|Genomes, Proteomes, and Medicine|
|Opportunities in Medical Science in the 21st Century|
|By Barbara J. Culliton
February 12, 2001
People say that only fools predict the future. However, with the recent past as a sure guide to biomedical research in the next decade or two, reasonable predictions about the future of medicine can be made. For while it is true that one can never be certain where research will lead, and that serendipity will always play an invigorating role in the research enterprise, it is nonetheless possible to see where we have come since molecular medicine and human genetics emerged in the 1970s and, from that, to tell where we are going.
The human genome has been sequenced and assembled.
It is possible to make human tissues in the laboratory that will grow into new blood vessels, skin, and cartilage. The future will see more of this. Stem cells from embryonic tissue offer great potential for therapy. Equally exciting, stem cells, taken from our own adult organs, will be the seeds for tissue and organ regeneration.
Gene therapy will work in time.
Using diagnostic tools derived from human genomics, as well as remarkable advances in imaging, serious diseases will be detected and treated long before symptoms appear. Conditions as disparate as Alzheimer's and osteoporosis are good candidates for disease prevention. Other diseases are candidates for full-fledged cures that will come from the application of human genomics and the new, related field of proteomics. Genes make proteins, proteins are at the core of human physiology. And proteomics is the study of proteins at work.
It is not unreasonable to predict that during the 21st century, many of the diseases that haunt humankindparticularly the chronic diseases that are a kind of plague in the developed worldwill be brought under control. The list is long. Here is a sample:
For the past quarter-century, the United States Congress has been consistent and generous in its support of the National Institutes of Health (NIH) and other federal agencies that fund biomedical research. Likewise, the pharmaceutical and biotechnology industries have taken advantage of a strong economy to invest unprecedented sums of money in research on new drugs and diagnostic tools. In fiscal year 2001, the National Institutes of Health is expected to spend approximately $20 billion on research. Indeed, during the past three years, the NIH has received appropriation increases of nearly 15 percent, reflecting a bipartisan support of biomedical research. At the same time, the Pharmaceutical Reseach and Manufacturers of America (PhRMA) projects that drug industry expenditures for research and development will reach nearly $26.4 billion. This clearly reflects a strong commitment to research that will lead to disease prevention as well as therapy in the coming years.
But it is important not to be complacent. The health of the American public, as well as the health of people worldwide, continues to depend on the research talent and capital of U.S. scientists in both the public and private sectors.
The Human Genome
In contemplating the future of medicine and the investment in research that will be required to make our predictions come true, it is important to understand that there is something fundamentally new about 21st-century biomedical research. Two truths, above all others, are clear from knowledge gleaned during the latter half of the 20th century.
First, "All disease is genetic." That is to say, the behavior (or misbehavior) of human genes is at the root of disease in one way or another. Second, complex diseases are the result of the interaction of many genes and the environment. Furthermore, every individual's unique complement of genes accounts for the fact that some of us are more genetically susceptible to one disorder than another.
It is necessary to know exactly how those genes work, and how they interact with other genes in the body, as well as with factors in the environment, in order to prevent or cure disease. And therein lies the promise of the human genome. Now that the sequence of the human genome is known, it is possible to take the next vital step: discovering why genes behave the way they do and why subtle differences between one person's genes and another's can be a matter of life or death.
Examples from medical genetics are illustrative. Scientists have discovered the genes that cause sickle cell anemia, thalassemia, and cystic fibrosis. They have identified genes associated with certain types of inherited cancerbreast and colon cancer, for exampleand they have pinpointed genes that are connected with inherited forms of Parkinson's and Alzheimer's diseases. This is very, very good. But it is not enough. It describes what is going on but does not explain why.
Genes, Environment, and Unique Susceptibility
Three disease modelscancer, lung disease and heart diseaseillustrate not only the complexity of genes and environment but also the fact that even with a depth of understanding, effective therapy for afflicted individuals does not follow like magic. Research has a long way to go, but the road ahead contains clear markers: defining genetic susceptibility; determining the biologic processes that are the underlying source of symptoms; understanding individual "host responses"that is, the ways in which one person's response to a gene/environment assault differs from another's.
