[2] It is in the light of these perspectives that I wish to examine how technology impacts and is likely to impact our lives. The four major questions to be postulated and used to shape the discussion are:

1. What is normal?

2 Nature or nurture? (i.e., how much of a person's psycho-physical make-up or phenotype is determined by nature and how much is determined by nurture?)

3. How far is too far? (or, should we limit technology?)

4. Who are we?

[3] The question of what is normal and what is abnormal is one that will have new meaning because of work with the human genome. When we examine DNA sequences, it is difficult to discern up-front which sequences can be considered to be variants of normal and which ones lead to development of disease. In most cases there is more than one version of the gene; in most cases more than one version of the gene is functionally correct. If we were to claim that there is always only one sequence that is "norma," then which sequence for eye color would be the "normal" one: brown eyes or blue eyes? This is an obvious case where we can claim that both sequences are variants of normal. Nevertheless, for other situations where the genes have unknown functions or multiple functions, this judgment becomes more difficult. 

[4] Let us start with an introduction into the genetic material. We know that the genetic material deoxyribonucleic acid (DNA) is composed of a sugar (deoxyribose), a base, and a phosphodiester backbone (for a review of this and below information, see endnote 1). There are four bases that make up the major constituents of DNA, and these four bases are represented by the letters A, T, G, and C. The genetic code from DNA gets transcribed into RNAs, and base triplets get translated into single amino acids of proteins; therefore the order of the bases determines what protein will be made. The codon sequence of TTT encodes a different amino acid and thus a different final protein than the sequence AAA. Different arrangements of bases in DNA make for different arrangements of amino acids and thus different proteins. Figures 1A and 1B show an outline of the central dogma of molecular biology. In Fig. 1A we see the usual pattern which is that DNA makes (through the process of transcription) RNA which makes (through the process of translation) protein. The DNA itself has a coding region that makes the protein and a regulatory region (also called a promoter) that defines how the gene will be expressed-i.e., which tissues will make the protein, when in development it will be made, what environmental factors will regulate it, etc. Figure 1B shows how mutations in DNA can affect any part of this process. A mutation is defined as a(ny) change from the normal sequence. A mutation in the coding region can lead to several possible consequences: (1) a silent mutation which will not be observed; (2) a change in the amino acid sequence of the protein which can lead to a change in protein structure and function; (3) a change in amino acid sequence so that the protein is truncated and only a portion of it is synthesized. The latter two types of mutations may have massive or minor consequences for the body depending on the gene, the mutation, other genes and the environment of the individual. Alternatively, a mutation in a regulatory region may lead to a change in the activity of a gene causing the gene to be expressed at inappropriate levels or in inappropriate locations of the body. 

[5] Based on this understanding, then, whenever a genetic mutation leads to a silent mutation such mutation is just a genetic variation from one person to another. For example the sequence ATCATCTTT codes for the amino acids Isoleucine-Isoleucine-Phenylalanine. The sequence ATCATTTTT also codes for the same amino acids. Two people with these two slightly different genomic sequences would make the same protein. Which of these two is the "normal" sequence? Is it the one that is most common in the human population? Is it the one that is most ancient in the population? Clearly, if we think about it from a disease perspective, both sequences are normal. 

[6] Let's move on to a more difficult example, where the mutation is not silent. For example, the ABO blood groups are caused by changes in DNA sequence that result in changes of the proteins. People with the A blood group have the sequence GTGACCCTTT which makes Val-Thr-Pro. People with a single deletion of one DNA base G have an entirely different sequence: Val-Pro-Leu. We know that both of these blood groups occur in the human species and that the O type is more common, yet we consider these different sequences normal variations in the human population.

