by Frank Ryan
Some of the first whole personal genomes to be sequenced included J. Craig Venter, the entrepreneurial scientist who led the commercial group to the first draft sequence of 2001, and James Watson, the codiscoverer of DNA. When Korean researchers compared their genomes to those of a Han Chinese, a Yoruban Nigerian, a female leukemia patient, and a Korean-originated scientist, the researchers were astonished to discover that the two Americans had more sequences in common with the Korean than with one another. I should add that what the Korean researchers actually compared were not whole genome DNA sequences but whole genome patterns of Snips, when they discovered some 420,083 novel, single-nucleotide polymorphisms previously unknown to the Snip database as well as the startling similarities and differences mentioned above.
Another interesting personal example was the 2008 sequencing of the mitochondrial genome of Ötzi, the Tyrolean Iceman, whose 5,300-year-old mummified remains had been discovered with the thawing of an Alpine glacier. This revealed that he belonged to a branch of the mitochondrial haplotype K1 that had not been identified in European populations up to this point. But when, in 2011, this was followed by Snip analysis of his nuclear genome, it showed a recent common ancestry with the inhabitants of the Tyrrhenian Sea, which is part of the Mediterranean immediately west of Italy, including the coast of Tuscany and the islands of Corsica and Sardinia. The report, by Keller and colleagues, suggested that he had brown eyes, belonged to blood group O, was lactose intolerant, and had a genetic predisposition to coronary heart disease.
When Pääbo and his colleagues were screening archaic genomes they made some startling additional discoveries. The different sections of our chromosomes have different paleontological origins in terms of people and time. It would appear that when we visit these different regions of the genomic landscape in our magical train, we really are glimpsing something of those different ancient peoples in their prehistoric worlds. A related discovery was that while some portions of our genome have a very modern evolution, other portions appear to have stayed the same for millions of years. When Pääbo and his colleagues calculated back to the likely date of the common ancestor of the “reference modern genome” and the Neanderthals, the results suggested an LCA some 830,000 years ago. But when they dated the last common ancestor of the same reference modern genome and the San people in Africa, they came up with a date of 700,000 years. Even stranger, when they dated last common ancestors for specific present-day DNA regions of chromosomes from people from different geographic locations over the Earth, they found some regions where they shared a common ancestor just 30,000 or so years ago, but other regions that suggested a last common ancestor 1.5 million years ago—the time of early Homo erectus. In Pääbo's own words: “If somebody could take a walk down one of my chromosomes and compare it to both a Neanderthal and the reader of this book, that chromosomal pedestrian would find that sometimes I would be more similar to the Neanderthal than to the reader, sometimes the reader would be more similar to the Neanderthal, and sometimes the reader and I would be more similar.”
For Pääbo's walk, my reader and I might substitute a train ride, and I think we might share a smile for a moment.
It is strange to consider that different regions of our genome have different evolutionary origins. But perhaps we shouldn't be so overly surprised by it when we realize that we share a thousand or more genes with worms and fruit flies and, in the opinion of my friend and colleague, the eminent evolutionary virologist Luis Villarreal, we have inherited key DNA and RNA management genes from viral lineages that date to billions of years ago. Sometimes an evolved genetic or genomic system simply works so well that the passage of time cannot improve on it, over millions, or even billions, of years. Yet this was exactly the point made by Darwin in his ruminations before the publication of his iconoclastic book. Our common ancestors, generation by generation, species to families, and back even beyond phyla and kingdoms, go back to the very origins of life on Earth.
I wanted to take us into a new era of biology by generating a new life-form that was described and driven only by DNA information that had been created in the laboratory.
J. CRAIG VENTER, LIFE AT THE SPEED OF LIGHT
The philosophers among the ancients believed that matter, and thus the Earth, was made up of four elements: earth, air, fire, and water. They further believed that the stars in the fiery heavens were made of a fifth and more wondrous element which was infused with the celestial power over life. These metaphysical elements are not the same as the chemical concepts of elements today, which are the building blocks of molecules, but they do bear an ideational comparison since, in a more holistic sense, the elements of the ancients were, in their imaginations, the building blocks of worlds. And we might continue the comparison in extrapolating the fifth metaphysical element to the remarkable sibling molecules, DNA and RNA, which make possible the evolution, heredity, and development of life. How daunting then to open our own imaginations wider still, to acknowledge that, for good or for bad, that quasi-miraculous fifth element has now fallen into the ambitious grasp of humankind.
Tinkering with the processes of life is not new to humanity. As long ago as the Stone Age, farmers learned how to select the seed grains of wheat and other cereal crops to get fatter, more nutritious kernels. Today virtually all of the seed grains “husbanded” by farmers are the results of hybridization—that same evolutionary mechanism of sexual crossing between different species. Humans have been learning from, and also intruding into, the secrets of nature for a very long time, but only very recently could we be said to have added a fifth to the hitherto four natural mechanisms of genomic creativity—those same mechanisms that natural selection relies on to enable the evolution of life on Earth. That fifth mechanism is the calculated genetic engineering of living genomes.
