Richard Lenski '77

Since evolution has occurred on our planet for several billion years, the obvious way to study it is by examining and interpreting fossils. In recent years, however, a new method has emerged. "We use DNA molecules to look back at history," explains Richard Lenski '77, distinguished professor in the ecology and evolutionary biology program at Michigan State University.

"Like the fossil record, it provides a way of looking back at history, making certain assumptions about parsimony--that is, choosing the simpler explanation before launching into the more complicated ones. This is molecular evolution. It tremendously complements the paleontological perspective."

Instead of studying fossils in the field, Lenski observes bacteria in the laboratory. "Studying microorganisms is logical because they reproduce very quickly, are easy to grow, and are simple to work with in many respects," he says. "Over the past ten years we've been able to observe more than 20,000 generations of bacteria."

In one key experiment, Lenski's team determined that the common bacteria E. coli evolve in a process called punctuated equilibrium. Over 3,000 generations, the average size of the E. coli doubled. But rather than increasing in size gradually, the bacteria tended to stay one size for several generations. Then, as a result of a single mutation that created a specific advantage for the entire population of bacteria, the colony underwent a significant growth spurt over a relatively short period. Once a rare mutation came up with a better design, it took only about 200 generations for the competitive advantage of larger size to predominate in the population of E. coli. During that brief period, the larger and smaller bacteria "were slugging it out," says Lenski.

What controls the rate of evolutionary change is a question that his work promises to answer. "With bacteria, you can look at the possibilities with well-designed experiments," says Lenski, who in 1996 received a MacArthur Fellowship, often referred to as "The Genius Award." "We have some control over bacterial evolution. We can create different environments and manipulate the mutation rate of bacteria by altering pathways that involve DNA repair."

His research involves one implicit assumption: that evolutionary change occurs in roughly the same way in all organisms. Given that fact, which few dispute, studying bacteria can reveal the nature of evolution in higher species, including humans.

But bacteria aren't the only microorganisms in Lenski's menagerie. His team recently started to study "digital organisms," self-replicating computer programs that mutate at random. Since they compete for time on a computer's central processing unit, these organisms adapt by natural selection to replicate faster and more efficiently.

Digital organisms have several advantages over bacteria. "One," says Lenski, "is the tremendous precision and replication that occurs with these computer experiments. We can also create varieties of digital bugs--from small and simple to large and complex--and ask how they evolve. We have previously published research on experiments that we did a couple of years ago using 250 different types of bacteria. With digital organisms, we were able to look at more than one billion different types."

Another advantage of the digital bugs is more fundamental to an understanding of the process of evolution. "Perhaps the most intriguing reason for studying digital organisms is that they are an entirely different manifestation of 'life' from all the organisms around us," says Lenski. "All those are based on DNA, genes, and proteins. We're looking for the foundations of evolutionary change that are independent of DNA and what we recognize in organisms around us. We're using a completely independent chemistry."

Philip Hanawalt '54

While evolution occurs in fits and starts, the DNA in all living things sustains a constant barrage of potentially damaging threats from the environment, notably from radiation and chemicals. Until recently, biologists believed that the molecule could survive most of those threats without harm. But now, doubts are emerging.

"We are learning that many environmental factors cause damage to DNA, and that DNA is not as stable a molecule as we once thought," says Philip Hanawalt '54, professor of biology at Stanford University. "It's subject to damage just by being in a living cell, and in particular because we breathe oxygen. Reactive forms of oxygen in cells damage DNA."

Hanawalt focuses on the mechanisms that cells use to repair their damaged DNA. "It's important to understand how living cells respond to the stress of having agents that damage DNA react with them," says Hanawalt. "We're using cutting-edge technology, such as arrays of DNA chips, that allows us to study all the genes involved when this happens."

This branch of genetics has implications beyond an understanding of how cells work. For example, a disease called xeroderma pigmentosa stems from a deficiency in DNA repair. That makes individuals with the condition extremely sensitive to sunlight, even when they are exposed for just a few minutes. Hanawalt's laboratory discovered a DNA defect in the early stages of development that produces Cockayne syndrome, a condition that causes sunlight sensitivity and worse. Its victims are dwarfs with mental impairment and extreme vulnerability to cataracts.

Research on DNA repair can also cast light on environmental threats. Hanawalt's team compared the relative damage to DNA caused by oxygen and radiation in the environment. "Oxygen damage to DNA is greater than that sustained from low doses of ionizing radiation," Hanawalt says. "We're concerned about levels of radiation in our environment. But it may be that levels we now regard as serious are too low to cause damage, and that we can tolerate more radiation than we thought."

That possibility stems from current research into the relationship between low-dose exposure to radiation or chemical toxins and the internal mechanisms in cells. "Exposure to low levels of radiation activates repair processes in the cell, so that it reduces rather than increases the level of damage in your DNA," says Hanawalt. "We may not have to spend billions of dollars to clean up radioactive toxins--perhaps just millions or hundreds of thousands of dollars instead." Hanawalt admits that no government will make a decision on such a drastic step until it has more solid research.

Meanwhile, his team and others are studying DNA repair in so-called undifferentiated cells, such as neurons. These cells differ from others in that, once formed, they never divide. Studying the cells could provide insights into problems of aging and certain neurological diseases.

Hanawalt has occupied a central role in DNA repair research for more than 30 years. He was a member of a group that discovered repair replication, the universal mechanism that replaces a bad strand of the DNA molecule with a good one, and has watched the discipline grow at a remarkable pace.

"Back in 1974," he recalls, "I ran the first international comprehensive meeting on DNA repair. I got 200 people to come to Squaw Valley, California, on a weekend too cold for skiing. Now there are probably five or six major meetings on DNA repair each year. The discipline has really blossomed. My only regret is that I'm approaching retirement age at a time when it's getting really exciting."


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