Fred Hutch News Service file
Dr. Harold Weintraub, known to everyone as Hal, wanted to know.
He wanted to know what makes a muscle cell a muscle, a nerve cell a nerve. The answers he uncovered opened the doors to stem cell research and made possible Fred Hutchinson Cancer Research Center’s developments in cord blood transplantation that now cure many people living with blood cancers.
He wanted to know what happens when genes are activated in the cell. The answer he and his colleagues found spawned the modern field of epigenetics.
He wanted to know why a certain experiment in his lab didn’t work the way it should have. The solution led to the discovery of a completely new class of molecular regulation.
And when Weintraub was diagnosed with brain cancer in 1994, he wanted to know what was growing, unseen, inside his head. Trying to solve that problem brought together the most brilliant minds of the time working on his form of cancer, the aggressive and usually deadly glioblastoma.
Twenty years after his death at the age of 49, his friends, family and colleagues remember Weintraub — and gather today at the Weintraub Graduate Student Award symposium established in his honor. The biologist who made incredible discovery after incredible discovery. The faculty member who laid the groundwork for other scientists to flex their creative muscles. The mentor who selflessly nurtured many young trainees. The father who taught his sons to never stop asking why. The cherished friend.
Dr. Stephen Tapscott remembers his former mentor best for how he approached failure. Weintraub not only wasn’t afraid to fail, he embraced those moments, saying that was when he could best understand the unknown.
Weintraub reminded him of Picasso, Tapscott said. The artist was known for making “found art,” incorporating pieces of refuse into his creations or building entire sculptures from found objects. So too, Weintraub the scientist crafted many beautiful and new ideas out of what others saw only as scientific detritus.
Tapscott saw this firsthand as a postdoctoral fellow in the Weintraub Laboratory, where he and Weintraub worked together to uncover how a single protein, MyoD, can drive muscle cell development. Today, Tapscott leads a laboratory team at Fred Hutch that builds on that legacy — Tapscott’s group has made seminal discoveries about MyoD’s role in normal cell development and muscle-related diseases, including muscular dystrophies and rhabdomysarcomas (tumors of the muscles).
Tapscott remembers that some of his favorite conversations with Weintraub started when Tapscott’s experiments had bombed — or so he thought.
“He’d pick up the pieces and put them together in a way that I hadn’t appreciated and make an insightful story out of what I thought was just failed work,” Tapscott said. “And then he’d hand it back to me and say, ‘That was a good idea. You did good with that one.’”
Many scientists conduct experiments to support their ideas, devising a hypothesis, carefully planning tests of that idea, and ultimately perhaps abandoning the line of work if the hypothesis is not supported. But when things didn’t work the way they were supposed to, that’s when Weintraub really dug in.
In the course of a series of experiments in his laboratory using specific pieces of RNA to generate genetic mutations in frog embryos (an invaluable research technique now known as RNA interference, which Weintraub helped pioneer), he and then-postdoctoral-fellow Dr. Brenda Bass were puzzled when their first attempts were completely unsuccessful. The RNA they injected into the embryos seemed to have mysteriously disappeared.
Weintraub and Bass wanted to find out why, Tapscott said. In the process they uncovered a completely new class of proteins that act in embryonic development to alter the very sequence of certain RNAs, making them seemingly disappear. That discovery itself launched a new field of exploration, one that Bass has carried on.
It’s an approach to research that’s not widely enough practiced, Tapscott said. It requires hefty doses of bravado and naiveté, along with a willingness to freely admit when you’re wrong. But there’s incredible value in Weintraub’s brand of science, he said, of “trying to understand where the difference is between your perception of reality and what reality is.”
Those fearless explorations paid off for Weintraub and the scientists he worked with. He made several key insights on a range of research questions during the only slightly more than 20 years that he led his own laboratory team.
Weintraub’s work on MyoD that Tapscott now carries on was influential not just for those studying muscle development and diseases, but for many in basic and medical research. Through their discovery of MyoD, Weintraub and Dr. Andrew Lassar, a postdoctoral fellow in Weintraub’s group at the time, were the first to show that they could convert one type of cell into another just by changing the activity of a few genes. Those experiments were built on later by others with the Nobel Prize-winning discovery that mature cells can be similarly changed into immature stem cells that contain a multitude of developmental potentials.
