Mark Groudine, MD, PhD, stepped back from a rich career at Fred Hutchinson Cancer Center in 2022 to become professor emeritus. During his four decades at Fred Hutch, Groudine exemplified the organization’s breadth of scientific and clinical endeavors: While contributing fundamental discoveries about the interplay between DNA packaging, DNA’s 3D organization and gene expression, he also was a professor of radiation oncology at the University of Washington. And during his tenure as director of the Basic Sciences Division, as Fred Hutch’s deputy director, and in two stints as the organizations’ acting president and director, Groudine helped guide Fred Hutch’s scientific directions and shape its culture of excellence.
“He poured his life into this place,” said Fred Hutch cell biologist and longtime Basic Sciences Division colleague Mark Roth, PhD.
Groudine helped reveal how the way that DNA is packaged and arranged influences which genes are turned on, or transcribed, and which are turned off. He co-discovered segments of DNA called locus control regions, which enhance the expression of genes located far away on the same chromosome. Groudine and colleagues also demonstrated how the spatial arrangement of DNA, including its location in different areas of the nucleus, can play a critical role in controlling gene expression and that this arrangement changes over the course of cell development as new genetic programs are switched on and off.
His scientific excellence and commitment to science and scientists were honored in 2016 when an anonymous donor established the Mark Groudine Chair for Outstanding Achievements in Science and Service. First held by Groudine himself, the Groudine Chair is now held by his colleague and collaborator, Fred Hutch cell biologist Susan Parkhurst, PhD.
“Mark is the cornerstone, the foundation of our institution’s quality of science since its inception,” said Fred Hutch President and Director Emeritus D. Gary Gilliland, MD, PhD, who led Fred Hutch from 2015 to 2020. “I hope that his legacy will be that we never forget our origins, but remember how important advances in science are.”
After obtaining a bachelor’s of science degree in zoology from the University of Wisconsin, Groudine received both his MD and PhD from the University of Pennsylvania, where he met fellow graduate student and future close collaborator and friend Harold Weintraub, MD, PhD. During his graduate work, Groudine spent a year as a visiting scientist at the Swiss Institute for Experimental Cancer Research, where he met then-postdoctoral fellow Robert Eisenman, PhD. Groudine, Weintraub and Eisenman would later be colleagues and collaborators at Fred Hutch.
Groudine pursued his dual scientific and clinical training during a residency in radiation oncology at the University of Washington and a concurrent research fellowship in the lab of Fred Hutch physician-scientist Paul Neiman, MD.
Today, we understand that DNA packaging does more than ensure that six feet of DNA can fit into the nucleus of a single human cell. We know that chromatin, the complex of DNA and its packaging proteins, plays a central, controlling role in gene transcription: Tighter DNA bundling helps keeps genes off, while looser bundling makes it easier to turn them on. And we know that how long DNA molecules are arranged in physical space is a factor in gene regulation.
The idea that the state of a gene’s chromatin affected its transcription “was conceptually new at the time,” said Fred Hutch colleague Toshio Tsukiyama, PhD, who studies how cells modulate chromatin to enter and maintain dormant states. “People used to think that chromatin is like a brick: It’s a pretty boring thing you need to have for structure.”
Groudine focused primarily on how cells control expression of the beta-globin genes, which encode hemoglobin, the oxygen-carrying protein present in red blood cells. Globin genes come in three versions: an embryonic, a fetal and an adult version. Red blood cells need to switch globin genes on as they develop — but which version is “on” depends on when in an animal’s life cycle the red blood cell is being produced.
With Weintraub, Groudine used chicken globin genes as a model to show that actively transcribed genes are more “open” (or loosely packaged) than genes that are not transcribed. They developed a molecular tool, using an enzyme called DNase I, to help scientists distinguish between more- and less-condensed areas of chromatin.
“He was fearless in his research,” said Doug Engel, PhD, a cell biologist at the University of Michigan who collaborated with Groudine and Weintraub on their work on chromatin and globin genes. “It’s not a unique characteristic, but it’s detected in the best scientists: They allow their work to do the talking for them. Mark did that.”
Groudine approached chromatin with an open mind and helped reveal its changeable, critical nature. His work on how the relationship between chromatin and DNA structure played into gene expression led him to co-discover locus control regions which are an array of independently acting enhancer elements that activate transcription of genes over very long distances. If the locus control region for a globin gene is missing, red blood cells can’t make enough hemoglobin and a type of anemia called thalassemia develops.
