ANNUAL SYMPOSIUM

Australia's science future 3-4 May 2000
Full listing of papers

Dr Doug Hilton joined the Walter and Eliza Hall Institute of Medical Research (WEHI) where he obtained his PhD in 1990. He then took a postdoctoral position at the prestigious Whitehead Institute of Biomedical Research in Boston, USA. He returned to WEHI in 1993 as a Queen Elizabeth II Postdoctoral Fellow in the Cancer Unit. He has now risen to be a Senior Research Fellow and laboratory head, and is the Director of the Cooperative Research Centre for Cellular Growth Factors. His current research centres on a new class of proteins, called suppressors of cytokine signalling (SOCS), which help to switch off a cell’s response to circulating hormones or cytokines.

Symposium themes - Molecular structure and recognition
Liberation! Biomedical science in the post-genome era
by Doug Hilton
hilton@wehi.edu.au

Abstract
The flood of activity associated with various genome projects sees the dam of knowledge filling rapidly. At the beginning of this year the sequence of the genomes of many hundreds of viruses, more than 50 bacteria, the yeast Saccharomyces cerevisiae and the nematode Caenorhabditis elegans have been determined in their entirety. Over the next 2 years, it is likely that the sequences of the human and mouse genomes, the genomes of important human parasites such as malaria and leishmania, as well as selected plants and insects, will also be determined. Rather than representing the end of the road for biomedical research, this Herculean effort marks a liberating new beginning. Instead of spending time identifying genes, a major task occupying molecular biologists for the last 20 years, we can focus, at last and without interruption, on understanding genes. Acquiring a deep comprehension of genes and the proteins and RNA they encode requires that we understand not only their physiological and biochemical roles, but also unravel, at an atomic level, the macromolecules with which each interacts to perform its particular function. Of crucial interest to the general public, the major investors in biomedical research in Australia, we must also grasp how each gene contributes to the onset and progression of illness and, most importantly, discover how to apply this new knowledge in prevention and treatment of common diseases in both the developed and developing world.

We're just at the beginning of the biotechnology revolution, 50 or 60 years behind the physical sciences. Our knowledge of the genome has exploded over the last 3 years and we are now at the stage of having all the pieces of the jigsaw puzzle in hand. The last 10 to 15 years have been the boring part. We are now ready to do the exciting stuff we can start to work on how genes fit together in a three-dimensional jigsaw puzzle. This will be achieved through a renaissance in genetics, coupled to biochemistry and physiology.

In the past, an enormous amount of effort has gone into identifying genes. This has been achieved through a range of laborious routes, including first purifying proteins and using their amino acid sequence to clone genes, the development of systems for cloning genes based on the function of their encoded proteins and cloning new genes based on homology with related genes. It is only when genes are cloned that we can begin to understand their function in a biochemical and physiological setting.

One example of this process is the SOCS genes, which stop cells responding to hormones. About 5 years ago a postdoctoral scientist, Robyn Starr, cloned SOCS1, we then found that there were about 20 previously undescribed relatives of SOCS1. Since then, my lab has spent more than half its time simply cloning these genes. This has put us in the position where we can now start to work out what each gene does.

One experiment that can teach us a lot is to generate mice in which we have deleted a single gene from the genome, so-called 'knockout' mice. We can then document the problems that occur. SOCS2 knockout mice have proven particularly interesting. We found that there was a failure to control body size, suggesting SOCS2 turns off growth hormone action. This was not what we wanted to study, since we are more interested in blood cell formation, but we had learnt something.

Having the sequence of the whole mouse genome makes old experimental approaches more feasible. We can now look at mice to find the interesting genes that produce the variations between individuals in a population.

For example, we can look at the genetic differences in mice which determine the numbers of platelets in their blood. We study mice within a pedigree sharing a mutation, then work out which parent donated what part of the genome, check the relevant DNA region using a genetic database and then put that gene back into the mouse to produce the selected number of platelets. Rather than using trial and error, we can now work on the genes we are interested in from the start.

For drug discovery, it is important to find targets. Rather than using a normal mouse, we can start with a mouse with disease. Most mutations are deleterious, reducing protein function. Drugs do the same thing.

Fat yellow mice are a model for obesity. We can now generate random mutations in fat yellow mice and find one that causes an offspring to be thin and black. The essential step is to find what was different about its genetic make-up and this can be achieved much more easily now. Once identified, the gene that eliminates a disease is likely to be a good target for a drug.

From the late 1700s to 1945 scientists described the chemical elements. Once they were understood, applications flowed. So the completion of genome sequencing marks a liberating new beginning. Instead of spending time identifying genes, scientists can focus on understanding them. It is futile to predict the specifics, but the benefits of the genomic revolution will boggle the imagination in 150 years.

Discussion

Animals have a key role in your research. Is it a leap from mouse testing to people?

Doug Hilton. It is now possible to identify the nucleotides that cause simple diseases. We can replace genes in animals. Mice can mimic changes in humans. The genomic revolution allows us to move to humans. Can we find something in mice that informs humans? There are many parallels between the different organisms.

The Human Genome Project has been hijacked by free enterprise. Bring us up-to-date with the Human Genome Diversity Project.

Doug Hilton. The US National Institutes of Health and Celera (the company doing most of the sequencing) have got samples from donors - 10 samples are being used to construct the Human Genome Project. Celera's participation probably means that the sequence will be known 2 or 3 years ahead of schedule.

There is more interest in knowing the differences between individuals than in knowing the basic gene sequence. Different samples, especially from isolated populations, will be very important. Pharmaceutical companies are also interested in the differences. One of the keys will be trying to ensure public access to this information.

Are there enough mice? How many do you need?

Doug Hilton. If you can hold 1000 mice, you will see mutations. In Australia the cost of mouse production is less than in the USA and Europe. That puts us in a very competitive position to conduct these kinds of studies.