Profile of Andrew R. Marks

Heart failure is the leading cause of death in developed countries and is often caused by blockage of coronary arteries. One of the recent medical technology successes in battling cardiac disease has been the drug-eluting coronary artery stent, which acts as a scaffold to keep arteries open and releases therapeutic agents. The development of such drug-eluting stents was pioneered by cardiologist Andrew R. Marks, elected to the National Academy of Sciences (NAS) in 2005. A research scientist at Columbia University College of Physicians and Surgeons (New York), Marks is Chair of the Department of Cellular Physiology and Biophysics and Director of the Clyde and Helen Wu Center for Molecular Cardiology.

Marks was appointed to the Institute of Medicine, also part of the National Academies, in 2004. He received the American Heart Association (AHA) Basic Research Award in 2005, a Distinguished Clinical Scientist Award from the Doris Duke Charitable Foundation in 2000, and an Established Investigatorship from the AHA in 1993. In his Inaugural Article published in a recent issue of PNAS (1), Marks and his colleagues studied how protein kinase A (PKA) hyperphosphorylation of the ryanodine receptor/calcium channel contributes to heart failure.

Medicine and Writing

Marks grew up in Manhattan, NY, in a medically oriented household. His father, Paul, is a physician-scientist who served as dean of Columbia University's medical school and as head of Memorial Sloan–Kettering Cancer Center (New York) for 20 years. Paul Marks was elected to NAS in 1973 for his work on cancer genetics and hematology. Andrew Marks says, “My father was a role model for me in several ways. First, he showed me how a physician can be compassionate towards patients and can help relieve suffering. Second, as I was growing up, our home was always filled with scientists from around the world. I was clearly encouraged by meeting and getting to know so many leading scientists. Third, my father has always said his first love was research, and I could tell this was true from the way he spoke about science. All of these factors influenced my decision to become a physician-scientist.”

Writing was Marks's other passion, and he enrolled at Amherst College (Amherst, MA) with a double major in English and biology. “I love to write, and I love science. In college I was not willing to give up either of them,” he says. “Originally, I wanted to be either an English professor or a journalist. [I] won a Dow Jones award in journalism that enabled me to spend a wonderful summer working as a reporter for the Wall Street Journal. However, I decided that science was more interesting and more positive. In journalism, one is often waiting for someone else to make a mistake—that makes news. In science, you have the chance to discover something no one else has ever seen before—that was more exciting to me.”

Andrew R. Marks

Marks's accomplishments at Amherst College even set academic trends. “After I completed my thesis in biology and my thesis in English in 1976, I learned that I was the first student in the history of Amherst to graduate with honors in two subjects. My son and daughter both attend Amherst now, and they tell me this is not so unusual these days,” he says.

Eventually choosing medicine over writing, Marks enrolled at Harvard Medical School (Boston) and received his M.D. in 1980. His interest in cardiology began then. “During my clinical training at the Massachusetts General Hospital in Boston, I found that the mentors who were most impressive to me were the cardiologists. They were role models, and I liked the idea of being able to treat patients who were in dire straits and make them better, right before your eyes. It was very exciting,” he says.

Following an internship and residency in internal medicine at Massachusetts General Hospital (MGH), Marks worked as a postdoctoral fellow in molecular genetics at Harvard Medical School. In the laboratory of Howard Goodman, Marks studied the glucocorticoid receptor, and then he moved on to a clinical cardiology fellowship at MGH. “I enjoyed the clinical training very much,” he says, “but I felt that science might be even more stimulating.”

Open to Arteries

Marks's research over the years has concentrated on the molecular mechanisms that lead to restenosis of coronary arteries, heart failure, and sudden cardiac death. He has focused on the role of intracellular calcium channels in muscle function and smooth muscle cell proliferation. Smooth muscle cells can proliferate in heart vessels in response to different types of damage, and myocardial infarctions (heart attacks) occur when arteries in the heart become narrowed and eventually blocked by a process called atherosclerosis.

