Dialogue with disease

March 24, 1995

Lucy Hodges meets Julie Theriot, a biologist who listens to bacteria talk. In her lab in Cambridge, Massachusetts, Julie Theriot is busy growing nasty strains of bacteria. She nurtures listeria and salmonella, as well as a bacteria called shigella flexneri, which results in an awesome statistic - 150 million cases of dysentery in the world and 500,000 deaths. Separately she tends live cells in an incubator.

What she does is to mix the bacteria with the cells and watch what happens under a powerful video-microscope. No animals are involved. There are no blood and guts at the Whitehead Institute for Biomedical Research. This is politically correct science. Theriot's live cells came from an animal that died ten years ago and have been immortalised in culture.

At the age of , Theriot has achieved what many budding academics spend years working towards - a lab of her own. She has a staff of three, a technician and two postdoctoral students, and her own budget. All of which come from her appointment as fellow at the Whitehead Institute, one of the top biomedical research institutions in the world, set up "to support innovative ideas by the finest young minds in science".

The Whitehead fellowships are incredibly prestigious. Typically, only one is offered each year. Theriot received $175,000 for equipment in the first year, plus her salary and that of a technician. Today a grant from the National Institutes of Health pays for some of the salary bill and operating costs.

Theriot is expected to go far. She is already winning awards for her research - last year it was the 1994 Women in Cell Biology Award. One of the things that fascinates her about her research on cells is the way bacteria can communicate with animals and human beings. "I think of all of life as being interdependent and interconnected," she explains.

Since starting her research career, she has been studying cell motility, in other words the way cells crawl around inside the body. Nobody knows how the process works 100 years after anyone first began to look at the phenomenon.

Today she is trying to work out how bacteria "talk" to the host cell in living things. Having discovered the protein on the surface of the bacteria that communicates with the host cell, she is trying to identify the corresponding protein on the host cell.

She is concentrating on the moment of communication between the bacteria and the host cell to see how it is the bacteria tell the actin (the protein) in the host cell to rearrange and form new structures and gets it to move around.

It amazes her that bacteria have been able to evolve ways of speaking so specifically to the proteins in our cells that they can tell them what to do.

Theriot is looking at how the bacteria infect the cells - the stages of the process and the messages that are sent before a host cell capitulates and becomes an infected cell.

In the case of shigella flexneri and listeria, the food-borne parasite that causes meningitis and stillbirths in human beings, the bacteria co-opt proteins on the surface of infected host cells to form "comet tails". The tails give the bacterium speed so that it can leap from an infected cell to an uninfected one, thereby spreading infection and reducing the bacterium's exposure to the human immune system.

The two species of bacteria -shigella and listeria - are entirely unrelated, yet they use the same strategy. To Theriot that suggests that the tail strategy developed independently more than twice in bacterial evolution.

Salmonella bacteria have a different method for invading cells. They persuade the host cell to undergo dramatic rearrangement before they even enter it. You can see what happens on one of Theriot's videos. When a salmonella bacterium app- roaches a human intestinal cell, the bit of the cell closest to the bacterium becomes disturbed. The whole structure of the cell changes. It develops huge waves (called splashes) that reach out and envelop the bacterium, drawing it into the body of the cell. The disease is now beginning to take over. Theriot wants to know how it is that the salmonella bacterium performs this trick.

The point is that once science has found the answer, medicine can step in and prevent disease from taking over the body by fooling the bacterium that it is inside a piece of smelly brie, for example, rather than in your gut, or persuading the host cells to ignore the signals being beamed at them.

All of which is comfortingly relevant. Theriot is conducting research that could help people, and that might lead to drugs that prevent hundreds of thousands of deaths.

It is trendy, too. Infectious diseases thought to have been killed off in the developed world have resurfaced. New multi-drug resistant strains of tuberculosis and pneumonia are popping up again in American cities, and the possibility of dying from such an infection has again become a reality. Theriot's research has come at the right time.

But what is important to the pure scientists is that her research is innovative. In the past, when scientists were looking at ways to fight disease, they would take bacteria growing on a petri plate and try to find chemicals to kill them. That is how penicillin and streptomycin were discovered.

But that was somewhat simple-minded, says Theriot, because the presence of bacteria in the human body is not what causes disease. What causes disease is the body's response. "Instead of trying to kill the bacteria, we can also try to mess up the way that they communicate with the host," she explains.