[7] In all species with segmented body parts, the structure of the body form is regulated by a series of so-called Hox genes. A change in one of these genes in the fruit fly can lead to an antenna being replaced by a leg and more pronounced genetic abnormalities can result depending on the exact mutation. In humans, developmental abnormalities have been associated with some differences in Hox genes as well. Many times these are very pronounced, but sometimes they are less obvious. Fig. 2 shows a picture of my dog Jessie who has five toes on her front left foot, but only four on her front right foot. Most dogs have either one or the other number of toes on both front legs, but she has a combination probably as a difference in a Hox gene. Which one of these is normal? Since both variations exist in the dog population, it is difficult to define what is normal and what is abnormal here.

[8] Based on these normal variations, most scientists tend to call frequent mutations that do not cause disease "alleles" and consider them normal, and whatever mutations give rise to disease "mutations" and consider them abnormal, but this division is not clear in all cases because of the interplay between genes and environment. Usually, if a gene confers a benefit it is kept in the gene pool, and if it conveys only deleterious consequences it is lost because it results in a reduced ability of an individual to survive long enough to have offspring. For example, the gene for globin encodes the major protein found in red blood cells that carries out the task of supplying oxygen to the body. When this gene is mutated in both gene copies in the genome, as for example in sickle cell anemia, anemia results. While this mutation clearly leads to development of disease, it is present in the human population in such a high frequency that we would expect it to be harmless. How is this possible? In areas where malaria is endemic (such as in Africa and portions of southeast Asia), people with the sickle cell globin gene are resistant to malaria. This means that people with two "normal" copies of the globin gene will die from malaria, and people with two copies of the sickle globin gene will die from sickle cell anemia. The only people who will be healthy in a malaria-prone environment are those with one "normal" copy and one sickle cell copy of the gene; these people will not develop malaria and will not have sickle cell disease. In our environment in North America, we have chosen to call the sequence of the gene for non-sickle globin "normal," but in Africa this designation needs to be reconsidered.

[9] In other diseases, such as Cystic Fibrosis where there is a deletion of three bases in many cases, this deletion clearly leads to a difference in the amino acid sequence of a protein which results in Cystic Fibrosis. Medical specialists have chosen to call the gene that does not give rise to Cystic Fibrosis "normal" and the gene that gives rise to the disease "mutant." Was there some benefit to this mutation in the human population that we have not yet identified and would have made this mutation "normal" in some other environment? Interestingly, even the trappings of society sometimes provide the "environment" where a harmful mutation can have increased frequency. Royal families of Europe have, for example, perpetuated the gene for hemophilia in their efforts to intermarry only with other "royal blood lines."

[10] Based on all of the above, probably one of the most important consequences of the completion of the human genome sequence will be in the identification of the spectra of possible gene variations and discovering which gene allele pairs are harmless in which environments, and then "proclaim" what is normal and what is not. As we identify the genes for not just physical but also psychological diseases, and discover which combinations of genes influence complex phenotypic traits, the definition of what is "normal" and what is "abnormal" may become blurred. Will we begin to define diseases based on genetics, especially for psychosocial diseases? How will we differentiate between a polymorphism (existence of two or more healthy alleles for one gene) from a normal gene with its mutations? What is the role of these genetic mutations in defining who we are?

[11] To answer these questions, we will probably need to come out of our shells as scientists and become more contemplative. Patriarch Ignatius of Antioch wrote: "Contemplation of nature transforms nature, not in the direction of Babel, but in the direction of the New Jerusalem. When an Orthodox hermit, well into the twentieth century gives poisonous snakes little cups of milk to drink, he knows them in a different way than the scientist¼" (2). We will perhaps need to learn about mutations in a different way than we have learned them before in order to put them in their proper context.

[12] This question has probably been the most important question that has plagued biologists in recent decades. How much of who we are is environmentally determined and how much is determined by our genetics? Thinking in this area has so far been shaped by studies of identical twins separated at birth and this area of research is likely to be much influenced in the future by studies of non-related individuals with large clusters of identical genes considered to regulate social behavior and anti-social activity, and mental and psychological diseases.

