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THE HUMAN GENOME PROJECT and the Medicine of the Future.

The most ambitious biological science project ever conceived is under way and will profoundly affect how medicine is practiced in the next century. This project is the Human Genome Project (HGP), and its goal is to determine the DNA sequence of every gene in the human body. The HGP is fueling rapid discoveries into the genetic basis of a wide range of conditions. By laying bare the human DNA code, scientists are creating a deep understanding of how our bodies work, an understanding that builds from the most basic level of genes.

A thorough understanding of the molecules of life promises to transform science and medicine: from molecules, scientists can better understand cells; from cells, researchers are understanding better how tissues and bodies work. The details are not easy to unravel, but researchers increasingly can trace how molecular alterations translate into physical symptoms. The HGP promises to yield insights about nearly all health problems and, ultimately, yield treatments for many conditions, whether inherited or not. Many, if not all, exceptional children will be affected by these discoveries, and some have already benefited. It is crucial that those affected by the discoveries should understand and appreciate what this project is about and how it will alter the medicine of the future.


Genes are not everything, but they are very important. Genes are encoded within DNA, the molecule that transmits traits from parents to children. The genes that we inherit instruct our bodies in the steps necessary to build cells, tissues and organs, and how to break down food and use those breakdown products to build critical molecules to maintain health. Other genes make signaling molecules while still others make molecules that receive and process those signals. How all the components of life come together from a set of genes is like the creation of a symphony from sheet music--the creation of a harmonious whole from nothing more than spots of ink on pages of paper. Like music, the language of genes may appear simple, but in a living creature, the building blocks--or individual genes are woven together with beautiful intricacy to create a complex organism. Decoding the language or code of our genes will allow scientists to understand in detail the enormously complex set of instructions that shape a human being.

To unravel the mystery of the code, scientists study both normal and abnormal genes. In this way, the importance of each gene can be defined and the consequences of gene dysfunction understood. An understanding of how each gene works can benefit us in many ways. Knowledge about normal and altered genes will assist diagnosis and treatment of a wide range of disorders. The Human Genome Project is the first step toward understanding the function of all of our genes and how those genes affect our health.


Even before the function of a gene is understood, knowing that a particular gene somehow causes a particular disorder can be very useful. The knowledge can be used immediately to help with the problem of accurate diagnosis. Many medical diagnoses lump together ailments that actually represent a group of overlapping, but distinct diseases. For example, cerebral palsy and autism are diagnoses that each include a tangle of conditions that are probably distinct in origins and effects. When a diagnosis includes a mixed set of conditions, a child's diagnosis does not necessarily reveal much about what kind of future that individual child is likely to have, nor how that child should be treated to minimize symptoms. Refined and accurate diagnoses lead to prognoses that are more reliable and allow more informed decisions to be made about care.


For only a relatively small number of conditions do scientists understand the molecular abnormality at the root of the condition and how that abnormality causes the disorder. The HGP will supply the resources to help reveal the origins of nearly all disorders. The HGP has dramatically increased the rate at which human genes are being discovered. Little more than a decade ago, disease genes could be identified only if scientists already understood the biochemical problem they were facing, a prerequisite that left most disorders as unapproachable mysteries.

Now, scientific journals report the discovery of a new disease gene practically every week. The HGP helps scientists find disease genes based purely on genetic features like genes' positions in DNA, which means the basis of a disease can be discovered without any inkling in advance about the cause. The pace of discovery is accelerating. Ten years ago, the gene for cystic fibrosis was found after an arduous nine-year search. Eight years later, a gene for Parkinson's disease was found in only nine days.

Understanding pathogenesis--or how exactly a disorder arises--can reveal targets for intervention to prevent, mitigate, or reverse health problems. Finding a gene does not always lead to easy answers; for example, the molecular defect responsible for sickle cell anemia has been known since the 1950s, and medications can control some of the symptoms of this ailment. However, no one knows how to cure it. The gene for cystic fibrosis was discovered in 1989; ten years later, no treatments based on the discovery are yet on the market. However, understanding the genetic alteration in cystic fibrosis has fueled energetic attempts to design better drugs. Now, more than a dozen such drugs, based on an understanding of the protein encoded by the cystic fibrosis gene, are in clinical trials.

Sometimes finding a gene yields more immediate benefits. For example, the gene responsible for a form of inherited colon cancer called familial adenomatous polyposis, or FAR, was discovered in 1991. The gene, called APC, is often mutated in cases of sporadic colon cancer as well. But when a mutated APC gene runs in a family, even children and teenagers can be at risk for colon cancer. With the discovery of the gene, genetic testing became possible. In the case of colon cancer, cure rates are very good when tumors are caught and removed early. Genetic testing can reveal who is particularly susceptible and should embark upon a program of regular, close surveillance for colon polyps. Meanwhile, family members who find they do not have genes that put them at risk can confidently forego the screenings.

