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P&S Journal

P&S Journal: Spring 1995, Vol.15, No.2
Inside the Howard Hughes Labs :Of Mice, Men, Women, Fish, and Other Things Research

Stories by Doug Brunk

If Howard Hughes could see the results of the medical institute he launched 42 years ago, the billionaire might grin as wide as the panhandle of Texas, his native state. His charity that initially backed a handful of biomedical researchers with a mere stipend now generously supports 279 principal investigators at 63 sites. One of those sites is Columbia, where eight scientists are hard at work in two formal Hughes programs and in other labs sprinkled throughout P&S.

"From an administrative perspective, one of the institute's strengths is that we're very service-oriented in the way of getting people what they need to do their work," says Marilin Riedler, manager of administrative services for the Howard Hughes Medical Institute (HHMI) at Columbia. "It's rewarding that we can be instrumental in assisting in the conduct of such exceptional science."

The Hughes efforts at Columbia include the HHMI Program in Structural Biology, which focuses on the biophysical nature of molecular structure, and the HHMI Program in Molecular Neurobiology, which is centered on the workings of the brain, how nerve cells signal, how neural circuits are formed during development, how animals perceive their environment and how they develop their behavior through learning. Though the science differs in these two programs, encouragement to exercise originality and independence-an HHMI staple-is evident.

Structural Biology

"If I were to use a single word to describe my life it would be frustration," says Dr. Wayne Hendrickson, who directs the HHMI Program in Structural Biology. "I'm forever feeling regretful that I haven't been able to attend to this, that, and the other. What saves the lab is that the people are extremely good."

Scientists affiliated with the structural biology program apply the basics of molecular biology, protein chemistry, and physics to uncover the framework of molecular structure. Each of the 19 students and postdocs works on his or her own project from scratch.

"There are common threads," Dr. Hendrickson says. "A focus of interest in general for the lab is associated with properties of molecules at the cell surface. But the specific molecular or biochemical systems that people work on tend to be fairly distinct. Direct collaborations among the various people are rather limited, so there are a lot of projects going on. It is extremely difficult to keep on top of all these."

Dr. Hao Wu, a postdoc, appreciates the kind of independence encouraged in the lab.

"Everybody has their own project. It makes you really think about what you're doing," she says. "Wayne is also supportive. If you need advice, he will definitely give his opinions which are usually very good, but he never pushes you to do anything. He's preparing you for the future this way."

Dr. Hendrickson says this hands-off approach stems from his own experience as a doctoral student in biophysics at Johns Hopkins University.

"Are you neglecting people or are you actively helping them mature?" Dr. Hendrickson asks. "My feeling is that by putting people in a situation where they need to look after their own things and they're periodically guided, you can get them to learn the maturity it really takes to be a scientist."

Two years ago the structural biology lab moved from the fifth floor to its current home in the west wing of the second floor of the Black Building. Dr. Hendrickson designed the three main rooms of the L-shaped lab to complement his leadership style.

"I make sure there's a sprinkling of students and postdocs," he says. "Part of the plan is that the postdocs who have some greater experience will be there to help out in the guidance of the younger students."

That philosophy benefits graduate student Xuliang Jiang.

"You don't get the response, 'I don't know,' when you ask a question here," Mr. Jiang says. "I get tremendous help from the postdocs. That's the best."

Dr. Francis Athappilly, a postdoc, describes it as "a very supportive and educative atmosphere. When you get a new idea, you talk to people in the lab. Oftentimes you get useful criticism. The breadth of experience in the lab is remarkable. Anyone can learn from the experience of others," he says.

"For example, when I was doing my genetic work I learned a lot from those who had done similar work. I was trained as a crystallographer. So when I expressed my first protein I was very thrilled."

People who study molecular structure share a common drive for definite answers. Speculation doesn't fly in this field. "There's probably a correlation between people who enjoy intricate, complicated puzzles because some of this is of that character-the methodology that one goes through," Dr. Hendrickson says.

