The joys of developmental neuroscience
A conversation with graduate student Andrea Yung
October 8, 2016
by Parizad Bilimoria
Andrea Yung relishes the process of discovery—whether it’s in the lab, in the kitchen or in the reptile hall of a museum. A conversation about how she got to graduate school and the experimental methods used in her daily work is peppered with words like ‘amazing’, ‘privilege’, and ‘fun.’ Her excitement is so fresh-sounding and the memory of her first experience working in a lab as a high schooler so clear that one might mistake Yung for a first year in the PhD program she’s part of.
But Yung is actually in her fourth year in the Program in Neuroscience at Harvard, not unaware of the challenges of submitting scientific manuscripts for peer review or the length of time it can take to generate new mouse mutants. She relays the big picture questions motivating her research with an experienced ease and is not far from pondering the directions she’d like to take in a postdoctoral fellowship.
Currently Yung is in the midst of experiments examining the molecular pathways that direct neuronal migration during embryonic developent—in other words, figuring out what controls the journeys our nerve cells make to get from where they are born to where they need to be to carry out their jobs. She’s working in the lab of Lisa Goodrich, Professor of Neurobiology at Harvard Medical School, which specializes in molecular and genetic approaches to understanding how neural circuits form.
“It’s really fun to go out and discover something new. There’s nowhere else you can do that the way you can in science. It’s a huge privilege to be a part of that.”
As a model for investigating this process, the lab studies the neural circuits underlying our sense of hearing, which include the spiral ganglion neurons of the inner ear. These neurons convey sound information to the brain and in mice can be followed all the way from their birth and migration to their integration into mature neural circuits and function in hearing.
“The function of our brain is based on these very precise connections that form between neurons,” Yung says. “And when your brain is first developing, all neurons originate from specific progenitor regions. Then they have to migrate long distances to end up in their final position. That initial migration is really important because if they don’t end up in the correct place, they can’t later form those correct connections.”
“So I’m studying how neurons get to the right place—by using a model system where they’ve ended up in a completely different place,” she adds, explaining that she is looking at what goes wrong in a mutant mouse (with a known genetic disruption) that results in a slew of extra neurons mysteriously arriving in the inner ear. This approach, reverse genetics, is a traditional one for probing gene function in many areas of biology—akin to a person trying to figure out what role a specific part plays in a complex machine by taking it out and then seeing how the machines functions without it.
This approach can be hard. As one might imagine, the whole machine might just break and it might be hard to pin down the role of the initial part of interest. This happens often to researchers studying mutant mice. For instance, the mouse Yung is studying doesn’t live long enough for the lab to do studies on hearing—which is obviously the first nervous system function anyone interested in the inner ear would want to test. Thus Yung is now generating a ‘conditional mutant’ – an animal in which the gene of interest can be turned off at specific developmental time points, in specific sub-populations of neurons—to try to better hone in on its function.
One of the philosophies that fuels Yung’s passion for basic science and keeps it going through all this hard work is that there is something tremendously valuable and inherently unique about being able to ask a question and follow whatever road the data takes you to. “Scientists don’t have to have an agenda,” she says.
“It’s really fun to go out and discover something new. There’s nowhere else you can do that the way you can in science,” she adds. “It’s a huge privilege to be a part of that.”
From axolotls to axons
Looking back, perhaps Yung’s future as a biologist was not a surprise. When she was a child growing up in San Jose, CA, Yung’s parents often took her to the Monterey Bay Aquarium and the California Academy of Sciences. Her favorite exhibits there were the exotic amphibian and reptile tanks. In particular, she was drawn to albino crocodiles, salamanders, snakes and axolotls.
Axolotls, also known as ‘Mexican salamanders’ or ‘walking fish’ are an endangered species of amphibians of great interest in neuroscience research, due to their ability to regenerate limbs. Yung recalls telling her mother she’d like one as a pet instead of a dog or cat.
Andrea around age 10, at the USS Hornet Sea, Air and Space Museum in Alameda, CA.
“I feel like kids’ interests generally segregate into dinosaurs or space and mechanics, and I was very strongly on the dinosaur side,” she adds. Until she was about 8 or 10 years old, Yung dreamt of becoming a paleontologist. But that ended, she notes with a laugh, when “I realized that involved camping, and I am not an outdoors person.” In high school, Yung took a biotechnology class where she learned to pipette and ‘run gels’—a standard procedure for separating and analyzing DNA, RNA or proteins based on size. The fun she had doing those lab exercises led her to email a long list of Stanford biology faculty until she found a summer internship opportunity.
