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Sweet Smell of Success

With persistence and pluck, Leslie Vosshall managed to snatch insect odorant receptors from the jaws of experimental defeat.

By | July 1, 2012

image: Sweet Smell of Success Leslie B. Vosshall: Investigator, Howard Hughes Medical Institute, Robin Chemers Neustein Professor, Laboratory of Neurogenetics and Behavior, The Rockefeller UniversityAllan Zepeda/AP, ©HHMI

Leslie B. Vosshall: Investigator, Howard Hughes Medical Institute, Robin Chemers Neustein Professor, Laboratory of Neurogenetics and Behavior, The Rockefeller University ALLAN ZEPEDA/AP, ©HHMI

As a teenager in the early 1980s, Leslie Vosshall spent her summers in Woods Hole, Massachusetts. “My uncle is a scientist and he’d rent a lab there,” she says. “He always needed someone to come and do the glassware. It was a plum job, generally handed out via the nepotistic network. Some kids didn’t do a good job, spending more time playing tennis and going to the beach. But I liked the whole process, and I pretty quickly graduated to doing actual experiments. It was so completely different from what I had experienced in high school, where the football coach had been pressed into teaching biology.”

Her uncle, Philip Dunham, and his colleague Gerald Weissmann “were good at making science seem like this big adventure into the unknown,” says Vosshall. “Every day we would try different things, and we could go for weeks where nothing worked. But when we did find something, I knew it was a big deal.”

Those summers were the perfect training for Vosshall, who would go on to experience long periods of failure followed by spectacular bouts of success in her search to identify odorant receptors in Drosophila and mosquitoes. Here she discusses why she finds mosquito bites therapeutic, big meetings depressing, and folding T-shirts a potential alternative to bench work.

VOSSHALL STALLS . . . AND STARTS

Instant gratification. “My intention in going to Rockefeller was to work with Günter Blobel. But I’m an extremely impatient, impulsive person. I showed up on September 1, ready to join his lab. But Günter and his wife, a great restaurateur, spend every September in the Piemonte in Italy. I thought, ‘Forget it, I cannot wait a month to join this guy’s lab.’ So I frantically went through the list of faculty to figure out who else I could work with and I came across Michael Young, who works on sleep-wake rhythms in the fly. I think Günter was probably glad I didn’t join his lab, because it took me a very, very long time to get any traction on my thesis problem.”

Failure, Part 1. “I was widely viewed as the most pathetic graduate student. I had no hint of any success for the first 6 years of my PhD. I think failure, as long as it’s followed by success, is a really good thing. It builds a certain resilience. And you have to be persistent if you’re going to work on difficult problems. But it was dispiriting. Because failure that is going to be followed by great success feels exactly like failure that is going to be followed by more failure.” To cope, Vosshall kept busy after hours. “I bought some Super 8 equipment and I made really bad Super 8 films. The fact that I was a really bad artist redoubled the importance of my trying to become a good scientist. Because I couldn’t fail at two things.”

“I had no hint of any success for the first 6 years of my PhD. I think failure, as long as it’s followed by success, is a really good thing. It builds a certain resilience.”

Sweet success. In the Young lab, Vosshall set her sights on a protein called “period,” PER for short, which, when mutated, yields insomniac flies. As flies move through their circadian cycle, PER moves from the cytoplasm to the nucleus. “I made a large number of mutations in this protein, trying to disrupt its ability to get into the nucleus. What I found was that there’s basically no way to keep it out.” Then her lab mates identified another mutation, in a gene called timeless, which also alters the flies’ circadian rhythms. Vosshall found that in timeless mutants, the PER protein gets stuck in the cytoplasm. “So we knew right away, this is unquestionably how timeless works”—by escorting PER to the nucleus, work published in Science in 1994.

