Evolution at the molecular level

Joshua Plotkin, assistant professor of interdiscplinary studiesPhoto credit: Candace diCarlo

Joshua Plotkin, the Martin Meyerson Assistant Professor of Interdisciplinary Studies at Penn, has been a fan of math since his youth. He majored in math as an undergraduate student at Harvard, studied it as a visiting student at Oxford University and also planned to continue studying it in graduate school.

But during the last semester of his senior year, Plotkin met a world-renowned scientist who would forever alter his life: Charles Darwin. Not the real Charles Darwin (because he died in 1882) but rather the Darwinian ideas discussed in a course on evolution.

Plotkin, who holds a Ph.D. in applied mathematics from Princeton and appointments in both the Department of Biology in the School of Arts and Sciences and the Department of Computer and Information Science in the School of Engineering and Applied Science, says he became captivated with evolution after taking the course and developed a kid-like fascination with the subject.

“It hadn’t struck me until then how surprising it should be that we all exist and that somehow, even though there’s a lot of thermodynamic randomness, nevertheless, living organisms exist and somehow they evolve and they’re really complicated,” he says. “That question alone just seemed so counterintuitive to me, how we could all have gotten here.”

Plotkin’s original plan to study math in grad school was shelved and he entered the much more “engaging” world of evolutionary biology.
Today, Plotkin is an evolutionary biologist who uses math and computation to study how organisms evolve at the molecular level. He has conducted extensive work on bacteria and viruses, specifically the flu virus, which he calls “a remarkable system for observing evolution in action.”

Plotkin came to Penn from Harvard, where he was a junior fellow of the Harvard Society of Fellows. He was also adjunct research faculty at the Institute for Defense Analyses, conducted classified research for the U.S. Department of Defense, and served as a field researcher on tropical forest diversity for the Government of Malaysia. Recently, he was named a 2009 Research Fellow by the Alfred P. Sloan Foundation.

The Current sat down with Plotkin to discuss what exactly it is that he does and what impact he hopes his work will have in the future.

Q. Can you explain in layman’s terms how you use mathematics and computation to study evolutionary biology?
A.
Before the discovery of DNA, there was a lot of evolutionary biology that didn’t involve much mathematics. Natural historians, dating back to Darwin, would make detailed observations in the field on how organisms varied, and make inferences about their evolutionary history. This was the beginning of the field. For a long time, and even today, this is still a way that evolutionary biology proceeds, by careful field observations. But the discovery of DNA changed everything. Once you have DNA, you have a common currency for comparing evolution between organisms. In other words, instead of studying phenotypic characteristics, such as a bird’s plumage, we now study the molecular evolution of the bird’s genome. Even though birds have wings and humans don’t, they both have DNA. And all DNA comes in this really elegant alphabet of As, Cs, Gs, and Ts. That immediately makes it amenable to mathematics, because we can count these [letters], we can see how quickly they change, and over time, we can develop a theory for how quickly they should change. And these theories reflect the same kind of processes Darwin described—natural selection, mutation, adaptation—but instead of describing them in terms of the phenotypic characteristics of the organism, we describe them in terms of the molecular characteristics of genome. You can imagine how mathematics could become useful because, all of a sudden, you have very simple systems involving As, Cs, Gs, and Ts changing in their frequency over time. You can describe how these different alleles change in frequency over time using some mathematical equations, and you could try to verify those equations by measuring genetic changes in populations.
 
Q. Are there similarities in how all organisms evolve at the molecular level?
A.
Certain molecular processes occur in human cells that don’t occur at all in bacterial cells, but for the most part, the really striking thing is that cells are actually very similar overall, at the molecular level. For me, that’s wonderful because I mostly study the molecular evolution of microbes. But the reason why I do this is not that I'm only interested in microbes, but because higher organisms share many similarities at their molecular level. After all, microbial proteins are subject to the exact same laws of physics and the exact same laws of chemistry that human proteins are subject to. To the extent that those laws of physics and chemistry are responsible for guiding evolutionary patterns, we might as well study them in microbes, where we have tons of data, and thereby learn things about molecular evolution more generally. And that’s my approach. I’m interested in microbes because, in part, they cause disease, but also because they’re just wonderful systems for studying evolution.