“The work that Mark and Hal did to show that important elements like promoters and enhancers for gene transcription have accessible or open chromatin structure is still true today,” Tsukiyama said. “It’s still the gold standard.”
Enhancers’ ability to affect expression of far-distant genes depends on the way that DNA strands are arranged in 3D space. Groudine and colleagues led work demonstrating that enhancer elements help ensure that genes are accessible to transcription factors (the molecules that transform information in DNA into RNA) by keeping them away from tightly compacted areas of chromatin. He also showed that the location of proteins and genes in different areas of the nucleus plays an important role in developmentally regulated gene expression, and the 3D organization of proteins and DNA within the nucleus changes to help determine which genes are on and off.
“Mark is a very creative thinker who sees the big picture but also does the nitty gritty work to make it real,” said National Cancer Institute Center for Cancer Research Director Tom Misteli, PhD, who also studies the 3D organization of the genome. “He has a high degree of creativity paired with an even higher level of rigor and scholarship. That’s a rare combination.”
Eisenman collaborated with Groudine when their interests in transcription factors and genetic control intersected.
“Mark was always amazing to me. He did great science, he was a very fast and astute thinker and, at same time, he was a practicing radiation oncologist,” Eisenman said.
As practicing physicians, Groudine and then-Basic Sciences Division Director Neiman, who remained a close colleage and mentor throughout Groudine’s career, were rarities in the division. During the early years of his career, Groudine was particularly interested in the use of neutrons in cancer treatment and for many years attended a clinic at UW where patients who had been treated with neutrons were evaluated. Colleagues knew Groudine must be heading to clinic whenever they spotted him wearing a tie.
Groudine also served as a board member at the Seattle Cancer Care Alliance and as a professor of radiation oncology at UW Medical School. In this capacity, he helped bring proton therapy, a more precise form of radiation treatment, to Seattle.
Even when he ventured into new scientific areas, Groudine brought his usual scientific acumen and spirit of collaboration, said Parkhurst. She acted as one of Groudine’s associate directors of the Basic Sciences Division and also worked with him to show that a protein that regulates the cell’s internal scaffolding system also influences gene expression by controlling the 3D organization of DNA in the nucleus.
“He likes to challenge you, and he's got really good ideas. It’s great to have that kind of sparring partner to make your science better,” she said.
Groudine approached his own science in a similar way, said Dirk Schübeler, PhD, who trained with Groudine and now directs the Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland, where he also leads a group dedicated to the study of gene regulation in the context of chromatin.
Rather than defending his models, Groudine continued to challenge and test them, Schübeler said: “That’s the hallmark of rigorous scientist.”
Marjorie Brand, PhD, a cellular biologist at the University of Ottawa who trained with Groudine as a postdoctoral fellow, praised his ability to cut to the heart of scientific problems and identify approaches to solving them.
In recognition of his achievements, Groudine is an elected member of several scientific honor societies, including the National Academy of Sciences, the National Academy of Medicine, the American Academy of Arts and Sciences and the American Association for the Advancement of Science.
Groudine also applied his intellect to building Fred Hutch’s culture and community.
“Mark devoted his entire career to shaping the Hutch into a terrific place to do research,” said Barb Trask, PhD, whom Groudine helped recruit to head the Human Biology Division, a position she held from 2000 to 2011.
Groudine fostered an environment that encouraged cooperation and discouraged competition for space or resources, she said: “He set high standards, strove for fairness, recruited great colleagues, and pushed for the infrastructure and resources that Hutch scientists needed to do well.”
By doing so, Groudine strove to carry on the legacy of close friend and collaborator Weintraub, who had helped found the Basic Sciences Division and contributed to its egalitarian, science-first culture. When Weintraub died of a brain tumor at 49, Groudine stepped beyond the lab and clinic.
“Once Hal died, Mark felt very strongly that he wanted to make the atmosphere of the place retain the same values, and he stepped up into leadership,” said longtime Fred Hutch colleague Denise Galloway, PhD, who directs the Pathogen-Associated Malignancies Integrated Research Center and holds the Paul Stephanus Memorial Endowed Chair.
Groudine first helmed the Basic division from 1995 to 2004, then took on center-wide administrative roles as Fred Hutch’s deputy director from 1997 to 2016 and executive vice president from 2005 to 2016. Twice, in 2010 and 2014, Groudine served as the organization’s acting president and director.
