Monday, June 05, 2006

Interview with Harold Varmus

Today I am publishing an interview with Harold Varmus, Nobel laureate, president of the Memorial Sloan-Kettering Cancer Center, former director of the US National Institutes of Health, and co-founder of the open access publisher Public Library of Science
This is number eight of The Basement Interviews, the introduction of which I am publishing on my blog. a The full interview (including introduction) is available as a downloadable PDF file (see below for details). It is being published under a Creative Commons licence.

Harold Varmus

Freeing the scientific literature

Harold Varmus, Nobel laureate, former director of the US National Institutes of Health, and co-founder of open access publisher Public Library of Science, talks to Richard Poynder.

Harold Varmus was born in 1939, on the south shore of Long Island, New York, a product, as he put it in an autobiographical note he wrote years later, of "the early twentieth century emigration of Eastern European Jewry to New York City and its environs."

His paternal grandfather, Jacob Varmus, had arrived in the New World from a small village near Warsaw just after the turn of the century, settling first as a farmer in Newburgh, New York, and subsequently working as a hatter in Newark, New Jersey. His paternal grandmother, Eleanor, was a victim of the influenza epidemic of 1918, dying when his father was eleven. Varmus' maternal grandparents — Harry and Regina Barasch — came originally from farming villages around Linz, Austria. Settling in Freeport, New York, they ran a children's clothing store.

Three years before Varmus' birth, his parents also settled in Freeport, where his father — who had trained as a doctor — established a general medical practice. From there Varmus' mother, Beatrice, commuted to a social services job in New York City.

A lake with alligators

When the United States entered the War, Varmus' father was assigned to an air force hospital near Winter Park, Florida, where the family resided until 1946. "My first memories," Varmus recalled later, "were to be of long beaches, and bass fishing on a lake with alligators." It was in Florida that Varmus' only sibling, Ellen Jane, was born.

After the family returned to New York, Varmus attended local public schools in Freeport; schools, he later characterised as being "dominated by athletics and rarely inspiring intellectually".

In 1957, after graduating from Freeport High School, Varmus entered Amherst College to prepare for medical school. His experience at Amherst, however led to a change of plan. As he put it: "The evident intensity and pleasure of academic life there challenged my presumptions about my future as a physician, and my course of study drifted from science to philosophy and finally to English literature."

He also became active in politics and journalism, and served as editor of the Amherst college newspaper. In 1961, after receiving an English degree — graduating magna cum laude — Varmus went to Harvard, courtesy of a Woodrow Wilson Fellowship.

Midway through his first year as an English literature postgraduate, however, Varmus dreamed that he had become an English professor and that he had missed a day of lecturing due to illness. Rather than being disappointed, however, his students were jubilant, pleased that their class had been cancelled. When he woke, it occurred to Varmus that if he were a doctor no one would be happy if he didn't show up for work — a thought that inspired him to return to his medical studies.

Varmus applied to study medicine at Harvard twice, but was rejected on both occasions. Concluding that he was not yet mature enough, the admissions committee recommended he first do two years army service. Undeterred, however, Varmus enrolled at Columbia College of Physicians and Surgeons (P&S).

Happy accident

Varmus began medical school with strong interests in psychiatry and international health. After serving an apprenticeship in a mission hospital in Bareilly, India, however, he drifted towards basic medical sciences.

In preparation for a career in academic medicine, Varmus worked as a medical house officer at Columbia-Presbyterian Hospital. In 1968, however, his plans for an academic career were interrupted by the Vietnam War.

In part to avoid the draft, Varmus applied for a research training post at the National Institutes of Health (NIH), where he was accepted for a clinical associate position in the laboratory of molecular biologist Ira Pastan.

At the time of Varmus' interview, Pastan was working on the hormonal influences on the thyroid gland. By the time Varmus turned up at the lab, however, Pastan's focus had switched to the study of the genetics of E.coli — an area with which Varmus was unfamiliar.

