Heads and Tales

By Karen Hopkin Heads and Tales Randall Moon has looked to tadpoles and stem cells for clues about embryonic development and cell fate. Now he has his eye on turning biology into therapy. RANDALL T. MOON Howard Hughes Medical Institute Investigator Professor of Pharmacology, University of Washington (UW) School of Medicine, Seattle Founding Director and William and Marilyn Conner Professor, UW Institute for Stem Cell & Regenerative Medicine F1000: Faculty Mem

By | November 1, 2010

Heads and Tales

Randall Moon has looked to tadpoles and stem cells
for clues about embryonic development and cell fate.
Now he has his eye on turning biology into therapy.

RANDALL T. MOON
Howard Hughes Medical Institute Investigator
Professor of Pharmacology, University of Washington (UW)
School of Medicine, Seattle Founding Director
and William and Marilyn Conner Professor,
UW Institute for Stem Cell & Regenerative Medicine
F1000: Faculty Member, Cell Biology
© Kevin P. Casey

It was one of those ‘eureka’ moments,” says Randy Moon of the experiment in which he first laid eyes on the awesome power of Wnt. Andrew McMahon of the Department of Molecular and Cellular Biology at Harvard University—who’d been a postdoc at Caltech at the same time as Moon—had reached a roadblock in his attempts to unravel the function of this secreted protein by knocking it out in mice. He knew that the protein accumulates along the future spine of a mouse embryo’s developing nervous system, and that it could be activated by a virus to give rise to mammary tumors. “So clearly it was involved in regulating cell signaling and behavior,” says Moon. “But exactly what it did and how it worked was completely opaque.”

That’s when Moon decided to lend a hand—or, more precisely, an egg. “I said to Andy, ‘You’ve got clones, why don’t you send them to me? I’ll make messenger RNA, inject it into frog eggs, and see if it has any effect,’ ” he says. “The expectation was that maybe it’d alter neural development. Maybe the embryo would have too much nervous system or not enough. I guess I was expecting something subtle.” But the two-headed tadpoles he wound up with were anything but.

“All of the embryos I’d injected ended up with a duplicated embryonic axis,” says Moon. “There were no molecules that had ever been described that could do that. I think within 24 hours of seeing those two-headed frogs I said, ‘I’m going to switch the entire lab to studying this gene.’”

And he has followed Wnt ever since. After putting a two-headed tadpole on the cover of Cell in 1989, Moon and his colleagues went on to tease apart the components of the Wnt pathway in a variety of organisms, from frogs to fish to humans. Now, with support from HHMI, Moon has adopted a more high-throughput approach to teasing apart the role that Wnt and its partners play in health and disease—and even potential therapeutics.

Here he swaps stories and shares his thoughts on the beauty of sea creatures, the value of restlessness, and sailing on the River Styx.

MOON LAUNCH

Hippie University. Moon earned his undergraduate degree from the New College of Florida in Sarasota. “The school had a pool that was visible from the highway. The sight of naked coeds bouncing up and down on the diving board caused not only great consternation amongst the local seniors, but myriad Letters to the Editor, as well as quite a few traffic accidents.”

Seduced by sea urchins. “The larvae have this crystalline skeleton. When you put them in polarized light, it jumps out at you, like little gems and jewels inside this swimming embryo. Once you see that, and look at all the other cool embryos that critters in the ocean have to offer, it becomes a pretty attractive field.”

“If you’re somebody who likes to ask questions and usually doesn’t like the answer you get, science is highly addictive—because the questions are endless.”

Lesson learned. As a doctoral student at UW in the early 1980s, Moon studied the regulation of protein synthesis in sea urchin embryos. An unfertilized egg doesn’t make much protein. But fertilization triggers a translation explosion. “The hypothesis was that there were inhibitory or regulatory proteins attached to the messenger RNAs, and that this masking mechanism would become unmasked after fertilization,” says Moon. What did he discover? “I learned that spending four years in the cold room smashing up sea urchin eggs by the gallon and running sucrose gradients and affinity columns was really not for me. The other thing I learned was that before you embark on the obvious next step in some scientific endeavor, it’s probably a good idea to try to replicate the underlying fundamental findings.” Previous papers had suggested that mRNAs from sea urchin eggs were “silenced.” Moon found that not to be the case. “So I wasted several years of my life,” he says. “But it did teach me to always validate my premises before marching forward.”

Language requirement. In the old days, students in UW’s zoology department had to be able to translate scientific articles from another language to get a PhD. “So I went to a lab in Palermo, Sicily, that was run by a famous Italian sea urchin embryologist,” says Moon. “I spent about three months there, hanging out in the sun, learning Italian, and trying to get some science done.” His first lesson? “Sicilians don’t actually speak Italian,” says Moon. But he did pick up some colorful local patois. “No one expects some American kid with a ponytail to be able to insult them and every relative of theirs in Sicilian. That alone was worth the trip.”

