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Human genome sequences — a potential treasure trove, but how useful?

Imagine trying to understand a country and its culture without knowing its language. Only a comprehensive knowledge of the language would give a newcomer the tools to begin to explore and understand the country. Publication of the human genome sequence in February this year (see box) was a little like equipping scientists with the language of the human body.

The scientific community’s reaction has been positive, but tempered by uncertainty over the time it will take for practical results to emerge. ‘‘Now,’’ says Dr Virander Chauhan, director of the International Centre for Genetic Engineering and Biotechnology in New Delhi, India, ‘‘we can truly start to turn the genetic sequences into information important for medicine.’’ But, cautions Dr Barry Bloom, dean of the Harvard School of Public Health in the USA, ‘‘there will be a long haul before the human genome is fully exploited — even in the West.’’ And Dr Allan Bradley, head of the Sanger Centre in Cambridge, UK, which is sequencing one third of the human genome, says: ‘‘When it comes to disentangling and understanding the human genetic message, we are only at the end of the beginning.’’

Nevertheless, no one involved in biological research doubts that publication of the human genome is a milestone. Just how the exploration will proceed, though, is anyone’s guess and will depend on the complexity of the disease being studied and on the relative needs and resources of each country. ‘‘Every country has its own dynamics,’’ says Chauhan. ‘‘In India, 50% of the population are TB carriers and we are the world’s largest repository for leishmaniasis, so I am advising our department of biotechnology that TB and leishmaniasis as well as malaria and HIV should be our priorities.’’

Whatever the national priorities, genetic medicine has the potential to produce diagnostics, vaccines, and therapies. Already, there are sequence-based genetic tests of rare monogenetic diseases (i.e. caused by single genes). Huntington’s chorea and cystic fibrosis are two better-known examples. These genes, says Professor Newton Morton, professor of human genetics at Southampton University, in the UK, and a member of the WHO committee on human genetics before it was disbanded, are genes which when faulty can alone have a large visible effect.

The Huntington’s and cystic fibrosis genes have led to prenatal diagnostic tests and to tests that reveal whether the parents are carriers, but not yet to therapies developed directly from knowledge of the sequence. The catastrophic impact that these monogenetic diseases have and their rarity means that researchers were able to locate the individual genes by family studies, then isolate and sequence the genes. These projects were not part of the wholesale genome sequencing effort, but they showed the potential and limitations of sequence data.

Clearly diagnostic tests are important, but their value is limited, argues Bloom, ‘‘if patients do not have access to genetic counselling about the possible consequences of their carrier status or to abortion clinics if needed’’.

Science targeted the monogenetic diseases first because they could be tackled through current knowledge. The holy grail, however, is to understand the complex noncommunicable diseases — cardiovascular disease, hypertension, diabetes, cancer, mental illness — that affect all of humanity.

Morton, an expert in the genetics of complex diseases, says hundreds of genes are associated with each of these classes of disease, each gene having, perhaps, a small effect. Moreover, extragenetic factors, from diet to pollution to lack of exercise, affect regulation of the genes.

Laboratories around the world are focusing on the complex diseases. Take type 2 diabetes in the general population (as distinct from specific families), which affects adults in both developed and developing countries. To date scientists are not absolutely sure of even a single causative gene (although one gene, called Colpain 10, is a possible contributing cause of type 2 diabetes among Mexican Americans). About a dozen locations on the human genome, however, have been identified where the DNA sequences of people with diabetes are different from those of someone without diabetes. Work to match those sequences with the human genome and to investigate whether the sites are in a region that includes genes or gene sequences regulating gene expression is now under way. The human sequence data are speeding up the process, says Dr Don Bowden, professor of biochemistry and medicine in the human genetic unit at Wake Forest University, North Carolina, USA, but it is hard to say when this work will result in either a therapy or a diagnostic kit.

For the infectious diseases there is an added hurdle: it is not just the human genome that must be understood, but also the genome of the infectious agent and, for malaria and other vector-borne diseases, of the vector. ‘‘When we have the complete sequence of the malaria parasite,’’ says Chauhan, ‘‘we might compare it with the human genome to find genes that are not present in humans, and then develop a drug that kills the parasite but does not affect the human host.’’

And then, of course, there are the many ethical considerations that this new technology raises. Among them are questions like: Who is to decide if and when genome data should be used to ‘‘enhance’’ genomes that are basically healthy (a critical question, since such re-engineered genomes could affect future generations)?

The debate on such issues has started. Whatever its outcome, though, ‘‘in 20 years time,’’ says Morton, ‘‘the sequence data will be central to every branch of medical science.’’ And as US scientist and Nobel laureate Dr David Baltimore of the California Institute of Technology wrote in Nature’s special genome issue (15 February 2001), ‘‘Although I’ve seen a lot of exciting biology emerge over the past 40 years ... chills still ran down my spine when I first read the paper that describes the outline of our genome.’’

Helen Gavaghan,
Hebden Bridge, West Yorkshire, UK

World Health Organization Genebra - Genebra - Switzerland