Religion & Science
May 13, 1997
[Editor's note: The following is the transcript of Professor Herbert H. Winkler's presentation on April 24 at The Harbinger symposium, "RELIGION & SCIENCE: The Best of Enemies - The Worst of Friends."]
by Herbert H. Winkler, Ph.D.
First, let me say what a genome is: our genome is all the genetic, inheritable, information that we have; a gene is part of a genome. The Human Genome Project is an international, but mostly American, research program designed to localize on the human chromosomes in detail the estimated 100,000 human genes, and to determine the complete nucleotide sequence of human DNA, all three billion pieces of information. Saint Jim Watson, the Nobel Prize winner, discoverer of the structure of DNA, and author of the epistle, The Double Helix, was the first director of the Human Genome Project. The scientific products of the Human Genome Project will be maps of genes on chromosomes and huge strings of DNA sequence -- information that will provide detailed information about the structure, organization and characteristics of human DNA. This information constitutes the basic set of inherited "instructions" for the development and functioning of a human being. From the beginning of this Project, it was recognized that acquisition and use of such genetic knowledge would have momentous ethical, legal and social implications for both individuals and society.
Thus, the goals of the Project, which we will return to in more detail in a few minutes, are:
In discussing this topic I will have to steer through the mine-fields of abortion, evolution, nature- nurture, and national health insurance. (With a few missteps, if I am not careful, I could end up with making Dr. Shelly Gottlieb look like the meekest of lambs by comparison.) But it is a necessary exercise, for although the purpose of the Human Genome Project is noble, we would do well to remember that "The road to hell is paved with good intentions," and the words of St. Paul "The good that I want to do, is that which I do not, and the evil that I do not want to do, is precisely what I do" (Romans 7).
C.P. Snow in his famous concept of two separating cultures told us in essence that all thinking citizens of the world must use both halves of their brains. We must give both the sciences and the humanities an important place in our culture. Consumer materialism and mindless leisure are the antithetical forces. One cannot have a fully developed human if that human never considers the ultimate why? questions. Even though whys are not part of the discipline of science, the why questions must be part of humanity's quest, including the scientist's quest. From different vantage points both the sciences and the humanities help us answer, or at least properly pose, these questions. For example, the answer to our questions about the purpose of creation may be theistic, atheistic, or agnostic, but we must wrestle with the question. To me this is the foundation of this lecture series.
We so often hear that they--for example, scientists--said this or that: they are going to do this or that, they..., they..., they... My point is that we, not they , are sequencing the human genome. Our tax money will pay the bills for the project; our purchases at the pharmacy will support the research in the private sector; our sons and daughter will do the research; our brothers and sisters will benefit or suffer as a result of these discoveries. Considering scientists as "they" is not always a slip of the tongue; it is sometimes an intentional alienation of the not us, and can be an attempt to avoid and shift responsibility. It is unethical to leave it to them . It follows then that Scientific Literacy is an ethical imperative. The lack of scientific literacy can result in excesses like the furor over the recent sheep-cloning results and the view of clones as sterile zombies in brown wool shirts. Scientists know so little about so much, or better, so much about so little. Society must collectively make informed decisions. We are here at this lecture series to inform one another.
An important concept is the irrelevance of historic time in scientific inquiry. In contrast to most events in our day-to-day life, scientific facts that we derive today will be with us always, and the scientific theories of today will be with us until they are modified or reversed. We may not be able to understand the ramifications of these facts and theories, but a future generation will. This long-term view is appropriate in all of scholarship, not just science. We don't know today what will be important tomorrow. If the human genome is not fully unraveled in the next decade, as is the plan, this is a trivial shortcoming. The human genome will be known, sooner or latter, and we will have to deal with the issues raised.
The religious monk Gregor Mendel, who lived in the present day Czech Republic, experimented with plant hybridization and presented his ideas, which became laws, in 1865. This was the beginning of formal genetics, but his work then went largely unnoticed for 35 years, so that genetics began again at the turn of the century. The role of DNA as the genetic material was not appreciated until half way through this century. Molecular genetics is a young, perhaps adolescent, science.
