DNA Gone Awry
Sergei Mirkin helps uncover the genetic mechanisms that can lead to devastating diseases

Sergei Mirkin began his career as a geneticist in a country that had once outlawed the study of genetics. As a young man in the USSR in the 1970s and ’80s, he learned from some of the best researchers of the time—scientists who were not only intellectually gifted, but nimble enough to negotiate the through-the-looking-glass quality of life in the Soviet Union.

“First and foremost, we want to understand what genetic process, what molecular process, is responsible for the lengthening of these [gene] repeats,” which lead to devastating diseases, says Sergei Mirkin. PHOTO: MELODY KO

In his lab there—which was part of the department where, during the early days of the Cold War, researchers had conducted top-secret work to help deliver the atomic bomb to Stalin—Mirkin collaborated with an unusual mix of biologists and physicists. One of the projects involved some “non-orthodox” DNA structures—oddly twisted or folded strands of DNA that contained numerous repeating sequences.

“It was an extremely esoteric subject, those repeats, and they seemingly had little or no biological importance,” says Mirkin, the newly appointed White Family Professor of Biology at Tufts. “Their odd structures, however, totally fascinated us, as they could hold the keys to the general principles of DNA arrangement. A great Russian poet, Anna Akhmatova, once wrote: ‘If you only knew from what rubbish poetry grows, knowing no shame’ . . . To a large extent, the same is true for science: those very same repeats, scientists know now, cause debilitating neurodegenerative diseases,” Mirkin says.

Now Mirkin hopes his research into how and why these DNA coding repeats occur will lead to treatments for afflictions such as Huntington’s disease.

Mirkin came to Tufts early last year, from the University of Illinois at Chicago medical school, which he joined shortly after arriving in the United States in 1989. At that point, even though the Soviet Union was headed toward disintegration, the Communist leadership still managed to control its citizens’ movements—but not tightly enough. The first opportunity that came along, Mirkin moved to the United States, even though the price was high: he had to leave his work and his social circle behind in Moscow and re-establish his lab from scratch.

DNA Gone Awry
In his lab in Barnum Hall, Mirkin and his colleagues concentrate on a phenomenon known as expansion of DNA repeats. DNA is, in essence, the blueprint for genetic transmission in all living things. It contains four bases—adenine, thymine, guanine and cytosine, abbreviated as A, T, G and C—that are arranged in various triplets, such as CCG or AGT, to code for proteins.

Occasionally, there will be a section of DNA that features a repeating piece of this code. A brief section of repeating code isn’t a problem. “When triplet repeats are short, they’re stable, and they cause no harm,” Mirkin says. “However, once in a while, they go berserk. And in a particular family, the part of the simple repetitions starts lengthening, and it goes out of control and gets longer and longer. And that leads to disease.”

Some 30 known hereditary disorders result from these out-of-control repeats. These include Huntington’s disease, a degenerative brain disorder whose symptoms typically appear between ages 30 and 45 (one of its most well-known victims was folk singer Woody Guthrie); Friedreich’s ataxia, a neurodegenerative disease with onset between the ages of 5 and 15 that affects mobility, vision, hearing and speech and can lead to a serious heart condition; fragile X syndrome, which is a common cause of mental impairment, from learning disabilities to mental retardation; and myotonic dystrophy, a disease characterized by progressive muscle wasting and weakness, combined with cataracts and cardiac defects.

These repeats can escalate from one generation to the next, causing a phenomenon known as “genetic anticipation.” It starts innocuously, with an asymptomatic individual’s DNA containing, say, 40 to 60 repeats, and no symptoms appearing. That person’s child may have more than 100 repeats and begin to exhibit mild symptoms of a particular disease, or develop the disease late in life. A grandchild, however, may have more than 1,000 repeats, and suffer severely beginning at a young age. Most of the mutations that cause these diseases are dominant: only one parent needs pass on the gene with an expanded repeat for the disease to strike.

“First and foremost, we want to understand what genetic process, what molecular process, is responsible for the lengthening of these repeats,” says Mirkin, whose research is supported by the National Institutes of Health. “What makes them longer and longer? It’s important, because if we understand this molecular process, then we can think of smart ways of treating these diseases or of preventing these diseases from happening.”

Mirkin says the particular contribution of his lab is that “we found that these repeats can somehow trick DNA replication—a process whose main purpose is to copy DNA without compromising its integrity—into lengthening them. This became possible by analyzing repeats’ behavior in a genetically defined system, such as a simple, unicellular organism, for instance bacteria or yeast,” Mirkin says. “In yeast, you can easily introduce a mutation in any given gene and look at the effect of the mutation on the process of the repeat.” And that is exactly what he is doing.

Luckily, all the main machinery operating on DNA, such as replication, transcription, repair and recombination, are remarkably similar between yeast and humans. “Once we have some understanding in a model system, then we can think of experiments that can be done on human cells,” according to Mirkin.

There are no cures for any of the diseases caused by DNA repeats. And “because the mutation is within an individual’s DNA, I think an ultimate cure is unlikely,” Mirkin says. But he thinks treatment to prevent the disease from worsening is possible in the long run, and there are several other labs researching the possibility of using drugs to prevent further extensions from occurring.

“The best-case scenario is to move [these diseases] into the category of ‘treatable but not curable.’ To do this, we need to have more knowledge of the molecular mechanisms of the [gene] expressions and diseases,” Mirkin says. He and his colleagues are asking the tough questions: how does the extension translate into disease? Why does the lengthening of a particular repeat lead to, say, neuronal death or muscle weakness?

Science and Politics
The vagaries of genetic science aren’t the only difficult things that Mirkin has had to master. As a scientist in the Soviet Union, he was all too aware of the volatile interplay between science and politics. Like many other scientists, he had been forbidden to leave the country. “I was considered to be politically unfit for travel,” he says. “And, admittedly, the KGB folks were not all that stupid: as soon as I got the chance to travel, I didn’t come back.”

Mirkin was one of a number of scientists who managed to slip through the grasp of the then-crumbling Soviet state. “The USSR was disintegrating, and scientific funding had practically ceased to exist,” he says. “All of the people I collaborated with are now working in the United States or elsewhere in the West. Which is unfortunate for Russian science, and this is a direct consequence of what happened in the ’90s, when essentially the funding for scientific research wasn’t there for over a decade.”

Science is “very tightly intertwined with politics” here, too, Mirkin says. The two biggest factors affecting science are ideology—“a purely ideological clash between certain groups that greatly affects what kind of research can and cannot be done in the United States, the classical example being embryonic stem-cell research”—and funding. “What we do is rather costly,” he says. “And so, somehow, our research has to be supported by the state, or by private establishments, which makes it political almost by default.”

The fundamental difference between politics here and in the Soviet Union, Mirkin adds, is that in Russia, “being on the wrong side of the political spectrum, you could be fired, you could be persecuted, you could even end up in jail.” Here, by comparison, “it is much milder—you can lose your funding; your research can slow down. But, hopefully, your freedom will not be endangered.”

Helene Ragovin is a senior writer in Tufts’ Office of Publications. She can be reached at helene.ragovin@tufts.edu. This story ran in the February 2008 issue of the Tufts Journal.