And most important, scientists will have to learn to assess the relationship between large numbers of genes (some still unknown) that are working in concert in health and disease. The technology for this (gene arrays, for instance) will have to be developed to show how gene expression occurs in time and place. After all, nothing about human physiology is static, so the tools for measuring what's going on have to be sensitive to a constantly changing internal environment.
No one needs to be told about the suffering and often premature death that cancer causes. But it is worth remembering that, although significant advances in cancer therapy have occurred during the past 25 years, many cancers remain beyond the reach of useful medical intervention. There is a long way to go. The good news is that research in molecular medicine, coupled with advances that are anticipated from genomic medicine, may well put most cancers into the category of treatable diseases. Cancer, like most disease, has genetic originseither through inheritance or gene mutations during the course of a lifetime. The excitement these days lies in understanding the complex pathways through which cells talk to or "signal" each other, as well as the processes that determine when cells will proliferate and when they will die. The better these pathways are understood, the closer researchers come to developing drugs that can interrupt tumors early in the gamestopping them before they get started on a destructive course rather than trying to destroy them after they have already grown.
New knowledge about mutant genes that play a role in regulating cell behavior make it possible to categorize human tumors in terms of the molecular mechanisms that sustain them. And, with the complete human genome sequence in hand, researchers will soon be able to examine all of the potentially aberrant genes within any given tumor, opening several genetic avenues to therapy and, equally important, to early detection in individuals of known susceptibility.
The future of research in lung disease "is centered on understanding the lung as a genetically determined, complex biologic organ," says Ronald G. Crystal, author of the JAMA paper on the lung. Crystal predicts that a major challenge will be to determine the hierarchy of gene expression that integrates the function of multiple cell types in the lung at any given time, in response to whatever the lung is exposed to at the moment. This is a very important concept in terms of "functional genomics" and "functional proteomics," new areas of research that will dominate the scientific landscape for the next decades.
During the past 20 years, genetic medicine has made significant progress, having identified the genes that underlie two inherited lung diseasescystic fibrosis and alpha-1-antitrypsin deficiency. What has also been revealed is the utter complexity of these (and other) diseases that go beyond the identification of a single gene. Susceptibility to lung disease is a complex interaction of the environment, genetics, and an individual's immune response.
After the initial "cystic fibrosis gene" was discovered, researchers rapidly figured out that there are at least 400 (yes, four hundred) subtle variations on that gene. Each variation is connected to different gene expression, as scientists call it. Some variants cause serious, fatal cystic fibrosis, some lead to mild disease, and some apparently cause no evident disease at all. Why? Proteomics hold part of the answer. Genes make proteins, and it is actually proteins that do the work of regulating health and disease.
In the case of cystic fibrosis, one important protein is well understood. If the levels of that protein are too low, the epithelial cells in the lung do not clear secretions normally, resulting in a mild plugging of the small airways. So, one might conclude, this is cause and effect. Not so. According to Crystal, the mild plugging does not cause cystic fibrosis per se. What happens is this: The plugged airways are unusually susceptible to infectious organisms like Pseudomonas that cause chronic inflammation; the airways are always swollen and red. At the clinical level, this is the problem.
Alpha 1-antitrypsin deficiency
This genetic disease may not have a household name, but it is common, lethal (it leads to emphysema), and potentially preventable. Again, the gene and the protein it makes are now known. But alpha 1-antitrypsin deficiency per se does not cause lung disease. An individual with low levels of the alpha 1 protein might do just fine for years if he or she did not subject the lungs to abuse from cigarette smoke. Here is a classic case of gene/environment interaction. A genetic susceptibility, combined with an environmental toxin, leads to serious disease.
An understanding of risk factors for heart disease such as hypertension, diabetes mellitus, tobacco use, obesity and lack of physical activity has greatly reduced the incidence of death from cardiac disease. But the known risk factors account for only about half of the nearly one million lives claimed each year by the nation's leading killer. Few of us appreciate that more women than men die of heart disease.
