Yale scientist Peter B. Moore gave a sweeping overview of the study of genetics and explained the biochemistry of gene expression in a talk at the Graduate School on April 15.

His lecture, "Down the Central Dogma Pathway with Gun and Camera: The Molecular Basis of Protein Synthesis," was the final offering in the 2001-2002 series "In the Company of Scholars" series, hosted by Graduate School Dean Susan Hockfield.

Moore, who earned his B.S. degree from Yale in 1961, joined the Yale faculty in 1969. He is the Eugene Higgins Professor of Chemistry and a professor in the Department of Molecular Biophysics and Biochemistry (MB&B).

"The place to start any story like this is at the beginning, and the beginning -- for all biological sciences in our time -- is this book," Moore said, showing a picture of the title page of "The Origin of the Species by Means of Natural Selection" by Charles Darwin. Urging his audience to read Darwin's "eloquent and carefully argued case for evolution," he went on to assert, "Darwin set the agenda for the biological sciences. There's almost nothing we do today that cannot be seen as a playing-out of Darwin's program."

Darwin's theory of natural selection depends critically on the way traits are passed from one generation to the next, Moore explained. But in 1859, the laws of inheritance -- i.e. genetics -- were totally unknown, and this was a major vulnerability of the theory of natural selection, a fact that Darwin himself appreciated, the Yale scientist noted.

It could be argued that the greatest biological achievement of the last 140 years has been the study of inheritance at both the organismal and the biochemical level, said Moore, adding that -- happily for Darwin -- the information gathered has strengthened, rather than weakened, the case for natural selection.

In fact, the first experiments that have the flavor of modern genetics were carried out about the time "Origin of the Species" was published, noted the Yale scientist. An Austrian cleric, Gregor Mendel, had carried out an extensive investigation of inheritance in pea plants. His results, published in 1865, were so far ahead of their time that they were ignored until about 1900.

"What genetics basically shows -- and it's already plainly evident in Mendel's paper -- is that the inheritance of traits can be thought of in terms of entities that have been called, and that we still call to this day, 'genes,'" said Moore. "The overt characteristics of an organism are controlled by genes, and every organism has two genes capable of controlling each of its characteristics, one from its father and one from its mother. What makes the whole thing complicated and hard to analyze is a phenomenon called 'dominance.'"

Dominance, he explained, is evident in the way eye color is inherited in humans: A person who has a copy of the gene for brown eyes from one parent and a copy of the gene for blue eyes from the other parent, will have brown eyes, just like a person who got the gene for brown eyes from both parents.

"Because you cannot be certain what the genetic makeup of an individual is by looking at him, geneticists distinguish between the genotype of an organism, the set of genes an organism carries within itself, and the phenotype, what it looks like from the outside," said Moore.

"When you look at the genetic literature starting with Mendel and running well into the 20th century, genes are very much like atoms were to chemists in the 19th century. Nobody knew what they were made of. Nobody knew how big they were. Nobody could prove that they actually exist, but all the data could be easily explained if it were assumed that they exist," he added.

Two important questions were implicit in the growing body of genetic data, he said: What is the phenotype of an organism chemically? And what is its genotype?

"If you take away the water that's in your body, and the mineral material -- bone -- and ask what's left," he said, "half of that mass is protein. ... There are on the order of 50,000 different ones in your body, and they basically do everything. Every chemical reaction that goes on within your body, virtually without exception, has a protein associated with it."

Moore showed a slide of the protein hexokinase, noting "Every cell on the planet has a hexokinase ... The fact is that my hexokinase and bacterial hexokinase and yeast hexokinase look exactly the same, and have amino acid sequences which are closely similar." Moore called that "strong evidence ... that all life forms on this planet descend from common ancestors -- and it is part of the biochemical proof that Darwin was basically right: Organisms do evolve."

The next major milestone in the understanding of genetics came in the first half of the 20th century, with scientists "squinting through microscopes at living cells -- or sometimes fixed and stained cells -- and watching them divide," said Moore, noting, "By 1940, there was little doubt that chromosomes were the genetic material."

Chromosomes are made up of roughly equal parts protein and DNA, he explained. "At the time this fact was discovered, people were largely clueless about both the chemical and the three-dimensional structure of DNA, but they already knew a lot about proteins. They were inclined to ascribe anything biologically interesting to proteins. But the fact of the matter is, experiments done between about 1940 and 1950 established beyond any doubt that the genetically active material in chromosomes is DNA."

The way DNA works was discovered by Watson and Crick, who realized that the pairing of the bases in double-stranded DNA had to be the key to both its replication and its genetic function, said Moore. In an article published in Nature magazine, Watson and Crick wrote: "The specific pairing we have postulated immediately suggests the possible copying mechanism for the genetic material." Moore called that "the most important sentence written in the second half of the 20th century in all of science."

Moore concluded his lecture by describing research that he has done in collaboration with Professor Thomas Steitz of MB&B and other colleagues over the past seven years
at Yale.

The researchers' work has focused on the ribosome, the enzyme responsible for the synthesis of proteins in all organisms. Moore and Steitz and their colleagues have crystallized large ribosomal subunits, and then determined their structure by X-ray crystallographic techniques. The work led to the computation of three-dimensional maps of the ribosome showing where its atoms are.

The most important single result to emerge from this work, said Moore, is the finding that the ribosome is an RNA enzyme, not a protein enzyme like the overwhelming majority of all other enzymes.

An important practical application of this pure research, Moore noted, is the study of how antibiotics destroy disease-causing bacteria. Many of the antibiotics in clinical use today inhibit the activity of bacterial ribosomes, which either prevents bacteria from multiplying or kills them outright, he explains. However, a growing number of bacterial strains have become resistant to antibiotics following repeated exposure to them -- Darwin in action, again, noted Moore.

The ribosome structures now in hand make it possible to see how antibiotics interact with the ribosome, and may make it possible to design new antibiotics that circumvent the resistance mechanisms that are reducing the efficacy of many antibiotics today -- at least for a while, Moore noted, until natural selection renders these new pharmaceuticals useless, too.

-- By Gila Reinstein

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