The following is Dr. Emanuel's keynote address at the recent dinner in Celebration! Benjamin Franklin, Founder

From Maps to Medicine: The Impact of the Genome Project

by Dr. Beverly S. Emanuel, Director of Human Genetics Center; Charles E. H. Upham Chair in Pediatrics

I would like to speak to you on behalf of the numerous scientists involved in the human genome initiative as well as my fellow geneticists, the individuals who will apply the fruits of the Genome Project to medical practice. This wonderful occasion gives me the opportunity to provide you with some background about the program and to speculate a bit about what changes the Genome Project will make to the practice of medicine in the future.

It is particularly fitting that I speak to you on the occasion of the celebration the 295th birthday of Benjamin Franklin, a scientist, inventor and revolutionary thinker! It was Franklin who so aptly stated that "the doors of wisdom are never shut", a concept which exemplifies both the current approach to scientific discovery as practiced within the medical institutions of our extraordinary city and the nature of the Genome Project itself. The celebration of the 250th anniversary of the founding of the Pennsylvania Hospital by Benjamin Franklin and Dr. Thomas Bond, honors another exemplary Philadelphia institution, another facet of the University of Pennsylvania Health System, where I am a faculty member.

I personally feel very much a part of the Benjamin Franklin story, although for fewer years than the 250 or 295, because I was born and raised in Philadelphia which means that the Franklin Institute (one of my favorite sites as a child), the Benjamin Franklin Parkway, the Benjamin Franklin Bridge and Franklin Field were all a part of my daily life. Further, my father, husband, children and I are all graduates of Franklin's University, the University of Pennsylvania, which was founded in 1740. Finally, when my 25thPenn class reunion was held, our class gift to the University was the wonderful George Lundeen bronze statue fondly called "Ben on the Bench". Many of us have sat with Ben and pondered the remarkable changes that have taken place since he walked the streets of Philadelphia. Thus, my Franklin ties go much deeper than the use of bifocals and odometers in my own daily life.

Many of you might be wondering--what is the Human Genome Project? The Genome Project is an exciting international, collaborative scientific effort designed to identify, analyze, and determine how all the genes in the human body are organized. The enormous amount of knowledge it will produce will make it possible to understand and modulate the genetic causes of disease and help keep people "disease free." The result of this monumental undertaking will be to provide us with a complete blueprint for each of the 100 trillion cells which make up the human body. So in the past 25+ years, the once-obscure discipline of molecular genetics has become the central science of medicine. At the heart of genetics is DNA or deoxyribonucleic acid--an extraordinarily long chemical molecule shaped like a twisted ladder. This double helix, deciphered by Watson and Crick in 1953, provides the instructions for everything a cell does--including causing disease. If we're trying to understand something at its most basic level, it makes sense to go and read the instructions, determine the sequence of the genes. This is why one of the goals of the Genome Project is to complete the sequence of the Human Genome.

Genes determine many of our features, such as eye and hair color, but genes can also be responsible for causing many diseases or predisposing us to develop disease. It is estimated that each of us has approximately 50-100,000 genes in our genomes. Each of these genes has the potential for being a disease gene if it contains an error in its DNA sequence. The successes of the Human Genome Project (HGP) have even enabled researchers to pinpoint errors in genes--the smallest units of heredity--that cause or contribute to disease.

The ultimate goal is to use this information to develop new ways to treat, cure, or even prevent the thousands of diseases that afflict humankind. But the road from gene identification to effective treatments is long and fraught with extraordinary challenges. In the meantime, biotechnology companies are ahead of the game with their commercialization of the Genome Project. Such companies are designing diagnostic tests to detect aberrant genes in people either suspected of having a particular disease or those individuals at risk for developing them. Genetic testing has become an increasingly important tool in medical practice.

