Tailor-made Drugs of the Future

Dr Martin Brookes

April 2002

The year is 2020. I am ill and I need to see a doctor. I head down to my local surgery to pay my GP a visit. The doctor listens attentively as I reel off the symptoms. Then, he asks me for my card. Not my credit card (that will come later) but my gene card – the one containing all the juicy details of my DNA. He sticks the card into the slot of his desktop computer, caresses a few keys and then waits for the outcome. A few seconds later he is writing out a prescription tailor-made to my own unique genetic profile.

We are used to the idea that if we have a certain ailment we are prescribed a certain drug. But people vary enormously in their response to drugs. What works for me may not work for you. Take the drug codeine, for instance. For 95% of the UK population, the drug does what it is supposed to do – it relieves pain. But for the remaining 5% (that's 3 million people) the drug has no effect at all. These people carry a particular form of a gene that makes them unable to convert codeine into its active form, morphine. Further afield, there are more than 400 million people in the equatorial regions of Africa, Asia and South America for whom aspirin is a dangerous drug. A simple genetic difference means that those who take it risk destroying their red blood cells, and contracting anaemia.

Understanding the genetic basis of our varying responses to drugs is the challenge of pharmacogenetics – the burgeoning branch of pharmacology. Ultimately, its long-term goal is to promote a new culture of medicine in which drug treatments take account of the genetic differences between people. Today, when a doctor writes out a prescription, he is working on the assumption that this drug works for most people most of the time. That's why the drug is available for him to prescribe in the first place. If this one doesn't work then maybe he'll try another one, and then another. But with each new prescription, costs start to rise and patients start to suffer.

Hits and miss treatments

For people with mental illnesses, such as depression and schizophrenia, the hit and miss approach to drug prescription can be especially harrowing. It can take months before the effectiveness of a psychiatric drug becomes apparent. If the drug fails, the patient has to go back to their doctor and start from scratch with a completely new treatment. This means it could be years before an effective treatment is found. Better knowledge of genetics could take the chance element out of the prescription equation.

In some cases, getting the prescription wrong simply results in ineffective treatment. For children suffering from leukaemia though, it can also mean the difference between life and death. One of the most common anti-tumour drugs used in the treatment of childhood leukaemia is 6-mercaptopurine. For a small percentage of the population, however, this drug can be fatally toxic or completely ineffective at standard doses.

Another striking example of the effects of genetics on drug response emerged among the ranks of the United States army during the Second World War. Soldiers fighting in the Far East were given the anti-malarial drug primaquine. But after taking it, Afro-American soldiers suffered much higher incidences of anaemia compared to their Caucasian compatriots. Years later, the cause of this different drug reaction was traced to a single gene called G6PD. It turns out that Afro-Americans are more likely to carry a form of the G6PD gene that makes them unable to metabolise the drug.

For society as a whole, the benefits of the new medical vision could be enormous. In 1998, a remarkable study published by the Journal of the American Medical Association reported that 106,000 people die each year due to adverse reactions to prescription drugs – making it the fifth leading cause of death in the United States. A further 2.2 million people are injured. Here in the UK, it's estimated that 1 in 15 hospital admissions is caused by adverse reactions to prescription drugs. More knowledge about the way in which drugs and genes interact with one another could go a long way toward improving these alarming statistics.

Identifying the genes

While tailor-made drugs are a relatively new idea, the origins of pharmacogenetics date back to the first half of the 20th century. Ideas were beginning to emerge about the heritable differences in people's response to drugs and chemicals. One of the first demonstrations was with the chemical phenylthiocarbamide (PTC). To some people, PTC tastes extremely bitter, while for others it's completely tasteless. In the 1930s, scientists discovered that this difference in taste perception followed simple rules of genetic inheritance.

Today we have the tools to help pinpoint genes involved in variable drug responses. Recent and rapid advances in molecular biology and biotechnology have made the whole business of finding and sequencing genes a practical possibility. The latest manifestation of this technological renaissance is the human genome project – the completed map of the human genetic blueprint. This vast database will be invaluable for the future of pharmacogenetics. There are specific sequences within the map that affect our susceptibility to diseases, and others that affect our sensitivity to the drugs designed to treat them. The trick will be in finding the sequences.