Genetics is also helping sort congenital heart defects, which affect nearly 1 percent of babies, into distinctive syndromes. One of these is velocardiofacial syndrome (VCF), caused by the absence or malfunction of a gene or group of genes on chromosome 22. Children with this disease often have cleft palate--but not all do--though they have the cardiac defect, which usually affects the aorta where it connects to the heart. A chromosome test called FISH (fluorescent in situ hybridization) can highlight whether a child suspected of having velocardiofacial syndrome is missing a piece of chromosome 22 to confirm the diagnosis. VCF is a good example of how a molecular test improves our understanding of a disorder. In the past, the syndrome was only thought to exist when a person had many manifestations (heart defect, cleft palate, and developmental delay). However, the availability of the molecular FISH test showed scientists that some people, including relatives of people with all the features of VCF, have only an isolated heart defect. This is a case where genetic tests have revealed that an underlying genetic alteration is more widespread than previously believed; not all people with a genetic alteration manifest traditional aspects of each syndrome. The genetic explication of these syndromes now means that children born into families where there is a history of these heart anomalies can be tested for a hidden genetic problem so the problems can be treated earlier. Also, the gene test can be used to diagnose children with unexplained heart anomalies; and if the VCF gene region deletion is the cause of the heart problem, that alerts caregivers to possible subtle developmental problems as well.


Genetic counseling is a process that includes risk assessment, education and psychosocial counseling. A precise understanding of the genetic basis for a health problem can help couples determine the risk that a disease will affect future children. If a disorder in one child apparently occurred by random chance, whether because of a rare new gene alteration in the affected child or because of an alteration during development not caused by genetics, parents can be reassured that the risk of recurrence in future children is small.

Congenital heart defects, for example, undoubtedly result from a combination of conditions, some resulting from alterations in a single gene, some from a group of genes acting together, and probably some non-genetic causes. In many disorders (e.g. congenital heart defect), the currently accepted statistics which represent the risk of recurrence, mix together many different conditions that arose for different reasons. No family wants to be counseled on the basis of a recurrence risk figure that reflects an average of these factors. Rather, they want a recurrence risk that accurately reflects their own situation so they can make family planning decisions that are right for their family.

Similarly, genetic counselors can best help families with their concerns when an accurate and specific diagnosis is available. Nearly all parents want a detailed and precise explanation of the cause of their child's problem. Generalizations are much less helpful. The ability to make an accurate diagnosis, provide a valid recurrence risk, and educate families paves the way for focused counseling on the challenges and issues that face the family. When an accurate diagnosis has not been made, much of the counseling process revolves around the issue of diagnostic ambiguity and the resulting frustration. When a specific diagnosis is made, counseling focuses more on coping with what is known about the disorder, dealing with the prognosis, considering reproductive decisions, and other related issues. In this way, genetic counselors can help families cope with the challenges they face and also help them deal with grief and loss.


The genetic underpinnings of many more conditions will become apparent in the coming years. The benefits of improved diagnosis and prognosis will spread to many more illnesses. However, achieving direct treatments and cures based on genetic research will take a great deal of scientific effort and time. Understanding in molecular detail the sequence of events that causes physical problems will yield insights on how to intervene in the disease pathway and interrupt it. In time, drugs will be designed to target specific gene products. Some drugs will interact with key proteins-whose place and time of action is understood--and perhaps adjust the level of action of genes.

Molecular genetics and the HGP are not the answer to all of these challenges. The completion of the HGP, expected by 2003, will herald the end of the beginning. That is, we soon will understand what causes most congenital and inherited disorders in human beings. It is a long road to the development of treatments and cures, but we have also traveled a long road from our former ignorance of the causes of these disorders. The HGP is allowing us to move forward with purpose and speed, and that should be a source of hope to all those who have been affected by these conditions.

Karin Jegalian, PhD, holds a Doctorate in Genetics from Massachusetts Institute of Technology and is a science writer at the NIH's National Human Genome Research Institute (NHGRI). Leslie Biesecker, MD, is an investigator at NHGRI focusing on the molecular and clinical characterization of multiple congenital anomaly syndromes and overgrowth syndromes. He is a board certified pediatrician and medical geneticist.
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Author:Jegalian, Karin; Biesecker, Leslie
Publication:The Exceptional Parent
Date:Mar 1, 2000
Previous Article:GENE THERAPY.

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