Q. You have conducted a lot of research on influenza. What makes the flu virus such a good subject for studying molecular evolution?
A.
Over the last 30 or 40 years, we’ve sequenced thousands of flu viral genomes. By comparison, we have sequenced only a handful of human genomes. And more importantly, over the last few decades, 20 percent of sites in the flu genome have undergone mutations, which is roughly the equivalent of several million years of evolution in typical human protein. In other words, over a few decades, we can see in influenza the rough equivalent of millions of years worth of evolution in humans. Because we have a full historical record of all these mutations, we have a tremendous opportunity to learn about molecular evolution, given that the laws of physics and protein folding are the same, to generalize our conclusions to all of life.

Q. Why is the flu virus changing so fast?
A.
There are really two reasons. First of all, its mutation rate is higher than that of humans. But the second reason, which is actually far more important, has to do with natural selection. Not only does it acquire mutations more quickly, but these mutations actually spread more quickly, as well. And that’s because the flu is so common. The flu virus infects something like one-fifth of the world population every year. And all the people who get a strain of flu, they usually recover from it and then they’re immune to that strain for the rest of their lives. Any novel strain is at an adaptive advantage. In other words, positive selection promotes new strains because they can reinfect the host, whereas the old strains can’t reinfect the host. This process tends to promote mutations to spread very, very quickly. It’s really because of the fact that flu infects so many people that it evolves so quickly. It has to evolve in order to reinfect them in following years. That's why you get flu every few years and that's why you have to change the flu vaccine every few years. You have to change it to try to match the predominate strain that has arisen.

Q. Is the flu virus affecting people the same now as it has in the past?
A.
Roughly yes, except for a few years in which there was a pandemic strain that came from bird flu. Typical strains that arise each year have roughly the same affect on people as in proceeding years, which is not minor. We think of flu as a nuisance but, nonetheless, flu kills roughly 20,000 Americans a year, mostly old people and really young people. The flu is a really underappreciated disease. To us it’s just a cold or a nuisance, but to many people it’s fatal. It has a huge impact on human health and morbidity.

Q. It sounds like the flu’s constant mutations would make it difficult to develop a vaccine.
A.
It’s unlikely that we’ll have a silver bullet that you administer once and protects people for their lifetime. Instead, we need a much more dynamic approach where we choose, on some time frame, maybe every year, a new updated vaccine to administer. We need to be able to choose that vaccine intelligently. Ideally, we'll choose the vaccine that’s going to match the most prevalent form of the virus each year; that’s the whole game. In some sense, we want to predict flu’s evolutionary future so that we can prepare with the right vaccine ahead of time. That’s by no means a hopeless task. We have made a lot of progress in predicting flu’s evolutionary future, but we still have a long ways to go.

Q. You have written that flu evolves more rapidly than almost all other life forms. Why is this so?
A.
Flu and HIV have remarkable rates of evolution, and basically for the same reason. They both have high mutation rates, but much more importantly, they’re both trying to evade the immune system, and so they’re under so-called positive selection to change. HIV does that within one infected individual. Flu does it over the course of the year, after affecting many different people. HIV is actually faster but they’re both some of the fastest evolving organisms on the planet. That’s why they’re hard to eradicate, either within one host, for HIV, or within the whole population of hosts, for influenza.

Q. Can you talk about your time as a consultant to the Government of Malaysia as a field researcher on tropical forest diversity?
A.
I am principally interested in molecular evolution, but I also have a background and continuing interest in tropical forest diversity. It’s really a different question entirely: What preserves the huge diversity of species of trees and animals in tropical forests? That’s an especially pressing question when people are cutting down forests at an increasing pace. If you have to cut down a certain number of trees in a forest, which ones are you going to remove so as to have as small an impact as possible on the resulting diversity of species that will be left over?

Q. Do you have a problem that you hope to answer with your work? Or a breakthrough you would like to make happen?
A.
I think I’m just lucky if any of my research ever helps public health. That certainly motivates me to study specific, mostly microbial systems. But that’s almost like an extra perk to my work. From day to day, a large part of my motivation is instead the puzzle of how the diverse organisms we see today arose. How did we develop the startling molecular diversity on the planet? It is surprising that life exists at all, given the laws of thermodynamics and entropy. That’s a deep and difficult question but I really believe that it is the job of the modern evolutionary biologist to work on that, and to give us an understanding of the molecular basis for life. That’s not the same as a medical breakthrough, even though some of my work may eventually help medicine—especially with things like influenza and HIV, which are essentially evolutional problems. But medical advances are part of a broader goal: To expose how evolution provided all of the wonderful diversity of life we see today.

Originally published on April 23, 2009