Where in the past any human-induced genetic modifications were brought about as the accidental effects of breeding farmed animals, pets, and crops; now, thanks to the golden age of genetics, we are poised to take the reins of deliberate genetic and epigenetic control. This is not some fearful, or wonderful, thing that will eventually come to be; it has already been happening for a generation in terms of the genetic engineering of animals and plants. If to date it has not intruded into the human genome, I'm afraid that logically it seems merely a matter of time before it begins to be applied to humans.
In the initial media response to the 2001 publications of the draft genome we witnessed that it heralded a new way of looking at ourselves. What else have we been doing in this book other than looking at ourselves anew? It is difficult to consider such possibilities dispassionately. Yet it would appear timely to do so. Scientists, including molecular geneticists, are neither amoral nor unethical. The obvious applications of the dawning golden age of “creative genetics”—or, taking on board the dawning importance of epigenetic regulation, should we call it “creative genomics”?—will be for the potential good of humanity, in terms of medicine, for improved provision of food, and, less explicitly, as part of the ongoing exploration of the wonders of nature.
What could be more justified than understanding the genetic basis of disease so we can make use of such understanding to treat affected individuals as well as preventing disease in future generations? These twin aims have already begun and are rapidly expanding in terms of preimplantation genetic diagnosis and the selection of healthy embryos. Some members of society will have ethical or religious objections to this. Pioneers of molecular genetics and “recombinant DNA,” such as James Watson, Sydney Brenner, and Paul Berg, pointed out that the prudent way to encompass such concerns is to ensure that non-scientists understand and are thus “intelligently aware” of such scientific enterprise and ambition so that the safety, moral, and ethical implications are routinely taken into consideration.
A good deal of the modern extrapolation of genetics and genomics does not involve worrisome genetic engineering. Much of the pharmaceutical research into epigenetics, including non-coding RNAs, is aime
d at medical therapies that change the epigenetic control for the better. This is already the basis of lines of research into cancer therapy. I can predict that it will also become the basis of many lines of research into autoimmune diseases.
As we have seen, our physical and mental health is closely linked to genetic as well as environmental factors. Genetic and epigenetic differences between individuals may determine the potential for addiction to drugs and alcohol. A similar individual variation may be important in our predisposition to many different diseases. This is ushering in new fields of investigation and prediction of disease, such as the closely related “personal genomics” and “predictive medicine.” Personal genomics—also referred to as “integrated personal omics profiling”—is an ambitious program of research aimed at providing a dynamic assessment of the physiology and health of an individual over time. One such investigation is the brainchild of Michael Snyder, professor of genetics at Stanford University, in which volunteers are subjected to genomic, transcriptomic, and proteomic high-throughput readouts, combined with screening of the individual's metabolic state and changes in auto-antibody profiles. The idea is to spot key changes in and interactions between genome, epigenome, and internal physiology during normal health and in the lead-up to disease.
Something similar is happening in other countries. In the UK, between 2006 and 2010, a registered charity called UK Biobank recruited 500,000 people aged between 40 and 69 years to undergo medical examinations and to donate blood for DNA, as well as urine and saliva samples for future analysis. The aim is to create a data bank that will improve our ability to prevent, diagnose, and treat a wide range of serious and life-threatening illnesses—including cancer, heart diseases, stroke, diabetes, arthritis, osteoporosis, eye disorders, depression, and forms of dementia. In 2005, in the United States, Dr. George M. Church announced the creation of the Personal Genome Project, aimed at recruiting 100,000 volunteers from the US, Canada, and the UK who would be agreeable to having their entire genomes sequenced and stored. This large collection of “genotypes,” or full DNA sequence of all 46 chromosomes, would be published, along with extensive information about the medical records, various physical measurements, MRI images, and so on, so that researchers will be able to study the links between genotype, the environment, and so-called phenotype—the physical makeup and progress of the volunteers. Not only will this help to plot genetic links to disease, researchers are planning to examine the reaction of society, including insurers and employers, to such extrapolations from the genotype to future health predictions. Despite the potential for discrimination, it seems that recruitment has been very successful. It seems likely that similar wide-ranging genetic and epigenetic screening programs will be conducted in many other countries.
In time, such personal genome projects may enable predictive medicine, which is based on the notion that, by predicting the probability of serious disease from an individual's genome, this will allow active measures to reduce the risk of disease in the future. Another way in which this might prove useful would be to predict the likelihood of iatrogenic disease—disease caused by side-effects of medical therapy. In a recent study of adverse drug reactions involving 5,118 children admitted for both medical and surgical therapy to a UK-based hospital, 17.7 percent experienced at least one adverse drug reaction. The authors thought it likely that the actual incidence of side-effects may have been higher because they excluded “possible” but unproven cases. Opiates and anesthetic drugs accounted for more than 50 percent of the reactions, and 0.9 percent caused permanent harm or required admission to a higher level of care. It is important to grasp that many such side-effects were not life-threatening, for example vomiting after a general anesthetic, but these experiences will have been frightening and memorable for children and would be better avoided, if possible. Another obvious potential for troublesome or even life-threatening side-effects is the long-term treatment of a very wide variety of diseases, both under hospital and general-practitioner management. Some of the most serious side-effects may become predictable, and thus preventable, by deciding from a choice of medication at the outset of therapy through modern “omics” investigation.
