The real excitement of genetics

THE EDITOR: Contemplating the life sciences, the historian of science discerns two pinnacles in the evolution of the subjects; the publication of Charles Darwin’s Origin of the Species, and the discovery by Francis Crick and James Watson of the DNA code, which contains the information that directs the molecular structure of living tissue. The epoch commencing with that event marked a significant achievement with the deciphering of the three billion base pairs that represents the human Genome, or the body of information, the formulae, that builds us into what we are, held in a length of Chromatin 1.8 metres long, and carried in the nucleus of every one of the trillions of cells that constitute our bodies. With the blueprint for protein structure revealed, it seemed that science was poised to yield fabulous fruits. Only two percent of the three billion base pairs of the entire Genome, or about 30,000 to 40,000 genes, a term revised now to read ‘transcriptional unit’, are active protein builders. The rest was thought by researchers to be junk, accumulated over the aeons of evolution. Which brings me to the cause of this letter to the editor.

For decades, textbooks of biology and zoology, genetics and associated subjects, stated that genes are carriers of heredity, and such doctrine is firmly embedded in intellectual tradition, which led to great optimism when the Genome was sequenced, an optimism that affected me also. That is, until I read two articles by W Wayt Gibbs in the November and December editions (2003) of Scientific American magazine. Here I will attempt to provide the merest sketch of what is being realised by researchers. The 98 percent of the three billion base pairs of the Genome that were thought to be inert, contain very active and powerful elements, in the form of RNA, a molecule that differs from DNA by a single element.

There are several types active in the cell, but the types occurring in the Genome, held on the Chromatin molecule, called microRNA and RNA switches are being discovered to be of immense regulatory significance on DNA activity. Alteration of these RNA components, even by as much as a single element, can lead to calamitous changes in the molecular structures produced by the DNA, or proteins. These RNA elements are very ancient; the riboswitches occurred billions of years ago, before DNA existed. Researchers have located hundreds of microRNA, 150 in humans, 75 of which appear identically in the Pufferfish.  The evolutionary line that led to us humans separated from that which led to the Pufferfish some 400 million years ago. The RNA forms the second layer of active genetic material. The third is a layer of chemicals termed the ‘epigenetic’ layer, that surrounds the Chromatin which bears the DNA and RNA. These chemicals seem to govern the general mechanics of that entire assemblage. By mechanics it is meant the dynamic activity of the Genome.

Chemicals such as Methyl act as locks, to close down particular sections of DNA, and are particularly effective in suppressing mutations, leading some researchers to conclude that Methylation errors and not DNA mutations might be the cause of cancer. In a test conducted by Jean-Pierre Issa at the M D Anderson Cancer Centre at the University of Texas, Decitabine, a drug that acts on the Methyl locks, was used on 130 patients with advanced Leukemia; eight of them had 99.9 percent of the cancer cells gone, in 22 others the disease went into partial remission. Vitamin B12 and Folic acid, found in spinach, are excellent sources of Methyl. Acetyl, another epigenetic chemical, amplifies the activity of the genes it attaches to. W Wayt Gibbs provides some references at the end of his articles for the curious reader. The realisation that various types of RNA and chemicals act to specify the expression of certain protein manufacturing genes, being thus significant factors in the mechanics of growth and form is a matter of profound interest to the philosopher of science.

The immensity of the concept, in which structures billions of years old are powerful determinants of our humanity, and which places the molecular basis of our forms, until very recently thought to be within comfortable access, again in a vague and indeterminate realm, is very difficult to grasp. In the period between Darwin and Crick and Watson, there were philosophers such as Herbert Spencer, who was speaking of evolution, in the sense we understand it, seven years before the publication of the Origin of the Species. Spencer, whose philosophy is “set forth in 12 volumes thicker and squarer than Gibbon’s each bound in a cloth which has acquired with age a reptilian colour and texture”, says P B Medawar, FRS, who, when invited by Oxford University in 1963 to give the Herbert Spencer lecture that year, found that he was the first man to have read Spencer’s Principles of Biology which the Royal Society’s library had purchased more than 50 years before. D’arcy Wentworth Thompson, who authored an 800 page essay called “On Growth and Form” was another philosopher, as was the great Erwin Schrodinger, one of the founders of Quantum Mechanics, and in whose little book, What is Life? (1944) James Watson found the first reference about a code that would allow molecules in cells to carry information. (Schrodinger was a scholar of Indian Philosophy, and a Vedantist). The reason for mentioning these few of many, is to point out that with respect to the DNA complex, there will be such philosophers and theories until the entire mechanism is known.

It took 50 years, from the discovery of DNA to the sequencing of the human Genome. In January 2004, as I write this, after reading the articles by W Wayt Gibbs, I recalled an interview in which John Rennie of Scientific American spoke to James Watson, published in April 2003.Responding to a question about how much was left to do regarding DNA, and whether there are still great discoveries to be made, Watson replied: “the major problem, I think, is chromatin (the dynamic complex of DNA and Histone proteins that make up Chromosomes). What determines whether a given piece of DNA along the chromosome is functioning, since it is covered with the histones? You can inherit something beyond the DNA sequence. That’s where the real excitement of Genetics is now — I’d guess that over the next 10 years, the field will be pretty played out.” Well, I think not. Fifty years from now, maybe.  But certainly not ten. And somewhere, in the intricacies of RNA, and stretches of parasitic DNA, will be found the key to defeat the AIDS virus.

SURENDRA SAKAL
La Romaine