Hawking, Collins 

Two Renowned Scientists Foresee Applications for Genetic Knowledge 

Genetic Engineering News v.11, n.3, 1feb01

Susan Aldridge

Two leading figures in the world of science, Professor Stephen Hawking, Ph.D., and Francis Collins, M.D., Ph.D., gave their views on the postgenomics future at the recent "EyeforPharma Europe 2000" conference in Basel, Switzerland.

Stephen Hawking, Lucasian Professor of Mathematics at the University of Cambridge (U.K.) is best known for his groundbreaking work in cosmology, and so was able to give a perspective from a standpoint outside the biotech business.

In his view, the range of possible life forms in the universe is extremely wide, perhaps even including electronic systems, like computers.

"Biologists are expert on the DNA tree of life," he said, "but maybe it takes someone outside biology to see the wood or forest. I can also say things about genetic engineering that those in the field may think but wouldn't dare utter publicly, because they feel [they might come] under attack:"

In Prof. Hawking's opinion, we'll never reach a final steady state but will carry on in increasing complexity. So far, our evolution has been slow because the natural mutation rate of DNA is slow. But now we do not need to wait: we can redesign ourselves through genetic engineering.

Human Engineering Inevitable

"Of course, many people will say that genetic engineering on humans should be banned," Prof. Hawking commented. "But I rather doubt if they will be able to prevent it. Genetic engineering on plants and animals will be allowed for economic reasons, and someone is bound to try it on humans. Unless we have a totalitarian world order, someone will design improved humans somewhere:'

This will create great social and political problems, which Prof. Hawking wasn't advocating, but only predicting. "In a way, the human race needs to improve its mental and physical qualities if it is to deal with the increasingly complex world around it and meet new challenges, like space travel," he said.

"And it also needs to increase its complexity if biological systems are to keep ahead of electronic ones, which are another form of life with a genetic code, and even viruses."

Prof. Hawking does not expect us to be exploring a universe populated by many humanoid races much like ourselves. "I think we will be on our own, but rapidly developing in biological and electronic complexity." He summed up: "In this talk, I gave you my view of how the human race may evolve in the future. It may not be in accord with democratic and egalitarian principles, but Darwinian evolution has never been politically correct."

Genetic Medicine

Dr. Francis Collins, director of the National Human Genome Research Institute at the National Institutes of Health (Bethesda, MD), gave his view on how genomics will play out over the next forty years.

The first benefits will be predictive tests, available for approximately 25 conditions, by 2010. Interventions to reduce risk will also be available for most conditions-a comforting prediction, since it will be seen as unethical to offer a test where there is no cure.

Gene therapy will begin to be successful, but for only a few conditions. The genetic-medicine message will begin to penetrate to the primary-care level. Meanwhile, preimplantation diagnosis will become widely available, he speculated. "I can imagine it being used ...to choose the best possible offspring," which he acknowledged will lead to fierce debates on the limits of the technology.

Regrettably, Dr. Collins predicted, access to all genetic technologies will remain limited to those in the West. By 2020, gene-based designer drugs for diabetes, hypertension, and other complex diseases will be coming onto the market, while cancer therapy will be precisely targeted to the molecular fingerprint of a tumor.

One spectacular advance will be the transformation of our view of mental illness. "I believe we will understand disorders like obsessive compulsive disorder and autism, and we will stop blaming the victim," Dr. Collins. There will also be advances in germline gene therapy, maybe through the use of artificial human chromosomes, which will be able to provide what ever an embryo needs.

Extended Human Lifespan

Ten years after that, by 2030, we will have cataloged all the genes involved in ageing, Dr. Collins foresees, and clinical trials to extend the human lifespan could be under way. A full computer model of the human cell will replace many lab experiments. And complete genomic sequencing of the individual will be routine, costing less than $1,000.

But public response to these groundbreaking advances won't be wholly positive-Dr. Collins predicts the emergence of major antitechnology movements. "There'll be serious debate about the notion of taking charge of our own evolution. It'll be a very noisy and vigorous debate."

