On the cusp of a paradigm shift in medicine?

Sir John Bell, a Canadian who holds the Regius Chair at Oxford University, recently gave a spell-binding lecture on the impact on medicine that developments in genome sequencing will have in the not too distant future. He traced important milestones in the approaches to medical therapy, starting with Sir William Osler, another Canadian who was also Regius professor at Oxford about 100 years ago. Noteworthy among many pearls of wisdom that came from Osler was the advice that “it is much more important to know what sort of a patient has a disease than what sort of a disease a patient has.” Osler’s “knowing the patient” philosophy revolved around the phenotype — based on taking a good history, observing signs and symptoms, and asking the right questions. This approach has been very effective and continues to be the dominant approach today.

The paradigm shift that Sir John Bell spoke about was the potential to know the patient much better by knowing his/her genome as well as the disease he/she has. Genomics is becoming a powerful tool in medicine. A single disease may result from changes in various genes, and genomics will allow us to separate the various genotypes, better understand the disease, and possibly treat accordingly. For example, scientists have used genome-wide association case-control studies in which they have screened the DNA of large numbers of people with type 2 diabetes to identify single nucleotide polymorphisms (SNPs) in the DNA that are associated with the disease.

A list of 19 genes associated with type 2 diabetes was recently reviewed by Wolfs et al (1). Fifteen of these genes were proposed to target the beta cells of the pancreas, 2 had unknown targets, and 2 were related to obesity. In October of this year a group of researchers, including Canadian scientists, added another gene to the list (2). The researchers showed that changes in the IRS1 (insulin receptor substrate 1) gene can lead to insulin resistance, a condition in which insulin is produced but fails to carry out its work. This was the first type 2 diabetes-associated gene that has been shown to target the cells that respond to insulin rather than the cells that produce insulin. Another interesting feature of this finding is that the defect in function of the IRS1 gene is caused by another gene about 500 000 base pairs away. The detection of these gene loci is leading to more precise molecular characterization of the complex disease, diabetes.

The promise of rapid, cheap, genome sequencing is a major force that is driving us towards the new personalized medicine involving a knowledge of each person’s unique DNA sequence. Nanotechnology holds the key and is being pursued by several companies and groups of scientists as a radically new approach to DNA genome sequencing (3,4). DNA is passed through a nanopore (a hole about 1/20 000th the diameter of a strand of hair), and as it does so it generates a signal which is specific for the particular base of the DNA that is going through. There are a few technical wrinkles to be resolved but all evidence is that sequencing by this methodology (which is fast and cheap) will soon be available. Several major companies, including IBM, are involved in the race towards the $1000 (or less) genome. The cost of less than $1000 and time of a few hours compare favorably with the 3 billion dollars and 13 years for the first sequencing of the human genome that was completed only 6 years ago. While we await this milestone, an enormous amount of genome sequencing is being done with second generation sequencers and a considerable amount of information on genes and disease is being generated and analysed. Knowledge from these studies is helping to understand differences between people with the same disease but different gene involvement. For example, there is one type of diabetes which may be caused by 6 different genes, giving rise to different clinical courses. One of these subtypes has been shown to be highly responsive to treatment with sulphonylureas rather than insulin (5).

The era of personalized medicine is likely to deliver more precise preventive and therapeutic measures geared to the individual’s specific genetic makeup. This will make a big difference in human health. Veterinary medicine is also likely to be significantly impacted, based on better understanding of animal diseases, health, behavior, and productivity.