Foresight

One thing she took to heart was how much fun science can be. “There was always this tremendous excitement about finding out something new,” says Shatz, who was there when the pair did the work that would win them a Nobel Prize in 1981. “Of course, I’ve since discovered that I’m not Hubel and Wiesel,” she laughs. “But that excitement is something I’ve always cherished.”

Shatz discovered that the eye sends visual signals to the brain very early in development—even before an animal can see.

And it’s something Shatz has experienced again and again, as she and her colleagues continue to make eye-opening discoveries about the mechanisms and molecules that direct the proper wiring of the visual system during development. Her findings have not only deepened our understanding of how the brain works, but have spurred entirely original fields of inquiry—including a new way of looking at how the immune system communicates with the nervous system, and how this web of interactions gets disrupted in disease.

Here she talks about the game-changing discovery everyone told her was wrong, the dark side of technology, and what skiing can teach about science.

SHATZ TAKES AIM

Eyes wide shut. As a young faculty member at Stanford, Shatz discovered that the eye sends visual signals to the brain very early in development—even before an animal can see. “We were studying how the connections between the eye and the brain form during development,” she says. “What we knew was that the initial immature pattern of connections is not the same as the adult pattern. The baby’s brain is not a miniature version of the adult.” The adult pattern emerges when the disorganized jumble of connections that the retina makes with the immature brain gets pruned and tidied: inactive synapses are eliminated; active synapses are stabilized and strengthened. “But these connections form in utero—before vision is even possible. So where was this activity coming from?” Shatz and her postdoc Rachel Wong—in collaboration with Denis Baylor and his postdoc Markus Meister, also at Stanford—studied embryonic retinas. “And we were surprised to discover that not only do the nerve cells in the eye generate their own signal, but that the activity is highly synchronous and coordinated. So these waves of activity are being sent to the brain until the eye is open and vision takes over. This was just a huge surprise.” And it turns out the phenomenon is not unique to the eye. “The embryonic spinal cord is also generating highly correlated waves of activity,” says Shatz. “So when a baby is kicking in utero, it’s basically rehearsing for movement, the same way these retinal waves are a rehearsal for vision.”

Who says seeing is believing? An even bigger surprise came when Shatz and her lab set out to find the molecules responsible. “This was in the old days, before microarrays were readily available,” she says. The investigators isolated mRNAs from fetal brains in which neural activity had been blocked, so that synaptic remodeling did not occur. And they compared this collection to mRNAs from normal animals to determine whether there were genes whose activity was noticeably altered. “To our huge surprise, we found that one of the most highly regulated genes was that for an MHC class I molecule. There was a twofold change—it was high in the normal brain and low in the brain with blocked activity. It was very striking.” And more than a bit puzzling. MHC class I molecules are used by the immune system to present antigens for recognition by T cells. “People told us we were crazy,” says Shatz. “Because everyone knew that neurons don’t express these molecules. We submitted the paper to Nature and got a letter back from the editor telling us to please go back to the lab and figure out what we had done wrong. So I thought: there are two possible ways of reacting to this. One is to say, ‘Yeah, I must have done something wrong. So I’d better figure it out or do something else.’ The other is to say, ‘I know this is right and I’m going to have to work really hard to prove it to everyone.’ Which is what we’ve been doing ever since.”

Mutual understanding. After the initial finding appeared in Neuron, Shatz and her colleagues went on to show that knockout mice lacking members of the MHC Class I family cannot remodel their visual connections, leaving them with the immature arrangement—work published in Science in 2000 and in a followup paper in Neuron in 2009. They also found that MHC molecules in the brain interact with another molecule previously thought to be confined to the immune system: a receptor called PirB. Mice lacking this molecule show defects in visual wiring and plasticity similar to those of mice lacking MHCs. “So we think we have found both ligand and receptor”—which work together to regulate the density of synapses in the developing brain. PirB is part of the innate immune system, which appeared early in the evolution of multicellular life. “What we’re probably looking at is an older signaling system that coevolved in the nervous system and in the immune system,” says Shatz. “And I think that’s just the tip of the iceberg.” Other labs are finding additional immune molecules in the brain. And three recent genome-wide association studies linked variations in the MHC gene cluster with schizophrenia and bipolar disorder. “These findings lead to a completely new way of thinking about how the immune and nervous systems could really interact—the concept that neurons and the immune system share a common molecular language. It’s still early days, and there’s still a lot of skepticism. But I think it’d be really cool if we could contribute to an understanding of what goes awry in disorders like schizophrenia.”

SHATZ PHILOSOPHY

Prodigal daughter. In 2000, Shatz returned to Harvard Medical School as chair of neurobiology—the very department that had debated whether to accept her as a student. “Almost all of my professors were still around and still contributing to the department,” says Shatz. “And all of a sudden I was kind of like their boss. So I always say that you have to be really nice to your students—because you never know in what form they’re going to come back to haunt you.”