While Varmus was dispirited by this, it turned out to be a happy accident, since the change symbolised a revolution that was taking place in medical research. As James Fallows explains in a 1999 New Yorker profile of Varmus, the thrust of medical research was at that time beginning to shift "from the operations of organs, or the disorders of whole organisms, like human beings or mice, to the mechanics of cells, and within them, specific genes."

In other words, rather than trying to target individual illnesses, researchers were adopting a new gene-level approach to medical research. As Varmus explained to journalist Susan Stamberg, in a US National Public Radio interview in 1999, the future of medical research now lies in "the development of a notion of the gene as a physical entity that we can understand, manipulate, dissect and use to advance the great themes in medicine."

As luck would have it, Varmus' new post at NIH put him at the centre of this new approach just fifteen years after Watson and Crick had discovered the structure of DNA. And by taking advantage of the evening courses offered to incipient physician-scientists at NIH, Varmus was able to undertake further postdoctoral training in molecular biology. He later developed an interest in tumour viruses.

In 1969 Varmus moved to the University of California San Francisco (UCSF), where he began collaborating with microbiologist and immunologist Michael Bishop — conducting research on bacterial gene expression and tumour virology. Specifically, he studied the behaviour of retroviruses, including aspects of their unusual life cycle, the nature and origin of their transforming genes, and their potential to cause genetic change, not least their ability to cause cancer.

At the time, many scientists thought that retroviruses caused cancer by injecting their genes into the host's own genome. In 1975, however, Varmus and Bishop found that these viral genes had in fact been "captured" from the host animals in the first place.

Their discovery demonstrated that cancer genes (oncogenes) can evolve from normal cellular genes, called proto-oncogenes. In short, retroviruses can transform normal cells into cancerous ones.

Nobel Prize

This new insight meant that many of the cellular genes involved in cancer could be isolated. "It's been known for a long time that cancer was in some sense a genetic disease," Varmus explained to the Boston Globe in 1989. "The importance of our findings is that one can identify explicitly the genes that play a role in cancer."

The groundbreaking work done by Varmus and Bishop was recognised as a major contribution to current understanding, and enabled the scientific community to conduct an aggressive and successful search for the genetic origins of cancer. In 1989, therefore, they were jointly awarded a Nobel Prize "for their discovery of the cellular origin of retroviral oncogenes".

As a Nobel Laureate, Varmus began to feel a growing expectation that he become an ambassador for science, not least from former UCSF colleague Marc Kirschner — who recruited Varmus to serve on advisory groups about the future of research. In 1992 Varmus also joined a group of scientists supporting the Clinton-Gore ticket, and the following year he was confirmed as the new director of NIH.

Having never chaired a college department, or indeed run anything bigger than a 36-person laboratory, Varmus faced a significant challenge in his new job. He was now in charge of 16,000 people and a large bureaucratic organisation composed of 24 quasi-independent internal institutes. Being director of NIH also required winning financial support from Congress.

In the event, he proved highly successful, getting NIH funding up more substantially than any other category of federal spending — from $11bn to $16bn. He also succeeded in persuading Congress of the importance of basic research — particularly studying cellular-level functions — rather than simply granting money for crusades against high-profile diseases like prostate and breast cancer.

At NIH, argues Fallows, Varmus "achieved a series of political victories that will affect scientific policy for many years to come and, at least by implication, may change the entire understanding of health, disease, and the limits of the human life span."

When, in June 1999, Fallows asked him about the secrets of his political success Varmus replied by e-mail: "I have the sense that you wish my life had more drama. I don't. As I have said before, my strategy has been to try to minimise it."


Ironically at the very time he e-mailed Fallows, Varmus had just embarked on a project that would maximise the drama in his life, and spark a long-running controversy that has still to run its course. In short, his new project was to prove the catalyst for the creation of the Open Access Movement.

