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CLASSES YOU MAY HAVE MISSED
LEWIS JACOBSON ON THE HISTORY OF GENITICS
When people look back on the history of science, advances in genetics will be seen as one of the major accomplishments of this century. Genetics has been revolutionized to an almost inconceivable extent. For instance, genetics has allowed us to understand the molecular basis of cancer. About 10 years ago, I talked with some science fiction writers, and their wildest imaginings at that time have been surpassed.

Genetics begins well before written history. The notion of inheritance--the transmission of characteristics from one generation to the next--is extremely old. Though the ancients had no idea of what we would now call genetics, they accomplished some stupendous feats of genetic engineering. For example, wheat and corn are both members of the grass family, but they don't bear much resemblance to wild grasses. Somebody must have done a very long-term job of selective breeding to domesticate those plants. Similarly, turning a wild ox into a domestic cow is a very profound feat of genetic engineering, probably done over many centuries. There was no abstract science of genetics then, yet nowhere in recorded history have geneticists done anything as dramatic as the domestication of plants and animals.

The modern history of genetics begins with Gregor Mendel, who studied characteristics of pea plants. When he crossed a purple-flowered pea plant and a white-flowered pea plant, all the plants in the first generation had purple flowers. Before Mendel, people believed that the characteristics of the two parents simply blended together and that the purple was stronger than the white. But Mendel then did a crucial experiment: He took those purple-flowered offspring and he crossed them with each other. He found that in the next generation 75 percent of the plants had purple flowers, but 25 percent had white flowers. And the whiteflowered plants in the second generation had flowers that were just as white as their grandparents'. The characteristic for white flowers had been hidden in the first generation but had remained intact as a unit and had been carried through to the second generation, where it could re-emerge.

Based on these experiments, Mendel formulated his great contributions to genetics. The first is the idea of a gene, a unit of inheritance carried intact from generation to generation. The second is the distinction between what we now call the phenotype (an individual's appearance or characteristics) and the genotype (the genes that individual carries). The genotype determines the phenotype. In this case, the gene for purple flowers is "dominant," and the gene for white flowers is "recessive," meaning that if a pea plant's genotype is one purple gene and one white gene, it will have purple flowers for its phenotype.

For Mendel the gene was a purely hypothetical entity. It had no physical reality. Mendel invented the idea of a gene. Science often involves inventing reality rather than discovering it. Scientists then ask to what extent their invention corresponds to reality: We test our ideas by experiment. So the gene was an invented concept that helped describe the results of Mendel's experiments.

Around 1865, Mendel completed his work, and for years afterward it was not very well recognized. One place where the science of genetics was restarted was in Thomas Hunt Morgan's laboratory at Columbia University. Between about 1910 and 1925, Morgan and his colleague Herman Muller gradually developed the notion of mutation: that genes can be made to change by environmental insults like radiation and that they sometimes change by accident. These mutations are permanent changes in genes, causing different phenotypes. Notice that Mendel, to get his ideas, had to assume that a gene didn't change from one generation to the next. It would have confused him terribly to have to deal with mutations. In science, progress frequently depends on simplifying assumptions that later turn out to be incorrect.

At about the same time, Morgan discovered that genes are located on chromosomes. Chromosomes had been known for decades as objects in the cell, but no one knew what they were for. Now, in one jump, genes went from being an abstraction, which Mendel invented to describe his results, to something carried on a physically observable object.

The very next year, 1911, Morgan and Alfred Sturtevant began work on genetic recombination, which is the idea that those genes physically located on a chromosome can rearrange over time. This further fleshed out the idea of a gene as a physical entity located in a physical place on a physical object. Twenty-five years later, Barbara McClintock discovered genes that move around on the chromosome with enormously high frequency. We now know that this process can be extremely important in triggering cancers: A piece of genetic information can arrive at a new place and alter its activity to produce a cancer.

The next major idea developed slowly over the first half of the twentieth century: the one- gene, one-enzyme hypothesis. The cleanest formulation of the idea comes from George Beadle and Edward Tatum and can be stated simply: A gene usually makes an enzyme--a kind of protein--and the gene's function is to specify the structure of that protein. A gene that does something as complicated as determining the color of a person's eyes makes one protein and only one. Today we know cases in which one gene makes two proteins, and many important genes make no proteins, but the generalization is still extremely important. Much of the revolution in genetics in the second half of the twentieth century followed from the question of how a gene specifies the structure or function of a protein.

In 1944, Oswald Avery, Colin MacLeod, and Maclyn McCarty proved that a gene is made of DNA. This firmly linked the disciplines of genetics and biochemistry. What had been the abstract concept of a gene was now something you could purify in a test tube and study chemically.

DNA's structure was solved in 1954, with Francis Crick and James Watson's famous double helix structure. The importance of this was the implication of the double helix structure: It contains the information for its own replication. The DNA molecule consists of two strands of substances called bases. There are four bases, A, T, G, and C, and there are strict chemical rules for the pairing of these bases. A is always opposite T on the other strand, and G is always opposite C. So if the two strands separate, and a new strand is assembled on each old strand according to the same

rules, you end up with two molecules identical to the old one. Watson and Crick's model showed how DNA could provide the information for its own duplication and passage from one generation to the next.

In 1961, Francois Jacob and Jacques Monod showed that a gene does not function all the time. There are switching mechanisms that allow genes to be turned on and off at different times, in different environments. All the cells in a human body have the same genes, but a cell in your eye doesn't look much like a cell in your liver. The reason is that there are different genes turned on and off in eye cells and liver cells. The genetic way to build a complex organism is to turn groups of genes on and off.

In 1961, Jacob and Monod also came up with the idea that the information in DNA was expressed through RNA. The information in DNA is read out into RNA, which is composed of bases similar to those in DNA, and the sequence of bases of RNA is translated into the sequence of amino acids in the protein. We call it translation because it is like translating from one spoken language to another. And within a few years, the translation dictionary between the sequence of bases and the sequence of amino acids was completely worked out. As a student, I was at the scientific meeting in 1966 on Long Island, where the genetic code dictionary was finally worked out and agreed upon. The exhilaration of that moment was staggering. A quest that had begun with Mendel almost exactly 100 years _ before had culminated. We understood not only what a gene was but exactly how it functioned to make protein, which in turn determines phenotype.

To give perspective, I'm not close to retirement yet, and the genetics textbook I used as an undergraduate did not mention DNA and barely mentioned proteins. Genetics was considered a science of crossing chickens or tomatoes. Now genetics is legitimately the domain of chemists and physicists. Not that genetics stopped in 1966. We have done an enormous amount since then. But when we worked out the genetic code dictionary in 1966, we basically understood what a gene was and how it worked. That's an extraordinary advance for a mere hundred years.


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