Arthritis: a family matter?
At your next family reunion, take an objective look around the room. You'll probably notice similar physical characteristics among many of the blood relatives - dark eyes, perhaps, or a large nose or a crooked smile. At the same time, you may find it hard to believe the petite woman with straight blond hair is a full sister to the three strapping guys with curly black locks.
The same kind of similarities - and contrasts - probably exist in your family's medical history. Often, as with the sister's blond hair and small build, a disease may appear to be a random occurrence. One family member might have a disease while others look like pictures of health. Unfortunately, diseases or the tendency to develop them sometimes run throughout the family tree. So the three brothers who have the same hair color and texture might also share diabetes or a predisposition to share disease or even spinal arthritis.
If this sounds perplexing, you're in good company. Since the dawn of clinical medicine thousands of years ago, physicians have observed that some diseases seem to run in families. They have also wondered why some members get a specific disease while others do not. The earliest basic explanations for this phenomenon began emerging almost a century and a half ago when the Austrian monk Gregor Mendel investigated inherited traits in green pea plants. Yet even today, scientists continue to question how our heritage can influence, or in some cases determine, our future health. But some major answers may be soon in coming, thanks to new and sophisticated technologies that Mendel could never have imagined.
Working with knowledge gained since Mendel's first findings, researchers in the 90s are aggressively probing the ultramicroscopic world of deoxyribonucleic acid (DNA) and its functional units, the genes. Often called "the stuff of life," DNA is a tightly coiled molecule found deep within the nucleus, or control center, of most of the body's cells. DNA is relatively simple in terms of irs components; it is made up of four chemical building blocks, called nucleotides, joined to one another by chemical bonds. There the simplicity ends however; it would have to when you consider DNA carries all the information that determines the form and function of living things - the genetic code.
From the moment you were conceived, you have had all the genetic information you will ever need. Half, in the form of 23 chromosomes, was contributed by your mother; the other half, another 23 chromosomes, by your father. It's the specific genes thousands of which are contained in each of those combined 46 chromosomes - that determine whether you have your father's tong nose and your mother's brown eyes. These genes, in part, also determine whether you'll be predisposed to the same kind of arthritis your grandmother had.
Scientists are now analyzing the genetic coding of molecules that appear on the cells of the immune system, the body's natural defense against disease. Through ongoing research, investigators around the world are identifying which genes are implicated in several specific diseases. Acting on these concrete clues, they are working to determine the actual mechanisms that may predispose some people to these chronic illnesses.
The potential payoffs of this unprecedented, rapid-fire progress appear to be enormous: in the short term, much improved treatment for a host of diseases including various forms of arthritis and other rheumatic disorders; in the long term, prevention.
A Key Role:
The HLA Connection
When the Human Leukocyte Antigen (HLA) family of molecules was first identified in the early 1970s, it ignited the whole question of how genetics relate to the acquisition of illness. HLA molecules coded for by specific genes apparently play a key role in regulating the immune-system functions of white blood cells.
Early on, scientists discovered that a specific rheumatic disease, ankylosing spondylitis, was more common in people who had a particular HLA molecule, HLA-B27, recalls Dr. Michael Lockshin, director of the Extramural Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). By the mid-1980s very specific genetic markers, as well as the distinctive amino acids that lead to susceptibility and illness, could be identified. Such findings unveiled the linkage between certain HLA molecules and several human disorders.
Dr. Lockshin foresees continuing advances on all fronts. "To me, the most important outcome will be prevention, although that's in the distant future," he says.
By understanding the cause of a certain disease and the type of person who may be susceptible to that disorder, it will be possible to intervene in the process. "For example," explains UCLA researcher Dr. Bevra H. Hahn, it's likely that some forms of arthritis begin when a person with the 'correct' susceptibility genes encounters an environmental stimulus, such as an infection or mechanical trauma." Therefore, she protects, disease could be prevented either by altering genes or by preventing environmental insults."
Dr. Lockshin, too, believes that gene therapies correcting a disorder by direct intervention in an individual's genetic makeup) may be conceivable in the distant future, but probably only in rare diseases such as the inheritable disorders of connective tissue. However, the immediate issue is understanding the mechanism of the diseases so that targeted therapies can be given, he says.
Below is a look at how molecular biology is increasing our knowledge of the causes and mechanisms of various arthritis-related diseases.
Ankylosing Spondylitis - Leading the Way
Just last year, 17 years after the strong association between HLA-B27 and ankylosing spondylitis was discovered, two Texas researchers confirmed the central role of HLA-B27 in the family of diseases called spondylarthropathies, which includes ankylosing spondylitis, Reiter's syndrome, psoriatic spondylitis and acute anterior uvertis, or iritis.
