Mutual Admiration, Mutual Inspiration

Summary

Marina Ramirez-Alvarado's job requires her to think small. Tim Stepanek has helped her see the big picture, too.

Tim Stepanek

"I think the important thing for me and for them [researchers] was to connect it with a patient. They work very, very hard — way over 40 hours a week. They don't often get the benefit of connecting the practical aspects of what they're doing with the reality of patients' lives. That's the exciting thing."

— Tim Stepanek

Marina Ramirez-Alvarado, Ph.D.

"Amyloidosis is rare, it's devastating and it presents complicated questions," she says. "As scientists, these are the kinds of things that attract us, because we can dig in."

— Marina Ramirez-Alvarado, Ph.D.

Tim Stepanek passed away in January 2006 after a long and heroic battle with amyloidosis and multiple myeloma. His family hopes that Tim's story will inspire others help support research to find new ways to diagnose, treat and prevent amyloidosis.

Together, they have formed an unusual partnership dedicated to finding a cure for a rare disease known as light-chain amyloidosis. For her part, Ramirez-Alvarado spends her days in a Mayo Clinic lab probing the molecular mysteries of the disease. That's the thinking small part. In Stepanek, she has a 6-foot-tall tangible reminder of the ultimate goal of her research: to one day help patients with amyloidosis.

Stepanek, meanwhile, has thrown himself into learning all about her work — and inventively supporting it — since he was diagnosed with amyloidosis in March 2003. That effort includes making a personal contribution to help fund research in Ramirez-Alvarado's lab, as well as organizing a kayaking event last fall that netted about $80,000 to bolster research. Stepanek also is interested in bringing together some of his contacts in the biotechnology sector with Mayo researchers to determine if they can collaborate in the long, arduous search for drug therapies to combat the disease. He also meets regularly with Ramirez-Alvarado to get updates on her research.

"Tim has been an inspiration to me in so many ways," says Ramirez-Alvarado, a molecular biochemist and director of Mayo Clinic's Protein Misfolding Lab. "He touches me so much sometimes he brings tears to my eyes. His enthusiasm and his passion just humanize my work in an incredible way. It has brought me more into the real world."

Stepanek also has multiple myeloma, a cancer of the bone marrow. Despite this "double-whammy," as he calls it, he remains energetic and optimistic about his future. After he was diagnosed with light-chain amyloidosis, Stepanek learned that there was a shortage of funding for amyloidosis research. Unlike Alzheimer's disease, a related illness, light-chain amyloidosis is a low-profile illness. It occurs in eight persons in a million annually, and there is no foundation dedicated to funding research.

"I said, 'I've got to raise some money, for my own sake, as well as for anyone else who might benefit," remembers Stepanek, who is 54. "I've got four kids, including a 12-year-old, and I plan to be around a while. So we've got to find some therapies."

Stepanek was diagnosed with multiple myeloma, in October 2001. He soon began seeing Dr. Martha Q. Lacy, a Mayo Clinic hematologist, for treatment, in part because it would give him access to clinical trials using new treatments. It was Dr. Lacy, also an international expert on amyloidosis, who determined that Stepanek had that disease in March 2003. Stepanek soon learned that Mayo Clinic treats well over 100 light-chain amyloidosis patients per year, and is one of the few institutions doing cutting-edge research on the disease. He decided to send a donation to back Mayo's research effort. That led to a call from Barbara Flasch in the Mayo Development Department. She wanted to know if Stepanek would like to meet the researchers whose work he was supporting. Both sides made quite an impression on each other in that one-hour meeting in the fall of 2003.

"The first time I met him, his commitment amazed me," says Ramirez-Alvarado. "He is realistic. He may die. But he wants to do something that may help someone else. That's huge. It's given him a reason to fight. He found an incredible way to concentrate his energy, and he's doing a lot for himself and for the field."

Stepanek, meanwhile, was struck by the personal warmth of the researchers. In his work as a venture capitalist, he has extensive experience with scientists. "They tend to be impersonal," he says. "That's just the way they are. The people at Mayo, not only are they at the top of their class in terms of their brilliance, but they're nice people and fun people to be with. That carries through the organization."

During that first meeting, Stepanek bombarded researchers with questions about the disease and what they were doing to unravel its causes. He doesn't pretend to grasp all the science.

"It was Greek," Stepanek says. "I think the important thing for me and for them was to connect it with a patient. They work very, very hard — way over 40 hours a week. They don't often get the benefit of connecting the practical aspects of what they're doing with the reality of patients' lives. That's the exciting thing."

Stepanek left the meeting energized. He wanted to do something more. He came up with the idea of a kayaking event to raise more money for amyloidosis research. It made sense for someone who has long enjoyed active sports and continues kayaking, bicycling, cross-country skiing, swimming and hiking in the face of illness. The Mad Dog Marathon (named for Mayo's Myeloma, Amyloidosis and Disproteinemia Disease Oriented Group) was held in November on Minnesota's Lake Minnetonka, near Stepanek's home. Ramirez-Alvarado was among the participants, who paddled for three hours on the chilly water. Plans are under way for another Mad Dog Marathon this year, and Stepanek's idea has spread to Wyoming and Colorado, where other Mayo Clinic amyloidosis patients are putting together similar events. Stepanek, it seems, has a knack for inspiring people.

