Biography of Barry S. Coller

Each year, more than 1.2 million Americans suffer a heart attack, and approximately 700,000 suffer a stroke. Both conditions currently rank in the top three leading causes of death in the United States. Three decades ago, researchers knew little about the role of platelets and their interactions with other proteins in contributing to these adverse health events. However, since the mid-1970s, physician and investigator Barry S. Coller has made great contributions toward understanding the mechanisms behind platelet aggregation and the receptors and ligands involved. Over the course of his career, Coller and his colleagues have contributed to elucidating the receptors for fibrinogen (αIIbβ3; GPIIb/IIIa) and von Willebrand factor (GPIb) (1, 2), which are crucial to the clotting process. Based on these findings, his team developed monoclonal antibodies that bind to these receptors, inhibiting platelet aggregation (3, 4) and thus slowing or stopping the cascade of events that leads to heart attack and stroke. The drug abciximab, developed from one of these antibodies (7E3), has been used to treat more than 2 million patients since its Food and Drug Administration (FDA) approval in 1994.

Currently serving as the physician-in-chief of The Rockefeller University Hospital and head of the Laboratory of Blood and Vascular Biology at The Rockefeller University in New York, Coller has earned numerous accolades for his body of work. He was elected in 1999 to the Institute of Medicine and in 2003 to the National Academy of Sciences. In his Inaugural Article (5), published in this issue of PNAS, Coller and his colleagues detail 7E3's binding site on the αIIbβ3 receptor. The findings not only contribute to elucidating the antibody's binding mechanism but also may help explain some unusual binding kinetics that Coller described in 7E3 almost 20 years ago. The results also provide new insights into the mechanism by which αIIbβ3 changes conformation with activation.

Armed with Enthusiasm

Coller spent his childhood in Queens, NY, surrounded by lawyers and physicians: his father and older brother were both attorneys, and his mother had attended law school, though she chose not to become a practicing lawyer. One of his uncles was a distinguished surgeon and scholar of medical history, and his future father-in-law was a pioneer in the field of allergic diseases. With interests in both law and medicine, Coller eventually settled on a pre-med major with concentrations in government and Asian studies during his undergraduate years at Columbia College in New York to distinguish himself from his immediate family members. “I thought that I'd be more on my own by choosing medicine, and that appealed to me,” he said.

Figure 1.

Barry S. Coller

After graduating magna cum laude from Columbia in 1966, Coller headed straight to medical school at New York University (NYU in New York City), a choice that kept him close to his family. As he became steeped in classes, and later rotations, he felt deeply attracted to the humanistic aspects of medicine. But as his medical training advanced, Coller became curious about a career in research. “I loved patients, and I loved dealing with and trying to help people,” he said. “But I also started to have a sense of the power of science to help a larger number of people.”

His interest in research came to a head during his fourth year at NYU while doing a neurology rotation. One of his patients, an older man with an artificial heart valve, had suffered a stroke. The patient was being treated with warfarin, an anticoagulant that had long been in use, but in searching the literature, Coller came across an article in the New England Journal of Medicine that suggested that adding dipryridamole, a comparably new drug, would reduce the patient's chances of having another stroke (6). Coller was curious about how dipryridamole affected platelets. Seeking an answer to his platelet question, he sent a letter to the article's senior author, Dr. Richard Gorlin at Harvard University (Boston). “He sent me back a very thoughtful letter saying, `You know, the real problem is that we don't understand that much about platelets,”' said Coller.

Seeing a pressing need for platelet research, Coller paid a visit to Marjorie Zucker, a world-famous platelet expert at NYU. “Really armed with nothing other than enthusiasm, she agreed to let me come into her lab and start to do some work,” he said. For the next 4 months, under Zucker's direction, he focused on studying the platelet retention test, an assay that examines the percentage of platelets that sticks to a column of glass beads when blood is passed through the column. Different diseases can influence the number of platelets that remain in the column, making the test a potentially useful diagnostic tool. However, noted Coller, “The test was a misery to standardize.” Coller eventually discovered that even minor variations in how the blood was handled dramatically changed the results of the test. Allowing the blood to sit undisturbed for a period of time improved the reproducibility and was a key to standardizing the test. These findings formed the basis of Coller's first research article, published with Zucker in 1971 (7).

