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Matt Scott: Molecular Architects


Q: What has the field of genetics opened up for your research?

A: When it first became possible to manipulate genes -- to take pieces of a chromosome and put it into a bacterium and grow it there and study it -- people started studying the genes in things that were very abundant. For example, the genes that make the red pigment in blood that carries oxygen.

But the greater mystery, in a way, was to identify genes that are the architects of the whole animal body, and these initially were not accessible -- it was too hard to find them. But genetics made it possible to find them, because the genetics essentially provided a map of the chromosomes. You could find out where in the chromosome was a gene that controlled the shape of a limb, or the size of the body, or the growth of the wings. Those kinds of genes had been very mysterious. No one knew how to think about them; nobody knew how to isolate those kinds of genes. But the map you got from genetics said there's a gene that does that right here. And if you go look at that part of the chromosome, you can find it.

Q: What do you mean when you say genetics gives you a map?

A: Let me say it another way: One of the best ways to find out how something works, if you're talking about biology, is to break it and to find out what you've broken. Genetics is essentially a science of breaking things and then finding out what you did. So, imagine an engine. You do something to break it, then you go in and try to fix it, you try to understand what's wrong in that engine. Well, genetics does that. You look for something that is strange -- in flies it might be the structure of the wing or of the head or something. Then you go try to find out what's broken and how it works because you know that that thing must be necessary to make the normal wing, head, heart, or whatever it might be. You're trying to find out what genes are necessary to make that particular organ, appendage, or structure.

More than a century ago, a guy named Bateson wrote a book and described all sorts of varieties in nature. He described things like polydactyly which is [a variation] in the number of fingers or toes on a person. He described insects that had legs growing out of their heads instead of antennae. He described all sorts of abnormalities in development, which essentially constituted a whole encyclopedia of mysteries that we have to try to understand.

Why should we bother understanding these things? Well, we want to understand the normal process that works so beautifully to shape these structures perfectly and functionally so they work extremely well. To understand that process, we look at cases where there's a change. Not always a detrimental change; sometimes just a difference. We try to understand what happened when those changes happened, and that tells us something about the normal process.

As people began to use standard laboratory organisms like the fruit fly, they noticed all sorts of strange things going on. Especially if they treated the flies with something that would change their genes in some way, like a poison of some sort. When they did that, they found flies with changed wing structures, changed legs, and some very special flies that had one part of the body in the wrong place, or a copy of a normal part of the body in another place. For example, the antennae would be transformed into legs. Or the eyes would start growing pieces of wing out of them. Very strange things.

The exciting thing was that these variations were useful in two ways. First of all, they might be evolution in process, a gradual change into a structure that might be more useful to the organism. The second idea is that the abnormalities might lead us to the mechanisms that create the normal body. And this, in fact, has proven to be the case. In laboratory organisms, it's possible to take a fly, for example, that's perfectly normal, treat it with radiation or chemical poisons that damage its genes, and then find a fly, amidst thousands of flies, that has a change in the wing structure, or a body part in the wrong place. Because we've damaged a particular gene, it allows us to identify the genes that are normally involved in building the structure properly.

What was incredible to realize was that mutations in a single gene, in just one gene out of the thousands that we have, could cause a dramatic transformation of a whole section of the body into another part. It wasn't so hard to imagine that damaging a gene would lead to a failure to build something, but that a single gene could cause a transformation of a part of the body into a copy of another part was amazing. It argued that there were some sort of central coordinating genes that must coordinate the activities of many other genes to accomplish this.

So out of thousands of genes scattered about the chromosomes in the genome are a few that have special properties. And the strange flies [Bateson wrote about] led us to those genes. Specifically, they led [biologist Dr.] Ed Lewis to those genes. He realized that these genes were affecting different parts of the body. Oddly enough, the genes were in a little cluster in one place in one chromosome. As Lewis looked at these genes, he said, "This one affects this part of the body, this affects the next part of the body, and this effects the next part of the body." That was an astonishing observation. And it preceded by a long time any sort of DNA analysis or molecules.

Q: What was so astonishing about it?

