HEALTH TRIBUNE Wednesday, July 5, 2000, Chandigarh, India

Human health: genomics & beyond
by Rick Weiss
nlike most doctors, Georgetown University physician and pharmacologist David Flockhart enjoys talking about his patients who didn’t get better from the medicines he prescribed, or who got even worse because of side-effects.

It’s a genome, not a cure-all
By Elbert Branscomb
here was great public fanfare and political attention last week when Francis S. Collins of the U.S. National Institute of Health and J. Craig Venter of Celera Genomics Corporation announced the completion of a draft version of the human genome. And there was good reason to celebrate. Sequencing the 3.1 billion T's, A's, G's and C's will revolutionise our understanding of how living systems work and propel us on new quests to mitigate disease.



Human health: genomics & beyond
by Rick Weiss

Unlike most doctors, Georgetown University physician and pharmacologist David Flockhart enjoys talking about his patients who didn’t get better from the medicines he prescribed, or who got even worse because of side-effects.

There was the woman who suffered excruciating pain after surgery no matter how much codeine he prescribed.

The patient whose tendons became so inflamed from taking a common antibiotic years ago that she remains debilitated to this day!

The woman who took Prozac only to find her blood pressure going through the roof!!

Flockhart likes these sorry stories because they highlight the great potential of ‘‘pharmacogenomics’’, a new field of medicine he and others are pioneering that promises to reduce treatment failures by matching medicines to patients’ personal genetic codes.

Among the many vaunted medical benefits promised by the Human Genome Project — the $2 billion effort to spell out the entire human genetic blueprint — none is as close to broad clinical use a pharmacogenomics.

The new science seeks to solve a simple but long-standing problem: Medicines are made and sold on a ‘‘one size fits all’’ basis, even though people vary substantially in how they respond to those compounds. As a result of this variability, more than 100,000 Americans die every year from side-effects of properly prescribed medicines and another two million are made seriously ill.

Now, with scientists identifying more and more genes that control individual responses to drugs, some leading-edge medical centres are starting to make prescribing decisions on the basis of patients’ genetic makeup. Five years from now, some experts, predict, it will be common for patients to take genetic tests before their doctors decide which drug, or what dose, to prescribe for them. That’s far sooner than anyone expects to see similar success rates in the more widely touted but failure-plagued field of gene therapy, which aims to treat people by giving them new genes.

Drug companies, as well as patients, stand to gain from the pharmacogenomic revolution. By testing new and experimental drugs only in volunteers whose genes pre-ordain a positive response, companies can generate data that will prove irresistible to the US Food and Drug Administration, streamlining today’s long and costly drug approval process. Some companies also hope to profit from the sales of the genetic tests that will be used to match patients with appropriate drugs.

But like so many advances in genetics, pharmacogenomics raises difficult questions, too. As the first attempt to meld the contentious field of genetic testing with the everyday practice of medicine, it will serve as a test case of how society will deal with issues of genetic privacy and discrimination.

Many people are already nervous about their genetic profiles falling into the wrong hands, for example, but so far few people have had a reason to take such tests. How will people react when a genetic test is required just to get a proper prescription?

Of equal concern, some of the gene patterns relevant to pharmacogenomics are ethnically linked, raising issues of racial stereotyping and access to care. One fear is that profit-conscious pharmaceutical companies will use pharmacogenomics to aim their drug development efforts towards genetic subgroups of people who can best afford to pay for them, further marginalising already undeserved minorities.

"What happens when the patient comes in and says, `I hear there's a great new drug for asthma,' and the doctor says.... `Yeah, but it's only for whites ?' " asked Mark Rothstein of the University of Houston's Health Law and Policy Institute.

Pharmacogenomics alters medicine's legal landscape, too. At what point should doctors and drugmakers be liable for not taking genetic information into account ? Already a group of patients has sued the maker of a Lyme disease vaccine, claiming that people with a particular genetic signature should not have been given the vaccine because they are especially prone to getting serious side-effects from the shot.

All told, experts said, pharmacogenomics presents a challenge to society for precisely the same reason it offers so much promise: because it focuses on people's differences.

"We believe strongly that this is a new era and the dawning of a golden age of personalised medicine," said Elliott Sigal , a senior vice-president at Bristol-Myers Squibb, one of several pharmaceutical companies that have launched pharmacogenomics programmes. It does raise important issues for society in terms of privacy, discrimination and insurance issues," Sigal said. "I think the Government will have to deal with these issues."

