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At the Crossroads of Hematology and Immunology

December 10, 2022


Irving Weissman, MD, has been awarded the 2022 Wallace H. Coulter Award for Lifetime Achievement in Hematology. He is the Virginia and D.K. Ludwig Professor of Clinical Investigation in Cancer Research, and Professor of Developmental Biology at the Stanford Institute for Stem Cell Biology and Regenerative Medicine.

Much like Dr. Coulter, this award’s namesake, Dr. Weissman does not fit the standard template within hematology and cannot be classified as a hematologist, though his contributions to the field are manifold. “I’m not officially a hematologist,” he said, noting his primary work as an immunologist. “All of my work ended up being relevant to hematology,” he stated, which is evident in his vast body of research on cancer stem cell biology, especially pertaining to hematopoiesis, leukemia, and hematopoietic stem cells.

His interest in science was heightened after reading the classic book Microbe Hunters by Paul de Kruif, which was given to him by a teacher. “It was about the lives of the people who discovered microbes — Pasteur, Koch, Ehrlich — all of these famous people. And it was slightly fictionalized, so you get a sense of their lives, and what it took for them to discover microbes.” What really struck Dr. Weissman was that all of the pioneers discussed in the book made a decision to take the knowledge they had gained about microbes and translate it for use in humans, whether as vaccines, sterile techniques, or other breakthroughs that are now common practice. “Before I ever even got into medical school, I thought, ‘you make a discovery, and then you … must try to translate it,’” he said.

Dr. Weissman is recognized for numerous bench-to-bedside breakthroughs, including the isolation of blood-forming stem cells in both mice and humans. This in turn led to the isolation of blood-forming stem cells that were free from cancer cells and that could then be delivered back into patients after chemotherapy. This was tested in a clinical trial of women with metastatic breast cancer in the late 1990s. “The women rescued with the cancer-free blood-forming stem cells, half of them didn’t die until 10 years later,” he recalled. “And today, 25 years later, one-third are alive without disease.”

The ripple effects of these early discoveries and clinical trials would be felt throughout the hematology and oncology communities and forever alter the understanding of stem cells’ role in the development of therapeutics.

As Dr. Weissman’s lab worked on the isolation of human acute myelogenous leukemia (AML) stem cells, a second breakthrough emerged. The group found that those cells were at a more differentiated stage of development. “They didn’t have the CD90 molecule; they did have CD34 [molecule]. So we could separate the stem cells, even from AML, and when we did, we compared the genes expressed by the leukemia stem cells and the normal stem cells and found a new molecule that I hadn’t even heard of called CD47,” he recalled. “[It] was on every leukemia stem cell at high levels, and then I realized that it was a ‘don’t-eat-me’ signal for macrophages.”

He noted that this had been proven in mice previously, but Dr. Weissman’s lab sought to investigate further in a clinical trial combining anti-CD47 — an antibody that blocks the don’t-eat-me signal —along with the noncurative standard-of-care drug azacitidine. In doing so, they showed that azacitidine increased the “eat me” signal on the leukemia cells specifically, and they blocked the don’t-eat-me signal with anti-CD47. He remarked that as a first-line therapy [for] AML in older patients, all responded. “And at the time that I last saw the data,” he said, “it looked like 60 percent were in complete remission for at least a year and a half.”

Dr. Weissman’s work in the stem cell realm was not limited to the laboratory. He had formed a company that was later purchased by a larger firm that ultimately did away with the stem cell program. He became frustrated that he could no longer perform “pure” stem cell transplants. So he, along with Dr. Robert Klein, wrote The California Stem Cell Research and Cures Act, also known as Proposition 71. The initiative appeared on California’s 2004 election ballot and would allocate $3 billion of state funds for stem cell research over 10 years. The measure would also mean that the state of California’s stem cell agency could fund research through phase I, or even perhaps phase II clinical trials at academic institutions. “So you didn’t have to form a company and lose the decision-making too early,” said Dr. Weissman. “And it passed.”

While proud of his many accomplishments, Dr. Weissman also wanted to acknowledge the impact of his many mentors over the years. In 1956, he sought out Dr. Ernst Eichwald and asked the pathologist if he could work in his lab in Great Falls, Montana. He worked with Dr. Eichwald in the summer during his college years, as well as Dr. Leroy Hood. During that time, he was urged by his mentor to follow his own “nose,” and when he was at Stanford, he worked with Dr. Henry Kaplan, who gave Dr. Weissman his own lab and technician where he could start exploring some of those questions. “I got to ‘follow my nose’ again,” he said.

Stanford’s medical school program allowed for a great deal of research time and flexibility to pursue specific interests. This took Dr. Weissman to Oxford, where he worked with the renowned immunologist Sir James Gowans and demonstrated the movement of immune cells from the thymus to immune-response lymphoid organs.

After the Oxford experience Dr. Weissman broke ranks and opted not to pursue an internship, and instead continue his own research. With the support of his mentor Dr. Kaplan, he was able to continue working at his lab at Stanford, and ultimately, that risk paid off when he went on to get tenure. He is grateful for the mentors in his life who did not “micromanage” him in their labs and taught him to trust and pursue his own way of solving problems. “How you train people is very important,” he said. “You say, ‘Devise an experiment to answer the question you’re at. Let me know what it is.’” Dr. Weissman carries this philosophy through to his own mentees, who are encouraged to build their methodologies in the lab and to seek answers with independence and the utmost confidence.

Dr. Weissman will accept the 2022 Wallace H. Coulter Award on Sunday, December 11, at 1:30 p.m. Central time at the Ernest N. Morial Convention Center in Hall E.

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