Members of the public are also doing things for themselves. More and more people are paying to have their personal genomes sequenced, some merely through curiosity about their genetic background, others because they want to know about their own genetic predisposition to disease. For example, a woman who fears, from her family history, that she might be more susceptible to breast or ovarian cancer might want to know if she is carrying specific genes that would increase her risk of these diseases, such as BRCA1 and BRCA2. This might allow her, in consultation with her doctors, to plan a course of action that would mitigate her risk.
All such investigations, as well as the therapeutic options that come from them, might invoke ethical, moral, or religious dilemmas. We live in a rapidly changing world in which complex personal and social issues are being brought into question in ways our parents and grandparents would never have imagined possible, with increasing need for genetic counseling, genomic prediction, and, perhaps soon, the potential for genetic engineering.
Even today, some folk are worried that this growing understanding and manipulation of genetics will lead to a new potential for eugenics. Already some people might argue that preimplantation genetic diagnosis, with rejection of genetically compromised embryos, is an unacceptable form of eugenics, even though most affected families would probably see it as the preferred option in very painful and difficult circumstances. A commercially-run clinic in California is already providing to would-be parents a predetermined sex of child. What else does the future hold? Is it going to become possible to genetically manipulate embryos to change their physical appearance, their stature, their athleticism, their intelligence? Will future generations of parents or governments instruct scientists to make use of DNA technology to breed what they regard as desirable genetic and epigenetic breeds of children?
I set out to write this book from the premise that it would attempt to provide a non-scientific reader with a basic understanding of how his or her own genome works. I can only hope that I have succeeded in that aim. The very notion that we might understand the evolution, structural makeup, and detailed function of the genomes that code for life, including our own human genome, is of epochal importance not only for science but also for all of us. I hope that it has become clear that such understanding is important, since it must be for society in general, and not scientists alone, to decide where we go from here. Natural selection, nature's powerful force that decides what genetic novelty will move through a population to change the species gene pool, does not aim for any kind of perfection. As Darwin himself patiently explained, it is determined by one thing: survival, or failure of survival, of individuals, and implicit in this is the fate as to whether or not they reproduce offspring and thus contribute to the species gene pool. There is no higher objective involved in the moral, philosophical, or religious sense—no forward planning whatsoever in the way human reason and ambition might conceive. But our capacity to alter genomes at our own whim changes that. Genetic engineering, if it is introduced into the human genome, will inject exactly such reasoned forward planning. This has important implications; the potential for the treatment and prevention of serious disease will obviously benefit society, but there will be other potentials that some might view as dangers. The moral and ethical implications are thus important. It is no exaggeration to say that what was previously the domain of science fiction is now increasingly science fact.
Genetic engineering of crops and farm animals began in the 1970s. From the beginning, this process encountered societal resistance, some protests being more emotive than rational. But scientists and governing bodies were persuaded by the potential for benefit—purportedly the feeding of the hungry in parts of the world stricken by adverse climates and ecologies. Critics saw the potential for harm through GM-modified genes “escaping” from the
genetically modified fields to enter the surrounding ecology in unwanted ways. The crossing of genes from one species to another is called “horizontal gene transfer.” As we have seen, genetic symbiosis, involving bacteria and viruses, and hybridization events are potent examples of this crossing of evolutionary boundaries in nature.
In 1976, the US National Institutes of Health set up an advisory committee to advise on the putative dangers of “recombinant-DNA,” and this was followed by “complex but relaxed” regulation from offices including the United States Department of Agriculture (USDA), the Environmental Protection Agency (EPA), and the Food and Drug Administration (FDA). This led to the establishment of a committee under the aegis of the Office of Science and Technology, which approved GM plants under the continuing regulation and control of the various regulatory bodies. In 2000, the Cartagena Protocol on Biosafety came into being as an international treaty to govern the transfer, handling, and use of genetically modified organisms. One hundred and fifty-seven countries are members of this protocol, which is seen as a de facto trade agreement. GM crops will, usually, have built-in modifications aimed at preventing sexual crosses with non-GM crops. They also have “traceability” built into their genomes, which would enable geneticists to discover the source of origin if GM-modified genes escape into the environment. In 2010, a study by US scientists showed that about 83 percent of wild canola plants in the hinterland of GM crops contained genetically modified resistance genes. While the scientists involved in GM research and agriculture now saw no significant risk to the environment or humans from this established escape, those opposed to genetic engineering remain unconvinced.