Failure-and-success, Part 2. In 1993, Vosshall joined Richard Axel’s lab at Columbia University as a postdoc. Axel and Linda Buck had recently identified the receptors that rodents use to detect odors. “I thought, ‘This is going to be great. We’ll find the odorant receptors in flies and then play with them.’ Two years went by, then three, then four. The more vocal people in and around the lab told me I should just give up and go to law school.” But she and her colleague Hubi Amrein tried every molecular biology trick in the book: using hybridization and PCR to look for genes similar to those discovered by Axel and Buck, even trawling through cDNA libraries they made from the olfactory neurons of locusts. “The litany of failures goes on and on. Then the Drosophila genome was sequenced and we teamed up with some bioinformaticists, also at Columbia. They sifted through the genome looking for all membrane proteins—and that’s how we found them. It was an 11th-hour save. When we went back through our freezers, which were filled with the thousands of clones we’d made, it turns out we actually had two of the receptors in our collection. They were just so weird-looking, we didn’t know what they were. So all those attempts to find Buck- and Axel-like receptors failed for a good reason: the insect receptors look like nothing else on Earth.” The discovery, published in Cell in 1999, helped her establish her own lab back at Rockefeller.

The switch. “In 2008, I made a decision that I was going to start studying mosquitoes. It was pretty terrifying. I’m afraid of heights and it was like standing on a building ledge and jumping. I had no idea how to breed them, no idea how to do genetics with them, no idea how to do anything with them. But I recruited a bunch of people who were willing to try. Now that we know what we’re doing, things are pretty streamlined. But we went through lots of disasters. We didn’t tell our neighbors we were making the switch, which was a big PR mistake. One of their technicians went into this hysterical campaign, saying ‘Leslie is spreading malaria.’ I didn’t pay enough attention to the fact that people actually resent being bitten by another lab’s experimental organisms.”

Playing favorites. In addition to assessing how female mosquitoes use cues such as CO2, body odor, and heat to find their next blood meal, Vosshall’s lab is examining why some humans are more irresistible than others. “We can absolutely replicate this effect in the lab: one person may attract 80 to 90 percent of the mosquitoes, and another will attract only 15 percent. Reliably. These differences are huge, and the task is to figure out: What are the mosquitoes smelling—and what does it mean to them?” The answer could lead to the development of more effective insect repellents.

Sacrificing for science. Mosquitoes can survive on sugar water, but to lay eggs, the females need access to blood. So Vosshall and her lab roll up their sleeves. “At first it was completely excruciating. I just stuck a hand in the cage—a total rookie move. You do not want to have a big, red, swollen, itchy hand. Now I wear a latex glove and put in my forearm. The mosquitoes all jump on at once, and they start puncturing the skin and injecting these numbing proteins. Your arm gets really warm and kind of numb and tingly. I actually do it while I’m holding meetings. We have this big tropical room and I’ll say, ‘I’m feeding for half an hour, come talk to me.’ It’s actually kind of relaxing.”

VOSSHALL GETS VOCAL

Data addiction. “Good science is gambling. Sometimes you make a bad bet and you lose a lot of money—and many years of  your life.” And, like gambling, science is addictive. “There’s no other reason you’d do it. There’s no way any rational person would repeatedly come up with nothing and still go back and keep trying. But the reward is so great you don’t care. It’s total junkie behavior. You’ll do anything to get a good piece of data.” Of course, those highs are pretty fleeting. “There have been maybe three moments in my career when I knew that I personally solved something. That’s a total of 6 minutes of extreme happiness over my 13 years as a student and postdoc. That’s pathetic. You really have to be a sick puppy to be in this industry.”

“Good science is gambling. Sometimes you make a bad bet and you lose a lot of money—and many years of your life. But the reward is so great you don’t care. It’s total junkie behavior.”

Skeeter Tweeter. Vosshall uses Twitter to spread the word about her latest laboratory exploits. “Maybe it’s my extroversion, but I find it fun. I’ve used social media to recruit volunteers for our human studies. The old model of being an academic in an oxford-cloth shirt and khaki pants who goes to conferences and writes review articles is dead. You have to interface with the public: they’re paying for all this work.”

Hands off. “I can’t say I was the greatest experimentalist in the world. I made great cDNA libraries and I was really good at manual Sanger sequencing. But these techniques are now extinct. So it’s probably best I’m no longer at the bench.”

Generation Y sequencers? Vosshall uses an Illumina sequencer to look for subtle differences in gene expression in a variety of neural tissues from mosquitoes—including insects that have dined on sugar versus blood, and those that prefer animals over humans. The downside of the new method: “The machines take an excruciatingly long time to run. You have to wait 2 weeks for an Illumina sequencer to do its work. Two weeks! What is it doing? Surfing the web? Logging on to Facebook? I know I should know more about what’s going on in there. But I’m very goal-oriented and I don’t really care. I just wish it would do whatever it’s doing faster.”