The human genome is essentially all that is physically passed down from generation to generation. But it is passed down into a cultural niche. The genome is not everything that make a human being human. Discussions of Nature vs. Nurture are real and germane. The cause and effect relations between the trait and the genes should be sought as energetically as possible, but the large number of variables often may be just too confounding. Personal and social human behavior should be viewed as the result of complex phenomena in which genes play a critical part, without being the whole. Nevertheless, it is the genome that sets an absolute limit as to what the total person can be.
The Human Genome Project can engender a great deal of fear, and I think properly so. Fear of what we will learn, fear of what we will do with what we learn, and fear of the Frankenstein monster. If one is going to choose genes for one's progeny and manipulate genes in a child to hopefully improve the child's life, then love and responsibility for that child must be paramount. But before we let fear drive us to the comfort of vegetative inaction and reverence for the status quo, let us ask: Is there a reasonable alternative to advancing man's knowledge of man? Can we afford to ignore the dictum to "Know thyself"? Are things so great in our world that we don t want to make changes? Fear of the unknown is justified, and the antidote is responsible action, not passivity. No guts no glory, and the glory of mankind in large part is what he creates through this mind.
In brief what are some of the broad questions raised when we consider the Human Genome Project:
Man has always been an explorer. He has yearned to explore what was unknown, to chart and quantify what was found, and to contemplate the found and the still-to-be-discovered. We are now embarking on a quest to discover the blueprint of humanity, to know what makes us us. The 21st century will be an age that defines the physical traits of a human being.
How much of this genetic stuff that we are discussing is theory and how much fact? It is almost all fact. Packed tightly into nearly every one of the several trillion cells of each human body is a complete copy of the human genome, which is composed of DNA. The human genome is all the information that makes up the master blueprint for building a man or woman. There is only one blueprint per individual, and it is the same from cell to cell in that individual. One hundred thousand or so genes are sequestered inside the nucleus of each cell. These genes are parceled out among the genetic structures known as chromosomes. Knowledge of the genome will provide new strategies to diagnose, treat, and possibly prevent human diseases. It will help explain the mysteries of embryonic development and give us important insights into our evolutionary past.
The amount of information contained in the human genome is huge. There are 3 billion base pairs, a base being the chemical unit of information. If we use a book as an analogy, then a base is like a letter of the alphabet, and the total genome is equivalent to 14 sets of the Encyclopedia Britannica, and each set is different. The price tag for mapping and sequencing such an enormous genome is also huge. The expenditure is almost $300 million a year. This is equivalent to buying 4 new F22 fighter planes a year!
We all know that proteins are good for us. When we eat chicken all of the proteins of the drumstick are digested to the component parts of the proteins. These components are amino acids. Our cells then take these amino acids and re- assemble them to make human proteins. These human proteins make our body function like it should. How do our cells know how to take these food-derived amino acids and assemble them in the correct order to make a human proteins -- where are the directions, where is the information? It is in the human genome.
Our body is composed of microscopic cells of a variety of different types: muscle cells, brain cells, etc. Within each cell is a nucleus containing the human genome, these long strings of DNA, on 23 chromosome pairs. A gene is a portion of that DNA responsible for supplying the information to make one particular functional protein. Genetic information to make a protein is coded by the four component chemicals of the DNA called bases; the four bases are known by the first letter of their chemical names-- A, T, G, and C. Three bases of any kind in a row, a triplet of bases, is called a codon. Different codons code for different amino acids, ATG for one amino acid, CGC for another, TTT for another, and so on. The codons are copied onto messenger molecules that travel within the cell to the protein-synthesizing factory of the cell where they provide the information to make a chain of amino acids that is arranged in the same order as the codons of the DNA string. This amino acid chain forms a unique protein that can perform specific and vital functions in our body. Each cell contains about 100,000 genes, and each cell, regardless of its type, has the same genetic information contained in the DNA. Although the genomes of all cells in an individual are the same, many genes direct the production of their particular proteins only in certain cells or at certain times and thus make cells different.
