Commentary
The Culture of Research
Samuel Broder, M.D., joined the NCI’s Metabolism Branch (now part of CCR) in 1972, became Head of the Clinical Oncology Program in 1980, and was appointed NCI Director by President Ronald Reagan in 1989. He subsequently moved from government research into the private sector. Broder is currently Vice President and Chief Medical Officer at Celera, a company that first came to prominent public attention for its part in the race to sequence the human genome, and which now has a strong focus in personalized medicine. Twenty-five years after his pivotal contributions to the discovery of the first HIV-1 antiretrovirals, Broder reflects on the impact of his early discoveries and the research environment within the NCI that made them possible.
Twenty-five years ago, in collaboration with industry, my team at NCI developed the first series of drugs that were active against HIV-1. We were a small group, but we had seen the lethal and terrifying effects of AIDS on patients and we wanted to do something to provide tangible and immediate relief.
I was fortunate to work with brilliant colleagues, including Hiroaki "Mitch" Mitsuya and Bob Yarchoan. The NCI also had a strong investment in basic science that proved of central importance to HIV pathology. At the time, NCI had a constant and almost unique commitment to search for viral causation of cancer and to discover retroviruses in particular. NCI also had a longstanding research interest in the relationship between immunodeficiency diseases and cancer.
And yet, as important as the people and the resources are that make up a research organization, I believe its success also primarily lies in its culture. In addition to its scientific focus, the intramural program’s research culture itself—one that encouraged taking intellectual risks to advance the forefront of knowledge, one that encouraged a strong relationship between bench and clinical work, and one that encouraged interaction with industry—was key to our success.
Pushing the Limits
In 1962, Arthur C. Clarke wrote in an essay titled "Hazards of Prophecy: The Failure of Imagination," that the only way of discovering the limits of the possible is to venture a little way past them into the impossible. That boundary, of course, is constantly shifting with advances in technology and insight. But, it is very important to have a research culture that allows you to cross that boundary in attempts to push the outer limits of the possible, without misconstruing it as a kind of failure. If pushing limits is not encouraged, then you will end up with people devising very conservative, tried-and-true research agendas, and it will be very difficult to shift the therapeutic paradigm for difficult-to-treat, lethal diseases.
Today, AIDS is a chronic manageable disease, with over 30 FDA-approved drugs available for its treatment. The death rate due to HIV has plummeted since the mid-1990s. At the same time, we still don’t have a way of eradicating the virus from the body.
Many people said, at the time that we were starting our research, that we didn’t know enough, that the basic science had not advanced enough for us to consider developing treatments. But, if we had waited for the technology to mature to the point that we could cure the disease before we took what we knew into the clinic, then we would still be waiting.
To some degree, the real value of the NCI intramural programs should be to push that envelope between what is possible and what is not possible. And to try to do things that other institutions just can’t do for many reasons, particularly in crossing the laboratory-to-clinic divide.
Wholeness of Motion
In my opinion, one of the most important features of the NCI intramural program is the tradition of locating research laboratories both physically and intellectually next to clinical wards. This juxtaposition strongly encourages physician-investigators to translate knowledge from their own research laboratories into clinical wards and back to the laboratory, without an intermediary hand-off to another group. It means that all the expertise required to solve a problem remains with that problem from start to finish. NCI has seen this model pay off over and over again.
We discovered a set of drugs, dideoxynucleosides—one of which was AZT—that showed activity against widely divergent HIV-1 isolates in tissue culture. They inhibited viral replication at much lower concentrations than necessary to cause toxic effects on target T cells. We also had a likely mechanism of action (inhibition of reverse transcriptase) and an understandable, intuitively obvious relationship between the structure and activity of these compounds, which proved important to the further development of this class of drugs.
Without reliable animal models of the disease at the time, we essentially moved from tissue culture to patients, enrolling the first AIDS patients at the NCI. Ironically, we saw positive effects in the very first study that we did. The effects sometimes didn’t last because, as we now know, no single agent could reliably work against HIV for long periods. But we laid the groundwork and illuminated a path that other agents could follow. Against prevailing wisdom, we proved that it was possible to treat pathogenic retroviruses like HIV-1 with antiretroviral therapy.
When I later became Director of the NCI, I was committed to facilitating translational medicine while recognizing that it is not possible to simply replicate the intramural program in other places. Under my tenure, the specialized programs of research excellence (SPORE) were founded, and I think they had a tremendous impact because they allowed people to form interdisciplinary research programs, including collaborations with industry, under coordinated leadership. One of my "secret" plans was to force people in institutions to work together and have that ability to move from lab to clinic even if they weren’t originally focused that way. People would tell me that the mere act of putting SPORE applications together did that, even if they weren’t funded.
We are moving into an era where there is an increasing separation of people doing basic research and people doing translational research, an era in which we lack the wholeness of motion that takes you from bench to bedside. This separation may create efficiencies of specialization, but I believe it comes with a cost hidden in the transition.
Trends in annual age-adjusted rate of death due to HIV disease in the United States, 1987-2006. Figure adapted from the Centers. (Photo: S. Broder)
The Private Sector
The other thing that NCI did much better than most other government research institutes at the time we were working on HIV was to encourage collaboration with industry. This was quite critical to our work and happened at a time before the Federal Technology Transfer Act of 1986 created a means to facilitate collaboration between government researchers and industry. Early on in our HIV research, I realized we would need partners in the private sector to develop drugs rapidly, and we were lucky enough to have a connection with scientists at Burroughs Wellcome who were keen to work with us.
Of course, I have since made my own transition from government into the private sector, and I have learned a great deal from both sides. I would like to see more cross-pollination between government and the private sector, and not just in the form of standard collaborations. I think we need to do more to encourage people from academic centers and biotechnology companies to take positions of relatively high rank in the NCI and then go back to the private sector again. The flow of new ideas and brainpower would be a benefit to all.
President Ronald Reagan visits the Broder laboratory at NCI. (Photo: S. Broder)