"The human immune system is really very well adapted to clearing out bacteria and so basically all that you need to do is to slow down the process of infection, slow down the process of disease causation".

Theriot has not always wanted to be a scientist. Perhaps because her father is a scientist - he is a high-energy physicist who works at the Fermi National Accelerator Laboratory (Fermilab) in Illinois where scientists have just discovered the elusive top quark - she did anything but science until her second year in high school. Her interest was finally sparked by a biology teacher whom she remembers for his teaching of evolution. This, she says, was a "ballsy" thing to be teaching in Wheaton, which is a home to Christian fundamentalism and at Wheaton College, where evangelist preacher Billy Graham was educated.

By the time she left school she had decided she wanted to be a physicist like her dad. "I'd been working at the Fermilab during the summers for the last two years of high school, building equipment for experiments and it just seemed like it was so much fun," she explains. "The attitude everybody had there was just very exciting. The idea of trying to find things no one had ever been able to find before."

Theriot opted for the Massachusetts Institute of Technology because it had the best undergraduate physics department. When it came to choosing a major, she decided on the double major of physics and biology. Her father talked her out of emulating him and going into high-energy physics. "It's extremely competitive, there's a very small number of jobs actually available and there's very few places were you can actually do the work," she says.

As an undergraduate Theriot enjoyed the physics classes more than the biology, because she found them more intellectually satisfying. But she preferred conducting research in biology. By her final year she had developed an interest in cell biology, which is why for her PhD she chose the University of California at San Francisco, an institution with a reputation for excellence in that field.

She spent five years on her doctorate, working most of the time under a British-educated professor, Timothy Mitchison, and looking at how cells crawl around the body. "When you start off you're just a fertilised egg and you're basically uniform throughout," she explains.

"And in order to go from being a fertilised egg to being a human you have to first divide up a lot, and individual cells differentiate and change their states. But then one extremely important part of development, besides cell differentiation, is that they move around relative to each other.

"So, for example, almost all the nerve cells in your body are derived from a little strip of embryonic tissue and at a certain stage of development they all start crawling out to where they're eventually going to go."

Theriot explains that even as an adult you have cells in your body that crawl around: for example, white blood cells. Whenever you have a bacterium or any sort of foreign agent in your body, signals are sent to mobilise the white blood cells. These cells roll along through your blood vessels, inching their way towards the foreign body and engulfing it. When Theriot was observing the crawling antics of cells, she was experimenting on goldfish skin. For some obscure reason, the cells of goldfish skin crawl very quickly so they are wonderful cells for looking at crawling. "I had this big tank of goldfish on my desk," she explains.

"One of the things I liked best about it was I was able to take primary tissue, the tissue directly from the animal, so there was no concern about it behaving unusually because it had been growing in the lab for so long."

The beauty of it for Theriot was that she didn't have to kill the fish. "I loved my goldfish. I had the same goldfish with me all the way through graduate school. Every so often I would grab one of them, pluck off a scale and put it back. It would huff around for a little while. But they don't have very big brains and they got over it pretty fast."

In case you were wondering, fish cells work like human cells. And there is a one-word answer to why crawling cells are important - cancer. When a person develops a tumour, it is not the tumour that kills them, but the fact that the cells in the tumour suddenly become motile and start crawling, spreading the cancer all over the body.

The crawling in metastatic cancer cells is very much like the crawling of fish skin cells, says Theriot. So, if scientists can figure out how it is they crawl and what the requirements are for crawling, they might be able to come up with some drugs that inhibit the activity, and thereby slow down the spread of the tumour.

But for Theriot the real reason for studying cell crawling is that it is a fascinating unsolved problem. All cells crawl at some point in their development and all animals have cells that crawl. "And if you ever see it, it's utterly fascinating how it happens,'' she says.

Her dissertation was on the crawling of cells. Towards the end of her PhD she began to look at bacterial parasites and the way they move. She decided this was what she wanted to keep on doing. The Whitehead fellowship, gambling that it has been a wise investment, has enabled her to do that. It is notoriously difficult to predict which scientists are going to be successful.

But Gerald Fink, director of the Whitehead Institute, describes Theriot as "a hybrid", in the great tradition of someone like Francis Crick. "Some of the very best people end up being not in a field, but coming from outer space into what is an established area," says Fink. And they sometimes end up changing the terrain quite dramatically.

Fink believes Theriot has what it takes to go a long way. And she can see the wider implications of what she is doing.

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