Making Life Difficult for Viruses

By Eric Sauter

Although the last 23 years at The Scripps Research Institute has softened the burr in his voice, the accent is still there, still purely Glaswegian, the proper name given to the local dialect spoken in the city where Lindsay Whitton, a professor in the Molecular and Integrative Neurosciences Department and a native Scot, first took his medical degree in 1979 and then his Ph.D. in 1984.

No sooner had he finished his doctoral studies than he was on a plane to San Diego to do postdoctoral work in the laboratory of Scripps Research Professor Michael Oldstone, a pioneer in viral infection.

It was his Ph.D. work that first hooked him on viruses. "My Ph.D. was on how viruses worked as little molecular organisms," he said, "because I really like to pull things apart and then stand back and see how evolution has honed the machine. That gives me pleasure in the same way that some people like to eat strawberries. It just makes me happy."

Listening to Whitton is to hear his version of what Glasgow locals call "The Patter," the humorous, imaginative language of the city. In Whitton's version, literary metaphor and deftly spoken opinion include subjects ranging from the city's eating habits to the evolutionary role of viruses. For example, you can hear him opine on the word "Scotch" as noun or adjective: "We don't have Scotch in Scotland. We have whisky and we don't admit to Irish whiskey or any other kind for that matter." Or, he'll tell you just why Glasgow is the heart attack capital of the world, a fact known to every cardiologist on the planet: "I was 20 years old, and an exchange medical student in Minneapolis, when I found out for the first time that pizza was not always served deep fried. The pizza shops in Glasgow prepare their pizzas, slice them, and then freeze the slices. When you ask for one, they drop them into the deep fryer."

His penchant for colorful and descriptive phrases crosses over to his science, delighting his students but sometimes frustrating his papers' reviewers. In a review article about the Coxsackie virus, which he and his laboratory continue to explore in a variety of viral pathogenesis studies, including the treatment of myocarditis, Whitton used a phrase that caught a anti-anthropomorphic reviewer's eye: "Not content with disabling its prey, the virus then exploits the remains." Unhappily, Whitton had to modify the clause, conceding that viruses could not feel content. Nevertheless, he continues to resist a dry scientific style, believing "it's better to express yourself as clearly and memorably as possible."

A New Perspective

Whitton's path to Scripps Research was also clear and memorable.

After medical school at the University of Glasgow, Whitton set out to do "a proper Ph.D." at the same institution. As he was completing his dissertation, the head of the school asked him if he wanted to try postdoctoral work at Scripps Research. After Whitton cleared up some momentary confusion between "San Diego" and "Santiago," he liked the idea. Not only did his Minnesota experience contribute to a generally positive impression of the United States and its science, he also welcomed the opportunity to avoid the distinct hierarchy in Scotland's medical profession. "I didn't want to apply recipes," he said. "I wanted to find out how things worked."

Whitton arrived at Scripps Research with his wife and young daughter expecting to stay for two years; he went back to Scotland once after that, returned to San Diego, and stayed.

Scientifically, the Oldstone lab offered him a new perspective on his field. "When I came to Michael's lab, he made me look at viruses as agents of disease." And that's what Whitton has been at ever since.

As Whitton himself has written, his research now focuses "on making life as difficult for viruses as they do for us." That is, he specializes in the study of antiviral immunity and viral pathogenesis. His work with antiviral T cells, specifically CD8 T cells, which attack viral infections with interferon, and CD4 T cells, which play a cardinal role in regulating immune response. He is also deeply involved in analyzing the potential of plasmid DNA vaccines, enhancing this promising type of immunization through the use of ubiquitin, a cellular protein that binds to the virus and tags it for destruction. These tagged proteins are better at inducing CD8 T cell responses.

Whitton also works with other Scripps Research scientists on the development of a DNA vaccine against the Lassa virus, which produces an acute hemorrhagic fever and kills about 5,000 people a year in West Africa, according to the Centers for Disease Control. His other work, studying the molecular basis of autoimmune diseases triggered by viral infections, involves colleagues at the University of Utah and the La Jolla Institute of Allergy and Immunology.

Like other determined Scottish explorers (Dr. David Livingstone does come to mind), Whitton travels in his own direction.

"I don't see myself as an applied scientist, although I would be delighted if the work I'm doing results in products that helped human health," he said. "I basically follow my interests and those are how the immune system works and how it fights viral infections."

When a viral infection occurs, CD8 T cells shower the cells with cytokines like interferon; the T cells that initiate production of interferon become dominant. But the expression of interferon on these T cells is tightly regulated, so the ones with most interferon receptors win by default. Whitton's laboratory has developed a new way to identify T cells that actively respond to genuine antigen contact in vivo, something that may prove useful in the study of autoimmune disease.

"The immune system kills two birds with a single stone, using anti-viral interferon not only to fight viruses but also to help regulate the abundance of the T cells that produce it. Think of interferon as a sword with which a T cell fights virus infection. T cells that synthesize interferon very rapidly  are allowed to multiply far more than their "slower" brethren; in this way, the immune defense against viruses is populated by the best soldiers, carrying the sharpest antiviral swords.  It is very satisfying to me that evolution has been so parsimonious in developing the process."

The Power of Evolution

Whitton knows—and appreciates—the power of evolution. "I try to couch my perspective on viruses from an evolutionary point of view," he said. "Viruses are very capable machines and only the capable survive. Evolution has honed the virus to do what it does."

It is the viral role in the evolution of humanity that he finds most intriguing, that one that seems to have kept his mind focused over the past 23 years.

"There is no doubt that viruses have significantly affected human evolution and have helped to mold the genome of many species on earth over time. There are viral fossils—what some have labeled junk DNA—in the human genome. We don't know why they're there and we don't know what they do. But they're not junk. They do something; we just don't know what that might be."

"The other way they have affected our genome is through rapid change. Viruses have ravaged the human population on several occasions. Smallpox killed more than 300 million people in Europe. Those of us of European descent are the children of the survivors of smallpox, our genome has been selected by the virus. When the Spanish came to the Americas, one of the reasons they were able to conquer the indigenous people was that they brought smallpox with them. No wonder that the natives who survived saw the Spanish as god-like. Here was this disease that was wiping out their families and friends, but these newcomers were immune to it."

Whitton is also aware of the threat viruses pose, even the ones we often think of as no threat at all. For Whitton, vaccines are the ultimate medical weapon against such a threat, the single most important medical advance in history (he concedes that antibiotics are a close second).

"Measles is an insignificant disease to us in the West because we have a vaccine for it, although measles is a fairly dangerous virus. If you infect a kid with measles, the chances of the child dying is one in 400; if you were playing the lottery, you'd think those were very good odds. That puts it in perspective. Malaria kills lots of people in the developing world in part because it affects the same geographical areas as measles. The measles virus causes immuno-suppression and interacts with malaria and as a result you get one to two million deaths in Africa each year that are measles-related."

Like Dr. Livingston, that uniquely Scottish blend of explorer and missionary, multiple impulses converge within Whitton, perhaps from training as both a scientist and physician.

"All you have to do is look at smallpox," he said. "A vaccination eradicated that disease from the planet. So far as I know, vaccines are the only medical treatment that should be given to pretty much everyone."

Send comments to: mikaono[at]scripps.edu

Scripps Research Professor Lindsay Whitton specializes in the study of
antiviral immunity and viral pathogenesis.

An image showing an effect of coxsackievirus. Click for details.