Alkaptonuria

The sequencing of the human genome is only the tip of the iceberg. It is the beginning of a revolution that many predict will transform medicine. How will genetics research affect physicians and patients and the practice of medicine? When investigators identify the function and association of human genes with common chronic diseases, diagnosis, treatment, and classification of human diseases will be changed forever. Genetic susceptibility testing allows patients to know their predisposition to disease long before symptoms appear. Physicians can intervene with customized advice so that the patient can prevent, modify, or avoid the predisposed condition by better understanding both his or her genetic and environmental risk for disease. The promise of a genetic approach to drug therapy involves moving from one size fits all to personalized medicine tailored to the individual patient. Physicians will become mentors and counselors, advising patients on the best treatment path given their unique genetic predisposit ion--even in this sophisticated, high tech field, the physician-patient relationship is likely to improve, highlighted by individualized therapies and personal attention.

KEY CONCEPTS

* Genetics Transforming Medicine

* The Human Genome Project

* Advances in Medicine

* Improving Disease Classification

* Genetic Susceptibility Testing

* New Therapies and Customized Pharmaceuticals

HOW WILL GENETICS transform medicine? The sequencing of the human genome is spurring investigators from all parts of the world to uncover the function of each human gene. Since most diseases have a genetic component, genetics will increasingly play a pivotal role in predicting, preventing, diagnosing, treating, and classifying all human diseases. The practice of medicine will be revolutionized and hundreds of millions of people will be affected.

The basics of genetics

In the nucleus of each somatic cell in the body there are two sets of the human genome, one from the mother and one from the father. Each set of the genome contains the same genes on the same 23 chromosomes. The genetic information is contained in the double helix molecule of DNA, composed of nucleotide base pairs. Almost everything in the human body is composed of proteins that are manufactured using the genetic instructions in the genes through a process of replication and translation that is mediated by messenger RNA. The biochemical reactions in the body are facilitated by proteins called enzymes and hormones that turn genes on and off.

Matt Ridley in Genome: The Autobiography of a Species in 23 Chapters comments on the relationship between genes and proteins: "A protein is just a gene's way of making another gene; and a gene is just a protein's way of making another protein. Cooks need recipes, but recipes also need cooks." [1]

Although we traditionally think in terms of one gene, one messenger RNA, one protein, and one disease if there is a mutation, we now know it can be far more complicated. Alkaptonuria is an example of the simple model of genetic disease. This mild disease that causes arthritis and black urine is due to a single base pair substitution at either the 690th or the 901st position of nucleotides making up the third human chromosome. When a patient has such a mutation, he or she manufactures a defective version of the protein homogentisate dioxygenase and, thus, suffers from alkaptonuria. [1]

Unlike the straightforward alkaptonuria gene, there appears to be no single asthma gene. There are at least 15 different asthma genes that are implicated in some forms of the disease, in some people, some of the time. A genetic marker on chromosome 11, for example, explains only 15 percent of asthma sufferers, and other candidate genes for asthma are being examined on chromosome 5, 6, 13, and 14. And it gets even more complicated. [1] Marsh found that ten out of 11 gene candidates for susceptibility to asthma were unique to only one racial or ethnic group. [2] Many believe that most of the most common chronic diseases--diabetes, rheumatoid arthritis, heart disease, depression, dementia, and common cancers-- are genetically more like asthma than alkaptonuria.

Realizing that many common diseases do not exhibit a one-to-one relationship between a single gene mutation and the expression of the disease, investigators are developing new research tools to study diseases like asthma. The traditional approach featured geneticists performing linkage analysis studies that examined the relationships between inheritance and genetic markers in families affected by the disease. This approach located the genes for Huntington's disease and cystic fibrosis, but proved to be unsuccessful in studying diseases like asthma.

Researchers searching for functions of genes are increasingly employing association studies of unrelated affected patients and controls, instead of the more traditional linkage studies concentrating on hereditary diseases in families. These association studies of complex multigenic diseases require large numbers of participants from around the world to differentiate between genetic and environmental causes. Searching for these genotypic-phenotypic associations requires access to well phenotyped, properly consented DNA and tissue samples and medical histories from diverse patients.

Genetics transform diagnosis

How does knowing the function of a human gene lead to new ways of diagnosing, treating, and classifying disease? When we know the function of a gene or, in some cases, how the genes do not function properly, we can develop genetic susceptibility tests. Some genetic susceptibility testing is being developed based on the use of biochips to detect genetic differences in a single nucleotide building block of DNA, known as single nucleotide polymorphisms (SNPs). The patient's sampled cheek cell yields up its chromosomes made up of a double-stranded DNA molecule. The extracted DNA is separated, duplicated, and placed on a testing chip containing artificial DNA with a known composition of bases. On the chip, as the patient's DNA binds with the artificial DNA, the SNPs become apparent as differences from the expected binding.

