Pathways to Discovery
Looking east at the University of Washington Medical Center, where, over four decades, Randy Moon would make groundbreaking discoveries in developmental biology and help found the Institute for Stem Cell and Regenerative Medicine (ISCRM).

One day in 1977, Randall T. Moon, a young scientist bound for Vancouver, B.C. was riding his BMW motorcycle north on Interstate-5 through Seattle. Off to the east, as he crossed the towering ship canal bridge, his wandering eyes fell on the University of Washington campus for the very first time. The sideways glance was a harbinger. On a journey from one point to another, it was the instinct to look all around him that would change the course of his life – and of science itself. Serendipity had rewarded his natural curiosity, as it would many more times in the future.

Wandering has always been a way of life for Dr. Randall T. Moon. Born in Rhode Island, and raised in a one-stoplight town in the countryside of northern Ohio, he completed high school in three years, as valedictorian, then left the rural setting as quickly as possible. In his first year of college, he dropped out of three schools in three quarters. A phone call from a recruiter promising a very liberal arts education and sunny weather drew him to New College, a small school in Florida with an eclectic list of bragging points: high faculty-to-student ratios, a campus designed in part by I.M. Pei, sweeping views of Sarasota Bay, and a worldview that favored student-driven intellectual pursuits. All of which suited Moon perfectly.

The young scientist in the 1970’s, a decade divided between studying marine invertebrate embryos and cross-country journeys on his BMW R75/5 motorcycle.

At New College, Moon found a model teacher in Professor John Morrill, a renowned figure with a sterling reputation in cell and developmental biology and a knack for inspiring hard work and affection from his students, several of whom would become members of the National Academy of Sciences. Morrill soon hired Moon as a teaching assistant, providing a source of income that allowed the financially-strapped student to stay in college.

Flush with energy and access to a full lab, Moon was inspired to focus on developmental biology by watching marine invertebrate embryos develop under microscopes. Then, at the age of 21, Moon was diagnosed with metastatic thyroid cancer. The subsequent surgery and radiation treatments led the college senior to conclude that standard medical interventions were lagging too far behind advances in biology – something he never forgot.

It was Moon’s love of biology that propelled him forward after cancer treatment. After receiving his B.A. from New College, Moon applied to only one graduate program, the Department of Zoology at the University of Washington. (He was drawn to UW, in part, by the prospect of studying at the Friday Harbor Marine Station in the picturesque San Juan Islands, where he would eventually complete a five-week course on Marine Invertebrate Development – not his last encounter with marine animal life.)

Moon recalls that the transition from the freedoms at New College to the more structured culture at UW was a rough transition. “At New College, nobody was going to tell you what to do. The faculty were there to help you in whatever direction your interests took you, and to make suggestions, not to issue edicts. To go from that to a relatively regimented environment wasn’t easy.”

Nonetheless, the admissions committee must have seen abundant promise in Moon. Despite his refusal to take the GREs because the exam didn’t measure creativity, and despite holding a diploma from a college that gave written evaluations instead of grades, the university welcomed Moon to the doctoral program in Zoology. Over time, the student and the school learned to adapt to each other. Under strict orders from the department to find an advisor by the end of the first year, Moon sought out a kindred spirit. “I had the good fortune to pick Merrill,” he says.

Randy Moon with his PhD advisor Professor Merrill Hille at the 2019 Randall T. Moon Lecture.

Merrill Hille became Moon’s PhD advisor in 1978 and remains a close friend more than forty years later. During opening remarks at the 2019 Randall T. Moon lecture, Hille spoke of Moon’s career with a mentor’s pride – the seven papers he published as a graduate student and seven more as a postdoc, the joy he found studying embryos, and his groundbreaking insights into the Wnt signaling pathway.

In Hille’s lab, Moon studied protein particles that were thought to regulate early gene expression in sea urchin embryos. His natural curiosity took him on separate trips to England, and to Palermo, Sicily, where he spent months with local researchers seeking, as always, new perspectives and the excitement of new situations. Hille says she knew from Moon’s performance in her lab that he was going to be productive.

“One of his solo published papers in my lab started as an assigned paper he submitted to a course on mouse development. It was so good, the professor told him he should submit it for publication. That paper, among many others, showed Randy’s expertise as a researcher and a writer. He was a voracious reader, at a time before the internet when you actually had to go to the library.”

Moon earned his PhD in 1982. He was soon on the move again. For the next three years, home would be Caltech, in Pasadena, California, where he worked as a postdoc, focused on Molecular and Cell Biology, in the lab of Elias Lazarides. After this brief and highly productive postdoctoral period, he was recruited back to UW to join the Department of Pharmacology in the School of Medicine as an assistant professor.