"There needs to be a certain amount of physical and mathematical experience and talent. There are a number of things you can say you really know, and you're not inferring from metaphysical data. You can say, 'This is the character of the system. Here's a picture of it.'"

Ideas for projects can spring from unlikely places. "One of my friends happened to find himself sitting on the subway next to a graduate student from another laboratory," says Larry Shapiro, a third-year graduate student. "They began to talk, and the existence of some of these proteins was mentioned. It filtered back to me, just through talk on the subway."

The framework of that conversation inspired him to pursue a project aimed at identifying the proteins discussed.

"I would say that's not uncommon," he says. "Many things come by chance. I don't know that the Hughes labs are any different in terms of the kind of scientific interactions that go on between people."

Scientists live by milestones that signify achievements, such as publishing work in a scholarly journal. But the Hughes lab run by Dr. Hendrickson takes these milestones one step further. He hosts champagne celebrations to mark the discovery of molecular structures and the completion of dissertation projects by Ph.D. students. "I also bring in non-alcoholic drinks to make sure everybody's covered," he says.

He labels the achievements on champagne corks with an ink marker. A growing cork collection rests on a shelf in his office.

"This started when things were reasonably calm and this didn't happen too often," says Dr. Hendrickson, who came to Columbia in 1984 and joined the HHMI two years later.

He smiles.

"Fortunately, for the lab and science, there are a lot of corks. Unfortunately, it costs a lot of money to buy this champagne. But it's fun."

The lab's conference room serves as the focal point for bull sessions, lunch, weekly staff meetings, and monthly birthday celebrations. Last summer Mr. Shapiro spearheaded a fund-raising effort to install a fish tank in the conference room. Today, a six-foot-wide tank stands opposite the chalkboard. The quiet hum of its filters and the gentle sways of the fish ease minds troubled by a mathematical equation or a molecular structure.

Dr. Hendrickson paid for the tank and his colleagues stocked it with gilled creatures and various plants. Mr. Shapiro affectionately named the largest fish "Wayne."

"I didn't buy Wayne, but it was important to have Wayne," Dr. Hendrickson says.

Wayne, the fish, can be just as hard to find as Wayne, the lab director, who travels extensively to gather and present research. He also spends a lot of time at HHMI's multi-million dollar synchrotron facility at Brookhaven National Laboratory on Long Island, which enables scientists to obtain diffraction data from crystals too small to measure with conventional equipment.

"We sometimes joke that Wayne is on the phone or out of the office when the fish doesn't come out from behind the moss," Mr. Shapiro says.

Long-leafed plants drape the conference room's window sill and postcards from around the world dot the wall behind the sink and beneath the cabinets. Two proverbs from fortune cookies taped to the refrigerator door read: "Hope for the best, but prepare for the worst," and "It is better to have a hen tomorrow than an egg today."

But the most noticeable shades of character stem from clippings of the popular Far Side comic strip that hang from numerous vantage points in the room.

"There's only one common thread we've been able to find in all the people in the lab, and that happens to be people who appreciate Gary Larson cartoons," Mr. Shapiro says.

Dr. Hendrickson deliberately chose to locate his office adjacent to the busy conference room area.

"I wanted my own office close to the hub of activity, not in isolation," he says. "I expect people to come to me. I almost never shut the door. I made sure that the construction people cut a window in my office door when I came here. I wanted people to see whether they could come in. I encourage people to see me whenever they feel they need to. That has disadvantages. The squeaky wheel gets oiled in that system, and the one that's not so squeaky might not get the attention it needs. When life gets busy, that's one of the things I regret the most."

Manuscripts written by graduate students and postdocs rest on a round table in Dr. Hendrickson's office. It's a common sight that embarrasses him. He pulls out stapled papers from a stack and holds them like a book.

"For the last two days we've been preparing a pair of research papers for publication that were to have gone out yesterday. They'll go out today," he says. "I've been working quite a bit on these projects for various reasons that have to do with technical things, the analysis of the structure, and things that I'm keen on."