Monoclonal Miracle

After Coller graduated from medical school in 1970, he began an internship and subsequent residency at Bellevue Hospital in New York City. He spent the next 2 years increasing his knowledge of internal medicine through interactions with patients, but, consequently, he had no time to continue research. Seeking an avenue to see patients while following his research interests, Coller applied for a competitive position as a clinical associate in the hematology division of the National Institutes of Health (NIH)'s clinical pathology department (Bethesda, MD). The position would not only give Coller more freedom to pursue platelet research but also, as an added benefit, it would fulfill his military obligations as a commissioned officer in the Public Health Service. His application was accepted, and in 1972, he began work in the laboratory of Harvey Gralnick, a scientist and medical doctor known for his blood coagulation research.

Coller's work in Gralnick's laboratory was a true mix of research and patient care. About half of each week, Coller did clinical hematology, such as performing bone marrow examinations, interpreting blood smears, and consulting with patients and other physicians. He and his colleagues spent the remainder of their time studying the biochemistry and function of von Willebrand factor, a protein found in plasma and platelets. The factor helps platelets stick to damaged blood vessels, which is crucial to stop bleeding, but also instigates heart attacks and strokes. In one of the group's most pivotal findings, they characterized the biochemical abnormalities in von Willebrand factor in patients with von Willebrand disease, which is characterized by abnormal bleeding and bruising (8–11).

Although Coller was obligated to spend only 2 years at the NIH position, he ended up staying for 4, publishing more than 20 articles with his fellow laboratory members. During those years, he maintained a connection to the academic world by teaching medical students at Georgetown University in Washington, DC, on the weekends. When the time came for him to leave Gralnick's laboratory and search for a job, he settled on a teaching and research position at Stony Brook Medical School, a newly built part of the State University of New York in Stony Brook. Coller was recruited to the position by Yale Nemerson, a coagulation expert from Yale University (New Haven, CT) who had noticed his previous work at NIH. “[Nemerson] brought his outstanding group with him there from Yale, and so even though it was a new school, I thought that I'd have a critical mass of colleagues,” he said.

Seeking to move into a new, but related, field, Coller decided to shift his research away from an exclusive focus on von Willebrand factor to study fibrinogen, a plasma protein that both participates in platelet aggregation and forms the basis of clots. Both fibrinogen and von Willebrand factor interact with platelets to stop bleeding, but the two proteins also can mediate the process that shuts down blood vessels during a stroke or heart attack. Coller and his colleagues began studying the biochemistry of fibrinogen, as well as the biochemistry of the two proteins' newly described receptors. Progress for Coller was slow in the beginning, but during lunch one day, Coller learned about a new technique that would change the focus of his career: “Somebody told me about monoclonal antibodies. I knew immediately what I wanted to do.” Fortunately, new faculty member Arnold Levine had set up a core monoclonal facility at Stony Brook and gave Coller free access.

Coller developed a miniaturized functional assay to screen hundreds of different antibodies in search of one that could block the fibrinogen receptor on platelets. He and his colleagues put fibrinogen on beads and then mixed the beads with a combination of platelets and the antibody to be tested. Normally, platelets clung to the beads, agglutinating them into a clump. Coller reasoned that if an antibody blocked the receptor, then it would prevent the platelets from sticking to the beads and prevent agglutination. In fact, the researchers found several such antibodies, and his group published their findings in 1983 (3). In the same year, Coller published a article with results from a similar assay using von Willebrand factor (4), making Coller's team one of the first to block platelet binding of both fibrinogen and von Willebrand factor with antibodies.

“Somebody told me about monoclonal antibodies. I knew immediately what I wanted to do.”

Coller's findings were more than just an interesting piece of basic science; they had immediate implications for identifying and studying an array of clotting disorders in humans. “I was looking for ways to help people with these [antibodies], so I was really eager to apply them to anything I could,” he said.

Drug Development

Equipped with these newly discovered antibodies, Coller's laboratory developed screens to identify patients with the rare disorder Glanzmann thrombasthenia in which genetic abnormalities affect the fibrinogen receptor (12) and can cause lifelong bruising and intermittent episodes of uncontrolled bleeding. The group also developed tests for prenatal diagnosis of Glanzmann thrombasthenia (13), as well as an assay to determine blood levels of a fragment of the von Willebrand factor receptor, an indicator of platelet survival (14, 15).

In the mid-1980s, Coller began to focus on determining the role that the fibrinogen receptor played in animal models of heart attacks and strokes, as well as whether any of his antibodies could be formulated into an effective human therapy or prevention method. To answer these questions, he and his laboratory members searched through antibodies developed for their previous experiments for one that worked on dogs as well as humans; such a quality would be ideal for testing potential drugs in an animal model. The researchers found their answer in the 7E3 antibody (16). After conducting the first animal experiments at Stony Brook (17), he worked with colleagues at the University of Wisconsin (Madison) and Massachusetts General Hospital (Boston) in two different dog models of human heart disease, one that mimicked an impending heart attack and another in which a heart attack was artificially prompted. By comparing it to aspirin and other conventional therapies, the researchers searched for signs that the antibody helped to prevent the closure of blood vessels, reopened closed blood vessels, and/or prevented the reocclusion of blood vessels after they were opened. “In both models, the antibody was more powerful than anything investigators previously tested, so that encouraged us to consider going forward,” he said.