Here, again, life and love of science intersected. Moon had not forgotten his experience as a cancer patient. As a new Assistant Professor he kept his eyes and mind open to the possibility that the pursuit of basic research might lead to a discovery of clinical significance. Opportunity knocked over Christmas break. While waiting for his partner, Susan Mailheau, to come home from working on her veterinary degree, Moon busied himself with a series of one-off experiments with the oncogene known as Wnt-1 that would define the remainder of Moon’s long career.

Serendipity and the Two-headed Tadpoles

We know now that Wnts are a family of proteins that play an enormously important role in human development, first in the embryo, and later as a driver of cell proliferation, self-renewal, and, in some animal species, regeneration of injured tissues. Weak Wnt signaling is linked to neurodegenerative disorders, bone disease, and other conditions related to cell deficiency. Elevated Wnt signaling is associated with some cancers.

It is difficult to overstate how fundamentally important these spectacular and mysterious Wnt molecules are to life and survival – and, how profoundly the direction of scientific research is often driven by unplanned events. While at Caltech Moon met Andy McMahon, a postdoc in another lab. This chance encounter would have reverberating implications for the future of developmental biology and medicine.

Two embryos of Xenoopus laevis show a control with one body axis forming (left) next to an embryo over-expressing Wnt1, showing the duplication of the body axis (right). The latter would result in the two-headed tadpole.

“I had started as an Assistant Professor in Pharmacology and Andy had his independent lab at the Roche Institute,” says Moon, recounting the history. “We began looking for collaborative projects. At the time, Andy was trying to knock out Wnt-1, a gene in mice that appeared to encode a secreted protein of unknown function. But he was hitting a wall.”

Instinctively, Moon suggested the opposite experiment.

“The idea was to flip it around,” says Moon. “Instead of seeing what happens when you remove the Wnt1 gene completely, I proposed saturating a frog embryo with the same protein.” Where McMahon had been hoping to show what function required the gene by removing it, Moon proposed a “gain of function” experiment that might reveal what the gene was capable of doing if more of it was added.

The reversal worked.

Andy McMahon and Randy Moon lakeside in Kirkland, Washington. Landmark experiments by McMahon and Moon were instrumental in defining Wnt pathways in embryonic development.

“Over Christmas break, I synthesized synthetic mRNA, injected it into frog embryos, and then allowed them to develop into tadpoles. We found the protein affected the embryo even before there was a nervous system and it led to a duplication of the embryonic axis.” Moon and McMahon had created two-headed tadpoles, nameless amphibians who are forever etched into the history of science.

McMahon is now at the University of Southern California where he is the Director of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research. “The result was stunning,” McMahon recalls of the experiments with Moon. “The axis was duplicated. Clearly two nervous systems were forming. A very exciting and productive month ensued as we performed more injections to confirm that what we were seeing was real. The paper we published together in 1989 is one of my favorites. It was a ‘wow’ moment with a good friend. What I most appreciated about working with Randy was the intensity of our brief collaborative period but also the fun. We worked around the clock, only finding time for a beer at the College Inn across the road where I was staying – it’s still serving.

Knowledge that some cells determine the developmental fate of other cells went back to Hans Spemann, whose work in embryonic development in the 1930’s started a decades long search for the mechanisms of cell growth at the molecular level. The abnormal growth Moon and McMahon observed in tadpoles was the first hint that Wnts were signaling molecules within the cells capable of promoting changes in cell proliferation and fate – in other words, how they replicate and the jobs they are instructed to do.

The collaborative period for Moon and McMahon was indeed brief, but also momentous. After the experiment, McMahon continued investigating Wnt signaling in mouse brains while Moon stayed focused on tadpoles, setting the course for decades of research to follow.

Moon’s PhD Advisor, Dr. Hille, speaks to the importance of the moment. “Only after Randy and Andy McMahon showed that the Int1 gene [later renamed Wnt1] was the Spemann organizer did we know what caused the transition from the cleavage stage [the first cellular division of the fertilized egg] to the formation of an embryo.”

Randy Moon at his induction into the American Academy of Arts and Sciences in 2013.

Hille adds that Moon identified not one, but three Wnt pathways, the canonical Wnt-signaling pathway that leads to the regulation of gene transcription; the noncanonical planar cell polarity pathway that regulates the cytoskeleton and the shape of the cell; and the noncanonical Wnt/calcium pathway that regulates calcium inside the cell. “Wnt became Randy’s lifelong study,” she says.

“After doing the RNA injections, I just shut down every other project in the lab,” says Moon. “Recognizing that Wnt had such important biological signaling capacity opened the door to studying what Wnts do, how they do it, by what mechanisms, and what the therapeutic potential might be.”

