Posted: Apr 10, 2011 6:09 pm
by Latimeria
Augmentation: The Availability and Acceptance of Germinal Choice Technologies

“Almost certainly, at some point a combination of scientific knowledge, technology, reduced risks, increased benefits, and societal acquiescence will cross a threshold, allowing human genetic engineering to proceed” – Lee M. Silver[1]

I wish to remind the reader before beginning that the spirit of this competition is to predict, and is thus neither prescriptive nor proscriptive in its intent. I feel this reminder is necessary primarily because many of the possibilities that will be raised quite often inspire strong reactions regarding the wisdom or ethical considerations of particular courses of action. As such, it would be a foolhardy endeavor to provide thorough reasoning to support the forecasts made herein without cataloguing at least a few of the potential and likely arguments that will arise along the way, especially the arguments that would support my prediction, but that is not to be confused with the author’s endorsement all such arguments. Whether the prospect of germ line intervention fills you with unbridled optimism for the future of our species, or whether your reaction is far more guarded and cautious than that, there can be no doubt that our species is gaining and has already gained profound new abilities that offer us the power to guide our own evolution. Questions abound regarding how closely the aims we would intend would align with actual outcomes, and such skepticism is a healthy attribute when wielding prodigious and largely untested powers. There has been enough change and variety in the hominid lineage of sufficient enough evolutionary significance to assign a variety of taxonomic identities, and enough power contained in our developing technologies to fundamentally change our very genetic constitution. The sheer power and trajectory of our capabilities to manipulate molecular genetics has led Juan Enriquez to suggest that Homo sapiens will undergo radical enough change in its capabilities and actions to be worthy of a new title: “Homo evolutis: Hominids that take direct and deliberate control over the evolution of their species… and others.” [2] The scope of this essay is to focus on those self-directed aspects of this technology.

The use of gene therapy to manipulate somatic cells for medical purposes is already well underway. We have a variety of tools to use for this purpose, including the engineering of lentiviruses to be used as vectors for gene delivery. Harnessing the already existing power of certain viruses to sneak their way into cells and integrate genes into the chromosomes of the host cell, doctors at the Necker-Enfants Malades clinic in Paris were able to successfully deliver a functional allele to serve the function of a mutant allele in patients with X-SCID in 2000. This genetic disease, which disables the immune system and manifests a host of symptoms similar to AIDS, was remedied successfully by delivering the gene necessary to fix the problem, making it a notable early success in therapeutic genetic medicine. However, the lentiviral delivery vector did not demonstrate enough site-specificity in precisely where the genes were integrated into the chromosome. As a result, normal genes were disrupted, in a process called insertional mutagenesis, and in a few cases this disruption of other genes actually caused leukemia, which tainted the success with tragedy [3]. The work of Mario Capecchi and other scientists has looked to circumvent this problem by using the natural process of homologous recombination to safely and precisely integrate a desired gene into a chromosome at a particular location. Aaron Klug and his colleagues at Cambridge University then began engineering proteins, called zinc finger nucleases, which “search out the desired DNA sequence and home in on it like a guided missile, increasing the efficiency of homologous recombination a thousand fold.[4] This approach has since been used successfully on many different organisms, including mammals, for genetic manipulation. The recent news of successful in vitro spermatogenesis [5] might provide even more efficient and safe methods of genetic engineering through the germ line.

To further establish the trajectory of human germ line engineering in order to tentatively project their course, between the present and the beginning of the 22nd century, let us look at what is currently available and has been accomplished. Pre-implantation Genetic Diagnosis (PGD) has been brought sharply into the public consciousness by science fiction such as the movie Gattaca, and the entrance of the term “designer babies” into common parlance. Gattaca serves as a compelling Orwellian warning of dystopic possibilities in the future, and underscores the fact that our genes are not the sole determinants of our fate. Our environment and our choices will always play an important role, including many of those complex areas where we might seek to manipulate our biology.