This testing allows patients to know their predisposition to disease long before symptoms appear. Health care providers are able to intervene with individual customized advice so that the patient can prevent, modify, or avoid the predisposed condition by better understanding both his or her genetic and environmental risk for disease. Every one of us has thousands of these genetic differences or SNPs, and most of them do not have clinical significance. However, the SNPs of interest are those that are in crucial positions on the chromosome, such that the translation into protein is abnormal or the amount of protein produced is impaired. Associating these genetic differences with specific diseases and determining the function of the proteins they encode will result in new ways to diagnose patients with disease.

These tests can tell us if individuals are predisposed to a disease, allowing earlier intervention by health care providers. The genetic differences may also predict the likely outcome of a disease, which can direct physicians towards recommending more aggressive or more conservative treatments as appropriate.

New approaches to therapy

Treatment will also be revolutionized by the new knowledge derived from genetic research. Understanding the function of the protein produced by the gene associated with disease can lead to new treatments in several ways. In some cases, the faulty protein can provide a target against which existing libraries of small-molecule compounds can be tested for therapeutic effect. In other cases, the protein may be a novel compound that can be used to treat the disease.

Pharmaceutical companies are also investigating the use of SNPs to predict which drugs will be most effective for which patients. Some of the SNP genetic differences are associated with adverse reactions to certain drugs or increased metabolism; the genetic profile of a patient will allow pharmacologists to tailor-make drugs for the individual patient.

A recent study published in the Proceedings of the National Academy of Sciences showed that patient response to the asthma drug albuterol is affected by several genetic polymorphisms of the beta-2 receptor. [3] Such findings could become the basis for simple blood tests that will predict which patients will benefit from a drug like albuterol and which will not respond. Presently, a drug that is effective in only 50 to 70 percent of the patients who receive it is considered a success.

The promise of a genetic approach to drug therapy involves moving from one size fits all to personalized medicine tailored to the individual patient.

Gene therapy can be thought of as inserting a functioning gene into a target tissue to replace a defective gene; it should allow physicians to treat the underlying causes of diseases like cystic fibrosis, asthma, and cancer rather than just the symptoms. Drug companies like Novartis invested almost $1 billion in this revolutionary approach, and advocates predicted early success that did not materialize.

The biggest challenge so far has been to identify a vector that can safely deliver the normal genes to the diseased cells in the body for a long enough time to cure the disease. An adenovirus was used as a vector in the University of Pennsylvania gene therapy trial that resulted in the death of the young patient who had a rare liver disease. This unexpected death has resulted in a re-evaluation of all gene therapy programs in the United States, and nobody is predicting effective gene therapy the next few years. [4]

The classification of disease will also be transformed by the new genetic information. When we discover the genes associated with a disease code for a specific enzyme, we will have a better way to classify and understand human diseases. Researchers are starting to realize that many common diseases represent collections of different conditions that may each have their own genetic cause. Articles are starting to appear that predict the classification of diseases like hematopoietic malignancies on the basis of genetic profile, rather than morphologic appearance under the microscope or the expression of immunologic markers by immunoperoxidase staining.

Cautionary note

Craig Venter, the CEO of Celera, said, "As a civilization, we know far less than one percent of what will be known about biology, human physiology, and medicine. My view of biology is 'We don't know shit."' [5] It is good to remember that the promise of the genomics revolution is just that-a promise; no one knows how it will all work out, and it is wise to remember all that we do not know at the present time.

We do not even know how many genes a human has. Three estimates published in the journal Nature Genetics ranged from 28,000 to 120,000, and scientists at a meeting at the Cold Spring Harbor Laboratory opened a sweepstakes with bets ranging from 27,462 to 200,000. The winner will be determined at the annual meeting of geneticists in 2003. [6]

It is important to remember that environment plays a role in human disease, and all of this investigation of genetics may highlight the role of environmental factors. If one identical twin develops juvenile diabetes, the other twin with essentially the same genetic inheritance develops the disease less than 50 percent of the time. A recent New England Journal of Medicine twin study from Scandinavia concluded that inherited genetic factors make a minor contribution to susceptibility to most types of cancer. The researchers concluded that environment has the principal role in causing sporadic cancer in the 44,788 pairs of twins studied. [7]

There are skeptics who question how much genetics will transform medicine. Professor Richard Lewontin of Harvard has written extensively about the limitations of some theories of genetics. "Were God to appear to me in a dream telling me the heritability of, say, coronary artery disease, to the fourth decimal place, I could not use that information for any program of amelioration, prevention, or cure, because it would tell me nothing useful about the pathways of mediation." [8]

The British medical historian Roy Porter is quoted in The New York Times, "Nowadays, with the genome project, people might say that all diseases have a genetic basis. In 20 years, they'll realize it was a gigantic mistake, in the way that throughout history almost all obsessional monocausal theories about how there's one model for disease-they're all due to the humors or all due to the devil or all due to bacteria or genetics-turn out to be wrong because the human body is so complex." [9]

Conclusion

The sequencing of the human genome by the Human Genome Project and Celera is only the beginning of a revolution that many predict will transform medicine. When investigators identify the function and association of human genes with common chronic diseases, diagnosis, treatment, and classification of human diseases will be changed forever.

