Your Inner Fish: A Journey Into the 3.5-Billion-Year History of the Human Body (17 page)

Von Baer watched embryos develop, compared one species to another, and saw fundamental patterns in bodies. Mangold and Spemann physically distorted embryos to learn how their tissues build bodies. In the DNA age, we can ask questions about our own genetic makeup. How do our genes control the development of our tissues and our bodies? If you ever thought that flies are unimportant, consider this: mutations in flies gave us important clues to the major body plan genes active in
human
embryos. We put this kind of thinking to use in the discovery of genes that build fingers and toes. Now we’ll see how it tells us about the ways entire bodies are built.

Flies have a body plan. They have a front and a back, a top and a bottom, and so on. Their antennae, wings, and other appendages pop out of the body in the right place. Except when they don’t. Some mutant flies have limbs growing out of their heads. Others have duplicate wings and extra body segments. These are among the fly mutants that tell us why our vertebrae change shape from the head end to the anal end of the body.

People have been studying abnormal flies for over a hundred years. Mutants with one particular kind of abnormality got special attention. These flies had organs in the wrong places—a leg where an antenna should have been; an extra set of wings—or were missing body segments. Something was messing with their fundamental body plan. Ultimately, these mutants arise from some sort of error in the DNA. Remember that genes are stretches of DNA that lie on the chromosome. Using a variety of techniques that allow us to visualize the chromosome, we can identify the patch of the chromosome responsible for the mutant effect. Essentially, we breed mutants to make a whole population where every individual has the genetic error. Then, using a variety of molecular markers, we compare the genes of individuals with the mutation to those without. This allows us to pinpoint the region and the likely stretch of chromosome responsible for the mutant effect. It turns out that a fly has eight genes that make such mutants. These genes lie next to one another on one of the long DNA strands of the fly. The genes that affect the head segments lie next to those that affect the segments in the middle of the fly, the part of the body that contains the wings. These bits of DNA, in turn, lie adjacent to the ones that control the development of the rear part of the fly. There is a wonderful order to the way the genes are organized: their position along the DNA strand parallels the structure of the body from front to back.

Now the challenge was to identify the structure of the DNA actually responsible for the mutation. Mike Levine and Bill McGinnis, in Walter Gehring’s lab in Switzerland, and Matt Scott, in Tom Kauffman’s lab in Indiana, noticed that in the middle of each gene was a short DNA sequence that was virtually identical in each species they looked at. This little sequence is called a homeobox. The eight genes that contain the homeobox are called
Hox
genes. When the scientists fished around for this gene sequence in other species, they found something so uniform that it came as a true surprise:
versions of the
Hox
genes appear in every animal with a body.

Hox
genes in flies and people. The head-to-tail organization of the body is under the control of different
Hox
genes. Flies have one set of eight hox genes, each represented as a little box in the diagram. Humans have four sets of these genes. In flies and people, the activity of a gene matches its position on the DNA: genes active in the head lie at one end, those in the tail at another, with genes affecting the middle of the body lying in between.

Versions of the same genes sculpt the front-to-back organization of the bodies of creatures as different as flies and mice. Mess with the
Hox
genes and you mess with the body plan in predictable ways. If you make a fly that lacks a gene active in a middle segment, the midsection of the fly is missing or altered. Make a mouse that lacks one of the genes that specifies thoracic segments, and you transform parts of the back.

Hox
genes also establish the proportions of our bodies—the sizes of the different regions of our head, chest, and lower back. They are involved in the development of individual organs, limbs, genitalia, and guts. Changes in them bring about changes in the ways our bodies are put together.

Different kinds of creatures have different numbers of
Hox
genes. Flies and other insects have eight, mice and other mammals thirty-nine. The thirty-nine
Hox
genes in mice are all versions of the ones that are found in flies. This similarity has led to the idea that the large number of mammalian
Hox
genes arose from a duplication of the smaller complement of genes in the fly. Despite these differences in number, the mouse genes are active from front to back in a very precise order just as the fly genes are.

Can we go even deeper in our family tree, finding similar stretches of DNA involved in making even more fundamental parts of our bodies? The answer, surprisingly, is yes. And it links us to animals even simpler than flies.

DNA AND THE ORGANIZER

At the time when Spemann won the Nobel Prize, the Organizer was all the rage. Scientists sought the mysterious chemical that could induce the entire body plan. But just as popular culture has yo-yos and Tickle Me Elmo dolls, so science has fads that wax and wane. By the 1970s, the Organizer was viewed as little more than a curiosity, a clever anecdote in the history of embryology. The reason for this fall from grace was that no one could decipher the mechanisms that made it work.