[13] Identical twins have identical sequences in their genetic code; they are in effect clones of each other. A large number of studies have been done examining identical twins that have been raised apart, and in particular the Minnesota Twin Study has had a large impact on thinking about nature vs. nurture and the role they play in our decision-making process. When people have studied diseases in identical twins, they have not found an absolute concordance. For example, diseases like cancer, Alzheimer's Disease, autoimmune diseases and many others are often expressed in one twin and not in the other, suggesting at least a combined influence of genetics and environment on the expression of the disease and perhaps even a strong role for environment. That environment can be physical (such as a virus infection or an environmental insult of some sort) or physiologic (stress, disease, etc.).

[14] In any case, for many diseases, the role of nature vs. nurture is not clear at this point. On the other hand, a variety of other behaviors that one would not have anticipated were identical in twins raised apart. For example, they show similar selections in clothing (including choice of prints and colors), the same lawn furniture on the front yard of the house, and even the choice of names for their offspring. Is there a role for genetics in these choices that we would have considered to be predominantly environmentally influenced? The twin studies suggest that this is the case, and further studies in genetics are likely to help determine what decisions we make are influenced by our genetics.

[15] In an effort to understand social behaviors, geneticists have used several approaches to identify the genes involved in their regulation. The Honeybee Sequencing Consortium recently reported over 22 genes that are involved in social interactions among honeybees and, while many of these genes are shared with the fruit fly, they are expressed differently in the two species resulting, it is believed, in the social behavior of honeybees. These genes are involved in a variety of different functions including vision, circadian rhythm, thermal regulation and learning/memory. Many of these genes are similar to those found in humans and may provide insight into human social behavior.

[16] Another project perhaps nearer to our hearts is the Dog Genome Project aimed at sequencing the dog genome and identifying aspects of the genome associated with particular behaviors we find in dogs. Because dogs live in the same environment as we do, eat similar food, some even watch TV and become couch potatoes, it is hoped that studying dogs will help us uncover important aspects of human social behavior. In an effort to use dogs to help humans with a variety of tasks, dogs have been specially bred for particular traits; some help in herding, others like my Jessie (Fig. 2) were bred to chase foxes out of their holes during fox hunts, and still others were trained as blood hounds to find prey that had been shot. Even when dogs are not employed in these functions, they still retain these traits. Many who have sheep dogs but no sheep claim that their dogs will work tirelessly to herd small children or other pets into a circle. These functions are likely to be genetically founded because it seems that they have been bred into the animals, and it is hoped that the doggy genome project will identify what some of these genes are. To date, the boxer dog and the standard poodle have been totally sequenced, and several other dog strains are on the list to be completed soon, while ribosomal genes (short segments of genome that can be used to track genetic closeness between species and subspecies) have been sequenced in a vast array of dog breeds. So far, we have learned which dog breeds are closely related and which ones are not; there were a few surprises in these studies and some dog breeds thought to be very ancient were found to be of much more recent origin. One recent study has shown that all body size differences in the various strains of dogs are related to a single gene and its expression-the insulin-like growth factor 1 gene. This gene had already been known to be involved in size regulation in many species (including humans), but what was surprising was the identification of a single gene as being solely responsible for the size differences of all dog breeds (3).

[17] As we begin to uncover other information from the various genome projects and the relationship of that information to humans, we are likely to find genes that influence human behavior, that contribute to human social and anti-social behavior. How much of our behavior is genetic and how much is environmentally determined? How much of our personality is genetic? From a religious perspective we are often taught to overcome the bad influences we have encountered in our environments-whether they are school, family or work. Are we now also to work to overcome our genetic makeup as well? In light of genetics and its role on human behavior, what is sin?

[18] Perhaps in order to understand our humanity we need to examine humans from a non-genetic context. Sergei Bulgakov noted the following about the human condition today: "The stumbling block for contemporary thought ¼is that the history of the world preserves traces neither of Eden nor of the perfection of the original man, which is why the biblical story is considered only a naïve legend¼.What should one's attitude be toward this story in the face of the existing critique? One can say that the remembrance of an edenic state and of God's garden is nevertheless preserved in the secret recesses of our self-consciousness, as an obscure anamnesis of another being¼.." (4).