Founding an Institute

Defining the Wnt pathway was a landmark moment for science, and an early career milestone for Moon, a stepping stone to becoming a Howard Hughes Medical Institute investigator, an elected fellow of the American Association for the Advancement of Science, a member of the American Academy of Arts and Sciences, and a member of the National Academy of Sciences.

At the UW, Moon and a legion of students learning alongside him continued to ask probing questions of the mysterious Wnt molecules that he and Andy McMahon had stumbled on years earlier. Questions about the role of Wnt signaling in early development, in regeneration, and in diseases all led to game-changing insights into Wnt signaling, published in dozens of prestigious publications for all the world to read.

The three founders of the Institute for Stem Cell and Regenerative Medicine (Tony Blau, Randy Moon, and Chuck Murry)

Yet, for Moon, the insights and articles were not enough.

By the early 2000’s other advances in developmental biology were reshaping the landscape of science and medicine. Embryonic stem cells – and soon, their less controversial cousins, induced pluripotent stem cells, were giving researchers new tools to study diseases, particularly those rooted in cellular deficiency (or excess), like Alzheimer’s, heart disease, diabetes, and cancer.

At the University of Washington – in the cradle of stem cell medicine – Moon sensed an opportunity to harness this massive latent potential by creating a new institute that would galvanize scientists working in multiple disciplines across biology, engineering, and pathology. Moon’s mission was also shaped by his personal experiences – first as a thyroid cancer survivor, then as a patient coping with Parkinson’s Disease (he was diagnosed in 2003). More than ever, the scientist was determined to make a lasting impact on patient care.

For years, serendipity had served Moon well, leading him to unexpected discoveries in and out of the lab. Now, he sought support for his vision for a new stem cell institute with single-minded focus. He found allies in Charles Murry and Tony Blau, two physicians who shared Moon’s enthusiasm for a facility that would allow researchers and clinicians to pursue breakthrough medical therapies collaboratively.

“From the beginning, Randy’s vision was that the institute needed to focus on developing new treatments for today’s patients,” says Murry, UW Professor of Pathology, Bioengineering, Medicine/Cardiology, and the current Director of the UW Medicine Institute for Stem Cell and Regenerative Medicine (ISCRM). “It was hugely influential that the most basic scientist among us advocated for stem cell therapeutics. Coming from physicians like Tony and me, this might have appeared self-serving or naive. Today, Randy’s vision has become part of our institutional DNA.”

Back in the early 2000’s, Moon, Murry, and Blau were swimming against powerful currents. Politicians at all levels of government were questioning the morality of embryonic stem cell research, calling for moratoriums that continue to bridle the field. Undaunted, the three scientists advocated relentlessly for a stem cell institute, eventually finding a champion in UW President Mark Emmert, who backed his pledge with a public statement articulating the university’s support of stem cell research. Further backing came from the School of Medicine and Dr. Paul Ramsey, CEO of UW Medicine, executive vice president for Medical Affairs and dean of the UW School of Medicine. These critical endorsements turned the tide for good.

The scientist sailing in Australia, where he had been invited to give a seminar. Joining him was his wife, Susan Mailheau (2007).

“President Emmert was decisive,” Moon recalls. “After hearing us speak about the potential impact of stem cell research on human medicine, he interrupted us and said, ‘This is a no-brainer. We have to do this.’ Dr. Ramsey was a constant source of support, and helped ISCRM find its new home. My chairman, William Catterall also played an essential role by serving on the Institute’s Scientific Advisory Board, and by helping to further solidify buy-in for ISCRM across the university.”

ISCRM, of course, is the Institute for Stem Cell and Regenerative Medicine, officially founded in 2006 with $23 million in private funding, much of it raised by Moon, who accepted an invitation from Dr. Ramsey to serve as the institute’s first director and occupy the William and Marilyn Conner Chair.

“My enthusiasm for establishing ISCRM was based on the extraordinary potential of the institute to improve human health and on the leadership provided by Randy Moon,” says Dr. Ramsey. “As the young investigator who discovered the role of a protein (Wnt1) in creating a two-headed tadpole, Randy developed a truly outstanding research program that provides foundational basic science guidance for regenerative medicine. In addition to his outstanding personal research, Randy was passionate about bringing researchers together to advance the field of regenerative medicine. As the founding director of ISCRM, Randy recruited faculty from multiple disciplines, designed an ambitious and visionary agenda to improve health, and communicated his passion broadly, including assembling a large group of community leaders who have raised support from donors and from the state of Washington. UW Medicine is very fortunate that Randy Moon served as the founding director of ISCRM.”

An Enduring Legacy

More than a decade later, Moon’s vision for ISCRM endures.