Those molecular manipulations have had huge ramifications for medicine, many of which are still unfolding. One ripple of Weintraub’s discoveries was a breakthrough by Fred Hutch transplant biologists Drs. Colleen Delaney and Irv Bernstein, when they found they could use similar approaches to get stem cells taken from human umbilical cord blood to multiply in the laboratory. That finding catapulted cord blood transplantation from a promising idea to a lifesaving reality for many patients with leukemia, lymphoma and other diseases.
All that started with a conversation between Weintraub and Bernstein in which Weintraub suggested the clinical researchers could try triggering blood stem cells to divide with the same gene, called Notch, with which he’d been experimenting on muscle cells.
“That you could take information that was derived from a muscle cell in a petri dish, to then have the idea that this could actually help someone with a leukemia, was a big leap,” Tapscott said in an earlier interview. “But it was the sort of leap that Hal was known for.”
By extension, that was the kind of leap the Hutch became known for, said Fred Hutch cell biologist Dr. Daniel Gottschling, who carried out his postdoctoral research next door to Weintraub’s lab at the Hutch in the mid-1980s. Gottschling now leads his own research team in Weintraub’s old office and laboratory, which is intermingled with the lab of Weintraub’s longtime friend and colleague, Fred Hutch Executive Vice President and Deputy Director Dr. Mark Groudine, in the research building at the Hutch that now bears Weintraub’s name.
“A lot of [scientists], especially now, are very cautious,” Gottschling said. “And Hal never did that, and he never wanted anyone around here to do that either. The duty of being a basic scientist is to figure out hard things.”
The diversity of projects in Weintraub’s lab was breathtaking, Gottschling said. Within the general purview of molecular biology, Weintraub studied and oversaw research working with yeast, worms, frogs, chickens, cells in petri dishes, and normal and mutant mice to try and answer basic questions ranging from the structure of DNA to how muscles form. He let curiosity drive him and encouraged his trainees to think big, too.
Weintraub helped found and shape the Basic Sciences Division, the group of Hutch researchers dedicated to answering fundamental questions of biology. His science was so inspirational and his personality so big that many around him found themselves pulled into his sway, and basic science researchers at the Hutch have made a conscious decision to follow the model of creative and risky exploration that Weintraub, Groudine, Dr. Paul Neiman (the division’s director at the time) and their founding colleagues established, Gottschling said.
It’s a model that lives on in research like that of Dr. Sue Biggins, who came to the Hutch in 2000 to study how cells shuffle the correct number of chromosomes to each daughter cell during division. Biggins started exploring that question through genetics, her forte. But she soon took a big step out of her comfort zone to pull the large protein complex that sorts chromosomes out of cells and study them in test tubes, a research feat that had never before been accomplished and ended up transforming her work and research field.
Weintraub’s daring inspired Dr. Mark Roth, who started his career studying how RNA and chromosomes are regulated but later wanted to do something really different. In an attempt to alter the very nature of cells, Roth started experiments dosing worms in the lab with a variety of toxic gasses. He didn’t succeed in his initial goal, but what happened to those worms when they were exposed to small amounts of hydrogen sulfide gas led to the discovery of what Roth now calls suspended animation, a reversible state of metabolic hibernation that could one day buy precious time for humans during delicate surgeries, heart attacks or strokes.
“It’s that spirit that we all appreciate that Hal embodied. You have to think about the problem differently,” Gottschling said. “Everyone had told Roth hydrogen sulfide is poison, and it is in some contexts, but the way he thought about it was a little different.”
Gottschling heard a lot about Roth’s experiments as they were unfolding, he said. Roth and Weintraub used to talk every day, but as Roth’s new lab neighbor after Weintraub’s death, Gottschling filled in for many of those conversations.
Dr. Nancy Hutchison remembers feeling star-struck when she first met Weintraub at a conference in the late 1970s, and even more nervous when her graduate adviser suggested she apply to train with him for her postdoctoral fellowship.
“This guy is doing the experiments that just open our eyes every time he publishes a paper,” she said. “I was kind of going, ‘Me, apply to Hal Weintraub’s lab?’”
