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Walter Gilbert: Opinions of a Nobel Prize winner

For Walter Gilbert, the era of the genome is close to the end, and, over the next few years, it will be that of the proteome

The inventor of one of the first methods of sequencing DNA, which got him the Nobel Chemistry Prize of 1980, the American Dr. Walter Gilbert was the star of the BIG Conference. At 69 years of age, the biologist from Harvard, where he commands a laboratory of bioinformatics that bears his name, is restless and a thought provoker. He stated that genomes only have another five years of life and evaluates poorly the strategy of looking for genes of the human being. “Our projects are still very poor. There must be more than 30,000 human genes.” He criticizes the African countries who want to have cheap medicines for Aids treatment. The founder of Biogen, from which he resigned, and presently the Director of Myriad Genomics, he condemns the form in which Celera got into the race for the human genome. His opinions are in this interview granted to Marcos Pivetta.

How do you compare the stage of genomic research today with that which you carried out when this area began?
I began 40 years ago and, at the beginning of the decade of the 70’s, it was still virtually impossible to carry out the sequencing of genes. The work of sequencing a fragment of DNA, with 20 pairs of bases, took almost two years. In 1975, almost by accident, I discovered a quicker method to sequence fragments of DNA, more or less at the same time in which Dr. Frederick Sanger (British, who divided the Nobel Prize with Dr. Gilbert) and his colleagues developed a similar method. These discoveries made it possible to sequence thousands of pairs of bases of DNA in a day or even in an afternoon. But nobody imagined that it would be possible to obtain all of the sequencing of human DNA.

Was this an impossible dream?
We were working on the first genes which had thousands of pairs of bases, but nobody thought of sequencing millions of pairs. However, as the methods of sequencing spread throughout the world, shortly afterwards there was an accumulation of genetic information. I remember that around 1985, I participated in the first discussion about whether it was technically possible to sequence the human genome. At the time, it was believed to be an absurd idea, too large a project to be carried out. However, I left the discussion convinced that that it would be possible and that it would be good for science.

Was there much resistance to this?
Many people didn’t see the benefits that this type of enterprise would bring, in terms of accelerating all biological research and in the search for new drugs. Only during the five years that followed, did it become obvious, after lots of meetings and reunions, that to sequence the human genome would be helpful. Then estimates began to appear of how much it would cost. In 1985, it was already spoken of in terms of US$ 3 billion, an amount that in a gross manner ended up being the total amount that the Public Consortium Project spent throughout the 10 years to 15 years. Officially, the Human Genome Project only began in 1990 when the governments of the United States and of Europe decided to support it. The initial goal was to finish the sequencing by 2005.

In February, the Public Consortium and Celera published almost complete versions of the human genome. When will we have a final version?
We have a sequence with 95% of the information. In a year it will be completed. It is necessary to make something clear. In a certain manner, after the methods of rapid sequencing were discovered, to finish the sequencing is purely a technical exercise. To understand the sequencing is another question, totally different.

Is it here that real science known begins?
Certainly. To understand the sequencing is to understand biology. It is the great challenge of the next few years. In principle, after the complete sequencing, a computer must foresee all of the genes and see the regions that codify proteins. This is not possible yet, because it depends on the terms of a level of understanding of the functions of the sequencing that as yet we have not reached. The discussion about the number of genes is fun, but empty. The number doesn’t matter much, it only gives a weak clue as to the complexity of the organism.

You stated that genome study has only five years of life and that afterwards it will be the turn of the proteome. What will be done until then?
What we are doing and what we will be doing over the next five years is to compare the human genome with that of other organisms, such as the cow, the mouse, the rat, the chimpanzee, plants and bacteria of all types. We will use analogies for all of the human genes and we will make a list. From these studies, we will also be able to understand the evolution of various species, see how the genes of an organism become the genes of another. This will help to give us clues about their functions, those of the human genes, and to give us very profound ideas about the origin of life, some 4 billion years ago. The larger problem will be what we call that of the proteome. How to identify all of the proteins of an organism and to see their interaction. We have to understand how the organism develops and functions. We have done fantastic things with the brain, but we don’t know which of the genes and the products of these genes – proteins, that are involved in memory. We know a part of the problem, other parts we don’t. These are the big questions of biology.

We laymen are waiting anxiously for the practical results of genome research. When will the new forms of diagnosis and treatment of disease effectively reach society?
This is already happening. New forms of diagnosis were suggested through genomic work and this area is growing rapidly. I myself am involved in a company that is investing in this, Myriad Genomics, which already has a test to detect mutations and predispositions for cancer of the breast and the ovary, another for cancer of the colon, and by the end of the year, we will be introducing a predisposition exam for cancer of the prostrate. Over the next five to ten years, more and more tests will be devised that detect in the person genes or defects in the genes that cause illnesses. All of the pharmaceutical companies are using this type of situation. During the next two years, the great effort of these companies will be in the area of proteome. That is, to attempt to understand the interaction of the proteins that lead to illnesses and to develop drugs. All of these efforts should lead to new drugs over a short period of time.

What for you is a short period of time?
Six years. It is necessary to carry out the clinical tests to show that the drug is efficient and safe and then it will be approved for sale. It is a slow process, but it is already possible to see an improvement in the quality of the treatments. For example, let’s take the case of Aids. It was discovered at the beginning of the 80’s and there was no treatment. The first drugs only came on the market at the end of that decade and at the beginning of the 90’s. Five years ago came the second wave of medicines and today there is a treatment that is very good, although there is not a cure yet.

What do you think about countries questioning the price of the drugs to combat Aids?
I don’t see them complaining about the price of the bomber jets that they purchase. It is a question of establishing priorities. The greater number of the African countries who are complaining spend a lot on their military sector.

The drugs against Aids, are they not expensive?
Yes, how about the price of a jet plane that launches bombs? No, that is extremely high. The drugs are expensive but in five or six years they should be cheaper. You can argue that they should already be cheaper. They are the fruit of a social process, a choice of society. We have a system of patents because society believes it better to have the drugs available more quickly, even though, for a short period, they will be more expensive. It is better this way than not to have the drugs in any form at all. They don’t make themselves. It is necessary to encourage people and companies to risk their money in an attempt to develop them. Of course there is an alternative. The government could pay for these drugs, for their development, but, in my opinion, it would result in a terribly inefficient system to carry it off. It is difficult to convince a government to invest in drug research, a risky activity. In the end, the drug might not work.

Coming back to the genome, was the entrance of Celera positive for sequencing?
I don’t think it was correct for Celera to exaggerate the efficiency of their method of sequencing. Incorrectly, they attempted to stop the work of the Public Consortium insinuating that it was a waste of money. In truth, they made an effort to try to establish a monopoly on the information of the human genome and to convince the American Congress not to give any money towards the public Consortium. It wanted to turn itself into a type of Microsoft in this sector. In reality, what it was saying was more or less the following: “Sequencing is so valuable that I want it only for myself.” I don’t think they have been successful in this intention.