Metal stents to hold open arteries were first implanted in the mid-1990s. Stents are typically implanted via balloon angioplasty, where an inflatable balloon on a catheter opens the blockages in the blood vessels, and the metal stent is inserted. Almost a million angioplasties are performed each year in the United States, and stents are inserted in most of these patients. The first stents initially worked well at keeping the arteries open and allowing blood to flow, but soon vascular smooth muscle cells were found to grow quickly in response to the inserted stent, occluding the vessel again. “I became interested in the early 1990s in the mechanisms that regulate smooth muscle cell proliferation. I was using a drug called rapamycin as part of my studies, and I discovered it could prevent the smooth muscle cells from growing and migrating,” says Marks. He found that rapamycin blocked cell-cycle progression and inhibited proliferation in muscle cells (2), and it up-regulated a cyclin-dependent kinase inhibitor, p27, to cause cell-cycle arrest (3).

With this discovery, Marks realized that a stent that could release rapamycin locally could increase its effectiveness (4). The first drug-eluting stent products went through clinical trials in the late 1990s, and today they are sold by several companies. The metal stent is shaped into a rigid wire mesh and coated with a polymer that contains rapamycin. The coated stents seem to work for as long as they are inserted, because the rapamycin only has to inhibit smooth muscle cell proliferation immediately after insertion. “The uncoated stents restenose, or become blocked, about 30% to 50% of the time. Now that's been reduced to less than 5%. It's revolutionized the treatment of heart disease,” Marks says. “Stent restenosis turned out to be a purely cellular problem, and that's why the treatment of using rapamycin, which inhibits cell-cycle progression in smooth muscle cells, turned out to be so effective. It directly prevented the cause of the restenosis,” he says.

Drug-eluting coronary stents are now used in the majority of American patients with blockages in their arteries. For future stents, the use of other therapeutic agents will be required. “We have an ongoing program to improve the stents, since the current ones don't work quite as well in diabetics. They represent a large percentage of patients with heart disease, so it's important to look for new drugs,” says Marks.

Calcium and Calstabin

Marks's other primary research interest resides in the intracellular calcium release channels of cardiac muscle cells. After a wave of depolarization travels along a stimulated muscle cell, calcium is released from the sarcoplasmic reticulum, where it binds to troponin C, beginning the muscle contraction cycle. Marks cloned the calcium channel responsible for this release in 1989 (5). The homotetrameric channel, also known as the ryanodine receptor, releases bursts of calcium when the muscle cell is depolarized during excitation-contraction coupling. He has studied this channel in depth and found it is intimately involved in heart disease, including heart failure and cardiac arrhythmias (6, 7).

In his PNAS Inaugural Article (1), Marks and his colleagues showed that a specific serine residue, Ser-2808, is the active site for hyperphosphorylation by PKA. Phosphorylation of the calcium channel was found to decrease the binding of the accessory protein calstabin (also known as FKBP12) to the channel, and Marks showed that PKA hyperphosphorylation of the serine residue worsened heart failure after myocardial infarction in mice. “We found that the substitution of an alanine residue for the critical serine residue that gets PKA phosphorylated in the channel results in protection in the mice against development of heart failure after heart attack,” he says.

Marks in the laboratory.

Calstabin and PKA play important roles in regulating the calcium channel's activity. Marks identified calstabin, a small stabilizing protein, in 1989 (5, 8). It binds to the cytoplasmic domain of the channel far from the pore to help the channel maintain its closed state and prevent leaks. “It kind of acts like a spring on a door to keep the channel closed when it needs to be closed,” he says. Calstabin provides protection against arrhythmia and heart failure (9).

“I liked the idea of being able to treat patients who were in dire straits and make them better, right before your eyes.”