Dr. joel D. Taurog of the Harold C. Simmons Arthritis Research Center and Robert L. Hammer, Ph.d., of Howard Hughes Medical Institute, both at the University of Texas Southwestern Medical Center, Dallas, performed the first successful experiments to reproduce these human arthritic diseases in laboratory animals - genetically altered transgenic rats.
This authentic animal model will enable these researchers to examine the development of the disease from its very earliest stages. "Our work is focused on the function of the B27 molecule - what it is actually doing and in which cells it is important," Dr. Taurog says.
Recently, researchers have been able to crystallize HLA-B27, allowing them to visualize the three-dimensional structure of the molecule and its active site. This should help scientists in developing ways of blocking the molecule's action in the disease process.
Rheumatoid Arthritis Identifying Susceptibility
An example of how researchers are increasingly able to precisely pinpoint specific genetic elements in a particular disease is shown in the work of Dr. Gerald T. Nepom at Virginia Mason Research ,enter and the University of Washington, Seattle.
For some time, it has been known that HLA-DR4 genes are associated with rheumatoid arthritis. Dr. Nepom and his colleagues were able to determine that only some subtypes of DR4 genes are actually associated with the disease, and were able to identify them Dw4 and Dwl4 - as the culprits.
This information allows us to construct sort of a blueprint for the events we believe go on in very early arthritis," says Dr. Nepom. "And that blueprint then allows us to look for the so-called Achilles' heel' for the disease, a weak point that can be exploited for therapy."
Chronic Lyme Arthritis Putting the Puzzle Together
Unlike rheumatoid arthritis, chronic Lyme arthritis is a disease in which the environmental trigger is already known, offering investigators a unique advantage. Chronic Lyme arthritis afflicts about 10 percent of persons who contract Lyme disease, a systemic inflammatory disorder caused by the tick-borne spirochete Borrelia burgdorferi.
At New England Medical Center, Tufts University School of Medicine in Boston, Dr. Allen C. Steere and his colleagues are working with both parts genetic susceptility and environmental triggers - of the puzzle. The research team, working with Dr. Robert Winchester at Columbia Presbyterian Hospital in New York, recently established for the first time that HLA-DR4 and, secondarily, HLA-DR2 genes account for susceptibility to chronic Lyme arthritis.
Although the molecular basis of the susceotibility may be different, Dr. Steere says it is of great interest that both chronic Lyme arthritis and RA are associated with HLA-DR4. Continuing research by Dr. Steere and his colleagues is focusing on what part of the spirochete may trigger Lyme arthritis. "That information might give clues to how a different [environmental] agent might work in rheumatoid arthritis," Dr. Steere says.
The researchers are now attempting to determine if there is a specific peptide fragment a compound of two or more amino acid molecules) of Borrelia being introduced into the immune-system cells of patients who are HLA-DR4-positive and who develop chronic Lyme arthritis. If so, does that trigger the T cells of the immune system to attack the body's own tissues, which is the classic "autoimmune" response?
Dr. Steere says this line of investigation raises the question of whether a modified peptide fragment could potentially be used as a treatment for these diseases. That, in effect, would involve one peptide canceling out another in a process that would selectively inhibit the destructive autoimmune response, without interfering with other activity of the immune system which is normal and essential.
Systemic Lupus Erythematosus - Working Toward Prevention
Similar research questions are being posed by Dr. Hahn and her colleagues at the UCLA Medical Center. They have been able to define a pair of genes - HLA-DR2 and HLA-DQIAZH that predispose patients who carry them to lupus nephritis. This is the kidney disease complication of lupus that afflicts 40 to 50 percent of people with the disease.
My personal bias is that lupus is a set of different syndromes that all have the same diagnosis," says Dr. Hahn. "And patients with predominant kidney disease are genetically different from patients with predominant skin disease. And both of those are different from patients who have recurrent clotting as their major manifestation."
Dr. Hahn's ongoing research is also focused on the possibility of finding ways to short-circuit the disease process with a peptide. "We're interested in asking whether we can use an appropriate blocking peptide to prevent the gene from affecting the immune system ," he explains. "If we could immunize a person so that a particular gene couldn't cause an inappropriate immune response, then that person should never get lupus."
Osteoarthritis Finding Defective Genes
The outlook for progress against a far more common rheumatic disease, primary generalized osteoarthritis, improved dramatically in late 1990 with research that uncovered a genetic basis for the disease. Unlike findings involving susceptibility genes in other rheumatic diseases, the hereditary culprit in primary generalized osteoarthritis turns out to be a gene defect, discovered in a collaborative study by Dr. Darwin J. Prockop of jefferson Medical College, Philadelphia, and Dr. Roland W. Moskowitz of Case Western Reserve University, Cleveland.
