library of Science (PLoS). In October 2000, they began circulating an open letter to the scientific community, stating, first, that a complete, freely accessible library of scientific publications would "vastly increase the accessibility and utility of the scientific literature, enhance scientific productivity, and catalyze integration of the disparate communities of knowledge and ideas in biomedical sciences." Publishers, they said, had an important role in scientific communication, and deserved a fair return for their work, but should not hold permanent ownership and control of content. Therefore, the PLoS members were pledging that, beginning in September 2001, they would "publish in, edit or review for, and personally subscribe to only those scholarly and scientific journals that have agreed to grant unrestricted free distribution rights to any and all original research reports that they have published, through PubMed Central and similar online public resources, within six months of their initial publication date." They urged their colleagues to sign this pledge, and ultimately gathered over 34,000 signatures. Many supporters, however, worried about where they and their students would be able to publish if the most prestigious journals still failed to participate in the online archive. This was a legitimate concern, because most science publishers remained skeptical about the open-access model, and angry about the proposed boycott. As discussions, arguments, and negotiations went on during the first part of 2001, the PLoS group became convinced that they would need to create alternative publishing options, both to demonstrate that an open-access model could work, and to provide a publishing avenue for those who had signed the pledge. They drew up a business plan and applied for grant funding to cover the first five years of operation. With a grant from the Gordon and Betty Moore Foundation, the PLoS publishing venture (also called PLoS) launched its first journal, PLoS Biology, in October 2003. This was followed by PLoS Medicine in 2004, and smaller specialty journals. Over a decade later, the venture is self-sufficient and well-regarded, with an international staff and main offices in San Francisco and Cambridge, and features an array of journal, science blogs, and research reports. Open access is still a work in progress. PubMed Central had archived over three million articles by September 2014, with 1,573 journal publishers depositing all their content. However, many more publishers--2,471--participate on a "selective deposit" basis, contributing only certain articles for open access, and providing full access only to subscribers.

Global Science and Global Health Efforts

As NIH director, Varmus had become much more aware that the fruits of biomedical research were distributed very unevenly. Scientists (and politicians) often favored funding research on the medical problems common in developed nations, rather than those of poorer, less developed countries. Control of basic threats from infectious disease, malnutrition, and so on has usually been handled by a patchwork of national and international agencies. Varmus supported the expansion of international health programs at NIH, and helped organize the Multilateral Initiative on Malaria, a research consortium focused on combatting that disease in developing countries, especially in Africa. Soon after arriving at MSKCC, he was invited to join the World Health Organization's Commission on Macroeconomics and Health. The commission's 2001 report, "Macroeconomics and Health: Investing in Health for Economic Development," evaluated the present and projected economic impact of the world's major resolvable health threats, showed how little funding was devoted to such problems, and gave specific recommendations and cost estimates for addressing them. The basic premise of the report was that while economic prosperity leads to better health, better health also drives economic productivity.

As Varmus has noted, the WHO report was well-received, and spurred some countries to attack their major health issues using a macroeconomics approach. But such work is expensive to carry out in the long run, and is often beyond the budgets of both governments and non-governmental organizations such as WHO. Increasingly, since 2000, funding for novel global health initiatives has come from philanthropic foundations such as the Bill and Melinda Gates Foundation. Early in 2003, the Gates Foundation started the Grand Challenges in Global Health (GCGH) program to define and address the major scientific and technical obstacles to reducing disease burdens in the poorest countries. Varmus chaired the board of senior scientists that selected fourteen grand challenges from over a thousand proposals. After the grand challenges were announced, the board worked with seven review committees to evaluate funding applications from 1500 teams of researchers. Forty-three initial awards were made, averaging about $10 million each. The challenges include such varied projects as developing needle-free vaccine delivery technologies, strategies to control insect disease vectors, and discovering biomarkers for health and disease. The GCGH program is ongoing and since 2007 has also included a small grants program called Global Challenges Explorations. Varmus chaired the Scientific Board until 2008, and now chairs the foundation's Global Health Advisory Committee.

Returning to NIH, 2010-2015

Varmus has long had great affection for the National Institutes of Health, and as president of Memorial Sloan Kettering Cancer Center, he continued to serve on NIH advisory committees. In 2010, as he prepared to leave MSKCC, he was advising the Obama administration on filling the director's post at the National Cancer Institute (NCI) and decided to accept the job himself. Asked about his reasons for returning to NIH, he said that despite the tight budgets of recent years, it was an exciting time to be leading the NCI, because the current knowledge of cancer genomics promised major advances in diagnosis and treatment. Varmus has also noted that being NCI director was much more fun than being NIH director--as he was able to devote most of his time to running the scientific programs (including his own lab) rather than to agency meetings or testifying before Congress. When Varmus resigned from NCI five years later, he could point to much progress even in a very challenging budget climate: advances in targeted cancer therapies and immunotherapy, improvements in clinical trials programs and grant procedures, and the establishment of new cancer centers.

In March 2015, Varmus left NCI and returned to New York to become the Lewis Thomas University Professor of Medicine at Weill-Cornell Medical College. He plans to continue his research at the Meyer Cancer Center there, and work with the New York Genome Center.