A: It was amazing that there would be genes that controlled a specific part of the body, when after all the substance in that part of the body looks just like the substance in the next part of the body over. Take, for example, an arm and a leg. If you look at the molecules in them, they have exactly the same stuff in them. And yet they're shaped differently. So these are the genes that are shaping things, that are giving differences in pattern and organization rather than changing the substance of the material.

You can take it even further. You can look at two arms. They are composed of exactly the same substances, but the pattern is a mirror image. How is that controlled? That's the kind of mystery that developmental biologists try to understand in figuring out how these genes work.

Ed Lewis had figured out that there was a cluster of genes close to each other. Each gene worked in a particular part of the body. They were lined up. So his idea was that these genes originally had been one gene acting on one part of the body. And that in evolution there had been a duplication and then triplication and so on of the genes. So now there were multiple copies of the original gene, each dedicated to a particular part of the body. So he predicted from his work that these genes would be related to each other in some way.

If you look at how our bodies are organized, we have these vertebrae that repeat down our backbones, with slight differences in the vertebrae. Sometimes large differences in the vertebrae. So it's a repeating unit with variations. In insects, their body segments -- everybody's familiar with the yellowjacket that has a striped abdomen -- are repeating units with little differences. Some of them not so little, because all the segments in the thorax have legs. All the segments in the abdomen do not have legs. Of the three segments in the thorax in a fly, only one has full-fledged wings. The other segments do not have full-fledged wings. So there are differences between the segments. We now know that there is a whole system of genes that controls the subdivision of the body into repeating units, whether it be vertebrae or the segments in an insect body.

These genes that Ed Lewis had discovered, that give different character to those segments, are the ones that act on one segment but not another to make them different from each other. The same genes that do that in a fly -- to put the wings in the right place and the legs in the right place and so on -- those same kind of genes give us the vertebrae their difference shapes and characteristics.

Q: How does this relate to evolution? What did people think before this discovery?

A: As recently as 20 years ago, people thought that every animal would have its own program, a genetic program that would control how that animal grows and what shape it ends up. Everybody knew there had to be a program like that because that's why we look like our parents, or like a blend of our parents. There are genes that we inherit from them that control the shape of our faces and the shape of our bodies. So we knew genes had to be able to do that. But everyone thought that genes would be completely different for frogs, and insects, and people, and so on, that the diversity of animals out there and the diversity even among people might be due to tremendous differences between genes. So it was an absolutely astonishing thing to discover that there are many genes in common between animals that look very different. All of our thinking was focused on the differences. And yet underlying those surface differences in shape of the body is this genetic program where most of the components are in common between insects and mammals.

People had known for a long time that the structure of the genes, the DNA, was the same in pretty near all organisms. People knew that the so-called genetic code was the same, that many of the proteins that do the sort of energy handling in our bodies were the same, even in very simple organisms like bacteria. And yet, when it came to shaping the body, everyone thought that at that point, all the similarities would stop. That every diverse kind of animal -- jellyfish, people, sea urchins, frogs, insects, and so on -- would all be different, that the genetic program would be unrecognizably different. And that therefore you couldn't study a simple animal in order to learn about humans.

That turned out to be completely wrong. In fact, now there's a common language among researchers in biology because it's realized that a discovery you may make studying flies, or frogs, or worms, or even yeast, will be applicable in many cases to study in human biology and human medicine.

Q: So what does it all mean?

A: What this means is that we, humans and all the other animals, descended from a common ancestor who had these gene systems already working, building that body plan. And what we see now, among all the animals, are just variations on a body plan that existed half a billion years ago.

We have much more in common with other animals than we ever dreamed, which is amazing and exciting because it offers a window into our past. We can now, in a much better way, try to understand where we came from. There's no question that our brains are something very special, and yet the mechanisms that built them exist in other animals. So what happened? We can now start to think about problems like that.

Another exciting aspect of this is that the similarity between other types of animals and us means that we can translate an understanding of animals we can study in the laboratory and in the field into medical discoveries and other discoveries that are very practical for application to human benefit.

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