What is a mutation and how could it cause disease? If a base in a codon is change by mistake (due to environmental or viral stresses), so that the normal codon, for example, ATG, becomes ATA, with the G changed to A, this is a mutation. This mutated codon, ATA, will code for a different amino acid than did the original normal codon, ATG. If this changed amino acid adversely alters the function of the protein, then one will have disease. If this mutation occurs in an egg or sperm cell, then this germ-line mutation, whether it causes disease or not, will be inherited by the next generation. If the mutation occurred in any cell other than an egg or sperm cell, then only the individual with this somatic cell mutation will be affected, and the mutation will not be inherited.
As I mentioned early on, two of the major goals of the Human Genome Project are to map and sequence the human genome. Mapping a gene refers to the process of identifying the particular section of DNA on a specific chromosome where that gene is. Few of the 100,000 human genes have been mapped.
Genetic mapping is the first step in isolating a gene. It offers firm evidence that a disease or trait is linked to the transmission of one or more genes from parent to child. Genetic mapping provides clues about which chromosome contains the gene and precisely where on that chromosome the gene lies. Genetic mapping begins with DNA isolated from blood or tissue samples from members of families in which a disease or trait is prevalent. Even before researchers have identified the gene actually responsible for a trait, markers (characteristic patterns that are inherited by family members along with an inherited disease) tell us roughly how close the gene is to these known markers. If each family member who has a disease also inherits a particular marker, chances are high that the gene responsible for the disease lies close to that marker. The more markers are on the map, the more likely one of them will be closely linked to a disease gene, and the easier it will be to zero in on that gene. Today we have markers spaced less than 1 million bases apart on average. Once we locate a marker that is very close to the disease gene, we can focus the gene search on a specific region of a chromosome.
It is too hard to find a gene of a thousand bases, or letters, in 14 different sets of Britannica even if we had 26 A-Z volumes in each set, since each of these volumes would have 10 million bases. Instead of working with that thick A-volume, let us divide the A-volume into aardvark to abacus, and abacus to acacia, and so on. We would then have mini-volumes that are easy to work with and can be copied and mailed to colleagues with existing technology. This is physical mapping: to know that this gene is located in mini-volume 1,119 which is between 1,118 and 1,120 and corresponds to a small part of a known chromosome.
To construct a physical map, scientists chemically cut apart a chromosome into workable-sized DNA pieces, and make copies of these pieces in the laboratory. Then the pieces are organized in the same order they were on the chromosome, information about this order is stored in a computer, and copies of the pieces are stored in laboratory freezers. When genetic mapping has indicated a gene lies in a particular region, scientists can retrieve the copied piece corresponding to that region, and begin looking through it for the gene. So, if disease X is closely linked with marker 9,333 and marker 9,333 is known to be on piece ( mini-volume) 5,468, we can start with this piece to find and sequence the gene rather than the entire human chromosome.
Once we know the location, the map position, of the gene of interest, the next question is what is the sequence of that gene, i.e., what is the sequence of the bases, the ATGCs. For example, a sequence could be ATAAGCCTAGGATC...for few thousand bases. If we know the sequence we can read the codons to deduce the chain of amino acids that make up the protein coded for by this gene. If we know the sequence of the normal gene from the Human Genome Project, we can compare it with the sequence found for the diseased gene and see what is wrong with the gene associated with the disease.
When the Human Genome Project began, the cost of sequencing was more than $5 per base pair. Today several laboratories have the capability to sequence at least 1 million base pairs of DNA a year, at a cost of about $1 per base pair, and improvements are constantly occurring. This technology was developed by sequencing the genomes of model organisms. The relative small size of genomes of certain micro-organisms make them ideal as a training ground for the human genome, and at the same time provides information on the small genome of infectious agents.
