How Irv Weissman learned to figure things out
Irving Weissman had an unconventional start in science. The son of a hardware store operator and grandson of a fur trader, he learned lifelong lessons in research at the McLaughlin Research Institute in Montana.
It was 7:15 on a Tuesday evening in early September and Irving Weissman, MD, needed a birthday cake, stat. His daughter, Rachel, was turning 22 the next day. Fresh from fishing the Bitterroot River, clad in khakis and a long-sleeved beige shirt and in stocking feet, he picked up the phone to begin cajoling a local bakery to rustle up a cake big enough to serve several dozen people.
“You’d think no one in this town wants to make any money,” he said, with a wry smile, after being politely rebuffed. Clearly, the rules in Hamilton, Montana, are a bit different than those in Palo Alto, California.
Undaunted, Weissman, 76, the director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine, dashed outside to confer with caterers slow-cooking three large prime rib roasts on the ranch’s patio. Could they make a cake by tomorrow? Inside, several groups of people sat on couches or discussed their research at tables in the corner of the large living room. Normally, the room sports a floor-to-ceiling view of the stunning Como mountain peaks, known locally as the Three Sisters. But that evening they were obscured by thick smoke from surrounding forest fires still raging in parts of the state.
Weissman, who also directs the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford, had invited more than 30 members of his laboratory and the lab of his former student Judith Shizuru, MD, to Montana for an annual scientific retreat at the ranch he co-owns with fellow scientists and longtime friends David Baltimore, PhD, and Leroy Hood, MD, PhD. Earlier that day, attendees had presented their research at the nearby Rocky Mountain Laboratories, where lethal diseases such as Ebola, influenza, plague and the lesser-known Rocky Mountain spotted fever are studied. The next day, they would be given the chance to don the protective gear used by researchers at the biosafety level-4 laboratories for a photo opportunity to commemorate their visit.
The yearly gathering has been a tradition since 1992. But Weissman’s Montana roots go much deeper.
A scientist is born
A native of Great Falls, Montana, about 200 miles northeast of Hamilton, Weissman is the son of a hardware store owner and the grandson of a fur trader who emigrated from Russia in the early 1900s to avoid being drafted by the czar during the First World War.
When Weissman was about 10, a teacher gave him a copy of The Microbe Hunters, by Paul de Kruif, which fascinated him. He recounted the experience a few days before the retreat at a talk celebrating the 60th anniversary of the McLaughlin Research Institute in Great Falls, where he first immersed himself in the pursuit of scientific discovery.
“From that book, I got an idea of what a life in science might be like,” said Weissman. “The microbe hunters were trying to figure out what caused infectious disease. They not only worked out what happened, but immediately applied it to medicine.”
Shepherding scientific discoveries into the clinic would prove to be the touchstone of Weissman’s career. As a high school student, he helped perform experiments that led to the first successful skin and organ transplantations in patients. As a Stanford faculty member, he was the first to identify and isolate human blood-forming stem cells responsible for the immune system, research that laid the foundation for possible new treatments for cancer, blood diseases and organ rejection.
He also helped devise and promote California Proposition 71, which was enacted in 2004, creating the California Institute for Regenerative Medicine to funnel about $3 billion to stem cell researchers in the state after President George W. Bush restricted federal funding to the field.
Along the way, Weissman learned many valuable lessons.
“I’ve found in my career that if you don’t do it, nobody is going to do it because nobody understands the field like you do,” he said. “Pharmaceutical companies make business decisions. If there’s a drug that makes them more money, that’s the one they will pursue. There’s no one out there looking for who will take the advances of medicine to patients.”
Learning how to think
In the early 1950s, Great Falls was the largest city in Montana, with a population around 40,000. It was named for a series of waterfalls on the nearby Missouri River, around which Meriwether Lewis and William Clark portaged in 1805. Low, rolling hills and buttes covered with prairie grasses surround the city, topped by a vast expanse of sky.
In school, Weissman was a good, but not exceptional, student. He struggled with memorization, and didn’t particularly enjoy reading. His mother was a classically trained pianist, and Weissman played the piccolo and flute.