The discovery of
Hox
genes in the 1980s changed everything. In the early 1990s, when the Organizer concept was still decidedly unfashionable, Eddie De Robertis’s laboratory at UCLA was looking for
Hox
genes in frogs, using techniques like Levine and McGinnis’s. The search was broad and it netted many different kinds of genes. One of these had a very special pattern of activity. It was active at the exact site in the embryo that contains the Organizer, and it was active at exactly the right time of development. I can only imagine what De Robertis felt when he found that gene. He was looking at the Organizer, and there in the Organizer was a gene that seemed specifically to control it or be linked to its activity in the embryo. The Organizer was back.

Organizer genes started popping up in laboratories everywhere. While doing a different kind of experiment, Richard Harland at Berkeley found another gene, which he called
Noggin
.
Noggin
does exactly what an Organizer gene should. When Harland took some
Noggin
and injected it into the right place in an embryo, it functioned exactly like the Organizer. The embryo developed two body axes, including two heads.

Are De Robertis’s gene and
Noggin
the actual bits of DNA that make up the Organizer? The answer is yes and no. Many genes, including these two, interact to organize the body plan. Such systems are complex, because genes can play many different roles during development.
Noggin,
for example, plays a role in the development of the body axis but is also involved with a host of other organs. Furthermore, genes do not act alone to specify complicated cell behaviors like those we see in head development. Genes interact with other genes at all stages of development. One gene may inhibit the activity of another or promote it. Sometimes many genes interact to turn another gene on or off. Fortunately, new tools allow us to study the activity of thousands of genes in a cell at once. Couple this technology with new computer-based ways of interpreting gene function and we have enormous potential to understand how genes build cells, tissues, and bodies.

Understanding these complex interactions between batteries of genes sheds light on the actual mechanisms that build bodies.
Noggin
serves as a great example.
Noggin
alone does not instruct any cell in the embryo about its position on the top–bottom axis; rather, it acts in concert with several other genes to do this. Another gene,
BMP-4,
is a bottom gene; it is turned on in cells that will make the bottom, or belly side, of an embryo. There is an important interaction between
BMP-4
and
Noggin
. Wherever
Noggin
is active,
BMP-4
cannot do its job. The upshot is that
Noggin
does not tell cells to develop as “cells on the top of the body” instead, it turns off the signal that would make them
bottom
cells. These off-on interactions underlie virtually all developmental processes.

AN INNER SEA ANEMONE

It is one thing to compare our bodies with those of frogs and fish. In a real sense we and they are much alike: we all have a backbone, two legs, two arms, a head, and so on. What if we compare ourselves with something utterly different, for example jellyfish and their relatives?

Most animals have body axes defined by their direction of movement or by where their mouth and anus lie relative to each other. Think about it: our mouth is on the opposite end of the body from our anus and, as in fish and insects, it is usually in the direction “forward.”

How can we try to see ourselves in animals that have no nerve cord at all? How about no anus and no mouth? Creatures like jellyfish, corals, and sea anemones have a mouth, but no anus. The opening that serves as a mouth also serves to expel waste. While that odd arrangement may be convenient for jellyfish and their relatives, it gives biologists vertigo when they try to compare these creatures to anything else.

A number of colleagues, Mark Martindale and John Finnerty among them, have dived into this problem by studying the development of this group of animals. Sea anemones have been remarkably informative, because they are close relatives of jellyfish and they have a very primitive body pattern. Also, sea anemones have a very unusual shape, one that at first glance would seem to make them worthless as a form to compare to us. A sea anemone is shaped like a tree trunk with a long central stump and a bunch of tentacles at the end. This odd shape makes it particularly appealing, since it might have a front and a back, a top and a bottom. Draw a line from the mouth to the base of the animal. Biologists have given that line a name: the oral–aboral axis. But naming it doesn’t make it more than an arbitrary line. If it
is
real, then its development should resemble the development of one of our own body dimensions.

Martindale and his colleagues discovered that primitive versions of some of our major body plan genes—those that determine our head-to-anus axis—are indeed present in the sea anemone. And, more important, these genes are active along the oral–aboral axis. This in turn means that the oral–aboral axis of these primitive creatures is genetically equivalent to our head-to-anus axis.