[19] New technologies are providing us with tools to treat and diagnose disease not only at the level of the whole organism but down to the single cell. We are developing approaches to manipulate cells and genomes and perhaps ultimately even humanity. There is a very rapid movement from technology to application, and this speed makes it extremely difficult to limit technology as it is being developed. Most often, socially applied limitations of technology occur at the level of the application of the procedure rather than at the development of the tool itself; while most technology is morally neutral, its applications can be both/either morally positive or negative and therefore belong to the area of life that society strives to control.

[20] Science in general is a technology-driven field, and the development of only a single new approach can often have a lasting and drastic impact. One need think only of the PCR (polymerase chain reaction) and what it has done for forensics, medicine, and biomedical research to see this type of influence. Before PCR was developed, one had to use large numbers of cells to analyze DNA; PCR technology allowed that amplification of DNA be possible from a single cell found in a hair follicle or a drop of blood, amplification so accurate and abundant that the complete genome of an individual may become available from a single cell. A simple version of this technique made it possible to identify who were the people at crime scenes from the hairs they left behind or dried droplets of bodily fluids, while more elaborate uses of this technique allow scientists to understand complex genetic processes occurring on a single cell level instead of requiring a large cell population. We see similar examples of this variation in the use of technology in our every-day lives-massive use of laptop and home computers, development of the iPod, cell phones, etc. on one hand, and supercomputing machines used by computer scientists on the other. It is in the arena of everymen's technology that the world and society have become stratified into those who have the technology and those who "don't do it" or even "can't do it."

[21] Here are a few major examples of biomedical technology that is currently impacting science and is soon likely to impact the society at large:

(1) Structural biology. This technology has allowed for the identification of three-dimensional structures for many of the most important proteins in the human body. The identification of the actual shape that a protein has while it is in the body has allowed for the design of drugs to target that protein and lead to the field of rational drug design. Drugs that inhibit the HIV, the virus that causes AIDS, were designed based on their ability to bind to one of the major proteins of the virus and inhibit it during viral infection. This was done in part by examining the three-dimensional structure of the protein, looking at how other proteins bind to that structure and then developing a drug that mimics (and competes with) those binding proteins. The selection process is done repeatedly in an effort to develop the best drug that inhibits the viral protein but has little impact on the remainder of cell function.

[22] (2) Genome technology and proteomics. One component of the Human Genome Project was to develop technologies that would allow for rapid sequencing of the genome and also rapid recognition of sequences that represent genes, as well as finding out in which tissues/organs that gene is expressed and when it is silent. Gene chip technology was developed for these purposes, and it allowed for the simultaneous screening of the 38,000+ genes in the human genome for expression patterns (when they are turned on and turned off) in a single overnight experiment. This approach generates a large amount of data that requires weeks for complex computer analyses; these experiments can classify tumors for responsiveness to various therapies, identify mutations that make a tissue more prone to tumor development, etc. Fig. 3 shows the results from an experiment in my laboratory where we screened the human genome for genes that are turned on in response to radiation therapy and particular chemotherapeutic regimens. Each line represents a single gene that is turned on in response to the therapy. This diagram shows the complexity of the data that are generated and yet the ease in obtaining so much information in a single experiment. While genomics technologies have examined the DNA and RNA, proteomics looks at large numbers of proteins at the same time and relates that to the genome of the individual.

[23] (3) Beginning of life and stem cell technologies. The advent of in vitro fertilization (IVF) provided a solution for couples who could not have children naturally. With the development of this technology, however, came the development of other beginning of life approaches including cloning and stem cell research. While these technologies were developed in response to reproductive issues and to study specific scientific questions, it soon became apparent that the use of stem cells for treatment of problems like Alzheimer's Disease, diabetes, spinal cord damage, and others could provide hope for individuals in serious medical conditions with little hope for cure. This also became controversial because some religious groups argued that embryos should not be sacrificed for others even if the result was a cure for a debilitating condition. This battle continues today as scientists attempt to develop acceptable approaches for the generation of stem cells and some religious groups express concerns about these very approaches. Stem cell research has great potential for providing cures for diseases that have no known therapies, and we are likely to see continued developments and research in this area.