“Mark lived and breathed the center, both scientifically and administratively,” said Fred Hutch virologist and President and Director Emeritus Larry Corey, MD. “He was an incredible source of history and knowledge. He knew everybody and was able to liaison between people in a wonderfully unique way.”
Gilliland lauded Groudine’s commitment to maintaining Fred Hutch’s scientific legacy.
“Mark was critical to keeping us a collaborative, well-harmonized institution,” Gilliland said. “He was pivotal in maintaining and developing the egalitarian approach that we have.”
Others noted how Groudine’s talent for seeing the big picture and the details helped him as a steward of the organization.
“He knew how to weigh all of the various indescribable nuances required to make the right decision,” Roth said.
Gilliland, Corey and fellow President and Director Emeritus and Nobel Prize Winner Leland Hartwell, PhD, all praised Groudine’s ability to balance competing needs of a diverse array of faculty members and ensure scientists had the resources they needed. Many Hutch scientists noted how much Groudine’s support helped advance their research programs.
“It was pretty inspiring to watch him take on more and more,” said Senior Vice President and current Basic Sciences Division Director Sue Biggins, PhD. “I noticed he really put everything ahead of himself. Our division and the Hutch benefitted tremendously.”
Parkhurst, whose own commitment to science and scientists was honored with the Groudine Chair, said that it was Groudine himself who showed her that everyone can make a difference.
“Mark was guardian of science at the Hutch,” Gilliland said.
Though Groudine’s scientific findings are memorialized in biology textbooks, he considers his greatest legacy to be the scientists whose careers he’s nurtured.
“He has very good skills in judging science, and so people recruited under his leadership in Basic Sciences were very creative people,” Hartwell said.
Groudine nurtured the career of Bruce Clurman, MD, PhD, who took on the roles of executive vice president and deputy director in 2016 when Groudine stepped down from administrative duties. Clurman, who holds the Rosput Reynolds Endowed Chair, initially joined Groudine’s lab as a senior fellow in Medical Oncology and Molecular Medicine, training in basic science while also treating bone marrow transplant patients. Like Groudine, he built a career balancing patient care with running a lab that studies fundamental biologic mechanisms and their roles in cancer. Clurman praised Groudine’s mentorship when he stepped into his administrative roles.
“He just wanted you to do the science that you thought was the most important,” Clurman said in 2016. “He’s been an unbelievable mentor and role model for me … He’s shown me how to lead by respecting people and by being very straightforward and transparent.”
Seattle Children’s physician and sickle cell anemia researcher Michael Bender, MD, PhD, who directs the Seattle Children’s Odessa Brown Comprehensive Sickle Cell Clinic, also praised Groudine’s mentorship. When Bender was a young postdoc, he contacted Groudine for advice after a fellowship in pediatric hematology/oncology fell through. Bender was hoping for advice — and received an invitation to join Groudine’s team.
Bender studied the globin locus of control region and, for a while after becoming an independent investigator, continued to make Groudine’s lab space his home base when he first accepted a position at Seattle Children’s.
“One thing that makes his lab so amazing is he really makes it about the trainees,” said Bender, who sees patients with hemoglobin disorders and continues to study hemoglobin genes. “When you come in, it’s not standard plug and play. You tell him what you want to do, and he helps you hash it out.”
Brand recalled her first encounter with Groudine: Still a student at the time, she’d expected to encounter the same scientific hierarchy she was accustomed to in France.
“He made me feel comfortable immediately,” she said.
Tsukiyama remembered a similar experience when interviewing for his first faculty position at Fred Hutch. During Tsukiyama’s second interview, Groudine took the prospective faculty member out to dinner. Anywhere else, Tsukiyama would have expected his host to wear a dinner jacket; Groudine wore a hiking jacket and generally dressed like he was heading to a basketball game. It hit just the right note.
“I thought ‘Wow, this is the place for me,’” Tsukiyama said.
Memorial Sloan Kettering Cancer Center President and CEO Emeritus Craig Thompson, MD, was co-mentored by Groudine and Neiman after he joined Fred Hutch’s fellowship program. Thompson had done medical research while in the United States Navy and wanted to learn molecular biology.
“They were tremendous at letting me into the Basic Sciences Division,” Thompson said. Though his laboratory bench was in Neiman’s lab space, Groudine welcomed Thompson to lab meetings and scientific collaborations.