One for the women. Accepting the position at Harvard “was probably one of the hardest decisions in my life,” says Shatz. Her science took a hit when she was forced to give up her funding from the Howard Hughes Medical Institute—the organization’s policy at the time. “But I felt very passionate about being a role model for women scientists”—and she suspected if she turned Harvard’s offer down, no other woman would get the nod.

Expect the unexpected. “If you design and execute an experiment and you get exactly the result you expected, then there’s something wrong with the experiment. If you’re paying attention to all the data, your experiment should be telling you more than just what you expected. It’s when you look outside the expected results—beyond the light that’s directly under the lamppost—that you can make a major discovery and come up with something really interesting and unusual.”

Chair of day care. “When I was recruiting faculty, I’d have to say I spent more time worrying about child care than probably any other one topic, because we were really trying to come up with ways we could support the careers of these young scientists, both men and women, at a time when many of them are starting families and both parents are working. It sounds silly, because you think it’s all about the science. But these personal issues can become very important.”

“You have to be really nice to your students—because you never know in what form they’re going to come back to haunt you.”

Method madness. “Many scientists are becoming overly enamored of new technology and have forgotten how to pose a serious question. And at the funding level, people have gone overboard in their excitement over the methods and have forgotten to some extent the problems that have to be solved. Don’t get me wrong: these new methods are fabulous. But I’m concerned that people seem to get more excited about the nth paper to use a new sexy method to confirm what we already knew, than they do about working on a problem that could not have been solved before we had the method.”

In from the fringe. “Because people are so overwhelmed these days, we tend not to spend as much time reading the literature. So a lot of the transfer and evolution of knowledge is happening informally at meetings. That’s both good and bad. It’s good if a field is already established and you’re a recognized part of it. It’s bad if the field is just starting and is still on the periphery. It means that new fields may stay fringe for much longer.”

The importance of being blinded. “I encourage my students to do experiments that are blinded, especially when it comes to looking at mice with different phenotypes. Sometimes I even go back and ask other people in lab to recode the data so it can be analyzed again independently. It means more work and it takes longer to do the experiment. But it’s a really good way to remove any bias, and it makes me much more confident in our results.”

Spicing it up. “Although I meet with every student in my lab regularly, we have a tradition that often they’ll save a little surprise for the group lab meeting. I think that the element of surprise helps make things more fun and exciting for everybody.”

SHATZ SHOOTS THE BREEZE

To thine own self. “My parents spent my entire childhood telling me not to worry about what other people thought. It made me a little tougher than I might have been otherwise, able to withstand criticism and to take maybe a little bit of a different path in life—both in becoming a scientist and also in choosing the kinds of questions I’ve worked on throughout my career.”

Just do it. “I was a very serious ballet dancer until I was about 24, and I also skied competitively. Ballet gave me a tremendous amount of discipline, and both sports gave me an understanding of courage, of what it takes to do something hard—and even potentially dangerous. There were times when I would ski with friends on these incredibly steep slopes where you literally could not see the bottom. You just had to push off with the expectation that you’re going to rely on your skill to get to the bottom. I think that’s a good analogy for what we do every day as scientists. In the lab, you have to take risks and you don’t know what the outcome is going to be. But you know that your skills as an investigator will serve you well—and that if you fall, you’re going to pick yourself up and learn from your experience.”

Biology lessons. “I never thought that family was something I was going to have to give up for science. I had a nice marriage that didn’t work, and we couldn’t have kids because I thought I could wait until I got tenure. This was at a time when women’s lib made us all think we could do everything, we could have it all. Well, it didn’t work for me. And that has been a big disappointment in my life. So my personal advice is that there’s no good time to have children, so have them when your biological clock makes it most feasible.”

Show me the finches. “This year I went with friends to the Galapagos, which is like a pilgrimage for a biologist. Funny thing, I thought, ‘Oh, I’m going to see all the Darwin finches and I’m going to see how different each one is: the beak of this one versus the beak of that one.’ Most of the animals on these islands are incredibly tame, because humans aren’t predators. But the finches are just so little and they move so quickly, they’re the one thing you actually don’t get to see!”

Exit strategy. “One of biggest challenges that faces me right now is to figure out a way to transition gracefully into whatever the next stage of my career will be, say, 10 years from now. I want to continue to help facilitate the careers of young scientists. But I don’t think our institutions are doing a good job of giving us options. Many places give you a teeny little office in a basement somewhere, with dripping water and rats all around, so you can come in and get your mail. But I think we really have to think about this issue in a much more creative way.”