Spotlight on

Dr. John M. Coffin, Director,
HIV Drug Resistance Program

Spotlight Archive

Most people in part-time jobs don’t have the potential to affect the health of thousands of people. But that’s just what Dr. John Coffin does in his two “part-time” jobs: splitting his time between NCI-Frederick, as the Director of the HIV Drug Resistance Program (DRP), and Tufts University, where he runs the Coffin Laboratory, part of the Department of Molecular Biology and Microbiology, and the Sackler School of Biomedical Sciences.

“At NCI-Frederick,” Dr. Coffin noted in a recent interview, “program directors, lab chiefs, and even the CCR director all have their own research programs and sections; often, they are head of a section, or a lab and a section, and split their time 60–40. I have the same two activities—they’re just split in different places.”

Dr. Coffin helps guide the DRP’s broad approaches; carries out general administrative, personnel, and budgetary duties; and plans special seminars, workshops, poster sessions and oral presentations. Among the various symposia and meetings he organizes each year are two favorites: a springtime “think tank,” held at NCI-Frederick, with an open forum on HIV-related topics, where participants give 10-minute talks; and the renowned Symposium on Antiviral Drug Resistance at Westfields Conference Center, Chantilly, VA (this year, scheduled for November 13–16).

Resistance the Number One Problem in HIV

For Dr. Coffin, one of the main attractions of creating the NCI-Frederick HIV Drug Resistance Program in 1997 was the chance to apply his theories to clinical situations to study the evolution of drug resistance from all possible angles. Unfortunately, he says, viruses quickly become resistant to drugs, thus negating much of the therapy’s effectiveness. “Resistance is, in my opinion, the number one problem in HIV,” he said.

“My job is to encourage people to keep thinking about resistance. I always ask, ‘Have you looked at resistance in this or that particular aspect?’ By having all these disparate groups doing different kinds of studies but focused on this one issue [resistance], I’ve found they also encourage one another to find a common ground,” Dr. Coffin explained.

Using various approaches, Dr. Coffin’s HIV DRP groups study the structure of enzymes, such as reverse transcriptase, one of the main targets of antiviral drugs; virus assembly; and interactions of virus with host-cell factors. Searching for the points that are appropriate for drugs and what the resistance to drugs at those points would be, they look at how the structure changes when a resistant mutation appears, and how that change affects the interaction of the virus with the drug.

The approach has yielded excellent results. Recently, for example, Dr. Vinay Pathak’s group, working on recombination, has discovered a completely new mechanism for understanding certain kinds of drug resistance and certain kinds of compounds like ACT. Dr. Coffin considers it a very promising lead.

Dr. Coffin’s research indicates that HIV replicates rapidly, even when apparently latent, and that mutations for drug resistance are already present when drug treatment starts. Somewhat like dominant/recessive genes, as the nonresistant virus is affected by the drug therapy, the mutation seems to overpower the nonresistant virus. “When you add the drug, the replication of the non-resistant, sensitive virus is blocked, so that the resistant virus just comes up. With combination therapy, you can drive the virus in most treated individuals down to less than 50 copies per milliliters of blood—50 molecules of virus RNA, an amazingly small amount of stuff!—but that’s not zero. We wanted to know what was happening in those patients who were ‘undetectable’ by standard tests, so we developed an assay that could see one copy per milliliter reliably and with good accuracy. And using that assay, we find that about 80% of patients who are well suppressed still have detectable virus. We’re trying to see where this little bit of virus in someone who’s been treated for one, two, or three years comes from,” Dr. Coffin said.

Collaborations Help Resolve Common Problems

Dr. Coffin noted that every group in the HIV DRP has important collaborations with researchers in other institutions, pharmaceutical agencies, and private industry throughout the world. “Bringing together groups with disparate ideas and scientific foresight to consider a common problem has been very successful for us. And I think there are many other areas where this could happen,” he said.

Dr. Coffin’s own focus of collaboration is with researchers in the clinical program, working with some research groups in Africa studying nevirapine, used to block mother-to-infant transmission of HIV. Dr. Coffin’s group developed a very sensitive assay for measuring the frequency of mutations to nevirapine resistance. “With this assay, we’ve been able to study how fast the resistance disappears with time because one problem with this resistance, of course, is that it can potentially compromise the effectiveness of future treatment,” he said.

