Awardee Profile - Joshua Plotkin

Joshua Plotkin, Ph.D.

Understanding Evolution

Joshua Plotkin, Ph.D., uses mathematics and computation to study evolution on its most basic level—the genome, the genetic blueprint of life. “I want to understand the whole molecular kit and caboodle behind Darwin’s big idea,” said Dr. Plotkin, a 2005 recipient of a Burroughs Wellcome Fund Career Award at the Scientific Interface.

In its most basic sense, evolution occurs when mutations in genes lead to changes in an organism. If a change is advantageous to the organism’s survival, the mutated gene is likely to be preserved in subsequent generations. Such mutations are described as being spontaneous, but even behind this spontaneity are factors that make one gene more susceptible to change than another.

Dr. Plotkin wants to understand what causes changes in an organism’s genome from one generation to the next. In his research at Harvard University, where he is a Junior Fellow in the Society of Fellows, he probes the workings of “positive” and “negative” selective pressures. Positive pressures comprise attributes of a gene that promote changes to take place, and negative pressures are those that cause a gene to remain stable or unchanged.

“It’s a major goal to sort out which proteins fall in which of these categories,” according to Dr. Plotkin.“By identifying the rapidly evolving proteins,we can start to figure out which genes are responsible for the specializations that distinguish one species from another, such as chimpanzees from humans.”

Many evolutionary biologists study such changes by comparing several different genomes in order to determine which genes stay the same and which change. Dr. Plotkin’s approach is to use mathematics and computation to create tools that can measure the positive or negative selective pressures across an entire genome.

One advantage to this approach, he said, is that he does not need multiple sequences of genes to compare and contrast, but rather he can elucidate hot spots for change or conservation within a single genomic sequence. This capability is particularly advantageous when only one set of data is available, as might be the case when studying a pathogen with only one known strain.

He tests his mathematical models by applying them to genomic data that other researchers previously have obtained by more traditional means. Models that hold up can then be used to predict change in species with limited available data. Such evolutionary studies aren’t merely interesting history lessons—they may, in fact, help save lives.The same genetic forces that produce adaptations in animals also influence the virulence of viruses and bacteria that cause diseases. Flora and fauna evolve over years and decades, but microbes can go through several life cycles a day, thus contributing to a rapid rate of evolution.

For this reason, Dr. Plotkin devotes much of his research to pathogens. Identifying rapidly evolving genes in pathogens may help researchers gain information about potential vaccine targets, he said. Conversely, identifying stable genes may help researchers develop new drug targets by pointing out what is essential to the pathogen’s survival.

Dr. Plotkin is particularly interested in the influenza virus. Composed of only 11 genes, the virus is a master of disguises. The virus’s surface is coated with a protein, called hemagglutinin, that undergoes rapid mutation, and each “new” coat fools the body’s immune system into thinking it has never seen the virus before. Ordinarily, the immune system would develop antibodies to fight off familiar invaders, but each time a mutated form of the flu virus appear, the immune system has to start from scratch.

According to Dr. Plotkin, the flu virus manages to infect 20 percent of the human population each year.The more the virus interacts with a variety of human immune systems, the more it experiences pressure to change its disguise by producing novel variants of its hemagglutinin coat protein.Dr. Plotkin’s evolutionary models may prove valuable in predicting how the coat protein will change and which strain of the flu will be predominant during the next flu season.

Dr. Plotkin describes his journey into biology research as circuitous. As an undergraduate at Harvard, he first studied pure mathematics. His interest in biology was sparked during a year of study at Oxford University, in the United Kingdom, where he met William “Bill” Hamilton, one of the leaders of what has been called “the second Darwinian revolution.” Dr. Plotkin set about to learn more about the molecular underpinnings of the life sciences.

“When I learned more about the structure of DNA, it all seemed so implausible to me,” he now recalls.“For instance, how could it be that all of life was encoded in a simple digital alphabet of nucleic acids? I couldn’t help but think about these questions.”

Although he was slated to attend graduate school in pure mathematics, Dr. Plotkin decided instead to combine his mathematics background and his newfound excitement about the biological sciences. He entered an applied mathematics Ph.D. program at Princeton University, studying under Simon Levin and Martin Nowak, both renowned for applying mathematical tools to the study of biology. “They had an enormous impact in shaping my scientific interests,” Dr. Plotkin said.

Likewise, Dr. Plotkin made an impact on his advisers and colleagues. “Many things are impressive about Joshua,” said Dr. Levin, who continues to work on projects with his former student. “He’s able to bring perspectives, on one hand from molecular biology and on the other hand from ecology, to bear on everything he addresses. He addresses each problem in a very serious way.”

In June 2007, Dr. Plotkin will leave Harvard for the University of Pennsylvania, where he will be an assistant professor in the departments of biology and computer science. He said he intends to pursue his research on pathogen evolution, and also to continue with another of his interests, using mathematical modeling to support biodiversity research in the tropical forests of Southeast Asia.

As a young researcher trying to apply new approaches to questions in both evolutionary biology and biomedicine, Dr. Plotkin found his BWF career award especially helpful.“The funding has allowed me to explore new areas in molecular evolution using unorthodox approaches,” he said. “Even though evolutionary biology has traditionally been viewed as an academic subject, it is increasingly clear that evolutionary approaches will shed new light on fundamental problems in molecular biology.”

By Nicole Garbarini, a freelance science journalist based in Tennessee.