The National Institutes of Health, America’s chief agency for biomedical research, looks like a sort of massive, slightly confused college campus. About 18,000 employees are split between some 70 buildings, a mixture of towering modernist labs, traditional brick structures and fancy Greek revivals. Shuttle buses ferry patients about, to take part in clinical trials. Each building is either sternly labeled by number (Lowy works in Building 37) or given a meaningful name, often to honor a legislator who once pushed through a round of funding.
The first two words that come to a classmate’s mind about Lowy? “Intense. Generous.”
We’re sitting in Lowy’s impressively windowed office, high above the trees. The Lasker Award, a gold winged trophy, perches on the windowsill, and the walls are lined with photos of charismatic locales. Lowy’s favorite depicts Italy’s Laurentian Library, designed by Michelangelo. Today, Lowy wears khakis, a blue button-down and a lanyard with his NIH badge. As he eats the lunch he brought from home, he walks me though his professional life up to and after the HPV vaccine.
He trained in internal medicine at Stanford and dermatology at Yale, finishing his studies in 1972. This was the time of the Vietnam War draft, and, to fulfill his selective service requirement, the draft board allowed him to do a two-year stint at the NIH. It turns out Harold Varmus ’61 struck much the same bargain, as did John Gallin ’65, now the NIH associate director for clinical research. Back in the 1970s, because these alums had each avoided going to Vietnam, Varmus gave their group a darkly ironic name: “the yellow berets.” All would apply their considerable talents to government careers, staying at the NIH long after the draft board mandated, with some stints at universities, declining to sign on with the pharmaceutical industry and its glossier salaries. In fact, in 2007, Lowy (along with Schiller) won the Federal Employee Service to America Medal.
Lowy has now been at the NIH for 46 years. And Amherst has had a snowball effect. Fellow alum (and English major!) Varmus was director of the National Cancer Institute from 2010 to 2015—and he chose Lowy as his deputy. After Varmus left, Lowy became acting director. Says Schiller, “A lot of people are top-notch scientists or top-notch administrators, but not many are top-notch at both. Doug is. And he gets twice as much done as anyone I’ve ever worked with.”
Lowy’s HPV work with Schiller has drawn the most attention, but Lowy’s other efforts have also advanced our understanding of cancer. At first he worked in the lab of the famed Wallace Rowe, who studied retroviruses that cause leukemia in mice. By 1975, Lowy, in his own lab at the NIH, was one of those at the forefront of working on the RAS family of oncogenes. RAS gets its name from rat sarcoma, since the viruses that contain RAS were first discovered in rats. The three RAS genes in humans are among the most prevalent oncogenes, contributing to some 30 percent of all tumors. “Doug’s early work with RAS was just as phenomenal as his later work with HPV,” says Peter Howley, a Harvard Medical School professor who studies papillomaviruses.
In the 1980s, Lowy, with Schiller, turned his attention to papillomaviruses, then much less studied than retroviruses. Eventually, they set out to create a human vaccine—though they had no background in vaccinology. There was no viable way to do that before trying a vaccine on animals. Thus they began scrutinizing the bovine papillomavirus (BPV), which causes warts in cattle, and tried to understand how a BPV infection causes these changes. Through trial and error, they discovered that the proteins that form the capsid, or outer shell, of BPV could produce virus-like particles (VLPs) that closely mimic the original virus, with one stop-the-presses exception: VLPs are not infectious, for they lack viral genetic material that replicates itself, and so can’t cause cancer.
Even better, because VLPs so closely resemble HPV’s structure, they could maybe “fool” the body into triggering a protective antibody response against infections. Here’s a metaphor an art history major would appreciate: VLPs are like Han van Meegeren’s forgeries of Vermeer paintings, so uncanny they duped experts and sold for a fortune as if originals. In 1991, Reinhard Kirnbauer, a postdoctoral fellow on Lowy and Schiller’s team, began trying to make bovine VLPs. To do this, the team homed in on two promising proteins on the BPV microbe’s surface, L1 and L2. L1 proved more viable, and rabbits were then injected with the BPV L1 vaccine. “We got sky-high levels of antibodies, a thousand times higher than what we looked for, levels you almost never see when you develop a vaccine,” says Schiller. “That was super exciting.” They tested it further over the next decade, each time refining the vaccine.
Yet when it came to testing the vaccine in humans, progress did not follow a clear path. I could chronicle a thousand crossroads, but let this one stand in for many: Lowy and Schiller figured they could transfer their BPV L1 success to an auspicious common strain of HPV, tagged as HPV16, and make virus-like particles from its L1 protein. But it didn’t take. Through much back-and-forthing, they hit on the notion that the problem lay in the standard source of the HPV16, which came from a cancerous sample: cancer cells are notorious for jumpstarting genetic changes, and perhaps the source had been compromised. So they tried working with HPV16 cells that only cause a benign infection, rather than a cancerous one. That made one crucial difference: it turned out the L1 protein from this new source featured a lone amino acid that was crucial to assembling the VLPs needed for a human vaccine.
I asked Schiller to characterize Lowy’s role in this process. “Some scientists have so many ideas, but they can’t focus on one,” he says. “Some know all the literature but can’t have any original ideas. Some are very into control so never move ahead and discover something. But Doug does all those things well.”
A long series of clinical trials began in 2001, run by Johns Hopkins, Merck and GlaxoSmithKline. In one, 800 volunteers received the vaccine and none developed a cervical infection—while 41 of those in the placebo group did. In 2006, the FDA approved the first vaccines for the virus, which tackled HPV 16 and HPV 18. After more than two decades, the researchers had triumphed at last.
On a whim, I asked Stephen Mitchell, an eminent translator of works like Gilgamesh and the Book of Job, if there are any lines from his works that apply to his Amherst friend. He consulted his 2007 version of the Tao Te Ching, and sent these: “Do you have the patience to wait / till your mud settles and the water is clear?”
But the vaccine’s rollout, like most rollouts, has not been perfect. It arrived in an era when there was a small but forceful backlash against vaccines in general, and when you add the issue of sex, the optics get more uncomfortable. To consent to give your children the HPV vaccine, you have think of them as future sexual beings. (The vaccine is recommended at age 11 or 12.) Some parents also worried that the vaccination might be a license for young adults to be sexually active.
Like most rollouts, this one has not been perfect. It arrived in an era when there was a small but forceful backlash against vaccines.
Another complication centered on the issue of race. Though HPV16 and HPV18, the strains targeted in the first vaccine, are the most common overall, African-American females are about 50 percent less likely to be infected by 16 and 18 than non-Hispanic white females. Subsequent vaccines tackled more strains, with the newest version, Gardasil 9, combatting nine, including the three most prevalent in the black female population. Learning all this prompted me to ask Lowy about Henrietta Lacks. She’s the African-American woman who died of cervical cancer in 1951, and whose “HeLa” cells, without her knowledge or consent, lived on to help scientists develop the polio vaccine, study HIV/AIDS and more. When Lowy presents on his work, he often ends by showing a picture of Lacks. HeLa cells carry evidence of HPV18. Had the first vaccine been available in her lifetime, he tells his audiences, she would have lived.
As of May 2017, 270 million doses of the HPV vaccine had been given out. This sounds remarkable, but it lags well behind the rates of older vaccines: In 2017, 49 percent of U.S. adolescents were up to date on the HPV vaccine, versus 93.7 percent for polio. Apart from their lab work, Lowy and Schiller have gone at these distributive problems holistically, consulting with groups such as the World Health Organization on how to promulgate the vaccine.
As Lowy says, “John and I have not just stayed in our corners.”