Another form of collaboration is the natural history study where the researchers primarily observe the virus and its behavior in patients. NIH has very stringent guidelines for treating a patient for HIV infection; in part, these revolve around respecting the wishes of those who, for one reason or another, don’t want to be treated. In one study, most of the patients that Dr. Coffin’s group sees are recruited through Dr. H. Clifford Lane’s group at NIAID. Dr. Coffin said, “It’s been a very powerful and a very generous collaboration on their part.” They also have “a very delightful, very productive collaboration” with Abbott Laboratories, looking at patients with very low, undetectable amounts of virus, and reanalyzing samples from one of their big clinical trials. “In these kinds of studies, we have the assays, but we rely heavily on other people in patient groups to actually get the samples we need to test,” Dr. Coffin explained.

A Born Scientist

Originally from Schenectady, New York, Dr. Coffin was always encouraged to experiment. At 12, with his mother’s help, he extracted the skeleton from a dead cat. “She helped me find a carcass, and we got Clorox^®. I don’t know how other people in the house stood it. Horrible smell,” he said, shaking his head at the memory. The love of science continues to a third generation: his younger daughter is a medical student, while the older one, already a computer professional, is taking pre-med courses.

Dr. Coffin’s peers certainly recognize his scientific expertise. His article “HIV population dynamics in vivo—implications for genetic variation, pathogenesis, and therapy” (Science 267[5197]: 483–489, 27 January 1995), was rated among the top 12 papers for the 1990s and even today is highly rated: according to the Scientific Library’s Web of Science database in June 2005, the paper has been officially cited 983 times. Together, his top two papers have been cited over 1,000 times; and if you look at his top 23 references, each of which has been cited at least 100 times, the total is 4,898!

In addition, Dr. Coffin has been Distinguished Professor and American Cancer Society Research Professor at Tufts University since 1992, Director of the HIV DRP since 1997, and a member of the National Academy of Sciences since 1999.

How Can You Tell a Discovery Is Important?

“An important discovery is one that changes your thinking about how something works. Important discoveries are important discoveries even if you can’t necessarily tag a clinical outcome onto them. The ’95 paper is an example of that. We’d looked at how evolution occurs in another retrovirus, not HIV, and the sort of ‘ah-ha moment’ was to realize HIV wasn’t behaving the way people thought it was. It had to be constantly turning over, and therefore, there had to be an evolutionary process that gave rise to mutations and so forth.”

Relaxation? What’s That?

With time divided between NCI-Frederick and Tufts University, you would think that Dr. Coffin would have enough to do. But no. He spends his weekends in a sort of third job: He is the proud, half-owner of a 65-acre farm that includes a 22-acre cranberry operation in the heart of southeastern Massachusetts. “We’re very isolated, a mile in off a dirt road, surrounded by a river, streams, and marshes. It’s really quite nice; prolific wildlife,” he said. Dr. Coffin and his partner belong to the Ocean Spray cooperative, and with a grin, he estimated that “Chances are, one-tenth of 1% of the bottle of Ocean Spray you buy at the supermarket is from our farm.”

What’s Next?

Since Dr. Coffin’s seminal paper was published in 1995, much research seems to have confirmed his theories. What’s next? “We have to do a better job in treating patients,” he said.

He believes that treating patients better means scientists must ensure “that basic discoveries are being translated properly...Basic research has been the strength of American science over the last 30 or 40 years in developing completely novel things for medicine.”

He continued, explaining, “Although we don’t do any real drug discovery here, we do have some screening programs going that could turn up something. The bit of screening that we do is more for developing screening approaches that drug companies might be able to exploit for much larger-scale things. I would urge that the people directing NIH-based research allow more flexibility in what people can do and how they can accomplish it.”

Finally, Dr. Coffin stated that “a new goal will be to develop ideas for drugs, ways of testing them, ways of understanding how resistance evolves, so that perhaps the goal of reducing HIV to a relatively easily managed chronic infection might still be accomplished.”

Maritta Grau, Senior Technical Editor
Scientific Publications, Graphics & Media
SAIC-Frederick, Inc.
National Cancer Institute at Frederick

Nancy Parrish, Senior Technical Editor
Scientific Publications, Graphics & Media
SAIC-Frederick, Inc.
National Cancer Institute at Frederick

Photography Department
Scientific Publications, Graphics & Media
SAIC-Frederick, Inc.
National Cancer Institute at Frederick

Jim Miller, Web Graphics & Development
Computer & Statistical Services
Data Management Services, Inc.
National Cancer Institute at Frederick