Custom treatment: Flockhart's surgical patient presents a classic example of the need for pharmacogenomics. After undergoing surgery on her ovaries, she was given codeine, the most commonly prescribed pain-killer in America.

"She wanted more and more of the stuff," Flockhart recently recalled. Before long, he said, "she was labelled a drug-abuser."

The truth was far simpler. Tests ultimately showed she was among the 7 per cent of Caucasians in the country who harbour an inactive form of a gene called CYP 2D6, that helps break down many common medicines, including codeine. Unable to metabolise the codeine into its desired breakdown product, morphine, the woman got no relief.

Flockhart's patient on Prozac had the same genetic variation, but in her case it led to an effective overdose instead of undermedication. That's because Prozac, like codeine, is also broken down with the help of the 2D6 gene. Since she could not metabolise the antidepressant, the woman suffered an over-accumulation of the drug, with high blood pressure and other side-effects.

The patient with tendinitis carries a different gene variant that triggers painful inflammatory reactions in response to so-called quinalone antibiotics.

Scientists know of six common CYP drug-metabolising genes, all of which operate in the liver and are responsible for breaking down about a dozen different drugs each. They have also begun to find other genes in other parts of the body, which people can inherit in various forms and that can affect how efficiently these people absorb, transport, use and excrete various medicines.

With the recent advent of simple tests that can reveal a person's genetic subtype from a drop of blood or a cheek swab, Flockhart said, " we're beautifully set up to look at variations in these things from person to person. It's a real opportunity to help a lot of people."

In a few settings, genetic testing is already helping doctors inform their prescribing decisions and even save lives.

At the Mayo Clinic in Rochester (minn), for example, Richard M. Weinshilboum and his colleagues have been using genetic tests to individualise treatments for children with acute lymphoblastic leukaemia.

The childhood cancer was universally fatal a few decades ago, but with the advent of a drug called 6-mercaptopurine, more than 80 per cent of the children can be permanently cured. In the years since that drug's introduction, though, two problems have plagued doctors: Why doesn't the drug work in every child, and why does it cause serious and even fatal side effects in some ?

The answers finally arose with the tools of pharmacogenomics.

Mercaptopurine, it turns out, is broken down in the body by an enzyme abbreviated TPMT. But 10 per cent of Caucasians and ‘‘blacks’’ carry a variant of the TPMT gene that renders the crucial enzyme relatively ineffective, and an additional one in 300 of these children lack the gene and the enzyme altogether. ( The variant is almost unknown in Asians) Unable to metabolise the drug, these children essentially overdose on even small doses, and often die from the immune system suppression that ensues.

At the Mayo Clinic and at St. Jude Children's Research Hospital in Memphis, doctors now routinely test for TPMT activity in leukaemic children before treating them. Children with especially high levels of the enzyme - who are, in essence, breaking down the drug before it has a chance to kill their cancers - are given doses up to 50 per cent higher than normal in order to get a therapeutic effect. And those who are effectively overdosing on the drug because of their relatively inactive TPMT genes are getting doses as low as one-fifteenth normal, providing all the anti-cancer efficacy of a normal dose but without the extra side-effects they once endured.

One result of the new focus on pharmacogenomics is that old definitions of diseases are breaking down. Cancers, for instance, which have traditionally been classified by their location in the body, are increasingly being typed further by their genetic characteristics and drug sensitivities, and medicines are being developed to take aim at those hallmarks. Experts predict that in the next few years a bevy of new genetic tests will show that many other diseases also deserve to be parsed and targeted according to their genetic signatures.

"We're going to learn it's not just 'MS'," or multiple sclerosis, said Kathleen Giacomini, a University of California at San Francisco researcher who is identifying genes that affect drug absorption and transport in the body. ‘‘It's going to be MS, a, b, c and d. And we can develop new drugs for each of these types.’’

Philosophical shift: The driving force behind the emergence of pharmacogenomics is a little-known follow-up project to the widely hailed Human Genome Project. Unlike the genome project, which sought to spell out a generic "consensus" version of the human genetic sequence, the follow-up project seeks to define the subtle differences in that code from person to person.