When he was about 15 years old, a friend of his mentioned a man named Ernst Eichwald, MD, who had been recruited in 1953 from the University of Utah to work as a pathologist at Montana Deaconess Hospital in Great Falls. Eichwald had made the move on the condition that he be allowed to spend part of his time as a one-man research program, studying the biology of skin transplantation in laboratory mice.
“Instead of working at the scrapyard for my father’s hardware store, I went to see Ernst, because my friend said it was fun to be around mice and rats,” Weissman said. “But the difficulty was that he was very hard of hearing, and he spoke in a thick German accent. So I couldn’t understand anything that he was saying, and I was pretty sure he couldn’t understand what I was saying. Finally, in a moment of desperation, I said, ‘I’ll work for nothing!’ Suddenly he understood and could talk to me. So I started to work with him in the summer as mouse caretaker, autopsy assistant and lab researcher.”
Weissman continued to work for Eichwald over several summers while he finished high school. During that time, Eichwald carried on his research in mice and chaired the transplantation committee of the National Academy of Sciences. In 1954, he established the Laboratory for Experimental Medicine, which eventually became the McLaughlin Research Institute. He also founded the journal Transplantation. From him, Weissman learned not just the fundamentals of scientific research, but also how to think.
“Luckily, Ernst never asked me what kind of grades I got in high school,” Weissman said. “Because I’ve never been in the top 10 percent of my class. Not in high school, not in college and not in medical school. I’ve been successful because of the research papers I wrote. One thing I learned right away from Ernst is that what people teach you from textbooks has very little to do with science. They’re trying to teach you the fundamentals, like the periodic table, but not the experiences that lead to an understanding of where that information comes from.”
Instead, Eichwald taught Weissman how to puzzle things out for himself. Once Eichwald described the result of an important experiment, but not what the result likely meant to the field of transplantation biology. “I had to guess what was going on, which I did fairly quickly,” Weissman said. “I realized from that moment on that I might not be able to memorize the periodic table or chemistry formulas, but I could think.”
Weissman began to conduct his own experiments in transplantation biology aimed at working out why an adult mouse would reject tissue from a nonmatching donor, but a fetal mouse exposed to blood-forming cells from an adult mouse of a different strain would then accept tissue from that strain of mice for the rest of its life. Work done at that time by Eichwald and Weissman later provided the foundation for organ transplants of all kinds.
As Weissman’s scientific career blossomed, he began to mentor younger students in Eichwald’s lab. As a high school senior in 1956, he was introduced to Leroy Hood — a fellow Montanan who was then attending his first year at Caltech and is now the director of the Institute for Systems Biology in Seattle. Hood remembers Weissman as a confident researcher who was already conducting seminal experiments in transplantation biology.
“I was a little intimidated by Irv,” Hood said. “I hadn’t done anything like that yet at all. From day one it was clear that he was going to be a terrific researcher.”
Weissman attended Dartmouth for a couple of years but then transferred to what is now Montana State University in Bozeman, where he graduated in 1961. By that time, he had already set his sights on Stanford for medical school because it was a five-year medical program that would allow him time for independent research.
At Stanford, he joined the lab of Len Herzenberg, PhD, and Lee Herzenberg, a husband-wife team of geneticists, before going to work at the end of his first year with Henry Kaplan, MD, a professor of radiology. Kaplan gave Weissman his own lab and a research assistant he shared with Saul Rosenberg, MD, then an assistant professor of radiology.
“It was unusual for a medical student to be given such resources,” Rosenberg said. “But I quickly learned that Irv was an extremely bright and experienced researcher. We got to know each other well that year, and I was impressed with his early experience, his dedication and his self-confidence.”
By his junior year, Weissman had recruited other medical students to work with him on researching how the immune system develops to distinguish “self” from “non-self.” In 1964 he spent nearly nine months in the laboratory of immunologist Jim Gowans, at Oxford University, where he showed that immune cells that induce tolerance are born in the thymus and then migrate through the blood to the immune-response lymphoid organs like the bone marrow and lymph nodes.