“This launched my career as a scientist,” Thompson said. “Mark was a particularly terrific mentor. … He really understood what it took to train somebody. He was tough, but he cared about science, he cared about people, and he ran a terrific lab. … Just getting to hang out and be a part of team projects in his lab was fantastic.”
Thompson treated bone marrow transplant patients during his fellowship and had initially expected to make a career of clinically focused research. But his experience with Neiman and Groudine altered the course of his career, Thompson said: “It changed me into what most people think today: I’m a lab rat.”
Trask and others remembered Groudine as a ready source of advice and as a scientific sounding board.
“Mark was a wonderful colleague to me personally, always willing to discuss ways to approach particular issues,” Trask said. “He clearly wanted me and other faculty to succeed. I am particularly grateful for his thoughtful advice and support, and for his friendship.”
When Parkhurst collaborated with Groudine, he was often drawn to her lab by the attractive array of snacks her team keeps in an anteroom just outside the lab.
“Almost every day come he’d down here and have snacks, and he would talk to whoever in my lab happened to be sitting in this room at the same time,” she said. “And he remembered what they were doing and would keep a conversation going with them over years. He made them feel really special. That really changed the way they viewed science.”
Groudine’s mentorship style and method of guiding young scientists toward breakthroughs continue to inspire Brand and Schübeler today, they said. And Groudine set an example that helped guide Schübeler’s own career path.
“Seeing Mark run a successful lab while having a demanding leadership position and while continuing to be humble was part of why I dared to take up the directorship at FMI,” Schübeler said.
Groudine’s encouragement and guidance extended beyond his own lab and included scientists in his colleagues’ labs as well as investigators whose careers he helped foster from afar.
“One of the strengths he brought to the field was that not only was he an outstanding scientist, but he was highly collaborative in a very competitive environment,” Gilliland said.
Misteli, who met Groudine when the genome organization field was still small, echoed these sentiments.
“I could tell right away I could trust Mark,” Misteli said.
He turned to Groudine when weighing whether to accept the directorship of the NCI Center for Cancer Research. Like Schübeler, Misteli was concerned about balancing the role’s administrative duties while maintaining his own research team, but Groudine encouraged him to take on the challenge.
And early in Misteli’s career, Groudine was open to an (at the time) off-the-wall proposal: using artificial intelligence methods to study the 3D organization of the genome.
“When I made my sales pitch, other people would give me this skeptical look. But Mark said, ‘Of course that is the way to do it,’” Misteli said.
Colleagues, collaborators and friends pointed to Groudine’s humor as an enduring quality and key source of his ability to helm his lab, help guide Fred Hutch and nurture scientific excellence in any environment.
“He’s an enormously caring individual,” Roth said. “He has such an incredible sense of humor, and everybody knows that he does. So it provided this outlet for people to feel comfortable.”
Corey also praised Groudine’s “wonderful wit” and often-sardonic way of cutting to the heart of the matter and pinpointing what was best for the institution or an individual.
“Fundamental science often fails. Being able to make jokes about that — considering the struggle — it makes things very much easier,” Schübeler said. “He was extremely supportive, even if you had trouble. It gives you the confidence, the trust to do more risky projects.”
That sense of humor extended to Groudine himself. A lab member posted a picture of Groudine labelled “Mentor.” Groudine added on: “Tor-Mentor.” His well-known habit of casually cadging colleagues’ food was memorialized in a caricature on the booklet for Basic Sciences Division retreats.
Other colleagues remembered Groudine’s sense of fun and wide-ranging interests, including an extensive collection and knowledge of Oceanic and African art. Thompson reminisced about the Fred Hutch city league basketball team that he, Groudine, Weintraub and other Fred Hutch members played on, as well as almost-daily noontime pickup basketball games.
“Mark was a consummate team member,” Thompson said. “When crunch time came down, you could count on him. I think that’s the way he runs his life: Full tilt, always in control, but at the limit of his abilities. And just wonderfully fun to be around.”
Brand recalled the souped-up sports car — a 1988 BMW M5 — that he drove when she first met him, and the conversation that introduced her to Seattle-area grunge music.
Roth said that Groudine brings humor, caring, intellect and communication to his interactions with others, and has a rare knack for picking out scientific diamonds in the rough and giving them what they need to succeed: “That’s not just science, that’s an art form.”
Matthew Ross contributed to reporting for this story.
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at firstname.lastname@example.org.
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