The goal is to identify hundreds of thousands of " single nucleotide polymorphisms," or SNPs ( pronounced "snips"), which are the tiny spelling variations that occur about once in every 500 to 1,000 letters within the three billion-letter human genetic code.

The recent shift by federally funded and privately financed gene researchers away from the genome project and over to the search for SNPs represents more than a scientific change of course. It brings with it a philosophical change of perspective that will focus not on people's similarities but on their differences.

That shift is necessary if personalised gene-based medicine is to take off. But it also brings new possibilities for genetic bias and discrimination.

"The great promise of pharmacogenomics is that it will target drugs and therapies to individuals," said Morris Foster, a University of Nebraska anthropologist who is studying the field's potential impact on society. " But the way it may work out is it will just end up emphasising social identifiers like race and ethnicity .... and exacerbate social inequities."

Not all of the genetic variations that affect how a person will respond to various drugs track along racial or ethnic lines. Indeed, doctors could easily run into trouble if they try to use race as a substitute for genetic testing: Think how many people might suppose that Tiger Woods is African American or Caribbean, one geneticist said, when in fact his mother is Thai.

But many relevant genes do correlate with race. While only 7 per cent of the Caucasians have the 2D6 variant that caused problems for some of Flockhart's patients, for example, more than one in four Asians carry a similar variant.

Those realities present interesting economic and ethical quandaries.

On the economic side, pharmaceutical companies could save millions of dollars by preselecting participants in a clinical trial so that virtually everyone benefited and no one got side-effects.

"Efficacy could be proven in small cohorts of a few hundred patients compared to 3,000 or 5,000 as we do now," said Gualberto Ruano, Chief Executive Officer of Genaissance Pharmaceuticals, a Science Park, Conn., company that is developing genetic tests to predict people's responses to various drugs. " This is going to change the economics of drug development radically."

It would also reverse the current federal regulatory push to include more diverse groupings of people in clinical trials - a push that arose a few years ago in response to concerns that minorities were being left out of the drug approval process. Under the new rubric of pharmacogenomics, though, expert reviewers might deem it unethical to test a new drug on people whose genes suggest they won't respond well to the drug, since those participants’ sole purpose would be to demonstrate side-effects.

At the same time, any drug that gained approval through such a process would have proven its mettle only in people with a narrow genetic or racial grouping, and would probably be approved by the FDA only for use in those people.

"That could be a problem," said Larry Palmer, a Professor at the Cornell University Law School who is studying the legal implications of pharmacogenomics. "You know the drug companies are going to market it as best as they can. and the average practitioner may use it without the deep understanding of the science needed to use to appropriately on the right individuals.’’

Moreover, given the chance to focus their efforts this way, would companies even bother developing drugs for people with rare genes? It’s too soon to say, but there is some evidence that some might not.

The author is a Washington Post staff writer 


It’s a genome, not a cure-all
By Elbert Branscomb

There was great public fanfare and political attention last week when Francis S. Collins of the U.S. National Institute of Health and J. Craig Venter of Celera Genomics Corporation announced the completion of a draft version of the human genome. And there was good reason to celebrate. Sequencing the 3.1 billion T's, A's, G's and C's will revolutionise our understanding of how living systems work and propel us on new quests to mitigate disease.

But those far-reaching expectations should be tempered with realism: Mapping the genome will vastly increase the amount of our knowledge, but most will be knowledge we can't put into practice quickly. When it comes to medical treatment, far from offering new certainties, the genetic information will raise new questions and present difficult choices.

Perhaps the most problematic fact about our current advances is the length of time it will take to realise their promise. It will be decades, in almost all cases, before information turns into real treatments and therapies. Think for a moment about the genetic knowledge we already have and how difficult it has been to act upon it: We identified the single gene that causes sickle cell anaemia some 50 years ago. But the blood disorder continues to leave millions of people worldwide suffering from fatigue and breathlessness to severe pain and stroke.

Scientists pinpointed the genetic cause of cystic fibrosis in 1989 , and yet some 30,000 American children and young adults continue to suffer from the debilitating disorder. And there is still no satisfactory therapy for Huntington's disease, the genetic cause of which was discovered some seven years ago. Anyone who inherits the disease can look forward to progressive dementia and disability beginning in middle age, and to death within the following 15 years.