Although it was known for centuries that certain traits or diseases are passed on within families, most of the mysteries of heredity have been unraveled only in the last quarter of this century. We now examine chromosomes under the microscope, identify carriers before they have affected children, diagnose some diseases by DNA testing before there are any symptoms, and a few human gene products such as growth hormone and insulin are being produced in commercial laboratories. Still, little can be done for most of those suffering from genetic diseases. As a result of the Human Genome Project and the logical extensions from this project, medical care for everyone will be revolutionized, because we all have potentially harmful genes that put our offspring at risk or put us at risk for disease in the adult years. Once the genetic components are identified, we can screen for those with a high genetic risk even before there are symptoms so that they can limit their environmental exposures to lower their chance of disease. Someday we will even be able to alter the genetic risk: we would replace bad or mutated bases with the normal bases and thereby reverse the mutation that caused disease. These procedures would be called: Presymptomatic Testing and Gene Therapy. Gene therapy has two varieties: 1) somatic-cell gene therapy, in which only the person treated will have the repaired gene, and 2) germ-line gene therapy, in which the DNA in the egg/sperm is repaired so that the new genes will be in all cells of the offspring and will be inherited.
What are some of the general objections to the Human Genome Project?
And more specifically for the last point:
The National Human Genome Research Institute recognized from its inception its responsibility not only to develop gene-finding technologies, but also to address the broader implications. That's why five percent of its annual research budget is to study the "ethical, legal, and social implications of genome research."
The first objection -- the process, the Big Science objection -- is principally of interest to other scientists. This criticism of the Human Genome Project is similar to that raised against other Big Science projects such as the manned space flight or the superconducting supercollider: The high cost is not justified. There was a lot of rancor within the biomedical scientific community, because funds are limited and a lot of other research is not done, and done more efficiently, because of Big Science. Conversely, others argue that coordination of the Human Genome Project is a more efficient way to conduct research in human genetics because it minimizes duplication of effort. Independent of any funding arguments, the Human Genome Project is engineering or collecting rather than Science with a big S. The sequence of DNA is a just tool in the Science of human biology. There is no real testing of hypotheses until we try and relate the gene sequence to the disease process. The Human Genome Project is Big science, but Big with a capital B and science with a small s.
Pam Long, the religion editor of the Mobile Register, pointed out that knowledge of nature is more a taboo in nature-based religion than in Abrahamic religion where nature and God are separate. True, at least; Western religion does not have the equivalent of Prometheus with his liver being eaten by an eagle and then regenerating so that this torture goes on for eternity. What was Prometheus' sin? He gave man the knowledge of fire, which was deemed sacred knowledge. However, there is still an element of the taboo in Christianity. The tabooed study of the anatomy of the human body in the Middle Ages might be like the study of the human genome today. Fortunately, ideas of what is sacred knowledge change with time. My personal interest is the genomes of bacteria. There is no hue and cry here; no one is after my liver. It is the emotional bias of looking at man that worries man. Are there secrets of life that must be kept secret; should we know all the information in the human genome? Most of us would argue that there can never be too much knowledge -- rather that there is not enough knowledge, and there is no wisdom in half truths. We are not in the garden of Eden. Post-fall humans must reverse Genesis and "Eat of the tree of knowledge or die."
On a less lofty plane, let's consider life insurance in the 21st century in a post-HGP world. How would you like your premiums to be cut in half? That would be easy -- just exclude those with high genetic risk factors. Let them get insurance elsewhere. Is this fair? What would be the cost of doing this -- both the financial cost to this minority and the moral cost to the majority? You may say the solution is simple -- just don't tell the insurance companies about their clients' genetic risk. But those who know they are at high risk could load up on insurance and get big payoffs as they die early from genetic disease. Now the rest of us have an increase in premiums -- we pay the cost. Too bad everyone is not a saint, the world would be so simple!