With time so precious, Dr. Hendrickson relies heavily on people like Nilda Belgado to keep things on course. As lab manager, she stocks supplies and stores tissue cultures for each project.

Like most laboratories of science, working hours vary in this lab. Mr. Shapiro worked extensively long hours last December during the final leg of a project. One day, after working from 10 a.m. to 7 p.m., he returned at midnight and worked until 5 a.m. the next day. While that was out of the ordinary, long hours are commonplace.

"Most people work 12-hour days, six days a week," Mr. Shapiro says. "That's the standard."

Donna Horn, the lab's administrative assistant, considers her colleagues on track with HHMI's mission to promote research and science education for future generations.

"I truly hope future high school and grade school generations will view science in a new light given the way laboratories such as Wayne's are run, that is, the level of independence and respect they're given," Ms. Horn says. "It nurtures their confidence and intelligence. There's nothing in life that's more important in a career sense. If elementary and high school teachers could simulate this type of environment and attitude stimulating the minds and creativity of the students, I think it is quite possible that there would be a lot more students seriously considering science and math as careers. Students deserve to be better prepared for the challenges they will face in the future, a future that can only become more complex than they can now imagine. I believe we will see a healthier future given the opportunities offered by such institutes as HHMI and given proper guidance from professors such as Wayne."

Molecular Neurobiology

Scientists used to thinking about questions in a straightforward way often find their notions challenged when they work for the HHMI Program in Molecular Neurobiology. The main lab for this program is located on the sixth floor of the New York State Psychiatric Institute Annex.

Wearing a rugby shirt, jeans, and work boots, Dr. Mark Mayford sits at a round table in the lab's conference room one winter morning editing a manuscript for publication. He commutes daily from New Jersey and is one of the first people to arrive at the lab before 9 a.m.

"It's a real challenge to use molecular biology to think about complicated questions in memory and learning," says Dr. Mayford. His five years as a postdoc bring long-term perspective on the lab. "The small answers are clear, but you have no idea how to put them together to answer the big questions."

He describes the goals of postdocs with self-deprecating humor. "The duties of postdocs are to come up with brilliant new scientific discoveries!" he says.

Dr. Eric Kandel, University Professor and HHMI senior investigator, directs the lab. Dressed in khakis and a V-neck sweater, he sits cross-legged in a captain's chair as he discusses the science he has studied for more than three decades.

"These are difficult, long-term problems," Dr. Kandel says. "Molecular biology over the last 25 or 30 years has moved to progressively more complex questions. It's gone from bacterial physiology-understanding how single organisms work-to multicellular organisms. Molecular biology is now addressing broader issues in multicellular organisms: how systems of cells interact to produce an output, how does the immune system work, how is the organism's form shaped by development. More recently, it has become possible to use molecular biological tools to ask how the brain works. The molecular underpinnings of mental processes is the last frontier of science. It's one of the great unsolved mysteries of biology. We don't know the answers here. We're at the verge of trying to define the problems."

The lab consists of three main groups: Those who study learning and memory in mice; those who study learning and memory in a small sea snail, Aplysia; and those who study the mechanism of synaptic transmission.

"Basically, all higher cognitive functions in humans-learning, memory, emotional changes-are thought to involve changes in the underlying molecular and cellular physiology of the brain," says Dr. Mayford. "But it's difficult to test that directly. You can't go in and start playing with human brains."

Dr. Mayford and his co-workers hope to gain a better understanding of human brain function by manipulating the genetic makeup of mice. "The nice thing about it is you can change a molecule, then you have an animal you can study over and over again in a lot of different situations. You can study its behavior, how the cells in its brain are firing, the patterns of electrical activity, and try to get an understanding of how deficits in brain function are caused by changes in molecules in the brain, and how that in turn leads to changes in the behavior of that animal."

Using the Aplysia as model, Dr. Dusan Bartsch studies the switch between short-term memory and long-term memory. "We are trying to identify new molecules, new proteins that participate in the transition between short- and long-term memory," says the Czechoslovakian-born postdoc.