But she did, and when she came to Fred Hutch she discovered Weintraub to be not only an eye-opening scientist, but a supportive and generous mentor. Weintraub encouraged Hutchison’s varied interests, even those that didn’t directly lead to scientific results. In addition to carrying out her own research, Hutchison also helped establish a new microscope facility at the Hutch and started working with local high school teachers in what would later become the Science Education Partnership, a science program for Washington middle- and high-school teachers she now heads. And all with Weintraub’s enthusiastic backing and input.
“He was sending all these people out into the world who have all become really important names in the work that they do,” Hutchison said. “And I don’t think that could happen without Hal’s work in mentoring.”
It was in that vein that his colleagues established the Weintraub Award. Groudine, Gottschling and several other scientists got together about a year after he died to eat, drink, remember and brainstorm the best way to honor their friend, using a special fund that Groudine, Weintraub and his family had established together shortly before Weintraub died. They tossed around the idea of a scholarship to support up-and-coming scientists, and then they decided to create something completely new — like Weintraub would have.
At the time, there were no other awards for exceptional graduate students in biology, those promising researchers at the very beginning of their careers. So that’s what they set on, and they decided to make it an international award, open to any student pursuing a Ph.D. in biology.
“It was a really fitting tribute,” said Dr. Susan Parkhurst, a basic scientist at Fred Hutch who took the idea and ran with it. Parkhurst oversees the award, now in its 16th year, and the accompanying symposium where the selected graduate students travel to Seattle to present their work at the Hutch.
When she and her colleagues were working to establish the award, it felt good to do something concrete to honor Weintraub, Parkhurst said. But bringing students, family and colleagues together for the first symposium in 2000 was an emotional day. Groudine introduced the awardees and shared stories about Weintraub from their long friendship — like the time Weintraub met François Mitterrand at a Parisian restaurant and the then-president of France admired the scientist’s high top sneakers, or the fact that Weintraub’s medical degree from the University of Pennsylvania was awarded — along with his doctorate — only with the promise that he’d never attempt to practice medicine (Weintraub was not interested in spending much time in the hospital during school, Groudine said).
The stories were bittersweet for everyone there.
“I still feel that way every time we have the symposium,” Parkhurst said. “I think Hal would be really impressed. He loved to hear good stories and good science, and these students give fantastic talks.”
Photo by Robert Hood / Fred Hutch News Service
Weintraub’s son Adam remembers his dad’s lab as being like a playground when he was a kid. The biologist taught Adam and his younger brother, Josh, to hop the bus directly to the Hutch after school let out. The boys would make haunted houses in the hallways using dry ice to generate massive amounts of steam. And their dad let them “help” with his experiments.
Adam, now 42, says the scent of the laboratory sticks with him.
“To this day I have the smell of those frog holding tanks in my nostrils …” he said. “Those memories are extremely vivid, and for us it had nothing to do with the [research] life, it had to do with exploration and wonder and curiosity.”
His dad didn’t care whether his sons followed his footsteps into science (and they didn’t — Adam is a photographer and bar owner and Josh is an artist), but he cared fiercely that they ask why things are the way they are.
Adam remembers his dad as very present — when he was physically present. When he was with his sons, he was really with them, but he’d often miss dinner to work late in the lab, concentrating on his experiments.
Groudine has seen the Weintraub boys grow up — he remembers tossing a 6-week-old Adam back and forth with Weintraub in his tiny apartment in Cambridge, England, where Weintraub and his wife, Nancy, were living when Adam was born — and he is now godfather to Adam’s 8-year-old son. He sees a lot of Weintraub in Adam, especially now that he’s a father himself.
“When he gets focused, he gets focused,” Groudine said. “He reminds me of Hal in that way.”
Weintraub was a star high school athlete: an all-city halfback in football and all-state baseball pitcher. He’d played competitive football in college and was a dedicated gym rat — the basketball court was one of his favorite places. He, Groudine and many of their friends would play lunchtime games at Seattle University nearly every day.
Almost everyone who talks about Weintraub describes his passion for basketball — those who didn’t play, like Tapscott, do so somewhat wistfully, as if he may have missed something by not attending games with his mentor. Weintraub wore basketball sneakers on and off the court, as well as an old sweatshirt, inside out as often as not.
It was during one of those days on the court in early fall 1994 that Groudine and Weintraub realized something was not right.