DNA-based tests are amongst the newest and most sophisticated of the techniques used to identify genetic disorders. They involve direct examination of the DNA molecule itself. Genetic tests are used for several reasons, including: carrier screening, prenatal diagnosis, and newborn screening. They are also used for presymptomatic testing for predicting adult-onset disorders such as Huntington's disease. Alternatively they are used for presymptomatic testing for estimating the risk of developing such diseases as a variety of adult-onset cancers and Alzheimer's disease. The recently commercialized gene tests for such adult-onset disorders (such as Alzheimer's disease and cancers predisposition) are the subject of much of the debate over gene testing. One of the most serious limitations of these susceptibility tests is the difficulty in interpreting a positive result because some people who carry a disease-associated mutation never actually develop the disease.

This is a complex issue because, in a broad sense virtually all disease has a genetic component. The vast majority of people never develop skin cancer, yet we all have at least a slight genetic predisposition for it. Given enough exposure to sunlight, nearly all of us would develop it. Thus, even though the sun's ultraviolet radiation is primarily responsible, our genetic makeup is a small but real contributor to the disease. However, there are some people who would get skin cancer even if they never went out in the sun. Their genetic structure is 100% responsible for the disease in the absence of sun exposure.

Even infectious illnesses may have an inherited component. Most people exposed to the human immunodeficiency virus develop AIDS. But some people exposed to the virus do not develop the disease, presumably because they have inherited a gene which confers immunity to the virus. Deciphering this underlying genetic component to many diseases is one of the aspects that makes the Human Genome Project so exciting.

The easiest genetic diseases to understand are those caused by a single gene that has gone awry. Single gene diseases include relatively rare disorders such as cystic fibrosis, phenylketonuria, hemophilia, sickle cell anemia and Huntington's disease. In a sense, the genes for these diseases act like a single time bomb ticking away inside the DNA double helix.

Much more common, and far more complicated, are the diseases caused by malformations in several or many genes that influence each other in complex ways that are poorly understood. Hypertension, diabetes, rheumatoid arthritis, multiple sclerosis, schizophrenia, Alzheimer's, coronary artery disease and numerous other diseases that afflict our species are caused by the interactions of multiple different genes. Each individual gene has a relatively modest effect, but together they determine whether someone is going to develop a disease or not. Multiple gene diseases or what we call polygenic diseases are far harder to understand than those which are caused by single genes.

Complicating matters even further, most genetic diseases result from an interplay between an inherited predisposition and factors in a person's external environment and lifestyle. It's not just the individual cards that you have been dealt, but it also depends upon how you play the hand. It's important to keep this in mind to avoid the dangers that can potentially arise from biological determinism--thinking that everything about an individual is predetermined by the DNA code written in his or her genes.

The DNA is located inside the cell nucleus. As I mentioned, the DNA is in the shape of a double helix which is wound over and over again. Unwinding it reveals the two strands that make up the sides of what is essentially a ladder-shaped molecule. The ladder's rungs are called base pairs and there are 3 billion base pairs of DNA in the human genome. The DNA is organized into individual units, called chromosomes. In humans there are a total of 46 chromosomes in each cell. There are 22 pairs of chromosomes which are designated as autosomes­chromosomes 1 through 22 and a pair of sex chromosomes, XX for females and XY for males.

For many years, in fact since the mid-fifties scientists have been able to look at the chromosomes at the microscope, count them and analyze them. In fact, in a clinical setting, many chromosome tests are performed to determine the genetic or chromosomal composition of an individual.

At present, despite the fact that we can see all of the chromosomes and analyze their composition in a gross sense, we have only identified the complete workings of a fraction of the genes which reside on them. One of the goals of the human genome initiative is to identify the tens of thousands of remaining genes, to isolate them and characterize what they do after assigning them to their precise positions on chromosomes.

Such efforts have already been successful in the search for the cystic fibrosis gene and in the search for the genes responsible for neurofibromatosis, muscular dystrophy, fragile-X linked mental retardation and myotonic dystrophy, some of the earliest disease genes to be identified. The list of identified disease related genes now grows on a daily basis. However, many additional diseases with their respective disease-causing genes remain to be successfully identified and characterized.

In order to accomplish this task, it was necessary to make maps of the human genome. Making maps of the human genome is not very different from making the maps that we are all familiar with. For example, if all that existed was an outline map of the United States and I asked someone who didn't know the geography of the United States where the location of a particular city was, it would be difficult without some roads or markers to help find the way. The same would be true of asking someone about the location of a particular new disease locus. It requires the assistance of a map.