Seen here at the Tom and Sue Ellison Stem Cell Core at ISCRM (from left to right): Former UW President Michael K. Young, Tony Blau, Randy Moon, UW Provost (now President) Ana Mari Cauce, and Chuck Murry

He established an ethos that made therapies for patients a central goal of the mission. “I was convinced that success for ISCRM would depend on collaboration between researchers and clinicians,” Moon has said. “The synergies between different researchers and clinicians is helping us drive a revolution in medicine. I believe regenerative medicine will bring us therapies that will cure diseases and injuries rather than merely treat the symptoms. This is really exciting, and ISCRM will be leading the world in some of these emerging therapies.”

He helped shepherd the young Institute to its current home in the South Lake Union neighborhood, where it is now part of a thriving biotech hub, alongside Fred Hutchinson Cancer Research Institute, the Allen Institute, and Seattle Children’s Research Institute.

He insisted that ISCRM have a high-throughput screening facility, secured the funding to make it happen, and hired the technicians. Today, the Quellos High-Throughput Screening Core is accelerating research in multiple disease areas employing cutting-edge technology and skilled specialists to perform automated screens that are helping physicians treat patients with several types of cancer.

The Moon Lab in Seattle’s University Village in 2006. Moon’s former lab members are now contributing to science and medicine in diverse roles: as professors, biotech analysts, and staff scientists in academic and private settings.

He mentored and inspired hundreds of trainees, undergraduate, graduate, and postdoc students, many of whom have gone on to make their own lasting contributions to science. One of Moon’s proteges is Jeanot Muster, now the Director of the ISCRM Aquatics Core, where researchers from across the institute come to study the mechanisms of development and regeneration, including Wnt signaling, using zebrafish as a model.

“When Randy hired me in 2004, he took a chance on this kid fresh out of college and became my teacher, mentor, friend, and father,” says Muster. “He taught me so much over the 14 years I worked for him, and still continues to teach me from afar. I wouldn’t be the person I am today without his guidance, support, and encouragement to chase the answers to the seemingly impossible questions.”

And he lent his name to the Randall T. Moon Lecture series, which recently brought Professor Philip A. Beachy to ISCRM to talk about his groundbreaking research into hedgehog signaling.

For Moon, the first ten years of ISCRM were ultimately marked by a mix of setbacks and successes, with plenty of the latter to celebrate. In the face of adversity – foremost, adjusting to life with a progressive neurological condition – he led ISCRM through its formative period, received competitive renewals from the Howard Hughes Medical Institute, and continued exploring potential therapeutic uses of Wnt signaling molecules, eventually co-founding Fate Therapeutics, a San Diego-based biotech company with a market cap of over a billion dollars.

Beauty and Elegance
Moon and Dr. Susan Mailheau, a small animal veterinarian, and his wife of 31 years at the American Academy of Arts and Sciences induction ceremony in 2013.

Decades have now passed since the motorcycle trip that brought Moon through Seattle. In the time since, the embryonic insights on Wnt signaling credited to Moon and his collaborators have helped give life to fields of science and medicine that hardly existed in 1977. The Institute he co-founded is putting many of those insights into practice, bringing mankind closer to novel treatments for our deadliest diseases. And his innate curiosity is now encoded in a new generation of scientists.

Moon himself is often described as a basic scientist, a label he wears comfortably. When asked what the term means to him, his response comes easily. “It implies somebody who’s interested in pursuing experiments, basically for the beauty and elegance of knowledge. If your approach to science is to understand a process like cancer, moving from point A to point B in a linear manner, you’ll rarely gain major insights owing to the complexities of biology. But if you make room for serendipity, and if you are willing to follow the data in tangential directions, then you just may have a few treasured moments in your career when everything falls into place and you discover something totally unexpected.”

 

Back to the Beach

Randall Moon is currently on long-term leave from the University of Washington and the Howard Hughes Medical Institute. He lives in Carpinteria, California with Dr. Susan Mailheau, a small animal veterinarian, and his wife of 31 years. They can usually be found on the nearby beach, working with groups that are authorized to protect and rescuing injured or sick marine mammals.

The view from Carpinteria, California, where Moon and his wife Dr. Susan Mailheau now live.

In the meantime, at the Institute for Stem Cell and Regenerative Medicine, hundreds of faculty, staff, and students are using the biological pathways Moon helped define to develop treatments for diseases, like heart disease, Alzheimer’s, cancer, diabetes, and muscular dystrophy, that impact billions of people all over the world.  Across 150 labs located at UW Medicine South Lake Union and the UW Medical Center, researchers trained in biology, engineering, medicine, and other disciplines are building on a foundation of collaboration, innovation, and wonder – the same instinct to look all directions that is written into the institute’s genetic code by the man who helped found it.