“Very unlike Hal, he missed some easy shots. And Hal always made hard shots,” Groudine said. “When I passed a ball to him a few times it went right by him. He didn’t see it.”
That strange game coupled with the headaches Weintraub had been having recently made Groudine worry, he said. When they got back from the game, Groudine immediately called Tapscott, a trained neurologist, for his opinion.
Tapscott examined Weintraub and found that his former mentor couldn’t see things in parts of his field of vision. An MRI performed that day revealed Weintraub’s brain tumor, and that night Groudine delivered the MRI films to a University of Washington neurosurgeon at his home. Weintraub was in the operating room 48 hours later for his first surgery to try to remove the cancer.
When he got sick, Weintraub kept exercising as much as he could through the chemo and after recovering from his surgeries, his son Adam remembered. But he also started eating a pint of Ben & Jerry’s ice cream every day — Heath Bar Crunch.
And he decided to attack the problem of his rapidly growing tumor the way he attacked everything else, by learning everything he could about it. He wanted to know what was in his head. “How’s it working and why?” Adam said.
Groudine, Tapscott and their colleagues organized a symposium on glioblastoma at the Hutch that fall. They invited basic scientists, translational researchers, clinicians. The brightest scientific minds working on neurology and brain cancer came together in Seattle to discuss what was known at the time and share ideas about possible treatment options, which were, unfortunately, limited.
Weintraub and Groudine talked it over and decided Weintraub shouldn’t attend the conference. It would be too hard, and too hard for his colleagues and friends. After the symposium and sifting through the literature, Weintraub picked a fairly risky treatment — a combination of surgery, high-dose chemotherapy and a bone marrow transplant. But there really weren’t alternatives, Groudine said.
Even today, glioblastoma is largely incurable. With treatment, patients now live an average of one to two years after diagnosis. Weintraub lived six months. He died at Fred Hutch (where he was treated) of complications from his treatment on March 28, 1995. Groudine, Nancy, Adam and Josh were by his side.
Weintraub and Groudine were friends from the day they met, although not the exact moment, Groudine said. They were both graduate and medical students at the University of Pennsylvania, Groudine just starting in 1970, Weintraub a few years ahead. They met by chance at a pick-up football game where they were put on opposite teams.
“We just went after each other, killing each other on the football field,” Groudine said. “We didn’t even shake hands at the end.”
After the game, Groudine started walking toward the building that housed Dr. Howard Holtzer’s laboratory. He had a meeting with the biologist to discuss joining the lab, and he noticed Weintraub walking the same way. The two eyed each other as they walked, but didn’t say anything.
In Holtzer’s lab, the professor introduced Groudine to Weintraub, who was conducting his graduate research there.
“Hal said something like, ‘If he does science the way he plays football, he’ll never amount to anything,’” said Groudine, now 66. “And we became extraordinarily good friends after that.”
The two ended up working together on how genes are packaged in the cell, wound around organizing protein complexes known as nucleosomes. At the time, everyone thought nucleosomes only existed on stretches of inactive DNA. Groudine and Weintraub found that active genes, too, contained nucleosomes. They then showed that nucleosomes change shape when genes are expressed, observations that led to the modern field of epigenetics and the broad study of how changes to nucleosomes can affect everything from gene expression to normal development to cancer.
The friends followed each other around the world to carry on this project. After his doctorate, Weintraub moved to Cambridge for a postdoctoral fellowship, and Groudine spent a year in Lausanne, Switzerland, at the same time. They crossed the English Channel several times that year to meet and talk science.
After he returned to the U.S., Weintraub started his own laboratory at Princeton University and Groudine spent the last year of his doctorate work there before moving to the Hutch. Weintraub then spent two summers in Seattle working with Groudine before deciding to move his laboratory to Fred Hutch as well.
After Weintraub died, Groudine accepted a position as the new head of the Basic Sciences Division in large part because of the huge void his friend left — both in the division and in Groudine’s life.
“Hal and I were the closest friends for 25 years,” Groudine said quietly, remembering their twice weekly dinners and nearly daily basketball games. And remembering, too, his friend’s legacy, he’s worked over the past 20 years to honor Weintraub’s vision for basic sciences research and for the Hutch.
Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Research Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.
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