Weird Science
Archive No.1

Pharmacogenomics
The science of personalized medicine

Pharmacogenomics will be part of “the next revolution in medicine.” -- Francis Collins, Director of the National Human Genome Research Institute.

Background

“Aspirin never does anything for me." "Tylenol is the only thing for my headaches.” “Ibuprofen is all that works for me.” How often have you heard conversations like that? A drug that works for one person does little or nothing for another. As annoying as it can be for a family to have to stock several pain medications, it could be worse. According to a recent article in The Journal of American Medical Association (vol 279, p1200), adverse drug reactions caused more than 100,000 deaths in the US in 1994. Most often these deaths occured in patients receiving a standard dose of the drug that killed them. They didn’t die from a drug overdose, but from the proper dose of a legally prescribed drug.

Why do some drugs work for some people and kill others? The answer lies in a person’s genes. A person’s genetic makeup decides what drugs will work -- and what will not -- for that individual. Some examples of how genetic variation effects drug metabolism include:

• Prozac only works on 40% of the populace, possibly due to variations in the cytochrome P450 family of genes
• Variations in this gene family also contributed to adverse reactions in people taking the drug Seldane, which was part of the reason for its removal from the market
• Researchers have found that one version of the ApoE gene is associated with a high risk of developing Alzheimer’s disease in old age -- and that people who have this version of the gene do not respond well to a common drug used in treating Alzheimer’s called tacrine.

The method used currently to find out if a drug works on a person is trial-and-error. Everyone has been through the situation of having a sore throat, or some other minor infection. You go to a physician who prescribes an antibiotic and tells you to come back in a week. If the antibiotic isn’t helping, a different antibiotic is tried.

Psycho-active drugs can take even longer to judge their effectiveness. Medications used to treat mental illness, such as depression, need to be taken for a month to six weeks before their efficacy can be judged. Trying out several different drugs, one after another, in search of the right one, can take months if a patient is unlucky.

Sometimes, in the case of a severe, or life-threatening, infection a physician orders an antibiotic resistance test. What happens in those tests is a sample of the bacteria is tested to find out exactly what antibiotic -- at what dose level -- kills the bacteria. Antibiotic resistance is based on the bacteria’s genetic makeup, i.e., certain genes make a bacteria resistant to certain antibiotics such as penicillin. The test is expensive -- normally around $100 -- but the antibiotic the patient receives after this test has a very high probability of success. (It should be noted that this test does not involve the genetic analysis of the bacteria. At some point in the future, though, it will be done by genetic analysis because that will be cheaper and quicker.)

Identifying the best drug for a person based on their specific genetic makeup is the core of pharmacogenomics. No more trial-and-error guinea pig testing on the patient; a person gets a drug that will work the first time.

So why don’t we already have personalized medicine? Too many genes to analyze is the key problem. There are multiple versions of every human gene. These different versions are called polymorphisms. Scientists estimate there are between 50,000 and 100,000 DNA ‘hot spots,’ called Single Nucleotide Polymorphisms (SNPs) that are of importance in drug reactions and the disease process. So far very few of these SNPs have been specifically linked to a particular drug or disease process. Genetic maps of the human genome are starting to fill in the pieces of the puzzle, allowing scientists to link SNPs to drug reactions. As this process continues to completion, a full human genome map will become one of the two keys that will make personalized medicine a reality.

The second key, which can also be used to help fill out the human genome map, is the development of technologies, including the pertinent software, that allow researchers to test thousands of genes, or more specifically, thousands of single polynucleotide polymorphisms, at a time. There are several of these technologies under development, but the technology most discussed is biochips, which are like semiconductors with thousands of pieces of DNA attached to them. Biochips can be used to test thousands of small bits of a patient’s DNA to see which drug will work for them.

There are ethical issues involved in diagnostic testing at a genetic level, but these issues are being worked on. Pharmacogenomics -- personalized medicine -- at least for some drugs, will become a reality.

The Process

There are two approaches being taken in the study of pharmacogenomics: association studies and candidate gene mapping. In association studies, a high density map of the human genome is done and studies are performed to correlate the disease and drug response with specific polymorphisms. One way to understand how this works, is to compare it with a blind person going down a long road trying to find where a tree is located based on finding a cool spot on the road. It isn’t easy, particularly since the cool spot may occur for a reason other than a tree.

The second method being used in pharmacogenomic research is the candidate gene approach. Using this method a gene is chosen that is known to be involved in a particular drug reaction. The researchers then identify all the polymorphisms (variations) of that gene and correlate them back to a specific drug response. To continue the analogy above: it is like knowing trees provide cool areas around them, but trying to discover what type of tree provides the best cool area, and which ones don’t provide much shade at all. The major difficulty in the candidate gene approach is finding the right candidate gene. And the fact that some drug reactions involve multiple genes.

The Future of Pharmacogenomics

Business analysts that follow the pharmcogenomics field believe it will be at least five years before personalized medicine becomes even a partial reality, and wide-spread use of personalized medicine isn’t likely to happen for closer to ten years.

Initially pharmaceutical companies weren’t very enthusiatic about the concept of pharmacogenomics as it could limit their markets. Having only those people whom a drug would actually help get a presciption for it is a smaller market than any one the drug might help. Stated another way, the trial-and-error method of drug prescription brings in more money. But personalized medicine has the ability to revive drugs that didn’t pass clinical trials due to adverse effects. It will also help move new drugs more rapidly into the market place. These are compelling business reasons that form the basis of the pharmacogenomics push.

As indicated above, pharmacogenomics isn’t just an academic interest. A number of very large companies are working in this field. Some of the most well known are: Genset, a French company, with a $42.50 M alliance with Abbott Labs; Glaxo Wellcome with its $9 M acquisition of the pharmacogenomics company, Spectra Biomedical; SmithKline Beecham with its joint venture with diaDexus/Incyte; Millenium Pharmaceuticals’ subsidiary, Millenium Predictive Medicine; Genaissance Pharmaceuticals; and Genome Therapeutics. This is just a representative listing of companies pursuing pharmacogenomics that have been mentioned in the literature. (Doubtless there are several more working on pharmacogenomics that haven’t made that information public.)

It is easy to see why Francis Collins feels that pharmacogenomics will be part of the next revolution in medicine. Not bad for a science that didn’t even exist five years ago.

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