Yung says she was tremendously fortunate to end up in the lab of Luis de Lecea, Professor of Psychiatry and Behavioral Sciences at Stanford. She worked with a graduate student who was studying the control of sleep and wake cycles using a technique that at the time was brand new—optogenetics—where light is used to turn on or off the activities of proteins of interest (genetically engineered to be light-sensitive) in living cells.
“Oh my god, this is so cool!” she remembers thinking when she saw the student flash blue light on a mouse brain and realized that the molecular changes induced in the targeted neurons were leading to observable behavioral changes, such as the mouse waking up from its sleep.
Indeed, she wasn’t the only one to have that response. De Lecea’s lab was one of the first to successfully use optogenetics in a behavioral study—and since then the method has gone on to change the face of modern neuroscience—allowing researchers to ask and answer questions about the role of specific neural circuits in controlling behavior with a precision that was previously unimaginable.
Yung ended up staying at Stanford for her undergraduate studies and taking an inspirational developmental neurobiology class by biology professor Susan McConnell. She then did her thesis in the lab of Tony Wyss-Coray, Professor of Neurology—studying the role of immune molecules in controlling adult neurogenesis, the hotly-debated and poorly-understood process by which a small number of new neurons are generated in the adult nervous system.
So when it came time to decide what to do after college, going to graduate school for neuroscience was an obvious choice. Yung entered Harvard with a clear interest in understanding how neural circuits form and found a welcoming home for her interests and personality in the Goodrich lab, which in addition to migration studies a wide range of other processes in neural circuit assembly and the morphogenesis of neurons. For instance, how do neurons become specialized for one circuit over another—say for the sense of hearing over other functions? What genes control this? How do the axons—the long, thin output structures that carry electrical impulses from one neuron to another—know when, where and how far to grow to form proper neural circuits? What are the genes that orchestrate these steps? What role do interactions with glia (non-neuronal cells) play in the circuit wiring process? And how might answering these basic sciene questions in mice help in combating clinical problems in humans such as hearing loss?
“What I’ve really come to enjoy is not just working on my project,” Yung says, “But also hearing about other people’s projects in the lab and seeing the lab as a whole move in new directions.”
On graduate school & gratitude
One of the most striking things about Yung is her sense of gratitude. She’s the first to point out that she was fortunate to go to high school in an area privileged enough to have a biotechnology class. That’s she fortunate to have had the parents with the time and means to take her to science exhibits as a child. And even with her dissertation project, when she has a success, she’s quick to acknowledge the element of luck and the contribution of others.
“I’ve been really, really lucky,” she says, and notes that she entered the lab soon after a postdoctoral fellow, Noah Druckenbrod, had found the interesting result of the mystery neurons in the spiral ganglion in the mouse that she’s now studying in depth. She also credits her enjoyment of graduate school to the positive relationship she has with her mentor. This is evident simply in the way Yung speaks about the Goodrich lab and the enthusiasm with which she notes the array of projects open to new lab members.
On the lighter side, in addition to their love of developmental neurobiology, both Goodrich and Yung share a fondness for cooking and baking, and the hypothesis that being able to bake well correlates with being able to do science well. “You’re aliquoting and mixing stuff and then putting it in an oven to incubate for a bit.” Yung notes, outlining how following a protocol can sometimes be a bit like following a recipe.
She brings in all sorts of cakes and cookies for lab meetings, and at the moment is gushing about a book she’s started on the art and science of Chinese cooking, Phoenix Claws and Jade Trees. She hopes to learn about the spices of different regions in China, banquet style meals and why a chef might boil and then fry something over just frying it, or vice versa.
“There are many people here who are my inspiration in that they are doing what they love and have a good work-life balance .”
Beyond the lab, Yung expresses has a deep sense of gratitude towards the graduate program and university itself. “I’m from the west coast, and Harvard gets a bit of a bad name for being a cold or inhospitable place,” she starts. “But people here are so nice and generous. It’s a privilege not just to work here and meet all the mentors I have, but also to be a part of the graduate program, which does a really good job of fostering its students.”
In fact, Yung admits that after all the tales of misery she’d heard about graduate school in general, what has surprised her most about the experience so far is her level of happiness. She actually prefers graduate school, with its focus on hands-on, exploratory learning over classes, more than college.
She emphasizes that personally knowing leading scientists at Harvard with a healthy life outside the lab is really encouraging as she ponders her next steps in academia. “There are many people here who are my inspiration in that they are doing what they love and have a good work-life balance,” Yung declares. “They show that it can be done.”