Now if you looked at the same map with one road, for example Route 80, which moves from coast to coast--from Philadelphia to San Francisco. If you were able to say that a gene was on the that road, it would help slightly, because you would have narrowed the search for figuring out precisely where that gene is located. However, if we were to mark the length of that road with 15 evenly spaced cities, or markers, it would be a different story.

In this case, if you said that the place in question, or the gene in question, was between Chicago and Des Moines and east of the Mississippi River, you would have narrowed the search for that place or that particular gene considerably. You would then know precisely where to look on the map.

This was one of the very first goals of the human genome initiative, to place a series of evenly spaced, "markers" on all of the chromosomes. These markers permit geneticist to determine where a particular disease gene is located, even if we do not know what the normal gene does. We do this by studying families that manifest the disease and seeing how the markers are inherited in association with the disease in affected families. These are what we refer to as genetic maps.

Physical maps permit us to look at a different view of the genome and these maps are much more detailed than genetic maps. These maps are made by analysis of the chromosomal DNA directly by isolating it and then sequencing it. For this type of map making we start with a particular chromosome, take the chromosome apart by isolating the DNA or genetic material from that chromosome and then put it back together in an ordered array. In the interim, we are able to study each individual fragment in greater detail. That is like making very detailed maps with precise addresses, street names and the like.

Why do we want to map the human genome? Because, this concerted effort will simplify the process and has already hastened efforts directed toward understanding the role that genes play in normal individuals and how genes cause specific diseases when their role is altered. Understanding what genes normally do will permit us to design more appropriate therapies, to correct the impact of defective genes on health.

At Children's Hospital and Penn we made the decision to map chromosome 22. We chose chromosome 22 for historical and practical reasons. It is the second smallest of the human chromosomes, being comprised of somewhere less than 50 million base pairs, or megabases of DNA. We wanted to know the answers to some very simple questions: What genes are on chromosome 22 and how are they arranged? Knowledge of the fundamental anatomy of the human genome, and for us of chromosome 22, was important to our ultimate goal of understanding how our body works when it is healthy, as well as when it is not healthy.

In addition chromosome 22 has a wealth of pathology associated with non-random chromosomal abnormalities providing us excellent source materials from patients with chromosome 22 related diseases with which to build our maps and a rationale for making the maps. These are the practical reasons. For many of us, it represented a logical extension of many years of scientific work which has focused on diseases caused by these abnormalities of human chromosome 22.

For example, an abnormal chromosome 22 is associated with several forms of pediatric and adult leukemia. In 1960, chromosome 22 was named the Philadelphia Chromosome by Drs. Peter Nowell and David Hungerford when they discovered its' involvement in chronic myelogenous leukemia at Penn and the Fox Chase Cancer Center. In addition, a number of other birth defect related syndromes are associated with abnormalities of chromosome 22. A missing piece of 22 or a deletion and an extra part of 22 or a duplication. These syndromes were described by pediatric physicians and colleagues in Philadelphia. Hence, we thought it would be appropriate that the Philadelphia chromosome be isolated, analyzed and understood in Philadelphia.

Eventually several of these disorders were studied in my laboratory. Little by little we have made remarkable progress toward understanding why this small chromosome is so prone to disease related rearrangements. As an example, I would like to briefly discuss our recent work related to one of the abnormalities of chromosome 22, the deletion which is associated with a diagnosis named DiGeorge syndrome or velocardiofacial syndrome. This is a defect which can afflict newborns with heart disease, immunologic defect, seizures cleft palate and learning differences. We found that this complicated disease is the result of these children having a portion of one chromosome 22 missing. We know how large the segment is, and that 30 genes are actually deleted. Understanding the organization of chromosome 22 has helped us to more accurately diagnose this disorder because we have been able to design a DNA based genetic test which can now be utilized very early so that the diagnosis can be made when the child is an infant. This has some very important ramifications for early therapeutic interventions to help the families of these children.