A few months earlier Varmus had been sitting in a San Francisco coffee house with Pat Brown, a Stanford University biochemist who had at one time collaborated with the Varmus Lab as a trainee, and remained a close colleague. Brown began telling Varmus about, the web site where physicists place pre-published versions of their papers for review, usually prior to publishing them in prestigious journals. This allowed physicists to speed up the research process, and maximise the impact of research papers by making them freely available to everyone over the Internet. Brown posed the question to Varmus: could not a similar initiative in biology provide the same benefits?

The question resonated for Varmus, and he spent the next few months pondering on it. The end result was E-BIOMED: "a proposal for electronic publications in the biomedical sciences", which Varmus distributed to the research community in May 1999. In effect, E-BIOMED envisaged a fundamental and very radical change to the way biomedical research is communicated.

The problem, however, was that Varmus' proposal implied a diminished role for science publishers, and the likelihood, therefore, that scholarly publishing would become a somewhat less profitable business. As such, E-BIOMED was greeted with a firestorm of protest and outrage — a response that NIH colleagues felt Varmus should have anticipated. "Varmus wrote the proposal himself and just sent it out to a bunch of people as a rough draft," comments one still puzzled NIH insider. "For us it was like 'Oh, my God: he clearly doesn’t know what he is getting into'.

"Sure enough," he adds, "the response from publishers was explosive. It caused all kinds of problems."

As Varmus now concedes, he certainly didn’t realise what he was getting into. Consequently, he was startled by the vehemence of the reaction from publishers, and surprised and angry when he discovered that, instead of engaging with him directly on the issue, many publishers had gone straight to Congress and complained directly to his appropriators.

Over the next few months there was a heated public (and private) debate. In the end, however, the strength of opposition from publishers was so great that when, eight months later, E-BIOMED was launched (re-branded as PubMed Central) it was a pale shadow of the revolutionary new "electronic publications" system that Varmus had envisioned.

Significantly, he had had to concede that publishers would have the final say on whether papers they published were placed in PubMed Central. And publisher response was derisory: even today, papers from only 251 of a possible 6,000 biomedical journals are made available on PubMed Central, and the content of some of these journals is only released after an embargo of between six and twelve months.

In retrospect, Varmus agrees that he was naïve not to have anticipated the furore. "I must have known that I was not going to be at NIH for much longer," he joked to New Scientist in 2003, "because this caused a tremendous political argument: what the hell was I trying to do to destroy the publication industry."

Indeed, Varmus left NIH within months of publishing the proposal, taking over as president of the Memorial Sloan-Kettering Cancer Center. Ironically, he says, his last public act at NIH was to sign the press release announcing the launch of PubMed Central.

Public Library of Science

By now, however, Varmus was firmly committed to the cause of Open Access (OA) — the more so, it seems, in light of the virulence of publisher opposition to E-BIOMED. In November 2000, therefore, Varmus co-founded — with Pat Brown and Mike Eisen — the Public Library of Science (PLoS).

Initially an advocacy group, PLoS was founded on the principle that if publishers were not prepared to act in the best interests of science, then the research community would have to twist their arms. And the first act of the founders was to invite fellow scientists to sign an open letter in which they pledged to boycott any journal publisher that did not make the papers it published freely available online within at least six months of publication.

PLoS attracted nearly 34,000 signatures from scientists in 180 countries; but while a small handful of publishers complied, most blithely ignored the PLoS letter. Worse, most of the scientist signatories were happy to disregard their own ultimatum, and continued publishing in the very journals that had turned a deaf ear to their request.

Unprepared to give up the cause of freeing the scientific literature, in 2001 Varmus and his colleagues reinvented PLoS as a not-for-profit open access publisher — inviting scientists to pay to publish their research in new open access journals, on the basis that in doing so they could ensure that their research was made freely available on the Web from the date of publication. A number of PLoS journals were subsequently launched, and more are planned.

To Varmus' gratification, the journals have attracted some first-rate submissions, and quickly acquired a reputation as high-quality publications. What is less certain, however, is whether the author-pays publishing model they utilise is sustainable in the long term.

In many ways, Varmus has taken his role as an ambassador for science to its logical conclusion. After all, if the effectiveness of scientific research can be maximised by disseminating it in the most efficient way possible, then any ambassador worth his salt would surely do everything he could to make that happen?