Of course, knowing the genetic underpinnings of a disease is a critical first step in understanding its causes. But it doesn't mean a cure is at hand; the road between the two will be long. In almost all cases, we don't yet have the tools to replace or suppress a defective gene. Nor do we have the non-genetic means, through drugs for example, to mitigate its destructive effects.

That's not to suggest that there will be no immediate medical impact. First, genetic diagnoses will become more widespread — we'll be able to identify many genes that cause, or predispose us to, specific diseases. Second, the practice of medicine will become genetically individualised and thus more effective: Prevention, diagnosis and treatment will be tuned to fit an individual's genetic make-up. But even this will most likely happen over many decades.

Even as the number of genetic diagnoses explodes, we will remain for some time pretty much helpless to intervene. We will know that a person has inherited a gene variant that makes him or her susceptible to, say, heart disease, autoimmune disease or cancer, but we won't be able to do much about it. Thus, for some time to come, our new genetic medicine will often have a rather cruel face — one that offers knowledge but no cure, one that requires potential sufferers to choose whether or not to know what the future may hold for them.

A second caution comes from the complexity of genetic effects. Although some diseases (such as cystic fibrosis, Duchenne muscular dystrophy and haemophilia) can be linked to a single gene, most of the associations between our genes and our health are far more complex. Most illnesses are influenced by a combination of many genes, often in complex interactions, and most of these interactions are still far from being understood. Typically, non-genetic factors — such as childhood exposure to infectious agents, chance events or other unknown influences — play a major role. All of these limit the predictive power of genetic information.

Our new knowledge will be hard to make sense of — and even harder to come to terms with.

As a result of these complexities, we can't expect the new genetic information to offer certainty. Most often, the association between our genetic make-up and our prognosis for disease will remain largely statistical. It will imply a mere shift in the chance of getting some disease — and perhaps a shift of just a few percentage points. In a sense, then, our genetic knowledge will toss us all into a fateful gamblers' den of playing the odds, and often for high stakes.

Would I want to know for example, that I have inherited a gene variant that means I have a 20 per cent chance (far above average) of suffering early-onset Alzheimer's disease -- especially if this degenerative brain disease cannot be avoided or cured? Should I learn this as a child? Or before I decide to marry and have children? Or ever? Do I want to know these things about my own children? Do I even want the mere possibility that I shall develop Alzheimer's to tempt me to find out how likely that possibility is?

Remember, genetic predispositions are just that -- predispositions, gambler's odds. They are not certainties.

This sort of statistical information is hard enough for an individual to absorb and deal with. But what should society make of it particularly when the disease in question involves nonmedical traits such as personality, emotions and behaviour? We are likely to find many genes that influence the risk for mental illness -- there already is evidence of genetic underpinnings for some of these illnesses. Should doctors encourage potential sufferers to seek treatment before its destructive symptoms appear?

Work done by researchers on the genetics of behaviour in animals suggests that we may find much stronger associations of this type in humans than most people currently expect. We all know, for example, that different dog breeds exhibit very different properties not just in their physical appearance but in their personalities, abilities and behaviour. And we know that all of these properties "breed true" (that's to say that they are strongly influenced by genetic differences). Will we find similar relationships in man? Opinions differ strongly here, but I doubt we can long rest on the comforting hope that differences in genetic endowments have little to do with our character traits. The big question will then be what we are to make of that knowledge.

There are many profoundly difficult issues in how we manage ourselves, in how we come to view our individuality, free will, legal responsibility and the inviolability-or not-of our genomes. Shall we be tempted to improve upon our genetic make-up in order to compensate for perceived personal inequities in our abilities and talent? As we gradually find the means of curing genetic diseases, such as cystic fibrosis or Lou Gehrig's, will we also be tempted to "cure" character traits such as nervousness or aggression?

And, finally, there is the issue of cost and inequity. It will not be magically free, this new world of gene-based medicine. It's likely that what we will be able to do medically, in terms of diagnosis and basic health care, will grow beyond what we can afford. If that's the case, we may face an increasingly stark and troubling connection between personal wealth and the maintenance of good health.

These are sobering thoughts. There is no mistaking that the recent announcement marked a profound achievement and the beginning of a revolution. But as we move forward, we should do so with an awareness that there are costs in having genetic knowledge that we shall not pay for in dollars. (Courtesy: Washington Post)

Elbert Branscomb is the Director of the U.S. Department of Energy's Joint Genome Institute, headquartered in Walnut Creek (California).