He sits at a table in the centrally based conference room and uses hand gestures to explain his work like a university professor delivering his first lecture.

"We are cloning new proteins which we think are involved in this switch," he says. "We are using Aplysia, but the goal is to see how general this mechanism is. Up to now, it seems to be fairly general between Aplysia, flies, and mammals."

Dr. Bartsch and his colleagues meet each week in the conference room to discuss their projects.

"Here the meetings are more like a seminar," Dr. Mayford says. "The lab is big. Sometimes I don't even know what everybody is working on. I can go talk to them, but if I spend my days running around talking to people I won't get any of my work done. So the lab meetings are nice in that you sometimes find something that you hadn't known, an advance that's been made by someone down the hall that you haven't caught up with in the last month or so."

Rene Baston keeps a pulse on each project. Formerly a technician in the lab, he became the lab's manager a year ago. "You have to learn how to run two and three things at a time." His routine duties include checking inventory, ordering supplies, coordinating with repair technicians when equipment breaks down, and monitoring safety and hazardous waste issues.

Like the New York metropolitan area, cultural diversity defines the lab, where 13 countries are represented.

"I enjoy working with young people from all over the world," says Seta Izmirly, the program coordinator. "It's very interesting and very informal. Everybody calls Dr. Kandel 'Eric.'"

"We share each other's cultures," says Stephanie Wein, the lab's administrative assistant. "We're always trying to figure out differences." Collaboration among lab members develops many friendships, sometimes marriage.

"My most rewarding experience is that I met my wife in this lab," Dr. Mayford says. His eyes widen.

"She was a graduate student. When I first got here-it was quite convenient-I happened to get the desk immediately adjacent to hers. It worked out quite nicely."

Seta Izmirly, who started in the lab in 1987, knows of at least three other couples who married after meeting in the lab.

"I don't know if we have a higher frequency of marriages than other labs, but I've found my wife to be quite compatible with me!" Dr. Mayford says.

"The people that are drawn here are usually pretty dynamic and usually are thinking along the same lines you are. There are a couple kinds of people in science, I think. There are some people who think, 'What can I do?' and there are other people who think, 'What's the most important question?' This draws people here: 'What's the most important question?'"

Paul Skehel, a postdoc from London, says Dr. Kandel displays a persistent curiosity that is contagious. "The thing that stands out about this lab is Eric's incredible enthusiasm and energy. I don't know if all Hughes labs are like this, but there's an enthusiasm that's backed up with support to follow where the enthusiasm is taking you. That's the feel for this lab. It's not an empty enthusiasm."

"Just to attend seminars with him is a very good experience," Juan Carlos Lopez-Garcia, one of three graduate students in the lab, says of Dr. Kandel. "He always comes with the most unlikely questions and reasonings based on his previous experience. It's been the kind of experience I've never had before, to interact with someone who is really in the frontier of neurobiology and to get the latest ideas in the field I've always been interested in. That has been very rewarding."

He also praises the interaction with people in the lab. "You can get help on whatever you need. You don't need to be wasting time on things that will not work, because there's always someone to give you a word of caution before you engage in something that is hopeless."

Dr. Kandel advises students to think for themselves as they tap into the workings of learning and memory.

"Obviously I'm concerned with what everyone does, but I don't feel that I want to necessarily impose my own thinking on every single problem in the lab," Dr. Kandel says. "I really see my function as enhancing people's productivity, setting overall direction, and encouraging people to think on their own in specific problems."

The sweeping view of the Hudson River and midtown Manhattan from Dr. Kandel's office windows reminds his visitors of the constant motion in life, the constant questions. He dangles his eyeglasses in his hands as he continues to reflect on his work.

"We're trying to do the very best science we're capable of," he says. "We have high standards and high aspirations. I think it's a very exciting time to be working in the field. There are some terrific problems, problems that are not going to disappear within the next couple of years. They're the kinds of things you can get your teeth into and work on for a whole career."


copyright ©, Columbia-Presbyterian Medical Center

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