As we approach the middle of the 21st century, expect comprehensive genomics-based healthcare as the norm, with disease predisposition being determined maybe at birth, and individualized preventive medicine widely available and effective. The average lifespan could reach 90 years. But worldwide inequities will remain, leading to serious international tensions.

Meanwhile, William Haseltine, Ph.D., chairman and CEO of Human Genome Sciences (Rockville, MD), gave some pointers to the pharma and biotech industries for the immediate future. "Our task," he said, "is to begin to provide a framework for this enormous gift ...curing human ills."

Ethical Considerations

Dr. Haseltine added that there are two basic schools of thought in life sciences today. One is based on the concept that life begets life and difference begets difference. Such profound observations have led to animal domestication and even to civilization itself.

But when we apply this approach to ourselves, most people find it repulsive, he said, referring to eugenics. "We are afraid of ourselves. But we have just been given the ultimate key, the genetic text to humans and our variation. What will be do with that knowledge? The answer is anything but obvious."

We can predict, on the basis of genetic tests, who will get a disease, but is it ethical to do this when there is no cure, and are we making use of tests even when there is the possibility of intervention? Dr. Haseltine cited the example of hereditary non-polyposis carcinoma, where the four or five genes involved are known, and challenged the audience to ask their doctors for a test.

"There is no business there yet," he said. "We are confident that we can reach into the body and change our genetic destiny, but how we do it remains to be seen. I believe that it will be many decades before this knowledge of our genes will bear fruit in terms of medical advantage. Most of us here will not see this in our working lifetimes."

The immediate payoff might be to allow the industry to define disease better and use the pharma machine to find drugs that will alter biochemistry and move forward. But, warned Dr. Haseltine, the answer to why a disease happens does not lead quickly to a solution.

For instance, we know more about breast cancer now, but there is no obvious new remedy on the horizon. There is a second way forward, however, and that is the methodology of the anatomist and the physiologist. More recently, this path has been taken by biochemists and molecular biologists, with the key question being how this machine works.

"Nearly all we do has this as its origin, rather than in genetics," explained Dr. Haseltine. "It's very different from what comes out of the Human Genome Project. The genome is the form in which genes are passed on, but the second approach has more to do with how it is actually used."

Gene-Anatomy

We are now in the process of creating a new basis for anatomy and physiology by understanding the complete set of expressed genes. In fact, the term "genome" can refer to this, too.

For the pharmaceutical industry, this has meant an increase in the number of drug targets. At the start of the last decade there was a list of 65-100 targets and, often, there would be an overlap of targets being worked on by different companies.

"There were black spots in areas where people wanted to work," Dr. Haseltine commented. "But that has changed. There are now mRNA collections that give a rational starting point and have driven deeply into the discovery process."

For instance, in osteoporosis, there are now five new targets that have been uncovered by modern gene-anatomy, looking at the genes that are expressed in osteoclasts. And, in all, there are probably now several hundred new targets. But this has not affected the ability to finish the job because there are downstream road blocks.

"It's the problem of introducing fully novel chemicals into the human body that may already be modified by other drugs," said Dr. Haseltine, noting that many new pharmaceuticals are taken by older people who may be suffering from a number of chronic and complex diseases.

Protein Drugs

"We will not get the increase in productivity needed for ten to fifteen years," Dr. Haseltine said. "Nothing I have seen has speeded up the process. I believe a better way of using this genetic information is to use proteins and antibodies themselves as drugs, although this has not been the favored path for Big Pharma, which prefers small molecules.

"Twenty years from now, I believe that half our new drugs will be antibodies and proteins. The companies that understand this will be the winners and those who stick to the chemical discovery approach will be the losers."

Dr. Haseltine explained that from the identification of a novel human protein to its clinical trial takes just six to nine months, while for an antibody the corresponding timescale is nine to twelve months.

The types of diseases that companies prefer to treat-basically those of ageing are exactly those that can be treated by proteins and antibodies.

"It is no accident that out of the first fruits of the genome revolution, five drugs are proteins not small molecules," said Dr. Haseltine. Four .ire from his company and one from Amgen (Thousand Oaks, CA). "Of the next ten, one will be a chemical entity and the rest protein. That is the route to success based on anatomy. It is the most direct application of our newfound knowledge." GEN

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