However, you can imagine that there might be some questions about this and other disorders. Not all children with the deletion are equally severely affected. Thus, there are questions regarding what is normal and what is a disability or disorder, and who decides? We know that the children with the deletion can have learning differences or speech difficulties. Are such disabilities diseases? Should they be prevented? Should they be "cured"? Does searching for a cure demean the lives or the very existence of individuals presently affected by disabilities? Genetic information is a powerful tool for improving our health, but it also can potentially be used in ways that are harmful. Protections against the misuse of genetic information are in place for certain aspects of genetic testing, but much work remains to be done.

An increasing number of gene tests (such as this one) are becoming available commercially. Nonetheless scientists continue to debate the best way to deliver them to the public and medical communities, often to individuals that are unaware of their scientific and social implications. While some of these tests have greatly improved and even saved lives, scientists remain unsure of how to interpret many of them. Also, patients taking the tests face significant risks of jeopardizing their employment or insurance status. Further, because genetic information is shared, these risks can extend beyond the individual who has been tested to other family members as well.

Within the next decade, researchers will find most human genes. Explorations into the function of each one--a major challenge extending far into the 21st century--will shed light on how faulty genes play a role in disease causation. With this knowledge, commercial efforts will shift away from diagnostics and toward developing a new generation of therapeutics based on genes. Drug design will be revolutionized as researchers create new classes of medicines based on an approach using gene sequence as well as protein structure function information rather than the traditional trial-and-error method. This new generation of drugs, targeted to specific sites in the body, promise to have fewer side effects than many of today's medications.

Human Genome Project scientists plan to finish the human sequence by 2003 and establish database of the most common sequence variations that distinguish one individual from another. This knowledge base will revolutionize biology and medicine. What will be different 20 years from now because the human genome was sequenced? How might my medical care differ as a result of "genetic medicine?"

It is likely that virtually complete list of human genes will give us a vast repertoire of potential new drugs. From the current repertoire of 500 or so drugs in 2000, at least six times this number will have been identified, tested, and commercialized in the next 20 years. All will be manufactured by recombinant DNA technology so they will be significantly purer just as human insulin and growth hormone are today.

I predict that an individual's medical record will likely include a catalogue of single base-pair variations that can be used to accurately predict responses to certain drugs and environmental substances. This will permit a patient to be treated as a biochemical and genetic individual. This will make medical interventions much more specific, precise, and hopefully more successful. In addition, the increased power of geneticists to predict susceptibility to specific diseases will allow an individual to alter his or her lifestyle to reduce the likelihood of developing particular diseases or to be treated with preventive or disease-delaying medications.

Some of the mysteries of early embryonic development will be solved. We should know the timing of expression of most, perhaps all, of the human gene set. We may have learned how to direct differentiation so that a desired cell type or even relatively "simple" organs and parts of more complex organs can be grown for transplantation. In 20 years, we will have made substantial progress towards true "cloning" of certain organs, but many difficult technical steps will probably remain before the successful cloning of a complex organ like a heart or liver.

So the Human Genome Project will have vast and largely positive impacts on people living in 20 years from today. Of the various predictions I have discussed, the knowledge about early embryonic development and gene function is likely to be the most profound because often the most powerful and extensive impacts come from fundamental knowledge, usually in unforeseen ways. As this astonishing treasure trove is introduced into society, we need to be alert to the challenges of the possible misuses of this knowledge about ourselves. Society as a whole, not just genome scientists or geneticists, must address these considerations. It has to be all of us.

The information generated as a result of the Human Genome Project is expected to be the encyclopedia or source book for biomedical science in the 21st century. It will assist us in understanding and eventually treating many of the more than 4,000 genetic diseases that afflict man, as well as the numerous diseases in which genetically-based predisposition plays an important role, heart disease and cancer to name just a few. This research will lead to improved strategies for preventing, diagnosing, and treating disease, and will bring genetic medicine to the forefront of health care in the 21st century. Over the years, we predict that as a result of this international effort, the genome initiative will produce great health benefits and will result in better health care for millions of individuals who suffer from genetically based diseases and for future generations of children and their parents.


Almanac, Vol. 47, No. 20, January 30, 2001