Coronary artery disease and hypertension are clear examples of complex diseases involving many genes. Crucial to vascular health is the normal operation of cells that line the endothelium, where circulating blood meets the arterial wall. Variation in genes expressed in endothelial cells can have the effect of elevating blood pressure, and regions of the human genome where these genes are likely to reside are known. Similarly, it is known that hypertension is associated with variation in the b2-adrenergic receptor gene, which plays a role in the relaxation of arterial muscle.
It is increasingly evident that chronic inflammation is central to the initiation and progression of atherosclerosis, the so-called hardening of the arteries. As genes and variants of genes associated with inflammation are defined (a task that has been acGNNted by the sequencing of the human genome), individuals at risk can be identified and targeted for specific preventive interventions. Robert J. Lefkowitz, co-author of the JAMA paper on the heart, says that with continued financial support for clinical and basic research, "remarkable improvement in the quality and length of life of individuals destined to develop cardiovascular disease can be confidently predicted."
Neuroscience: Neurology and Psychiatry
After heart disease and cancer, stroke is the third leading killer in the U.S. But taken together, disorders of the nervous systemdiseases like Alzheimer's, Parkinson's, multiple sclerosis, depressionaccount for more hospitalizations, more long-term care, and more chronic suffering than nearly all other disorders combined. By most estimates, more than half of the genes in the human genome are expressed either exclusively or preferentially in the brain. The key to understanding, treating and preventing most neurological and psychiatric disorders in the next quarter-century is likely to be how new applications of genomic and proteomic technologies are put to use in the relatively new discipline of neuroscience.
Considerable progress has been made in neuroscience in recent decades toward the goal of understanding the mechanisms involved in the formation of precisely organized connections and patterns of nerve cells, or neurons, in the brain. Much of the progress, particularly in understanding molecular mechanisms underlying signaling and transmission between neurons, is due to technological advances that allow us to trace connections between different parts of the brain and to visualize and record the activity of individual neurons in conscious, behaving animals. The most significant advances, however, may be the techniques of molecular genetics that have permitted the identification, cloning and sequencing of an ever-increasing number of neural genes.
These methods have been used to identify genes and, in some cases specific mutations responsible for neurological disorders such as Huntington's disease, inherited forms of Parkinson's disease, and Alzheimer's disease. It is known, for example, that a string of repetitive and unstable DNA that tends to expand within a specific gene is the underlying mutation in Huntington's disease. A similar phenomenon, called DNA expansion, underlies related neurological disorders and is the cause of the most common form of mental retardation, fragile X syndrome. Although it took almost a decade before the actual Huntington's gene was isolated and its protein described, the example illustrates how the identification of the genetic basis of a disorder can often lead quite rapidly to the analysis of the resulting disease.
Unfortunately, experience with inherited forms of neurological disorders such as Parkinson's has shown that the underlying biology of a disease that runs in families can be quite different from that of its counterpart in the general populationwhat scientists call naturally occurring, or sporadic, disease. That different genesand variation in genescontribute to related but biologically distinct forms of the same disease underscores the importance of both taking a broad, genomic approach to research in the 21st century.
When the complete human genome sequence has been appropriately annotated, according to Maxwell Cowan and Eric R. Kandel, co-authors of the JAMA paper on the brain, the pace of research in neuroscienceincluding both neurology and psychiatrywill proceed at an unprecedented pace. "So rich will be this harvest," says Kandel, "that it is not too bold to state that it will completely transform both clinical disciplines and put them on the sound scientific foundation that has long been one of their principal, if unstated, goals." Concurrent research on proteins is expected to yield new targets for drug development, resulting by 2020 in the development of more personalized therapies and less reliance on serendipity in the research enterprise.
Stem Cell Therapy, Gene Therapy, and Organ Regeneration
For years, scientific dogma held that once an embryonic cell "differentiated" during the first stages of life, that cell's identity was fixed: A red blood cell would always be a red blood cell, a neural cell in the brain could never change course, and an adult liver cell would always be just thatan adult liver cell. The wonderful thing about science is that new knowledge changes dogma. It turns out that many kinds of adult cells and organs are what scientists call "plastic," that is, capable of changing shape or form. Some cellsliver among themare now known to regenerate. If you surgically remove a portion of someone's healthy liver, it will grow back, raising the obvious potential of figuring out how to make diseased livers grow healthy tissue.