Studying a large, three-generation family chosen because several of its members developed severe generalized osteoarthritis at an early age, Dr. Prockop and his colleagues found a faulty gene - a mutation in the collagen 11 gene - only in those family members who developed the disease. The faulty production of collagen 11 results in defective cartilage that is extraordinarily susceptible to wear and tear - thus the process of osteoarthritis, in which the cartilage, and consequently the joints, are destroyed.
"It may take us another year to find out if there are other families who have exactly the same mutation or other mutations of the same gene," says Dr. Prockop. Originally, analyzing one of these genes took over three years. Now we have it down to three months. Within a year, we hope to make it three days."
A Family's Odds
Until genetic or other types of research find a cure for the different forms of arthritis, there remains a more pressing issue in the minds of many parents with arthritis and many couples contemplating parenthood: Will my child inherit my arthritis? Likewise, seemingly healthy people whose parents have arthritis may wonder, Will I one day get arthritis, too?
In most cases, the answer is no. Unlike Huntington's disease - a genetically transmitted disease that causes mental deterioration and eventual death - where a child stands a 5050 chance of developing the disease if one parent has it, children of people with many forms of arthritis are unlikely to ever experience arthritis themselves.
Even those who inherit the predisposing genetic type appear to have a low risk. HLA-B27, for example, is found in about 7 percent of the general population, according to Dr. Taurog. "Yet in 98 percent of this 7 percent, it causes no trouble. Overall, only about 2 percent of B27-positive individuals will develop one of the seronegative spondylarthropathies."
Dr. Nepom offers some encouraging words to people who carry the Dw4 or 14 genes that have been associated with rheumatoid arthritis: "Even in identical twins who share identical genetic codes, if one twin has rheumatoid arthritis, less than 50 percent of the time the other twin will have RA," he says. "So it's clearly not just genetic. There is some environmental trigger such as a virus that somehow operates to short-circuit the wires to make the signal turn on in a tissue where it shouldn't be on. "So it's important to realize that what we've done is identify the mechanisms and genes for susceptibility, but that's not the complete story of the disease." An Exciting Present and A Bright Future
The story of today's rapid-fire progress in molecular biology and immunogenetics is one not only of advancing technologies, but of unprecedented cooperation and collaboration among researchers around the world. Data are shared on an international basis. Investigators from different university laboratories are collaborating on research projects. In the United States, where much of this work is being carried out, scientists from many disciplines are working together in the Multipurpose Arthritis and Musculoskeletal Disease Centers across the nation. The Arthritis Foundation is also actively supporting research; indeed, some of the advances discussed here were supported by the foundation. Many of the 155 researchers currently funded by the Arthritis Foundation are studying the role of genetics in arthritis. The foundation will continue to fund this and other wi types of research to fulfill that part of its mission: to find the cures for and prevention of arthritis. This teamwork portends great future progress in conquering today's incurable diseases.
If the future is bright, it is so not only because of the present, but also because of past progress - and a longstanding national commitment beginning in the late 1940s and early 1950s when the U.S. began sponsoring basic research. Everything that has happened since then builds," observes Dr. Prockop. "It's a marvelous story. We as Americans can be very proud of the money and the talent that we put into it."
GENETIC DISCOVIERY POSES TOUGH QUESTIONS
Should information about your genetic makeup be open to inspection by strangers the way your credit history is? What information about you are insurers and employers entitled to? How much should you know about the genetic traits you carry?
Troubling questions arise as medical technology advances. Indeed, science today stands on the verge of a advances. Indeed, science today stands on the verge of a new frontier in the world of medicine, much as Columbus did when he set out to find a new route to the Orient. It is a new frontier of genetic discovery. Like the new world Columbus discovered, it offers immense opportunities - and immense ethical challenges.
The vessel on which today's explorers have set sail is the Human Genome Project, a massive international effort to map the complete genetic international effort to map the complete genetic blueprint hidden within the nucleus of every human cell. Obeying this blueprint, genes carry the instructions that make cells and tissues work properly - or malfunction, if the gene is defective. With each new scientific discovery comes the hope of improved diagnosis, a cure and ultimately even prevention of a particular disease. As the accompanying article by Michael Briley reports, the prospects for uncovering the genetic origins of many forms of arthritis have never seemed brighter.
Yet the flood of information has set alarm bells ringing around the world. At the National Center for Human Genome Research (NCHGR) within the National Institutes of Health, millions of dollars are being spent in an effort to limit the ethical, legal and social implications of the work its own funds are supporting. A bill has been introduced in Congress to protect the privacy of genetic records maintained by government agencies or their contractors. In California, legislators passed the nation's first law to prevent employers and insurers from discriminating against individuals because of their genetic characteristics. The governor vetoed it, but it's likely to be reintroduced in a revised form. And from scientists around the world come calls for international agreements to govern the uses of genetic information.