THE WORLD ACCORDING TO MOON

The beauty of youth. Moon landed his position as an assistant professor at UW at the age of 29. “I think it’s the perfect time to start a lab. You’re as young as you’ll ever be, as bright as you’ll ever be, as hardworking and focused as you’ll ever be, and you have as few distractions as you’ll ever have. By the time people are in their mid-30s, they have families and other responsibilities. Going to work just becomes one more thing on their agenda—as opposed to being an all-consuming calling, which is how it should be.”

The importance of being restless. “Every five years or so, we more or less completely reinvent how we approach things in the lab. Changes in technology are part of what drives the transition. The other part is my own restlessness. I’m always trying to look ahead to ask what are the new toys and new tools we can use to address new questions. The last thing I want to do is become somebody who spends a million dollars on an electron microscope and then sticks a sign on the door saying, ‘I’m an electron microscopist.’ That just seems supremely boring. I’d much rather be nimble and opportunistic and be able to change direction as technology changes and as the questions change.”

At the wheel. “The thing that surprises me the most about science is the fact that there really is nobody running the ship—both at the local and national levels. Which means that if anyone has a new idea, all he has to do is pipe up and chime in to get almost any reasonable idea heard and acted upon.” In addition to launching UW’s Institute for Stem Cell & Regenerative Medicine (ISCRM), Moon started an externship program that allowed graduate students to spend two or three months at a local biotech company. “It was the kind of thing that was possible to start because we decided, ‘What the heck. There’s nothing like it. Let’s make it happen.’”

To do or to know? “When we launched ISCRM, our goal wasn’t to do biology for decades and tease apart how stem cells do things. Our goal was to focus on therapies. So even though most labs here are run by PhDs, we’re very therapy-oriented. Understanding how things work would be nice. But that takes second place relative to the therapeutic endpoints we can achieve.” The experiment that brought that point home for Moon was one in which he and his colleague, Mick Bhatia of the McMaster Stem Cell and Cancer Research Institute at McMaster University, found that injecting Wnt directly into the abdomen of a mouse increased the number of stem and progenitor cells in bone marrow two- to threefold. If the approach worked in people—for example in cord blood transplants—fewer cords would be needed and bone marrow regeneration would be faster. “So you could effectively increase the number of people that could be treated and reduce their stay in the hospital,” says Moon. “If you could do all that simply by activating Wnt, in the end you wouldn’t care exactly how it worked. You’d just care that it worked.”

To experiment is human. “The limitation of science is that it’s done by people—people with all their imperfections. Which means science is never going to be clean. It’s always going to be quirky. Some people like to think that science is done antiseptically in some sterile environment, done by the book, according to some guidelines about whether some paper should be accepted or what constitutes a good grant. But these are all subjective things. That’s the fun—and annoying—part of science.”

Stepping away from the bench. “I did my own experiments until I was a professor. But I realized that when I’m doing an experiment, I pretty much don’t like to be bothered. So if someone comes and interrupts me—like a student or postdoc who has a question—I’ll say, ‘Go away. Come back later.’ And that’s incredibly selfish and unfair. So I decided that I could either do my own experiments and have a very small lab—or, if I was going to have students and postdocs, then I owed it to them to get out of the lab and go to my office and talk to them when they wanted to talk.”

Are we there yet? “It’s pretty unlikely we’ll come up with a predictive model of embryonic development in which we’ll be able to plot out the information flow in four dimensions and really understand how you go from a fertilized egg to an adult.”

Question dogma. “Most good scientists are not easily satisfied. So if you give them some simple answer, they’ll probe and go deeper. Whatever the accepted dogma might be, they’re willing to say, ‘What’s the evidence behind this? Who says that this is right?’ That’s why people who are at the interface between different areas of science often come up with the biggest discoveries. People who are deeply embedded in the field have generally bought into the prevailing dogma. Whereas people who move from one field into another will challenge that dogma because they didn’t grow up with it being gospel.”

Good scoop. “I’m not particularly covetous of things other people have done. If I were, that would imply that I had some shortage of ideas relative to time. I prefer to think my lab members and I have so many ideas and so many things we can do, that if somebody answers something we were interested in, I’m happy. Because that’s one less thing I have to worry about doing myself. Instead, I can integrate that information and move on to the next question.”

Science as addiction. “If you’re somebody who likes to ask questions and usually doesn’t like the answer you get, science is highly addictive—because the questions are endless. You can always push things to another level. That’s very appealing in a Sisyphean kind of way.”