The results from his initial experiments (18–20) were so promising that, in 1986, the Research Foundation of the State University of New York licensed 7E3 to a start-up biotechnology company called Centocor for drug development. Coller was immediately met by skepticism, however, by many in the field. “I knew that we had something that was more powerful in inhibiting platelets than anything before, but whether or not that would actually translate into helping people was far from certain. Most people thought we were nuts and that [7E3] wouldn't do anything,” he said. “But at that point, it was clear that we really needed the kind of expertise and resources that you could only get in industry.”

For the next several years, Coller continued to test 7E3 in animal models, working to establish proper dosages (21). Eventually he assisted Centocor in taking the antibody to clinical trials (22). In 1994, shortly after he left Stony Brook to become chairman of the Department of Medicine at Mount Sinai School of Medicine (New York), the FDA approved abciximab, a drug based on the antibody. “It felt great when the drug was approved, but it was a very long and very exhausting process,” said Coller. “There were many points along the way where it looked like we probably were not ever going to get over the finish line, so by the end, it was sort of exhausting and anticlimactic.”

According to Coller, more than 2 million people have been given abciximab since 1994 as a preventive or therapeutic agent for heart attacks. Several small studies have suggested that abciximab may help patients suffering an acute thrombotic stroke, and a large clinical trial is currently ongoing to test this hypothesis definitively. Coller also has tried to improve the safety and efficacy of abciximab by designing an automated assay that can be performed at the patient's bedside to insure that the patient is getting the proper dose (23, 24). In fact, the assay is based on the original fibrinogen-coated bead assay used by Coller to identify the 7E3 antibody. This assay was licensed to another biotech company, Accumetrics, and Coller has helped the scientists at Accumetrics convert the assay into a fully automated system.

Never Complacent

Since his move to become physician-in-chief of Rockefeller University Hospital and head of the Laboratory of Blood and Vascular Biology in 2001, Coller has continued to study the 7E3 antibody. He and his colleagues have remained focused on understanding the 7E3's biochemical interactions with fibrinogen receptors. In his Inaugural Article (5), published on page 13114 Coller's team studied which regions on integrin β3, one of the two surface proteins that make up the αIIbβ3 fibrinogen receptor, control 7E3 binding. The researchers transfected cells with human cDNA variants expressing fibrinogen receptors, each with amino acid substitutions in areas thought to affect 7E3 binding capability.

By allowing the antibody to interact with receptors on these cells, the researchers, building on studies from Yoshikazu Takada's group at The Scripps Clinic (La Jolla, CA) (25), found that the region between C177–C184 and W129 was necessary for 7E3 binding. Although these regions are not close in the linear sequence of β3, the crystal structure of αVβ3 solved by Amin Arnaout's group at Massachusetts General Hospital (26, 27) demonstrated that these regions are not only close to each other but also are very close to the site where fibrinogen binds. Almost 20 years ago, Coller demonstrated that 7E3 binds more slowly to unactivated platelets than to activated platelets but that small binding fragments of 7E3 did not show this effect (16, 28). Although mysterious at the time, these data now furnish support for the hypothesis put forth by Timothy Springer's group at Harvard Medical School (Boston) (29) that integrin receptors convert from a bent to an extended conformation when activated. “Thus, 7E3 has provided fundamental knowledge about the dynamics of integrin protein structure in addition to contributing to the diagnosis and therapy of disease. Not bad for a single antibody,” noted Coller.

Although he and his colleagues have made immense strides in understanding 7E3 and its interactions with the fibrinogen receptor, Coller still is looking for new applications for his antibodies and has embarked on studies using high-throughput robotic screening of chemical libraries to look for new therapeutic agents. Coller plans to continue to study possible adhesion receptor targets to treat sickle cell anemia, a project his laboratory has been involved with for the past 3 years (30, 31). Because one of his projects to produce “artificial platelets” became stymied as a result of difficulties in achieving the same rheologic properties as human platelets, Coller is considering a human stem cell project that would someday create genetically personalized platelets for individuals through therapeutic cloning. “We still have a lot of dreams here,” he said. “Harnessing the power of the scientific method to alleviate suffering from disease is one of humankind's proudest achievements, and I feel very privileged to participate in that great cause.”