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Promise and Progress - Capturing The Stem Cell

A Cancer Revolution

Capturing The Stem Cell

Date: December 1, 2004

They are the key to life, our blood cells—red ones, white ones, immune cells, and platelets—manufactured deep within our bones, coursing through our 60,000 miles of arteries and veins to nourish, heal, and protect us. Our blood is constantly changing, constantly renewing itself, churning out some 260 billion cells a day. Lost among this river of cells is the origin of this ongoing cycle, and what could be the key to curing certain cancers, the blood stem cell. Lost until Curt Civin figured out how to pull it out of hiding.

It seemed like a workable enough theory. The problem was that while most every expert believed in the therapeutic potential of the hematopoietic stem cell, the cell that controls the type and number of all blood cells, how to retrieve the cell from within human bone marrow remained a mystery and a quest most in the field had given up on. Curt Civin, however, was not so easily dissuaded. “Only about one percent or one out of every 10,000 human bone marrow cells are stem cells. Finding one is like looking for the proverbial needle in a haystack,” says Civin. For him, an expert in leukemia, which is a disease caused by stem cells gone awry, the elusiveness of the stem cell was particularly haunting. “Here was a very rare cell which produced all the blood and immune cells, and we couldn’t get our hands on it for biochemical or genetic studies,” he says.

Despite the odds, it became his life’s work, the focus of more than two decade’s worth of research. Because most scientists considered the problem too difficult to tackle, funding was hard to come by and a working body of knowledge had not yet been developed. Civin would have to blaze his own trail.

In the early 1980s, he was following the work of other researchers who had used cellular red flags known as monoclonal antibodies to filter out proteins, carbohydrates, lipids, and even some mature blood cells. If these blood cells could be separated using monoclonal antibodies, why not stem cells, Civin wondered. The trouble was that the stem cell antibody was likely going to be as difficult to nail down as the stem cell itself.

This is where his knowledge of leukemia cells would come in handy. The critical difference between the cell types is that the stem cell ultimately develops into a functioning mature blood cell while the leukemia cell just keeps copying itself. “A leukemia cell is like a stem cell that gets frozen or stuck in an early stage of development,” he says. The only sure thing Civin knew about the stem cell was that it was rare, so his first step was to throw away all of the antibodies that bound to a lot of marrow cells.

Civin and his colleagues created a variety of monoclonal antibodies and spent month after month testing them in test tube models for their ability to pick stem cells out of normal bone marrow. His breakthrough came in 1984, when his laboratory identified a monoclonal antibody that recognized only about one percent of the cells in the bone marrow. The numbers seemed right—stem cells make up about one percent of the bone marrow—but he would still have to prove it. His antibody was CD34—a literal stem cell magnet.

The definitive test for his antibody would be a bone marrow transplant. The cells captured with CD34 would have to form blood after a lethal dose of radiation, and they did. Animals given the purified CD34 cells produced all types of blood and immune cells and they survived, while the ones given non-CD34 cells did not and died.

Next in line for CD34 transplants were several extremely ill patients whose only hope of survival would come from an experimental therapy. These transplants began a revolution in bone marrow transplants, reducing patients’ risk of an immune system rejection complication called graft versus host disease.

His CD34 discovery would also provide the solution to the double-edged sword of cancer therapy—maximizing the killing effects of anticancer drugs without jeopardizing the patient. Many times, doctors are forced to stop therapy or lower doses in a “cat and mouse” game that gives patients a chance to recover and avoid potentially fatal complications, but during this break the cancer may keep growing. Civin’s way around this was to use CD34 to grab only the patients’ stem cells from their bone marrow before therapy, then give back their stem cells to rejuvenate the blood cells lost to therapy.

Civin’s CD34 approach quickly garnered the attention of the biotechnology world. Other uses for CD34 stem cells had large scale potential and mass production of this stem cell magnet would soon follow. The use of CD34 was approved by the Food and Drug Administration in 1996, and since then, thousands of patients have been treated worldwide using Civin’s technologies. His discoveries have earned him nine U.S. patents for biomedical inventions related to stem cell research and, in 1999, the Intellectual Property Owners Association Inventor of the Year Award.

After years of painstaking research on what he considers the most interesting cell in the bone marrow, it is elusive no more. Everyone knew the stem cell was real, but for more than two decades no one could get their hands on it. CD34 cells have now been studied extensively in over 10,000 research articles. CD34 antibodies are used diagnostically to identify and count stem and leukemia cells in patients’ blood and bone marrow samples as well as therapeutically in stem cell transplants. So, now, as a result of Civin’s work, it is an icon of cancer therapy.