Still, the use of existing in vitro fertilization (IVF) techniques typically produces more viable embryos than will be implanted, and the use of PGD to perform genetic screening using a combination of biopsy procedures can offer informed choice and the possibility of selecting which embryo(s) to implant. Particularly for those with a family history of a single-gene Mendelian disease with very high penetrance, PGD can be a tantalizing option whether as an adjunct to infertility treatments in progress or as an elective procedure unrelated to infertility. Image
Figure 1: Cell removal from embryo for biopsy [6]

If a woman intending to have a child is a known carrier for Lesch-Nyhan Syndrome, will the assorted governments of the world all tell her that she must roll the dice with traditional conception and possibly give birth to a child who will undergo a short life of unimaginable suffering, or will some allow her the choice to avoid this? Certainly a ban would not exist everywhere; arguments for human compassion and even a new moral imperative to protect children using assisted reproductive technologies will win the day in some arenas. PGD has already been approved by the Human Fertilisation and Embryology Authority in Britain to allow couples to avoid passing a variety of single-gene disorders to their children. The list now includes Beta Thalassaemia, Cystic Fibrosis, Duchenne Muscular Dystrophy, Huntington's disease, Haemophilia, and a variety of genes that can predispose individuals to developing cancer. [7]

But the possibilities of germline intervention go far beyond the prevention of transmitting harmful alleles. PGD could be used to screen for “savior siblings” in which HLA matching is the goal of the PGD. This could, for example, allow parents to have a child that is a tissue-match with an older sibling suffering from a disease treatable by hematopoetic stem cell transplantation. It could be used for gender selection, and many other phenotypic characters as well.

Those outcomes possible for these PGD technologies discussed thus far would still be direct inheritance of all gene variants directly from both parents, just a conscious control of precisely which variants. However, a Science Magazine editorial in 2001 alerted a wider audience to a subtle form of germ line engineering that has already taken place dozens of times in assisted reproductive technology which technically provides the offspring with genes from three parental sources. By using ooplasm from a donor egg, usually to increase the viability of an older woman’s eggs, the mtDNA from a third party is actually transferred to the offspring. At a glance, this may seem relatively innocuous, but it does symbolize a significant barrier that has already been crossed, even if done “inadvertently” as the editorial title suggested. It ought to make one pause and reconsider just how many biological parents a child could have, and even whether biological parents must meet the traditionally assumed gender requirements for reproduction.

But here is where things begin to get really interesting. In 1997, researchers reported the successful creation and maintenance of an entirely synthetic chromosome that was added to a human fibrosarcoma line and remained stable and active for six months. [8]

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Figure 2: The arrow in the above figure points to a synthetic human microchromosome.

If a stable synthetic chromosome were added to an embryo, this could theoretically contain any genetic information that the engineers of the chromosome wish to put inside, which could be engineered to be control gene expression, and even in a tissue-specific manner. It would have a large capacity for information (larger than other available vectors) and would not require insertion of genetic material into any existing chromosomes. In fact, these genes all being in one place could make it quite easy to replace and upgrade synthetic chromosomes during reproduction each generation. If prostate cancer develops, a few genes on your artificial chromosome might alert you to the medical problem by turning your urine blue. A medical professional could then trace the cause and administer a chemical, otherwise inert, to activate a synthetic cell receptor and initiate programmed cell death of the unhealthy tissue.
Sometimes individuals discussing genetic engineering applied to humans set up a table with two dichotomies: Somatic versus germline engineering, and therapy versus enhancement. The line between therapy and enhancement is a blurry one at best. Is it prevention or enhancement when parents intervene to avoid disease-related genes with only moderate penetrance in late adulthood? If parents wish to transmit a variant of the CCR5 gene, which has been shown to confer immunity to HIV, in which category does that fall? We could discuss these issues as mere possbilities, but a projection regarding what will actually occur would be wise to take into account the relative degree of public support for using PGD for various purposes. Figure 3 shows the results of polls conducted in 2006 through The Johns Hopkins University to uncover public attitudes towards the application of PGD for a variety of purposes among Americans.