“Once I knew that the thymus was the place that made T cells, and that I could mark them, I decided I wasn’t going to do an internship and residency, but was going to do research,” Weissman recounted in an oral history done by the American Association of Immunologists in 2013. Kaplan was alone in supporting Weissman’s choice. “Everybody, including Saul Rosenberg, got on my case. They said, ‘You’re never going to be anything if you don’t do your internship.’”
“I felt his decision was a mistake,” Rosenberg recalled. “He was talented enough to do both clinical and research work. But on the other hand he wouldn’t have had the time to dedicate to research that he’s had. He chose his path and that has worked out very well for him.”
They said, ‘You’re never going to be anything if you don’t do your internship.’
The next two decades saw Weissman doggedly identifying where the many cell types in the immune system were made and how they worked. In 1988, he and his colleagues identified a panel of antibodies that could be used to isolate blood-forming stem cells from mice, a feat that had never before been achieved. Three years later, they did the same with human tissue.
The purification of these cells suggested the possibility of regenerating tissues, organs and cells damaged by disease or trauma with a person’s own stem cells, and eventually set the stage for the formation of the California Institute for Regenerative Medicine, a unique research funding mechanism designed to avoid a repeat of a painful research episode Weissman would experience in the 1990s.
A transformative lesson
The traditional path that a promising research finding takes from laboratory to clinic requires the involvement of investors or pharmaceutical companies to finance the expensive clinical trials and commercialization of a new drug or technique. In the late 1980s, Weissman and his colleagues formed a company, SyStemix Inc., to explore the promise of blood-forming stem cells.
At the time, women with advanced metastatic breast cancer were often treated with high-dose chemotherapy in a last-ditch attempt to wipe out tumor cells throughout the body. But this treatment also killed stem cells in the bone marrow, and patients had to be rescued by a transplant of their own stem cells.
Weissman, together with Shizuru and Stanford physicians Karl Blume, MD, and Robert Negrin, MD, realized that the unpurified blood cells traditionally used to reconstitute the immune system often also contained cancer cells. They believed that using purified blood-forming stem cells could avoid disease recurrence, and SyStemix began a clinical trial to test the idea in 1996.
“The idea was that we could use the antibodies identified by Irv to give a patient a tumor-free graft of her own cells,” said Negrin, a professor of medicine at Stanford. “The initial results were remarkable. The women who received about 1 milliliter of purified stem cells recovered as quickly and as well as those who received the traditional treatment of several hundred milliliters of unpurified peripheral blood.”
However, a series of pharmaceutical mergers in the late 1990s left the trial, and the rights to the antibodies necessary to isolate pure blood-forming stem cells, in the hands of the pharmaceutical giant Novartis, which abruptly terminated support of the SyStemix stem cell programs in 2000, after the trial completed enrollment in 1998. The decision was likely due, Weissman believes, to the fact that Novartis was at the time pursuing small-molecule drugs like the anti-cancer medication Gleevec that would give a higher return on their investment than the stem-cell treatment.
“So not only did we not learn the results of the breast cancer trial, we didn’t get to continue our planned studies into whether these blood-forming stem cells would allow us to also induce tolerance for transplanted organs like hearts or kidneys. Because they found other drugs that would make them more money, faster. It was simply a business decision.
“So. That was part of my learning.”
In a 2011 paper, Weissman and Shizuru reported that five of the 15 women at Stanford who received the purified cells were still living compared to just seven of the 74 who received unpurified peripheral blood.
Through the ‘valley of death’
The experience soured Weissman on the involvement of for-profit companies in the translation of research into clinical treatments that could help patients. It also highlighted a phase in medical research known as the "valley of death," which refers to the fraught time between the identification of a promising finding in a laboratory and when it becomes standard clinical practice, during which money, time and resources are often scarce.
“I realized that this was going to happen again and again and again,” Weissman said.
“We were always going to end up taking our research to a certain point and then either venture capitalists or big pharmaceutical companies were going to get it because, unlike universities, they have the funds and the resources necessary to support large clinical trials.”
In 2001, President George W. Bush severely restricted the use of federal funds for human embryonic stem cell research. In response, Weissman and real estate developer Robert Klein, who was associated with the Juvenile Diabetes Research Foundation, worked together to write a proposition to provide $3 billion for stem cell research in California. The proposition passed in 2004.