[24] (4) Nanotechnology. The eye of a needle is 1mm in size, a single red blood cell is 5 microns, a typical virus is 75 nanometers, and a DNA helix is 2 nanometers in width. Nanotechnology is the use of materials that are smaller than 100 nanometers in size in at least one dimension and that may or may not have altered chemical properties when they are of this size. Why is nanotechnology becoming so important right now? Most cells are microns in size (thousands of nanometers); when we synthesize devices that are much smaller than cells, we can use these as tools to manipulate cells. Blood vessels in tumors, for example, are 20-500 nanometers wide; what materials can we synthesize this small that can reach a tumor through these tiny blood vessels tumor vasculature is as wide as the rest but more leaky? What types of agents can we design that can enter a cell and alter cellular function? Nanodevices hold this promise-they are small in size and they can be engineered with organic matter to produce hybrid materials with hybrid functions. Fig. 4 provides a schematic diagram of how a nanodevice can be used to provide a single agent that delivers a drug to a particular type of cancer cell while at the same time providing imaging capabilities that can detect particular genetic mutations. Nanodevices are currently being explored as new imaging tools for diseases, therapeutic agents for cancer and other diseases, drug delivery systems, and more (5).

[25] All of the above technologies are going to continue to develop at a very rapid rate, making it difficult to regulate these areas of research. At this point in time, regulation occurs generally at the level of the application of the technology, and often after an application has been attempted that is considered dangerous. For example, while cloning technology may have benefits for stem cell research, regulation of cloning was not considered imperative until "attempts" were made at cloning human beings; while these attempts were not successful, their potential use scared regulatory bodies into making legislation that would prevent human cloning. Of course, this legislation generally applies to what can be done with government funds, not what can be done with private funding. The impact of the religious communities on the regulation is minimal, occurring only through the public dialogue rather than a specific engagement of the religious communities to address the matter.

[26] In reflecting on the applications of technology, perhaps it is wise to consider the words of St. Basil the Great who wrote in ancient times about medicine, the technology of his day: "Medicine is a gift from God even if some people do not make the right use of it. Granted, it would be stupid to put all hope of a cure in the hands of doctors, yet there are people who stubbornly refuse their help altogether." Elsewhere in the same article he wrote: "All the different sciences and techniques have been given us by God to make up for the deficiencies of nature¼Not by chance does the earth produce plants that have healing properties. It is clearly evident that the Creator wants to give them to us to use." (6).

[27] Perhaps the most important question is how new scientific knowledge will impact our concepts of ourselves as human beings. In the context of our evolution and our genetics, it is becoming more difficult to define exactly what is a human being. How much are we the human population and how much are we individuals? We are animals, but are we also different than animals? While it is clear that science is impacting these issues, it is also likely that the answers to the question of human identity are not in science-although they may be made more difficult because of the science that is being done.

[28] One issue that has significantly impacted this question has been the DNA sequence comparison between chimpanzees and humans. The sequence of the chimpanzee genome has shown that there is over 98% identity between humans and chimps (humans amongst themselves show a 99% identity), and a comparison at the protein sequence level has shown that there are small amino acid differences in some proteins; most of these appear to be conservative changes that do not make a vast difference in the function of the protein. Because of apparent differences in cognitive functions, much work has been done comparing chimp and human brains for the genes that are turned on and turned off during brain development and the timing of these events. In general, over 80% of genes in the human brain are produced in larger quantity than the same genes in the chimp, suggesting that differences in human and chimp brain function may be at least in part caused not by different proteins but rather larger quantities of the same proteins. Some scientists have attempted to examine expression of all neural genes and their changes, and estimates are that some 100-4000 genes have differences in gene expression when comparing chimps and humans (7). Despite these differences, the striking similarities between chimps and humans are remarkable and brings to mind questions of who we as humans are compared to our nearest living relative. This question is even more dramatic when we consider extinct proto-humans like Neaderthals. Recent experiments have examined sequences of mitochondrial DNA (separate from our usual genetic material, found in organelles in the cell called mitochondria) from Neanderthals and compared them to mitochondrial DNA of modern humans; these sequences demonstrate that Neanderthal mitochondrial sequences fit into the range of sequence variation we find in humans today (8). Based on all of this, it seems it is going to be difficult to come up with a scientific definition of what it is to be human.