Treating Leaks

During normal exercise or when the “fight or flight” response is activated, PKA phosphorylates the ryanodine receptor at Ser-2808, resulting in a leaky channel. “When the channel becomes PKA-phosphorylated, calstabin can't bind as tightly, and the channel's more active, so it releases more calcium, resulting in stronger muscle contraction. This system is part of the normal mechanism that helps you increase cardiac output in order to meet the metabolic demands of organs during exercise,” he explains.

“About 6 years ago, I was studying the regulation of the channel by stress, and I looked at the effects of PKA phosphorylation on the channel and discovered that it increased the activity of the channel by releasing this stabilizing protein,” Marks says (6). “I found that patients with heart failure have chronically PKA-hyperphosphorylated channels that are leaky because they don't bind the stabilizing subunit tightly. The consequence of this is that you have a calcium leak inside your heart, and that weakens the muscle, because the calcium is required for muscle contraction, and that same leak also triggers sudden cardiac death due to abnormal rhythms in the heart,” he says (7). This finding provided Marks with a potential therapeutic target for heart failure, with a known mechanism-based treatment. “The idea I came up with is to bind the calstabin to the channel even when it's PKA-phosphorylated, as a mechanism of stopping this leak without blocking the channel pore, because blocking the channel pore would be lethal,” Marks explains.

Marks and his colleagues identified a small molecule that promotes calstabin binding to the calcium channel (10). Called calcium channel stabilizer, the molecule binds to the calcium channel directly without blocking the channel's pore, and it enhances calstabin binding and prevents leakage. The small molecule has been found to prevent sudden cardiac death and improve heart function in animals. The molecule seems to work in cardiac and skeletal muscle, which Marks says could lead to further applications for other diseases that affect skeletal muscle and for patients with weak skeletal muscles caused by chronic diseases such as kidney failure, heart failure, AIDS, and cancer. The skeletal muscle calcium channel is two-thirds homologous with the cardiac one. Marks has formed a company to try to take this small molecule from the laboratory into clinical trials.

In addition to his prolific research efforts, Marks has been the Editor-in-Chief of the Journal of Clinical Investigation since 2003. Since 1996, the journal has been one of the few publications whose contents are freely available online immediately, and Marks wants to keep it that way. “We're very proud of that,” he says of their open access publication model, which is supported by institutional print subscriptions and author page charges.

Future Channels

Looking to future research endeavors, Marks says, “We're particularly interested in continuing to understand how the ryanodine receptor channel works at a molecular level, and towards that end we're interested in getting a better understanding of the structure of the channel.” Study in the area of skeletal musculature is another goal. “Skeletal muscle fatigue is a problem for millions of patients with chronic diseases, and there's no way currently to improve it. We have some early data suggesting that a leak through the ryanodine receptor channel could contribute to skeletal muscle fatigue,” he says (11).

Furthermore, Marks has been involved in building bridges to international scientific communities, specifically in Israel. Five years ago, he heard that academics in Europe were organizing boycotts of Israeli academics to protest that country's political policies. “I felt that targeting the academic community was a bad way to go about doing it. I don't think we should mix politics and academics. I also didn't feel the academic community was the problem in the Middle East. I thought this was a misguided effort that could potentially be very damaging to Israel, and if it were successful in hurting Israel, it could be used against people or other countries in the future,” he says. As a reaction, Marks founded the International Academic Friends of Israel in 2001, an organization that supports scientific conferences and sessions in the country, mostly by organizing events and subsidizing travel fees for foreign speakers. “We organize about two to five international meetings a year. Israel's a smaller country, and it can have a big effect there,” he says. “I've received a lot of positive feedback so far.”

Having grown up in the hustle and bustle of Manhattan, Marks returned to his hometown of New York City in 1990, with his wife and three children. Now 50, he lives in Larchmont, NY, on Long Island, just east of the city. From Long Island, he has easy access to his laboratory in Manhattan, as well as his sailboat. “I'm very happy here. I love New York, and Columbia's a great place. There's still a lot more research I want to do, and I can't think of any other place I'd rather live,” he says.