A Fish That's Almost Human?

Aug. 1, 2007 — -- A tiny fish the size of a minnow is helping scientists unravel some of the most complex secrets of life and it could have a profound impact on the effort to treat various human diseases and understand how we became what we are. That's because the zebra fish is so closely related to humans that we might as well call it cousin.

"It's damn similar" to us, said Mary Ellen Lane, an expert on the zebra fish and a Rice University researcher on genetics. For every gene that Lane and her associates have isolated in the small, striped fish, they've found a human gene that functions in the same way. Humans and zebra fish share at least 80 percent of the same genes, which is why this freshwater fish has become an obsession among scientists around the world.

It grows from a fertilized embryo to a mature adult in just three months to four months, which makes it an ideal candidate for genetic research. In a sense, Lane's Houston lab is an evolutionary hot spot because she brings about genetic changes that pass from generation to generation, sometimes resulting in new animals that look or behave quite differently from their ancestors.

The embryo matures outside the mother and it is transparent, so the changes can be observed under a low resolution microscope and documented through time-lapse digital photography. That might suggest that scientists are close to learning all there is to know about genetics, but what they are really learning is the field is so incredibly complex that it may be decades before they have some of the most important answers.

"As we answer every question we generate 10 more," Lane said.

But the zebra fish stands ready to lend a hand, or at least a fin, to figuring out just what is going on, and which genes are doing what, as it develops its neurological system. Researchers are able to chemically tweak various genes, making them more or less expressive, and see what changes.

"Sometimes nothing happens. Sometimes you get an embryo that is just dead and not very interesting. And sometimes you get an embryo that looks very, very interesting, but different from the way it's supposed to," she said. "It might have one eye instead of two, or it might have a head that's bigger or smaller, it might have no ears. We've essentially been able to understand the genes that are involved in all of these processes."

However, the quest is made much more difficult by the fact that genes change during the developmental process, performing one function today and another one tomorrow, and so on. So if the gene is "knocked off," as Lane put it, at the wrong time, it won't be around to complete a possibly vital chore later on.

And some genes, like the one she is studying now, do both good things, and bad things, for the zebra fish, as well as humans. The gene, known as LMO4, plays a role in determining the embryonic size of the brain, but it has also been implicated in causing breast cancer and other cancers in humans.

Lane zeroed in on LMO4 because of a fundamental question in genetics.

"Basically, we have our genes because they do something good for us," she said. So why do we have genes that can cause cancer? She set out to determine the gene's normal function. It turned out that it didn't have just one normal function. It has many.

"When we knocked it out, or overexpressed it, we got this very complicated mess," she said.

Partly through trial and error, Lane and her associates determined that the embryo changed dramatically, depending on when that particular gene was altered. It had to be available to complete the good things it's supposed to do, like determine the size of the eyes, before it could be eliminated and thus reduce the chance of cancer.

The researchers are able to exercise some control over the gene by using a technique that seems simple, at least compared to the complexity of the problems they are trying to solve. They use a thin glass tube, which is heated and drawn to a sharp point, making a very tiny needle. Various chemicals can be inserted into the embryo, thus causing the gene to become more or less expressive, or even die. Then they sit back and watch the results.

That allows them to determine which changes in the embryo are caused by which genes. And that is a big part of the puzzle.

"When we look at the embryo we want to know how this egg becomes an embryo, and how this embryo becomes a fish," Lane said. "It uses genes, but which genes and when, and how does it use them and what do they do?"

The zebra fish is nearly a perfect platform for that, but no platform is perfect. The researchers can't direct the chemicals to a specific gene. They can simply inject the chemicals into the embryo, or fish, and hope they find the right gene. It works some of the time, so to be sure they have enough samples, a lot of zebra fish join the effort.

"You inject 500, which you can knock off in a day or two, and you'll get a bunch of good ones," Lane said.

It's a pot luck?

"Yup."

Pot luck, of course, isn't good enough for human application, so before any of this makes it to your neighborhood clinic, all the details have to be worked out. There can be many unanswered questions, and it will take many years to answer them all.

Still, it's an amazing improvement over the scientific world that Lane first entered.

"When I started grad school in 1988, a lot of very, very smart people, including some Nobel Prize winners, were saying that humans and flies and mice have a few common genes, but their genomes [or genetic codes] are going to be very different."

In other words, a zebra fish couldn't be all that helpful, because everyone knows a fish is very different from a human.

Wrong, as it turns out.

"This was the big shock at the end of the last century [remember, that's just seven years ago]," Lane said. "I think it's something like 80 percent of all zebra fish genes have a human homologue [a similar gene.] There's even some similarity at the organizational level."

"Nobody expected this."

And it's safe to add that nobody expected genes to be so complicated, and so tricky. Some day, perhaps, enough of the questions will be answered to make those genes behave the way they're supposed to, thus wiping out a wide range of human genetic illnesses.

But as Lane said, "It's a long road."

Lee Dye is a former science writer for the Los Angeles Times. He now lives in Juneau, Alaska.