[29] One thing that is difficult to capture in genes is the fact that humans have a cultural heritage that we pass on from one generation to the next. We certainly pass on our genetic heritage to future generations in our children and grandchildren, but we also pass on a cultural heritage that does not require genetics. Evolution operates at the level of the populations, and they (populations) preserve the genes of the most reproductively fit individuals; but humans have societal groups that are different than populations, with rules of behavior that alter "reproductive fitness" of individuals. At the same time, very often individuals who leave no progeny make significant contributions to the cumulative transmission of experience through millennia. Humans can adapt to their environment quickly by changing the environment to suit their needs. Birds had to evolve the ability to fly through genetic changes that took millions of years; humans could create planes to meet the same needs.

[30] Humans need to be placed in the context of environment. We share elements and materials with the earth, being made of carbon, water, oxygen, etc. We share genes and genetic pathways with other species including our protein encoding genetic code which is identical for all species on earth. We are unique in some aspects that are difficult to define¼ Our creativity? Our responsibility? Our love? Like all species on earth, we are products of our environment and our genes, but we are the part of creation that contemplates.  The answer to who we are  is not likely to be found in science-we must look elsewhere, and it is religious communities that can help in this goal. The word "anthropos," which is Greek for human, comes from the word "anathrein" which means to "look up." Humans, unlike most animals, look up, are heavenly yet earthly, spiritual yet material. Using St. John Chrysostom as a source, Kallistos (Ware) says "Our human task is to be syndesmos and gephyra, the bond and bridge of God's creation." (9) To further this point, it is useful to reflect upon comments by John Zizioulas on this issue: "The belief in human superiority received a blow from Darwinism when Charles Darwin proved that not only humans but also animals, although to a lesser degree, are capable of thinking. So if the human is in the image of God, God must be so due to other capabilities than his/her ability to think, and it is these capabilities which we must learn to value." (10)

[31] Who are we? Perhaps that is the quest that humanity has been driven to answer throughout all the millennia.

Endnotes:

1. Watson, J. D., Baker, T. A., Bell, S. P. and Gann. A. Molecular Biology of the Gene (5^th Edition), Benjamin Cummings Publishing, 2003.

2. Patriarch Ignatius IV, 1989 quoted in "Orthodox Patriarchs and Hierarchs Articulate a Theology of Creation," pamphlet published by the Society of the Transfiguration, 2002.

3. H. G. Parker et al., Science (2004) 304: 1160-1164

4. Bulgakov, S. The Bride of the Lamb, Grand Rapids, MI, Wm B Eerdmans Publishing Co., 2002.

5. Cancer vol 107, no 3, pp. 459-466

6. Basil the Great, The Greater Rules, #55

7. Pennisi, E., "Mining the Molecules that Made our Mind", Science (26 September 2006) 313(5795): 1908-1911.

8. Green, R., Krause, J., Ptak, S. E., Briggs, A. W., Ronan, M. T., Simons, J. F., Du, L., Engholdm, M., Rothberg, J. M., Paunovic, M., and Paaho, S. "Analysis of one million base pairs of Neaderthal DNA," Nature (2006) 444: 330-336.

9. Ware, Kallistos. Through the Creation to the Creator, London, UK, Friends of the Centre, 1997

10. Zizioulas, J. quoted in "Orthodox Patriarchs and Hierarchs Articulate a Theology of Creation," pamphlet published by the Society of the Transfiguration, 2002.