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Brain storms

July 12 2003

We've come a long way with genes, but unlocking the puzzle of the brain is still a huge challenge to science. Deborah Smith reports.

The human brain was on the mind of many - from stellar scientist to young student - at this week's International Congress of Genetics in Melbourne.

Professor James Watson, one of the Nobel laureates who discovered the double helix structure of DNA 50 years ago, declared that if he were a young researcher again, that's what he would focus on, because "it's a wonderful puzzle".

Another laureate, Professor Sydney Brenner, who helped crack the DNA code, told the 2750 at the conference that biological evolution was an obsolete technology. "The brain is more powerful than the genome."

And his co-winner, Sir John Sulston, who helped sequence all 3billion letters in our DNA blueprint, predicted it was well within the bounds of imagination that the human brain would unravel the complexities of the human mind by the end of this century.

The brain might seem an odd emphasis, given the congress was mostly about understanding the body - not just our body, but that of many other creatures on Earth.

But it was appropriate. Everywhere the eye turned at this event - the first of the five-yearly gatherings held since 1899 to be staged in Australia - there was intellectual endeavour or achievement to be seen. It was hard, in fact, to stop thinking of the power of the human brain.

Those who attended, including more than 500 university students, spent a week listening to 270 talks and chatting over coffee.

Look one way, and relaxing in a chair, was Professor Charles Yanofsky, a man who has spent 40 years delving deeper into how DNA produces just one substance, tryptophan, and who had major discoveries about the complex mechanisms that control genes to report.

Look in another direction and there was another laureate - Professor Robert Horvitz, who helped discover cell suicide, a normal process that can lead to cancer when it goes wrong, or our own immunology expert, Professor Peter Doherty.

In a packed theatre, Professor Susumu Tonegawa, who got his Nobel prize for genetic discoveries about the immune system, explained his latest passion - his unique technique for studying memory in mice by knocking out different genes in tiny portions of their brains.

Downstairs, in a huge basement, the less famous, but no less enthusiastic, displayed their intellectual wares, with 1400 posters of genetic research pinned up. At lunchtime the place was abuzz, as authors stood by their posters and discussed their finds with other delegates.

Like the multitude of cells in the brain, these scientists, drawn from around the globe, were working on very different, often very tiny, bits of the puzzle of life. Only by making connections would there be a chance of them solving the bigger picture.

And if there was one brain that was going to unite them, it belonged to Dr Francis Collins.

In his opening lecture, Collins, the director of the US National Human Genome Research Institute (NHGRI), a devout Christian who was schooled at home in Virginia until the sixth grade, laid out a plan for international collaboration by the world's brightest researchers to try to alleviate the burden of poor health for all in the world.

Twenty years ago, he said, most scientists had dismissed the idea of sequencing the genome as crazy. But it was completed in April this year, two years ahead of schedule.

"We're in the genome era. Let's make the most of it," he exhorted.

The project has shown humans share 99.9 per cent of their DNA. But the 0.1 per cent differences were incredibly important, helping explain why some people get cancer, or heart disease or diabetes, he said.

If all the millions of tiny variations in the human population could be identified, and a comparison made between the DNA of large numbers of people with a disease and those without, it should be possible to identify the many genes linked to a complex condition. The problem? "It would cost about $US10 billion [$15billion] for each disease."

The short cut is the international HapMap project, begun last year. It will map only some of the genetic variation and cost $US100million. Collins said an important aim was to include DNA from people on all continents, so it would be applicable to all populations on Earth. And he was determined to ensure the HapMap, like the publicly available human genome sequence, would be a "free gift" to the world.

Comparing the sequence of our genome with that of other creatures has proved more useful than expected in identifying important genes and the next creature to be funded by the NHGRI is the boxer dog, chosen from 60 breeds for its low genetic variability.

Australian studies of more distant species, such as our marsupials, have already revealed that the male Y chromosome in humans used to be the same as the female X chromosome 300 million years ago.

The institute is funding a marsupial genome, but is weighing up the South American opossum against our tammar wallaby. Australian scientists are hoping Thursday's announcement by the Federal Government of $2.5 million to establish a centre to study the wallaby's DNA could tip the scales.

Another of the institute's "bold visions", Collins said, was to tap into isolated research on molecules that might influence the effects of disease genes. By setting up a testing system of the like available only to big pharmaceutical companies, individual researchers could quickly evaluate the potential of their substances. "It may be our best opportunity to find new drugs," he said.

Genetic research raises many ethical issues, not least how people will react to tests that can predict their future health. And human unpredictability in this regard was confirmed in a Canadian study on tests for Huntington's disease, an incurable - and fatal - brain disease.

They found few people used the test for family planning, more people in their sixties than expected wanted it, and there were serious emotional side effects in people who found they were negative.

Professor Miroslav Radman, of the University of Paris, raised another contentious prospect: that of genetically modifying people by adding genes that protect against cancer to our genome. He said a few extra copies of p53, a tumour suppressor gene, could have benefits down the generations.

And while there was criticism of gene patenting at the congress, American consumer advocate Sharon Terry argued there were benefits. As a parent, she patented a gene after discovering both her children had a rare, genetic skin disease, known as pseudoxanthoma elasticum, so she and other affected families could have greater control over research on the disease.

The congress mood was upbeat with several experts predicting cures for some cancers and discovery of many disease genes in the five years to the next gathering.

Understanding the brain was a much longer-term prospect, said Tonegawa. "We will be asking interesting questions for the next 50 to 100 years. But we have already made quite a bit of progress."

He has just uncovered a chemical pathway in the brain that he believes will prove to be a major cause of schizophrenia, a discovery that flowed from his creation of a genetically modified mouse with the mental illness. He predicted many more genes than the one announced this week would be found that increase susceptibility to schizophrenia by acting on this pathway.

Collins said public unease about the search for genes linked to behaviour was understandable, given discoveries could lead to discrimination rather than benevolence. "I'm concerned in the sense that I don't think we have arrived yet at a social consensus about how this information should best be used."

He said more guidance on ethical issues raised by science needed to be sought from the world's great religions. But science had nothing to say about the existence of God.

"I have no intellectual problem being a scientist who requires the most rigorous data before I can believe something about the natural world, and also a believer in God," he said.

"If God has any meaning at all, He has to be outside the natural world. Science is the wrong tool to try and understand Him."




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