Practicing physicians are in a unique position to facilitate this important linking of genes to common diseases. Because the association studies of unrelated patients require thousands of research subjects and controls to differentiate between genetic and environmental affects, DNA and tissue samples have emerged as a rate limiting step. Physicians can play an important role in encouraging their patients to take part in such research and in requiring that the research be conducted ethically and with sensitivity toward the research subjects. Such participation represents a shift from the usual doctor-patient relationship with its more immediate rewards and benefits; the rewards of genetic association studies will not be immediate, but rather long term and for the benefit of all patients.

Many patients have become disenchanted with modern medicine because more sophisticated technology has often been associated with impersonal encounters that lack intimacy and the special relationship with a caring, empathetic physician. Genetic susceptibility testing is sophisticated technology that will require a close relationship with providers who can deal with the psychosocial, ethical, and legal issues associated with inherited susceptibility. It is ironic and encouraging that this most advanced technology may lead us back to a more traditional doctor-patient relationship featuring individualized therapies and personal attention.

Norton Zinder puts where we are in perspective: "This is the beginning of the beginning. The human genome alone doesn't tell you crap. This is like Vesalius. Vesalius did the first human anatomy. Before Vesalius, people didn't even know they had hearts and lungs. With the human genome, we finally know what's there, but we still have to figure out how it all works. Having the human genome is like having a copy of the Talmud but not knowing how to read Aramaic."

Kent Battles, MD, is President of the Genomics Repository of Genomics Collaborative, Inc., in Cambridge, Massachusetts.

References

(1.) Ridley, M. Genome: The Autobiography of a Species in 23 Chapters. New York: Harper collins, 1999.

(2.) Marsh, D.G., et al. Linkage Analysis of IL4 and other chromosome 5q31.1 Markers and Total Serum Immunoglobulin-E concentrations. Science. 264: 1152-6, 1994.

(3.) Drysdale, et al. Proceedings of the National Academy of Sciences, September 12, 2000.

(4.) Langreth, R, Moore, S.D. Delivery Shortfall: Gene Therapy, Touted As a Breakthrough, Bogs Down in Details: Human Tests Prove, at Best, Inconclusive; Novartis Reins in Its Investments: 'Not Proud of It Right Now.' The Wall Street Journal. October 27, 1999.

(5.) Preston, R. The Genome Warrior, The New Yorker June 12, 2000, pp. 66-83.

(6.) www.ensembl.org/genesweep.html.

(7.) Lichtenstein, P., et al. Environmental and Heritable Factors in the causation of cancer: Analyeses of cohorts of Twins from Sweden, Denmark, and Finland. New England Journal of Medicine. 343: 78-85, 2000.

(8.) Lewontin, R. It Ain't Necessarily So: The Dream of the Human Genome and Other Illusions. New York: New York Review of Books, 2000.

(9.) Lyall, S. A Historical Alchemist Turns Medicine into Gold. New York Times, April 24, 1999.

Genomic Biotech Companies

Drug development companies

Millennium Pharmaceuticals

Cambridge, Massachusetts

Milestones: Partnerships with Bayer, Monsanto, Pfizer, Eli Lily, American Home Products, Astra, and Roche.

Human Genome Sciences

Rockville, Maryland

Milestones: Partnership with SmithKline Beecham. Drugs in clinical trials

Data subscription companies

Celera Genomics Group

Rockville, Maryland

Milestones: Partnerships with Novartis, Pharmacia and Upjohn, Amgen.

EST Shotgun sequencing of human genome.

Incyte Pharmaceuticals

Palo Alto, California

Milestones: More than 25 subscriptions.

Drug discovery platform company

Genomics Collaborative

Cambridge, Massachusetts

Milestones: Global physician collection network, global repository, GCI Discovery Technology.

Genomic Resources

Genome: The Autobiography of a Species in 23 Chapters

Matt Ridley

New York: Harper Collins, 1999

A delightful, well-written, and scientifically accurate account of the human genome. This is the best starting place for the non-geneticist who wants an overview of genetics.

It Ain't Necessarily So: The Dream of the Human Genome and Other illusions

Richard Lewontin

New York: New York Review of Books, 2000

A thought-provoking discussion of the difficulties medicine will face in realizing the promise of the genomics revolution.

Section, F. The New York Times, June 27, 2000. Ten excellent overview articles published on the day of the White House announcement.

www.getdna.com

This website of Genomics Collaborative of Cambridge, Massachusetts, contains general introductory material and a discussion of ethical issues.

Profiles: The Genome Warrior

Richard Preston

The New Yorker, June 12, 2000, pages 66-83.

An irreverent and highly revealing account of the behind the scenes jockeying for position to receive the Nobel Prize for the sequencing of the human genome. Preston manages to get both the science and the gossip right.

COPYRIGHT 2001 American College of Physician Executives
COPYRIGHT 2002 Gale Group