Why should there be so much concern about an enterprise that offers so much hope?
Consider this scenario: Suppose you are a young, healthy person with no apparent problems. Suppose a genetic test unexpectedly reveals that you carry the HLA-DR4 gene that may predispose you to developing rheumatoid arthritis. Consider, too, that rheumatoid arthritis is a leading cause of work disability and an illness that may require intensive medical care, with its associated costs. Suppose now that a
employer or insurer has access to this genetic information about you.
Would that employer be willing to hire you, knowing that your working life might be curtailed by illness? Would he be willing to provide you with health insurance, knowing you could be a bad risk? Could he - or you - even find an insurer willing to cover you? Knowing that genetic traits may be inherited, would a insurer conclude that you, your children, or even your si lings are good risks?
How about you? Knowing that you carry a gene for a potentially debilitating illness, would you go ahead and make long-term plans for your career? Would you plan on having children? Would you live your life happily, unworried by what the future may hold?
And if you answered no to all these questions, wouldn't that be a sensible response on the part of the employer, the insurer, yourself?
In many cases the answer, again, would be no.
A test result, taken by itself, does not provide information about the full diversity of genetic variation. Even in those cases where genetic tests can predict with a high degree of certainty that you will be affected by a genetic disease, those tests usually don't show when you will be affected or how severely.
Furthermore, you might spend your life waiting for a calamity that never happens. A genetic defect might predispose you toward a certain disease, but the defect might require as a trigger" an outside factor that you never encounter.
Between the detection of a genetic link to a particular disease and the potential outcome could be years or decades of productive life.
Factors like these are prompting scientists and legislators to take a hard look at the consequences of the present explosion of genetic information - and to develop safeguards on its use. The scientific effort is spearheaded by the Ethical, Legal and Social Implications Program (ELSI) at NCHGR. It covers a variety of issues:
Employment. While genetic testing is not widely used by employers at present, it could pose a serious t many healthy individuals known to carry a gene for a severe chronic illness like rheumatoid arthritis.
"We're studying the possibility of using existing law - the Americans with Disabilities Act to prohibit discrimination in the workplace based on genetic test results," says Eric Juengst, Ph.D., ELSI'S director.
In addition the American Medical Association's Council on Ethical and Judicial Affairs recently issued an opinion to help physicians decide when genetic testing for employment is appropriate - and when it is not. Essentially, the council's opinion was that such testing is valid only when there is a possibility of genetic susceptibility to illness caused by chemicals or other substances in the workplace, and then only in very limited circumstances.
insurance. The threat of being denied insurance is already a reality for many, according to Dr. Paul Billings, chief of the Division of Genetic Medicine at California Pacific Medical Center in San Francisco. He cites the example of a whole family being denied insurance because the father carried a gene for a particular disease. "I know a case where restrictions were extended even to an adopted child," says Dr. Billings. "Testing makes insurers see people as groups instead of as individuals. We need public education about the difference between being a carrier and being a person with a disease."
ELSI is helping develop model guidelines that states can use to regulate this type of insurance practice, Juengst says.
Family Planning. The new field of genetic research has given birth to a new career: genetic counseling. Genetic counselors provide information to prospective parents about the genetic traits they could pass on to their children and about inherited disorders detected in the fetus. Advice is not permitted - only a laying out of all the facts and all the options. Still, Dr. Paul Fernhoff, a clinical geneticist and associate professor of pediatrics at Emory University in Atlanta, worries about how his patients make their difficult choices.
"In the past, the disorders we detected were significant mental or physical defects," says Dr. Fernhoff. "But we're that don't show signs and won't cause problems for many years, as in some of the connective tissue disorders. What scares me is what people do with the information we give them to help them make informed reproductive decisions. Mostly, people make rational and ethically acceptable decisions. But we may not know all the decisions they make. They may use the information in ways we don't know."
Mental Anguish. Knowing that you may at some unknown point in the future be affected by a severe mental or physical disorder can be a source of intense anxiety. It can lead to inappropriate career and life choices. Some experts even question the value of informing a person that he carries a gene for a disease for which there is no known cure or treatment. ELSI is sponsoring research to establish guidelines for counselors to help them minimize the confusion and stigmatization genetic testing can produce.
Unlike Columbus, today's scientific explorers and their patrons in government have foreseen the ethical hazards of their venture. The challenge for genetic pioneers will be to maximize its benefits and minimize its risks.