Those who know Tim Stepanek are not surprised at the way he has immersed himself in the amyloidosis cause. "There was no dwelling on, 'I can't believe this has happened to me? This is not fair,' " says his daughter Anna. "I'm sure those things go through his mind, but that's not where his focus is. His focus is on doing something about it." Stepanek has enjoyed many personal and professional successes in his life. He and his wife Cathy have been married 33 years and have four children, David, Mark, Anna and Claire. All remain close. Stepanek has forged a good career in the world of finance. And he has always pursued a healthy, active lifestyle. Perhaps the best example of the latter is a cross-country bicycle trek Stepanek undertook with his brother Steve. From 1992 to 1996, the pair covered 3,310 miles in 11 trips. They started in Anacortes, Washington, and ended in Kittery, Maine. They would do one leg, return home, and then resume their cycling from the point where they left off. It took 44 days of cycling, averaging 75 miles a day. One day, they pedaled 214 miles across North Dakota, almost two-thirds of the state. "There was a tailwind," Stepanek says. Stepanek also has competed in the American Birkebeiner cross-country ski marathon, which covers 51 kilometers between Cable and Hayward, Wisconsin.

Now, Tim Stepanek finds himself in another race: to find a cure for amyloidosis. He's running as hard as he can, and he takes comfort in knowing that Ramirez-Alvarado is right beside him. The two clearly are more than a researcher and a patient who share a deep interest in a disease. They have become friends. That much was clear when Stepanek visited Ramirez-Alvarado's lab in June. They shared broad smiles and big hugs as they greeted each other.

"Tim opened my eyes in a huge way," says Ramirez-Alvarado. "I'm very thankful to Tim because of that." Stepanek has put a face on the disease for Ramirez-Alvarado and her lab colleagues. All the work they do is aimed at eventually helping patients like Tim Stepanek.

Marina Ramirez-Alvarado has long been fascinated by the study of proteins, which perform several critical functions in the human body. "I fell in love with proteins when I was an undergraduate," she says, "and they just keep amazing me." She received her Ph.D. from Heidelberg University in Germany in protein folding and protein design. Since arriving at Mayo Clinic in 2002, Ramirez-Alvarado's interest in proteins — at one time almost purely intellectual — has taken a more practical cast. Finding out for the sake of finding out has yielded to a new desire to find real treatments for real people. Amyloidosis has its roots in a misfiring of the body's immune-system machinery. The bone marrow, which produces antibodies designed to fight off infection and disease, instead creates a cluster of cells that produce faulty antibodies, known as monoclonal immunoglobulin light chains. These light chains accumulate as amyloid fibrils in organs. Ramirez-Alvarado likens the proteins that form antibodies to a strand of spaghetti. In order to function correctly, they must twist and fold and coil themselves into a certain configuration. There are many shapes that work, but each protein must find the right one. If the protein misfolds, the flawed antibodies cannot be broken down by the body. The amyloids accumulate, first in the bloodstream and eventually in the heart, kidneys, nerves, blood vessels, liver and spleen. Over time, this buildup causes these organs to cease functioning. Ramirez-Alvarado and her colleagues are trying to determine what occurs on a molecular level that causes the proteins to take the wrong shapes.

In order to do that, Ramirez-Alvarado and her colleagues are studying protein-folding kinetics, when the proteins find the proper shape, and the pathways of protein misfolding, when the proteins do not find the correct shape. The work begins with getting samples of proteins donated by patients with light-chain amyloidosis. The proteins are subjected to various inputs, such as changes in pH levels through the use of sodium chloride (salt) and sodium sulfate and variations in temperature, to determine the role of those variables in the folding process. A machine called a circular dichroism spectrometer uses a beam of light that is deviated to reveal the shape of the protein.

Of particular interest to Ramirez-Alvarado is the relationship between protein folding and disease aggressiveness. Some patients with light-chain amyloidosis live six months after diagnosis; some survive 10 years. Understanding the mechanisms of amyloid formation will enable researchers to predict the behavior of other amyloid diseases, and ultimately, Ramirez-Alvarado believes, to finding cures.

"Amyloidosis is rare, it's devastating and it presents complicated questions," she says. "As scientists, these are the kinds of things that attract us, because we can dig in."

Meanwhile, Tim Stepanek says his treatments seem to be keeping his twin afflictions in check. He had a stem-cell transplant at Mayo Clinic in May 2003 to treat his multiple myeloma, and his physicians believe that may also help to hamper the "amyloid factory" in his bone marrow.

"Getting good care allows my attitude to be good in that I don't second-guess anything that might be happening," Stepanek says. "I don't feel there is anything else I could be doing or should be doing, so there's no point in worrying about it. The care at Mayo is second-to-none and the attitude of everyone I have dealt with — secretaries, nurses, doctors — is terrific."