MOONLIGHTING

Vacations. “I’m fairly ardent about sailing. It’s both challenging and relaxing at the same time. You can get to places off the beaten path, like little Greek islands that have maybe five people and one little restaurant on them. You just pull up during happy hour, have dinner, and stay a day—or a week. My wife, Susan Maillheau, and I have sailed around Greece three different times with Tomas Pieler of the University of Göttingen and his wife Karin. Greece has so many amazing places you can get to only by boat. And it’s pretty cool to be navigating around and say, ‘Hey, here’s the mouth of the River Styx. Let’s pull in and go for a swim.’”

Biking adventures. “When I was in college I had a BMW motorcycle. One summer I crisscrossed the continent, from Florida to L.A., then up to Seattle, into Vancouver, east across Canada, and back down to Florida. I learned that it’s possible to go 1000 miles, only stopping for gas. I also learned that Canadian motorcycle gangs aren’t as scary as they seem to be.” Half a dozen burly guys on Harleys accosted Moon at a fueling station. “I thought, ‘OK, this is the end,’” he says. “But all they really wanted to do was chat. They even invited me to one of their parents’ houses to eat watermelon.”

Hitting the road—literally. “Riding my motorcycle, I got run over twice. Both times, it was my second day at a new school. And both times, it was by an old guy driving a Chrysler Imperial.”

Facing mortality. “Besides almost being squished twice in motorcycle accidents, I had metastatic thyroid cancer when I was 21. That put a certain focus on the way I perceived things. It told me: don’t wait for tomorrow if you want to get something done; you’d better get started now. The experience didn’t push me into studying cancer, but it has made me much more sympathetic to the interests of patients who really just want therapies that work. I get an E-mail or phone call probably once a week from someone who wants to know about stem cell therapies. Although it might be tempting to ignore such requests, I make time to reply. These people are our support group, and they’re the reason we created the stem cell institute.”

 MOON’S GREATEST HITS

Demonstrated for the first time that a single secreted protein, called Wnt, is sufficient to specify the dorsoventral body axis in a developing frog embryo.

Pieced together the molecular chain of events by which fertilization of a frog egg ultimately directs the formation of a body axis.

Identified many components in the Wnt signaling pathway and, in particular, showed that Wnt regulates beta-catenin—a protein that translocates into the nucleus where it influences gene expression.

Pioneered high-throughput approaches for exploring the role of Wnt signaling in diseases such as Alzheimer’s and cancer.

With colleagues Chuck Murray and Tony Blau, launched the University of Washington’s Institute for Stem Cell & Regenerative Medicine in 2006. Helped raise $23M in donations in its first year of operation, including $5M from former Starbucks CEO Orin Smith.

Cofounded the San Diego biotech company Fate Therapeutics, which aims to use small molecules to boost a patient’s endogenous stem and progenitor cell activity. In 2010, Fate was named one of the 50 most innovative companies in the world by MIT’s Technology Review. “Not bad for a company that’s only three years old,” says Moon. “Especially when the list includes places like Apple, Amazon, and Microsoft.”

Comments

Avatar of: Christopher Lee

Christopher Lee

Posts: 50

November 3, 2010

Please delete this if it's off the mark.\n\n?I learned that spending four years in the cold room smashing up sea urchin eggs by the gallon and running sucrose gradients and affinity columns was really not for me."\n\nDon't worry, all scientific research has boring bits.\n\nThe comment rings a bell, though. Do people still spend their nights running affinity columns? I specialise in small molecules, but twenty-odd years ago, while working for a pharmaceutical company, I was asked to help isolate a membrane protein. I knew that any kind of chromatographic immobilisation tends to inactivate less fragile proteins than that one. Ours couldn't even be solubilised until I made some specially purified digitonin to use as detergent. Apart from that, technical innovation was not really wanted.\n\nA chromatographer knows that proteins give tailing peaks, so when you elute an affinity colum, your product is inevitably a bit contaminated.\n\nI couldn't understand why affinity chromatography must involve immobilisation. If you couple your ligand to biotin, your target protein should run almost normally on a gel filtration column (which doesn't immobilise). Inject a bolus of avidin, and it should run ahead of the crowd. Numerous variants should be possible; I don't have access to the recent literature, but have the impression that the technique became fossilised sometime during the 1980s.
Avatar of: Douglas Easton

Douglas Easton

Posts: 32

November 4, 2010

I was also in the urchin embryo smashing crowd at UW. Now I do different things but still fondly remember the UW Zoology departmen and the myriad of bright energetic young scientists, including Randy. The sailing was great for reducing the level of frustration.\n

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