Scientists have also learned that, in some circumstances, the adult brain is capable of rewiring itselfof making new neural connections to get around diseased cells. As Jeffrey M. Leiden, co-author of the JAMA paper on "Gene and Stem Cell Therapies," says, "The discovery of plasticity in the brain was remarkable. The discovery of neural stem cells within adult neurons was a huge surprise to everybody." In fact, neural stem cells can be transformed into what researchers call "hematopoietic lineages," which is to say blood cells and bone marrow cells. This has implications for everything from neurodegenerative diseases to paralysis to stroke. It may even be possible, one day, to culture stem cells from a patient's own adult cells for reimplantationa technique that would avoid limitations of immune rejection of tissue taken from one person and given to another.
The opportunities seem endless, as do the possibilities for human gene therapy. In each case, the concept is simple. Take a stem cell that can be reprogrammed, or a healthy gene that can replace a defective one, and you have a way to treat disease that would be absolutely curative. Needless to say, the path from concept to delivery is strewn with both anticipated and unanticipated challenges.
Gene therapy is accused of not living up to its (overstated) promise because the technology for getting the right gene into the right cells, and then getting them to "express" or make the right proteins, has, so far, eluded researchers' best efforts. But gene therapy is barely 10 years oldsuccessful chemotherapies have taken decades to developand it is foolish to dismiss its potential or to write it off because of a tragic failure in the death of a single patient. It may seem harsh to say it, but there is virtually no example of experimental medicine in which some of the earliest, bravest volunteers did not die.
Though we do not think of it this way, gene therapy is already a common treatment of certain cancers. Bone marrow transplantation, after all, is a combination of gene and stem cell therapy in which embryonic marrow cells are given to patients with various forms of leukemia and lymphoma, for example. Sometimes, toxic genes are given to eradicate cancer. Physician-scientists are experimenting with the retinoblastoma gene in cardiac patients who have had balloon angioplasty because the gene, which gets into smooth muscle cells in blood vessel walls, seems to keep the vessels open.
The creation in the laboratory of implantable tissues and even whole organs is another area of medicine that, once nearly unimaginable, now seems entirely feasible. Everyone is familiar with the grim fact that there are more people whose lives could be saved by organ transplantation that there are organs to go around. People get on waiting lists but die before their turn comes. By 2025, this may be history.
Already, engineered tissues to replace blood vessels and to repair the bladder are in early clinical trials. The US Food and Drug Administration recently approved the use of engineered skin and cartilage. Bioengineered corneas are being tested to restore vision, and laboratory-grown liver tissue is being tried as a "bridge" to sustain patients awaiting liver transplantation. There is also hope that stem cells from the pancreas can be engineered to become islet cells in patients with diabetes. Here, stem cell research and tissue engineering come together, as will no doubt be the case in dozens of other examples.
Bioengineering, Imaging, and Robotic Surgery
There will come a time when surgeons routinely operate on organs without either touching them or looking at them directly. Non-invasive surgery may be the norm in 2025. Elegant, flexible tools and sharp images of the target organ will enable surgeons to make heart repairs without cracking the chest open, making recovery far easier for patients.
Advances in imaging technology, which now make it possible to see chemicals at work in the living brain or to obtain high-resolution pictures of tumors, contribute to basic understanding of human physiology as well as diagnostic medicine. The field, which presently includes MRI (magnetic resonance imaging), CT (computed tomography) and PET (positron emission tomography) scans, makes it possible to identify disease in soft tissues, such as the heart or the breast. One of the main challenges is the need to increase the ability to obtain real-time images of molecular or cellular events in a patient as they are occurring. With the right support, this will happen.
Consider this potential application of imaging a decade hence. A woman knows that she has the gene for BRCA1 or BRCA2two genes known to predispose to cancer of the breast. At present, she relies on mammograms for early detection of a tumor. But even regular mammography cannot detect a tumor before it forms. Real-time molecular imaging could, however, offering the possibility of heading off cancer by getting direct images of early genetic and molecular markers that reveal a tumor in the making.