This brings to focus a seemingly simple issue: the privacy and confidentiality of genetic information which may affect one's insurability and social acceptance, the problems of reporting of genetic testing results, and the conflict that develops between privacy , exploitation, and public health. Can patients make enough sense of the morass of genetic data that physicians will soon present to them? Will they have the background information? We have a great crowd here tonight, but there are a lot more people who are not here! Will these patients be able to make informed reproductive decisions? Will the ability to respond to this genetic testing be related to the patient's income and ability to use a health care system? Will access to this information and the medical follow-up be based on the ability to pay? Of course it will be; that is the way we do things! Will society exact a penalty, not only on today's poor but also on their descendants?
Until fairly recently the only means of prevention was for those who knew of severe genetic disease in their family to not have children. This was accepted by quite a number of responsible people. The development of amniocentesis for prenatal diagnosis allowed such parents to have normal children and raised many of the social issues that have resurfaced with the Human Genome Project. There are two issues: (a) the genetic diagnostic procedure, and (b) the termination of the pregnancy. From the scientific point of view, miscarriage is Nature's way of disposing of a grossly defective fetus. Human involvement in the decision implies concepts of defectiveness that extend beyond sheer survival, which is the only criterion that Nature employs.
"Eugenics" is a term of accusation and automatic condemnation. It will forever be associated with Nazi superman projects. Some eugenics-minded authors, however, were not racist murders. They were just unscientific and sinned in thinking that they knew what kinds of human beings ought to populate the earth. What eugeneticists wanted to do was to increase the frequency of socially good genes in the population, but that was too difficult, so they focused on attempting to decrease the frequency of allegedly bad genes in the population. Unfortunately they did not know how to do this either! As a result of this ignorant approach, by the late 1920s, some two dozen American states had enacted Eugenic Sterilization Laws, and such laws were declared constitutional in a 1927 U.S. Supreme Court decision.
Modern medical genetics tries to avoid these pitfalls and this guilt-by- association. Medical geneticists are not out to make superior people, but to combat disease. This "medical-disease" model works fine for life-threatening diseases. Who would deny gene therapy to a child whose life could be saved by this therapy? But what about cosmetic or benign disease? For example, let us say we agree that it is a good thing to fix by somatic-cell gene therapy an embryo where the infant will inherit a missing hand and certainly would have a difficult time in life.
But consider the child who will be missing ten fingers, but have the hand, do you still fix the defect? If you say "okay, don't split hairs," then what about missing 9, 8, 7, ...2, or only one finger? You see the point. It is easy to get on a slippery slope. What is the ethical thing to do about inherited minor disfigurations that are unwanted, and perhaps stigmatizing, but do not impair function. Regardless of how we vote on this matter, will we permit a parent to decide whether to risk passing on the unwanted family trait to the next generation?
Human diversity, the variety we see every day in the human population, is prized by most people, and Nature loves diversity. Diversity, or rather the lack of it, is a key argument against the selection schemes of eugenics. Who knows whether the gene/trait that we remove or alter today, will be advantageous five hundred years from now? However, embracing diversity can become more difficult when we are directly involved. Influencing who your daughter marries is a eugenic decision. Elimination of small pox from the planet has decreased diversity, but who objects. An evil person who presents a diversity argument to the blessed St. Peter at the Pearly gates to the effect that the evil are under- represented behind those gates and in need of affirmative action will be told to "go to Hell."
Is it always too arrogant to do germ-line therapy, where the alteration will be inherited by all future generations, in contrast to somatic-cell therapy that affects only the individual receiving therapy? Germ-line therapy is a monumental decision. Clearly, any attempt to systematically improve mankind in the future needs to stress: 1) the value of the individual and respect for individual freedom, and 2) regulation to the norms of society while respecting all minority positions. With individual freedom comes a guarantee of diversity. While many will want blonde, blue-eyed children, the Chinese will choose the classic Chinese beauty, not the western ideal. As the new father, Richard Snead (one of the symposium organizers), has indicated that he would choose baldness and big feet as his ideal. If parents, and not fascist governments, are making informed decisions concerning gene therapy the world could become a better place -- maybe. But regulations will be necessary, and who will decide the social norms and safeguards. Would you trust these decisions to the boys in Montgomery, the gang in Washington, or the members' various animal herds, Lions, Elks, Moose, etc.? Would you even trust yourself? This caution is good, but I would hope after tonight, if asked, you would be willing and pleased to serve on a committee to study, and even implement, in a thoughtful way, these issues. The knowledge of genetics is a powerful tool, with great potential for great good and with great potential for great abuse. That abuse could be by a government, which is why voluntary individual choice must always be a cardinal axiom. However, the ethicist Kevles was right when he said: "If a Nazi-like eugenic program becomes a threatening reality, the country will have a good deal more to be worried about politically than just eugenics."