Varmus' ambassadorial activities have not been confined to the US either. In March 2004, for instance, he appeared as a witness for the UK Select Committee enquiry into scientific publishing, which subsequently recommended that the UK government mandate all publicly-funded researchers to make their papers available on the Web.

Undoubtedly, Varmus will also have been involved in the behind-the-scenes lobbying that, in May 2005, saw the introduction of the NIH OA Policy, and the introduction into the US Senate in December 2005 of the CURES Act of 2005. No doubt he played a part in lobbying for the recently announced Federal Research Public Access Act of 2006 (FRPAA) too.


What sort of man is Varmus? Describing him as a "lean, energetic, and intense presence", Fallows pointed out that — for someone in such a public position — Varmus managed to maintain a surprisingly low profile at NIH. Indeed, his colleagues at the time often referred to him as "the invisible administrator."

So successfully did he maintain public invisibility in fact that when, in 1996, Varmus gave the commencement address at Harvard, the university newspaper, Crimson, reported widespread disappointment that an apparent nobody had been invited to speak.

Why then seek to play a leading role in such a controversial — and increasingly high-profile — movement as Open Access? "I believe that science is one of those activities that improves the state of the world," replies Varmus, "and once you realise how important publication is in the series of acts that constitutes the doing of science, and once you understand the incredible transformation of that publication process that the Internet, and software, and the whole digital world, now promises it is hard not to be pretty passionate about trying to make that part of the scientific universe work more effectively."

How significant a role has Varmus played in the Open Access Movement then? Critics often claim that his naivety has hindered more than helped. For instance, they argue, the E-BIOMED proposal only encouraged publishers to dig their heels in and resist change.

Varmus' supporters, however, contend that, like the music and movie companies, science publishers would inevitably have done everything they could to resist the impact of the Internet — since the new distribution models it permits pose a significant threat to their profits. Moreover, they add, as a Nobel Laureate and former NIH director, Varmus has provided the movement with an authority and credibility that it would otherwise have seriously lacked.

Importantly, comments the NIH insider, once alerted to the issue Varmus was immediately able to appreciate what was required, and then took personal responsibility for the task of making it happen. "Harold deserves credit for seeing that this was a real problem that needed to be solved, because most institute directors, and most scientists, just don’t have the insight."

Certainly Varmus is now widely viewed as a key figure in the OA Movement. In 2004 he and PLoS co-founders Eisen and Brown were given a Wired Rave award "For cracking the spine of the science cartel".

And in a recent profile of him, the magazine described Varmus as being "the prophet of open access." A prophet, moreover, who has become locked into a real-life struggle "that has turned this icon of the scientific establishment into a powerful subversive."

For all that, Varmus has a somewhat parochial view about Open Access, and makes no claims to understand the wider free knowledge movement, or even to particularly care about the role of Open Access within that wider movement, although he does support the principles of Creative Commons, whose licences PLoS utilises for its journals.

This disinterest in the bigger picture is a little surprising perhaps, because there is undoubtedly a commonality in origin, and in purpose, between the Open Access Movement and the various other free and open movements. If nothing else, they are all creative responses to the possibilities of the Internet, not least its ability to enable much greater collaboration and information sharing.

What is clear is that, in the same way that large and complex software projects now cry out for an open source approach to development, gene-level medical research requires an increasing degree of openness to be effective. The greater need for "open data" was graphically demonstrated, after all, by the huge efforts that NIH put into competing with privately-held Celera to sequence the human genome (by means of the Human Genome Project, or HGP). The fear was that vital biological information would be privatised if Celera became the only game in town, an outcome that would have obstructed scientific research.

In an online environment research papers will also increasingly be viewed as inseparable from the data on which their conclusions are based. And if both the data and the evaluation of that data need to be more widely and freely accessible, then Open Access will have to be treated as part of a larger and broader development.

