The Journal of the American Dental Association
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J Am Dent Assoc, Vol 135, No 6, 692-693.
© 2004 American Dental Association

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VIEWS

A clearing in the forest

The wondrous genome

It seems to me that in the life sciences, more than any other field, every good answer generates two good questions, or five or ten.

Since its inception in 1990, the Human Genome Project has been much featured in this and other publications. And rightly so: a thumping great success in every respect, it has yielded techniques and discoveries that will forever change the way we think about growth, development, disease and therapy. Reality has outpaced science fiction as genetic techniques displace traditional methods in such widely diverse areas as diagnostic testing, forensic identification and pharmaceutical manufacturing. Direct gene therapy isn’t there yet, but it’s only a matter of time.

This month, though, I don’t intend to dwell on the particulars of the Human Genome Project, exciting though they be. Instead, I invite you to join me as I step back to contemplate what this remarkable accomplishment teaches us about the science of life.

When Watson, Crick and their collaborators worked out the structure of DNA, there was a sense that we were pretty close to understanding life, inheritance, evolution, and all that. The elegant double-helix structure provided an equally elegant means for the molecule to reproduce by "unzipping" itself to create perfectly complementary strands. Moreover, a 1950s world coming to terms with the binary language of computers had no difficulty with the idea that just four chemical bases could tell the whole story of a living organism. High school students learned and understood the essentials. Some details remained to be worked out, of course, but there was light at the end of the tunnel. All scientists had to do was "break the code."

And gradually, those details began to emerge, teased out with patience, effort and some of the most ingenious experimental techniques ever devised. The breakthrough invention of the polymerase chain reaction, or PCR, provided a way to obtain measurable quantities of DNA fragments, and laid the foundation for much of what followed. Various researchers found ways to use enzymes and viruses as biochemical probes, knives, flags and glue. Others devised a way to determine the DNA base-pair sequence that can best be compared to blowing it up and weighing the fragments in electrophoresis gels.

Then along came the Human Genome Project, promising a clear, ambitious goal with funding to match. Thus encouraged, scientists and engineers "industrialized" the process. The sequencing operation, while still (usually) based on electrophoresis, was speeded up by orders of magnitude relative to the laboratory instruments previously in use. Cutting-edge information theory was exploited to access and interpret the massive sequence data as they emerged from the laboratory. And the whole enterprise was divided up in an orderly fashion among research centers around the world. In April 2003, it was announced that the human genome sequence was complete, two years early and well under budget.

So now we know, among other things, that

– human DNA contains about 3 billion base pairs;
these base pairs are grouped into somewhere between 25,000 and 35,000 genes, depending on whom you ask;
– only about 2 percent of the DNA material is contained in the genes and used to define protein synthesis, the rest being so-called "nonencoding" regions;
– the genetic code is actually made up of "words" called "codons," each comprising exactly three base pairs;
of the 64 possible codons, 61 are directly associated with particular amino acids (the building blocks of proteins); the remaining three are "stop" codons, analogous to punctuation in the genetic story;
– since only 20 amino acids are required to synthesize the proteins in human tissue, more than one codon is available to encode most amino acids;
– one and only one of the four DNA bases (thymine) is converted to a different one (uracil) when RNA is synthesized; it turns out that uracil is needed for amino acid synthesis, but thymine is a more stable choice for long-term storage in DNA.

This barely scratches the surface of genomic lore, but even this gives the flavor of what we’re dealing with: a mechanism not merely complex, but intricate, elegant and highly reliable as well. The double helix was just a first glimpse.

With this new knowledge have come new questions. Why, for example, does one of the stop codons, on rare but repeatable occasions, encode a 21st amino acid? What, if anything, is going on in the other 98 percent of the human DNA? And, when you think about it, are 35,000 genes really enough to define a human being in full? This last question is prompting some researchers to look for other mechanisms (such as extrachromosomal inheritance and genetic imprinting) to explain nature in the face of what has turned out to be an uncomfortably brief genome.

It seems to me that in the life sciences, more than any other field, every good answer generates two good questions, or five or ten. There is no end of the line. And while a particular level of understanding might be good enough for present purposes, smug complacency is never justified. There’s always a deeper level, even more amazing and strange, just waiting to be discovered.

I used to compare science with peeling an onion: picking away successive layers to get incrementally closer to the truth. But now I think a better metaphor would be the pioneer family clearing its homestead in the middle of a trackless forest. No matter how many trees they cut down, no matter how many acres they bring under cultivation, the cabin remains encircled by an ever-growing ring of trees. There will always be more trees to fell, more work to do.

Sometimes, when we become obsessed with the difficulty of chopping down our own particular tree, we need to step back and look at the bigger picture. Thanks to the Human Genome Project and its ilk, this clearing is far broader than it was just a few short years ago.



MARJORIE K. JEFFCOAT, D.M.D., EDITOR

E-mail: "jeffcoatm{at}ada.org"



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