Infectious Diseases: The Present and Future Scourge
Twentieth-century challenge: eradicating infectious disease. Done, in large measure. Twenty-first century challenge: eradicating infectious disease. Bacteria are clever organisms that are not eradicated easily, so here we are in the new century and the leading cause of death worldwide remains infectious disease. Deaths due to infection are by no means due only to poverty, although that is a major issue. Five of the 10 leading causes of death in the U.S.including pneumonia, AIDS, and cancerwere directly or indirectly related to infectious disease. Since 1973, tuberculosis, malaria, and cholera, long thought to be controlled, have re-emerged, often in more virulent forms. In the same time period, more than 30 previously unknown disease agents have been identified.
The recent approval of an oxazolidone by the Food and Drug Administration was the first new class of antibacterial drugs to be approved in more than 25 years. Yet many scientists believe we are at the dawn of a new age of antibiotic discovery driven by revolutionary developments in chemistry, structural biology, engineering, and genetics. Over 30 bacterial genomes have been sequenced, and many others are now being decoded. But even with a sequenced bacterial genome, it is no trivial matter to identify antimicrobial drug targets. The process of identifying targets in pathogens may depend on the ability to compare bacterial and fungal genomes with the human genome sequence and use technologies such as microarrays to discern key genes that are turned on and off during infection.
The Future of Drug Discovery
Genomic information and bioinformatics, the science of interpreting sets of data too large for the human brain to compute, is revolutionizing the search for drug targets. "Target identification is essentially routine with the power of these technologies," says August M. Watanabe, co-author of the JAMA article on drug discovery. "The selection of the right targets remains the key strategic challenge." Genomics has enabled a new systems view of biology that is essential to drug development and success requires expertise in both animal systems and human biology. After the identification of the hormone leptin as a molecular defect in obese mice, scientists rapidly identified its human counterpart and the gene's expression in human obesity.
As the ultimate objective of drug discovery research is pharmacological interventions, an analysis of the target's expression in all human tissue is critical. Watanabe predicts that in the next decade as research intensifies it is likely that disease "platforms" will emerge where pathways will be prioritized for complex diseases and multiple targets for therapy will be identified, all of which will need clinical investigation. An example of a disease platform where genetic and genomic technologies have had such an impact is the area of obesity research, where numerous options for intervention have been described in a flurry of recent research.
The authors of the articles included in the special JAMA issue, supported by the Albert and Mary Lasker Foundation, are inherently conservative scientists who prognosticate with great care. The advances that they predict in the next quarter century are therefore apt to represent minimal estimates of the progress that we can expect of the current biomedical revolution.
Skeptics often cite the well known bromide that medical research does not extend the human life span. It is held in many quarters that the advances in human life span that we have seen in the last century are almost entirely due to common sense public health measures and not to advances in the science of medicine. In general the authors would probably agree with that statement while pointing out that the discovery of antibiotics was certainly a major contributor to the increase in life span observed in the last century. But they would also argue that the purpose of biomedical research is not to extend the human life span; it is to improve its quality. Thus artificial joints have taken middle aged and older patients out of wheel chairs and given them a normal life in the company of their grandchildren. New growth factors like erythropoietin created by the genetic revolution have provided relief from transfusion for patients with chronic kidney disease and new immunosuppresives have given those patients far better lives through successful kidney transplantation.
A central issue not discussed in this series is the cost of all of these advances. What will we, as a society, be willing to pay for relief from the ravages of chronic disease. As we age, will the younger members of the labor force be willing to shoulder the financial burden created by the costs of these new developments. We already see that employers are not willing to go it alone. They are passing these costs on to the workers who will pay an increasing fraction of the costs from their own paychecks. It would appear that there will be few barriers to discovery if NIH is properly funded by the United States Congress and future administrations. But will the public be willing and ready to shoulder the costs of the application of the discoveries that are on the way? That is a huge societal issue that must be discussed frankly and honestly with all Americans. We hope that the next administration will shoulder that responsibility and that all Americans will join in an effort to take away the pain and misery of chronic disease.
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