At the time of Christ, life expectancy was 22 yrs (due to many infant deaths); 1800 years later it was 40 yrs; in 1955 it was 55 years; at the beginning of the 21st century it will be about 80 years. These are truly impressive increases brought about by mankind's efforts over 2 millennia. Can you imagine what the next century, much less the next millennium, will bring? As much as we remember the good old days, certainly the quality of life has improved over this time, not just the length of life. But, what does it profit a man to gain the whole world and yet lose his immortal soul? And, what does it profit a man to live to 150 years but only enjoy the first half of his allotted life span? The goal of science and society must be to improve not only the quantity of life but also the quality.
Genome research can lead researchers to new frontiers in drug development. With the sequence of the human insulin gene we can make real human insulin in bacteria, instead of using pig insulin. Once all the genes are identified and their bases are sequenced, it will be possible to produce virtually any human protein, valuable natural pharmaceuticals, as well as new molecules designed specifically to block disease-producing proteins. In the future we will probably insert the gene into the diabetic's pancreas and have the patient make their own insulin, and eventually it should be possible to modify the mutant gene of the embryo/egg. Such single-gene diseases are relatively easy targets. However, disorders caused by the interaction of several genes, such as hypertension, atherosclerosis, and most forms of cancer and mental illness, are much more daunting. But knowing the entire human genome will make it theoretically possible, if not sooner then later, to identify every gene that contributes to disease. One day, though not tomorrow, it may be possible to treat genetic diseases by correcting errors in the gene itself, thereby replacing the patient's abnormal protein with a normal one, or by switching the faulty gene off. We don t know for sure today if we can fix bad genes, but clearly we cannot fix them without this knowledge of the human genome.
The Human Genome Project is not the Holy Grail. But I am very optimistic. There is a long road ahead: don't forget that once we have the maps and sequences in hand, the hard and interesting science of understanding how genetic changes bring about disease states begins, not ends. However, for today, let me conclude by quoting two items. The first is the cautions of the ethicist Kevles: "I would say that the major challenge is two-fold. First, on the part of the ... Genome Project people ... to refrain from making claims that I think will inevitably be exaggerated about what they have found concerning the role of genes in human makeup and human behavior. ... The media absorbs them uncritically, and then people take them for truth, and then a few months later it's found that they're wrong... The other challenge is that the lay people ... ought not to be victimized by not only exaggerated claims but also misinformation about what the Genome Project is, what it's going to produce, and what kind of dangers it poses. It seems to me that the challenge is to introduce a truth and reality ... into the discussion of its nature and its prospects."
And the second quotation is from the 1995 declaration of the UNESCO International Bioethics Committee: "No intervention affecting an individual genome maybe undertaken, whether for scientific, therapeutic or diagnostic purposes, without rigorous and prior assessment of the risks and benefits pertaining thereto, or without prior, free and informed consent of the person concerned. No one may be subjected to discrimination on the basis of genetic characteristics and that aims or has the effect of injuring the recognition of human dignity or the enjoyment of his or her rights on the grounds of equality." Amen.
Dr. Herbert W. Winkler is Louise Locke Distinguished Professor of Microbiology and Immunology at the University of South Alabama. Funding for the symposium is provided by a grant from the Alabama Humanities Foundation, a state program of the National Endowment for the Humanities.