“We put into that bill, called Proposition 71, that academics could keep doing the research funded by the state agency through the ‘valley of death,' through clinical trials,” Weissman said.
In the 11 years since Proposition 71 was passed, the National Institutes of Health has initiated four clinical trials using stem cells. In contrast, the state stem cell agency has funded, or supported research that has led to, more than 20 clinic trials to study the ability of the cells combat diseases from skin cancer to blindness to spinal cord injury.
Through the years, Weissman always maintained his ties to Montana. In 1991, he, Hood and their mutual friend and colleague, David Baltimore, PhD, bought the ranch near Hamilton. Baltimore is a former president of the California Institute of Technology. In 1975 he shared the Nobel Prize in Physiology or Medicine for learning how tumor viruses interact with the DNA of the host cell. Weissman, Hood and Baltimore share time at the ranch, fishing and talking science.
Or at least Baltimore and Weissman fish. In fact, after science, Weissman appears to prefer to talk about fishing above almost anything else.
All of my research can be viewed as a direct result of the lessons I learned 60 years ago from Ernst Eichwald.
Hood is another story. “Irv thinks I’m some kind of a mutant,” he said. “We’ve spent many Christmases at the house together, and our families have grown quite close. But I’ve never enjoyed fly-fishing. What Irv and I do is we enjoy drinks together — drinks, food and talking about science.”
Late last year, the McLaughlin Research Institute, founded by his old mentor Ernst Eichwald, celebrated its 60th anniversary with a symposium featuring Weissman, one of its most notable alumni.
“There’s a whole list of alumni of the institute who have done really well scientifically,” Hood said, “including five or six like Irv who have made a real impact.” Hood and Baltimore serve with Weissman on the institute’s scientific advisory board.
Weissman doesn’t hesitate to credit the importance of the institute in his early scientific life.
“All of my research can be viewed as a direct result of the lessons I learned 60 years ago from Ernst Eichwald, who let me come into his lab and, instead of telling me what something was, made me think it out for myself; from Jim Gowans, who believed in purifying immune cells to find out what they could do in the body; and from Henry Kaplan, who taught me how to translate discoveries into patient therapies,” Weissman said.
Now, Weissman and institute director George Carlson, PhD, along with Klein, have begun discussing the possibility of introducing a bond initiative like Proposition 71 to Montana, on a smaller scale. “This could be one way for researchers in the state to continue to conduct exceptional scientific research, particularly in the area of neurodegenerative and brain diseases, in the face of decreased federal support,” Carlson said.
Back at the ranch
On that September evening in his low-ceilinged, well-appointed ranch kitchen, Weissman whipped out an electric carving knife, donned a brown “Montana Trout Unlimited” apron and cut thick slabs of perfectly prepared prime rib to serve the colleagues, lab member and friends shooting pool in the large room next to the kitchen, sipping beer from a local brewery on the patio or wandering in damp and laughing after fishing in the ranch’s trout pond.
People discussed their plans for the last, unscheduled days of the Montana trip. There’d be a bluegrass band at the ranch Wednesday. But what to do that weekend?
The buzz of talk subsided briefly as people ate. Then, around a large wooden dining table, Weissman, Shizuru and their lab members went back to doing what they do best: figuring things out. Topics ranged from trouble-shooting experiments and planning future collaborations to how to ensure on the national stage that scientific research remains valued and supported by the public and its leaders.
One thing’s for sure: Weissman’s never shied away from a challenge. What’s more, he feels his unique brand of do-it-yourself problem solving, fostered by Eichwald and Kaplan, applies to all walks of life and every situation.
“Regardless of what career you chose, it’s the people with the common sense to work things out for themselves who will really make a difference in this world,” Weissman said.
Night fell. People trickled out on foot to their various sleeping quarters while the dark water of the river, full of fishy promise, slid by silently at the edge of the lawn. A bat or an owl swooped low overhead, and, due to Weissman’s persistence, someone, somewhere was making plans to bake a last-minute birthday cake.
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