The importance of being honest. “I have no tolerance for secrecy or paranoia. When new people join my lab, I tell them: ‘Whatever you guys presented at lab meeting on Monday, I’m going to give a talk about it at another university tomorrow. I’ll be telling them everything we’re doing, even if it ends up being wrong.’ I think that being open and communicating with your direct competitors is really important.” When Vosshall started working on odorant receptors in mosquitoes, she e-mailed everyone she could think of to see if anyone was doing something similar. “Two people wrote back and said this guy in Sweden is doing it. Now we’re collaborating with him. He takes the scent of dirty socks and uses his expression system to see if the receptor responds. It’s a brilliant approach”—one she hopes will lead to the cues that attract mosquitoes to their human hosts.

Funding foul. “When I started in this business in 2000, if you wrote a good grant you would be funded. This is not the case now. I deal with it by not writing grants. I know it’s stupid and a bit pouty, but I just can’t stand the rejection.” And she doesn’t care for the current climate of rationing. Vosshall, now an HHMI investigator, had an NSF grant turned down in 2006—despite receiving near-perfect scores. She was later told that grants with lower scores were given priority because she had other sources of funding, where the other labs did not. “That’s not how it’s supposed to work. Is that how we run professional sports? ‘Let’s let this guy pitch. He’s not as good, but he hasn’t had a chance recently.’ This may work well in elementary school. But it is not how it’s supposed to work in science.”

Neuroscience downer. Vosshall prefers conferences that are smaller than the Society for Neuroscience annual 30,000-attendee jamboree. “I find it just the most depressing thing. You do get to hear great overview talks by senior members of the community. But the experience of trudging around these vast convention centers where there’s just too many people—you feel so completely insignificant. It’s very isolating and makes me wonder: Why am I here?”

VERILY VOSSHALL

Olfactory exploration. “I’m a total perfume fanatic. I’ve amassed this vast collection. Some I buy because I’m curious and I wear them a few times and then don’t wear them again. Others are old standbys. I buy a lot of very expensive niche perfumes that cost $200 to $400 for 50 mL. They’re beautiful and perfectly crafted, but you have to be a maniac to spend $400 on 50 mL of chemicals.”

Slave to nonconformity. “I’m a bit of a contrarian. I don’t like mass-media music, I don’t like mass-market art. I don’t like trendy things. When my husband and I named our daughter, we used the Social Security Administration’s database to cross-check our list.” Their criterion? “The name could not have been in the top thousand in the last century. So our daughter [Ophelia] has a really unpopular name. We never can find her a personalized keychain.”

Groovy. “I have a Victrola at my house in New Jersey and I collect 78s. My husband and I have a huge LP collection. Whenever possible, we get our records on vinyl. I’m heartened to see that it’s coming back for new releases. It’s really the only format that allows an adequate canvas for album art. I’m glad to see the CD die.”

T-shirt foldase. Vosshall says she probably wouldn’t survive outside the lab. “I’ve been in captivity my entire life,” she laughs. But if she had to earn a living in the real world, she’d head to the mall. “I could totally see myself in retail—being the person who refolds T-shirts at Old Navy and is unhelpful to customers. Keeping things straight in a completely mindless way would totally appeal to me.”

Playing hooky. “My inability to prioritize tasks prevents me from a) publishing papers in a timely manner and b) doing anything culturally interesting. My new resolution is to take one afternoon every week and go to a museum or a gallery. I hardly ever get out of the lab. I’d love to not check my e-mail and head to the Met.”

 

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Comments

Avatar of: Marcos Hardy

Marcos Hardy

Posts: 1457

July 17, 2012

Wonderful interview to an extremely intelligent, and very funny, scientist. The best I've read in a long time. Every graduate student and post-doc... and lab administrator... should read this tale of honest science and resilience.

Avatar of: James Kohl

James Kohl

Posts: 53

July 17, 2012

Dr. Vosshall's evidence that the epigenetic effects of nutrient chemicals (e.g., sugar and blood) on intracellular signaling and the subsequent stochastic gene expression that enables de novo olfactory receptor gene production in invertebrates seems to extend well to the epigenetic effects of pheromones on the same molecular mechanisms for the adaptive evolution of new genes and speciation. Doesn't it?

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