Likewise, the new-style licensing models being developed by organisations like Creative Commons will become an ever more important component of the infrastructure that will be necessary if the various free and open movements are to flourish; and many of the new software tools being developed to support these movements will undoubtedly need to be based on Open Source Software.

In short, Open Access, HGP, Open Data, the Free and Open Source Software movements, Creative Commons, and the many other free and open movements, are all logical adaptations to the realities of today's increasingly complex knowledge environment. More importantly, they all face a common threat: the threat that, rather than being made more freely available, information could be increasingly privatised.

Excessively draconian use of intellectual property laws, for instance, could significantly hamper these movements, and hinder the improved collaboration, more rapid development, and greater creativity — be it artistic or scientific — that today's digital world promises. The ability of scholarly publishers to resist OA, after all, is based on their insistance that, as a condition of publication, they are given copyright in the papers they publish, thereby acquiring ownership of them. By working together the various free and open movements could therefore surely achieve their separate aims more effectively.

Interest in the arts

But it would be wrong to suggest that Varmus' vision of the world is in any way narrow. Despite his evident passion for science, Varmus retains a strong interest in the arts. In the talk he gave at his Nobel Prize ceremony, for instance, he included lines from Beowulf, which he recited in Anglo-Saxon. He has also written film reviews for the New York Times, and invested in Broadway plays. And when he visits foreign cities he often proposes meeting up with associates and friends in art galleries.

Varmus is known for his casual clothes — often khakis and rumbled open-necked shirts — and is a keen sportsman who loves outdoor sports, particularly bicycling, running, backpacking, skiing, and fishing.

In 1969, he married Constance Louise Casey, then a reporter for Congressional Quarterly in her home town of Washington, DC. They have two sons: Jacob and Christopher. Varmus' younger sister now works as a genetic counsellor in California, and his brother-in-law is the novelist John Casey.


Although this interview was conducted by telephone, I had seen Varmus in the flesh when he gave evidence to the UK Science & Technology Select Committee. A tall, slim man — with, as Jamie Shreeve put it in his Wired profile of Varmus, "sparse, reddish brown hair" — he sat in a slightly hunched position throughout, leaning forward on to the desk as he explained the merits of Open Access to British politicians.

Indeed, sitting next to BioMed Central founder Vitek Tracz, Varmus presented a striking contrast. A small restless man, Tracz spoke quickly, and at some length, causing the chairman at one point to ask him "to keep the answers a bit shorter and answer the question". Varmus, by contrast, delivered his views briefly and precisely.

And where Tracz was full of nervous energy, Varmus exuded a quiet confidence and unflappability. He also revealed a consummate skill for flattering politicians, a skill no doubt honed at NIH. His final words to the Select Committee were: "It has been a pleasure for me to see this high-minded conversation. I appreciate it greatly."

While entirely courteous, Varmus was less ingratiating with me. When I e-mailed him to ask for an interview I heard nothing for several weeks. Eventually his secretary invited me to suggest some dates, and asked how much time I needed for the interview. I requested two to three hours: I was offered 60 to 90 minutes.

The week before the interview was scheduled I was asked to send a list of questions so that Varmus could review them over the weekend. On the day of the interview, however, he declined to answer any questions not directly related to Open Access, arguing that in the time he had allotted for our conversation he was not able to address any other topic.

And even though we finished our discussion before our scheduled time was up, Varmus still declined to answer questions on any topic other than Open Access. He suggested that if I wanted biographical information I could use what was already in the public domain.

He also appeared unusally controlling about the text of the interview, asking several times to have sight of it before publication (When however I later e-mailed the text — to both Varmus and his secretary — I received no feedback at all). At one point in the interview he complained that I was talking over him.

All in all, when I put down the phone I knew very little more about the kind of person Varmus is than before I picked it up — other perhaps than that he seems a very focused person, and apparently keen to protect his privacy.

So let me leave the last words to the NIH insider, who spoke to me on condition of anonymity. "Harold Varmus", he said, "is a visionary who has very little feel for how people are going to react to what he says and does. But he isn’t generally concerned about that. He is also a man without guile."


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