In their hunt, scientists have been focussing a lot of attention on genes that are most active in the liver, the body's own detoxification plant. The liver is a good place to look because it's where the drugs that we take into our bodies are chemically processed before leaving it. The search for likely genes has already met with considerable success. The evidence so far suggests that a family of genes known as the cytochrome P450s are responsible for the metabolic disposal of most of the drugs used in medicine today. Coming in a wide variety of different forms, the cytochrome P450s seem to play a crucial role in determining how we respond to specific drugs.

Variation in the CYP2D6 gene can affect the way people respond to anti-depressant drugs, such as nortriptyline. Some people have forms of the gene that make them metabolise the drug slower or faster than normal. For about 6% of the British population a totally inactive CYP2D6 gene means that they are unable to break down nortriptyline at all. For anyone with a variant form of the CYP2D6 gene, standard doses of the drug don't provide effective treatment. In 'slow metabolisers', the drug can't be broken down fast enough by the liver, so it accumulates in the body, producing unpleasant and potentially dangerous side effects. In contrast, 'fast metabolisers' break down the drug too quickly, and under standard doses it is eliminated before it's had time to work.

Some teaching hospitals and academic institutions have already introduced pharmacogenetics programs for the treatment of psychiatric disorders and childhood leukaemia. In the case of psychiatric patients, a simple genetic test is performed on a small blood sample in order to identify which form of the CYP2D6 gene they carry. With the results, doctors can prescribe dosages of the drug that suit the patient's genetic profile – less for slow metabolisers and more for fast metabolisers.

But actually tracking down the genes involved in variable drug responses presents a real practical problem. As humans, we may share 99.9% of our DNA with one another, but that still leaves 0.1% – and millions of DNA differences – between any two individuals. Ever advancing genetic technology continues to ease the burden of this search, but finding out which differences will affect drug design still looks set to be a long and lonely road.

Another practical hurdle to the pharmacogenetic vision is that drugs and the genes they interact with rarely form neat one-to-one relationships. The effectiveness of a drug may not just depend on how it's metabolised by a single gene in the liver, it may also rely on complex interactions with many other genes. What's more, this effectiveness may be inhibited or exaggerated by the action of other drugs that are prescribed concomitantly.

Future expectations

While diagnostic testing is still in its infancy, the hope is that it will soon extend to cover all kinds of diseases from Asthma to Alzheimer's, and heart disease to HIV. All types of cancer treatment could benefit from diagnostic testing. Part of the reason why people respond so differently to the same chemotherapy treatment is because of their different genes. If we could gain a better understanding of which cancer drugs and which genes work best together then the debilitating side effects of chemotherapy could be eliminated.

Current research into pharmacogenetics is concentrating on identifying the genes that cause people to respond differently to existing drugs. For the future, we are promised totally new drugs designed with specific genetic profiles in mind. Instead of pharmaceutical companies pursuing a 'one drug fits all' philosophy, there will be subsets of drugs, each designed with specific individuals or populations in mind. How this idealistic vision will square with the economic realties of drug development, however, is unclear. Since it takes about 10 years and US$500 million to get a new drug from the laboratory to the market, the prospect of more drugs, each with a smaller market share, may seem remote. While the pharmaceutical giants may be happy to refine the target audience of their existing drugs, they may require substantial incentives to develop new ones with only genetic minority 'customers' in mind.

Familiar ethical issues are already making themselves known. Health insurance companies may be the ones to gain most from this new technology. Will people be obliged to reveal their genetic identities if the results expose them to higher insurance premiums? If economic decisions end up outweighing ethical ones then pharmacogenetic research could hurt those that stand to benefit most from designer drugs – the genetic minorities.

Critics say

Critics argue that pharmacogenetics projects an idealised vision of itself, espouses unrealistic goals and places too much emphasis on genetics as the root cause of different drug responses. The way in which people respond to a drug may depend on factors such as their health, weight and diet as much as on their genes. And with the emphasis and research money invested in genetics, there is a danger, critics say, that non-genetic factors will be marginalised, and that the balance of our knowledge will suffer as a result. These are legitimate concerns. The success of biotechnology and huge research programs like the human genome project have certainly helped to create a new gene-centric culture in biology. Indeed many biologists adopt a reverence towards genetics as if it were the root from which all ideas must grow. Nevertheless, the short-term goal of pharmacogenetics – better prescriptions for existing drugs through diagnostic testing – seems reasonable and within reach.

As we gain more and more genetic knowledge, the trial and error approach to drug prescription may start to look profligate and painful. If simple genetic tests were available, people could get the drugs and dosages best suited to their make-up. We could save lives, suffering, and money. Some improvements in the field of medicine seem inevitable. But the doctor's surgery of the future? That'll be the real test of this genetic revolution.

Find out more

Channel 4 is not responsible for the content of third party sites

Websites

Designer Drugs
www.guardian.co.uk/genes/article/
0,2763,435522,00.html
Article giving an indication of the brave new world we might inhabit in the next 30 years when diseases and infections will be treated with prescriptions tailored to an individual's own genetic make-up. Contains links to other related articles.

Pharmacogenetics and Pharmacogenomics
www.private-rx.net/invivo/pharmacogenetics.shtml
Lots of designer drug questions answered. Several useful links.

Pharmacogenomics
www.naturesj.com/tpj/
Specialist website of The Pharmacogenomics Journal allowing users to view abstracts in advance of print. Mainly aimed at geneticists, molecular biologists and those working in biotechnology.

Pharmacists – The scientists in the high street
www.rpsgb.org.uk/pdfs/scifactsheetphco.pdf
An information sheet primarily aimed at pharmacists but giving a good overview of the current state of pharmacogenomics prepared by the Science Committee of the Royal Pharmaceutical Society of Great Britain.

The Human Genome
www.wellcome.ac.uk/en/genome/hgp.htm
Mapping of the human genome started more than a decade ago and involves thousands of scientists from 20 centres in 6 countries. This easy to follow site offers an insight into the history and the future of the project.

Prozac
www.drugscope.org.uk/druginfo/drugsearch/
DrugScope is the UK's leading drugs charity and centre of expertise on drugs for both professionals and the public. An alphabetical database offers easy access to information on Prozac.

Books

Encyclopaedia of Psychological Disorders: Designer drugs by Carol Nadelson (Chelsea House Publishers, 2000) £19.95
A look at the history, nature and effects of designer drugs such as Ecstasy, PCP, fentanyl and meperidine.

Prozac Nation by Elizabeth Wurtzel (Quartet Books, 1996) £8
A personal account of the author's battle against depression. It describes her experiences with this devastating illness and her fight to rid herself of dependence on Prozac.

Listening to Prozac by Peter D Kramer (Fourth Estate, 1997) £7.99
Psychiatrist Dr Peter Kramer uses the experiences of his own patients to look at Prozac and other mood-altering drugs. He was severely criticised when the book was first published by seeming to advocate the use of Prozac to achieve personality changes not directly related to the disease of depression.

Pharmacogenomics: The search for individualised therapeutics edited by Julio Licinio and Ma Li Wong (Wiley-VCH, April 2002) £39.95
The first comprehensive book on pharmacogenomics. This new discipline will pave the way to understanding the key genetic differences between individuals leading to the tailoring of pharmacological treatments.

The Human Genome by Jeremy Cherfas (Dorling Kindersley, March 2002) £4.99
Part of the Essential Science series, this title is a beginner's guide to the sequencing of the human genome and, with that, the implications for the future. A clear, concise, colourful book suitable for school children and academics alike.

Essential Psychopharmacology of Depression and Bipolar Disorder by Stephen M Stahl and Nancy Muntner (Cambridge University Press, 2000) £18.95
An easy to follow, fully illustrated book, explaining the basic neuroscience of mood disorders and enabling readers to understand the pharmacology of antidepressant drugs and their interaction on neurotransmitter pathways.

top ^