PGD Public Opinion Poll.JPG


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Figure 3: Hudson. PGD: public policy and public attitudes. Fertil Steril 2006. [9]

Perhaps, as Ronald Green has defended at length, many of the earliest applications and arguments over acceptability may be related to athletics, and epitomize the obfuscation of the distinction between therapy and enhancement.[4] The use of erythropoietin (EPO) as a performance-enhancing drug has been banned by the World Anti-Doping Agency.[10] We all produce this hormone that stimulates erythrocyte production and affects the amount of oxygen our blood can carry, and it is generally acceptable practice to perform high-altitude training to stimulate this, and when an athlete like Eero Mäntyranta inherits a rare allele which has the same effect, that of course did not bar him from racking up Olympic medals in cross-country skiing. Direct injection of exogenous EPO, or the use of an engineered virus as a delivery vector to artificially deliver the EPOR gene that helped Mäntyranta, are both generally held as unacceptable in athletics. However, the inequality of the genetic lottery that contributes to athletic success does not create a level playing field. Many other complex traits, such as cardiovascular health, height, musculoskeletal frame, and lung capacity all affect athletic prowess, and vary between individuals. Some compounds which are normally considered performance-enhancing drugs, like HGH, are administered to those identified as having a particular disorder. It is important to note here that the lines drawn between what we consider to be disease states, deficiencies, “normal” phenotypes, and enhancements are extremely tenuous. If you are looking at a complex trait, such as learning disabilities, a population level analysis will give you a bell curve for standard measures of memory and intelligence. Diagnosing the lower end of the bell curve as having a disability is in essence a comparison, a diagnosis that is relative to the rest of the population’s distribution. Beginning to implement these new therapeutic strategies would itself shift the bell-curve for such polygenic traits and thus create a new “norm” for comparison. Where, then, is the line drawn for calling a phenotypic state a “disorder”?

Many of these methods have been demonstrated to be attainable, but the cost of genetic screening is on course to be affordable to an increasingly larger segment of the population. While many of us are familiar with Moore’s Law as it applies to the steady exponential increase in computing power, the precipitous decrease in the cost of genomic sequencing, in large part dependent upon these changes in computing power, led Richard Dawkins to describe the trend shown below as “Son of Moore’s Law” in an essay of that title. [11] Figure 4 shows this decrease over time, and the progression towards the “$1000 Genome”, a somewhat arbitrary figure which many nonetheless envision as a “Holy Grail” in genome-based medicine because it represents a significant level of affordability.
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Figure 4: Cost per genome sequenced over time.

While the aims of germline interventions are not far from what the pure etymology of the word “eugenics” would suggest, well-known proponents of GCT, including Lee Silver, James Watson, Gregory Stock, and many others are careful to divorce these new capabilities from anything which has historically fallen under than moniker, and such a distinction is justified. The goals and methods of these and others in the transhumanist camp are unlike those past movements which were based on inadequate science, employing crude methods such as sterilization, imposing value judgments externally, and resulting in ethical tragedies of the highest degree. The goals and the methods employed here justify an entirely separate assessment, as the emphasis is on individual empowerment to electively participate in reproductive decisions that offer greater control while having the opportunity to be advised by the best science we have including informed consent regarding areas of uncertainty. In fact, cogent arguments regarding procreative beneficence, the moral obligation of parents to use options in reprogenetics to improve the health of their children, such as those advanced by Julian Savulescu, have put forth a serious challenge to those who merely ponder whether GCT are morally permissible. The question can become whether we must recognize a new moral imperative.

With this individual empowerment of choice, it is not unreasonable to assume that in certain areas the choice will lead toward uniformity, both in terms of what is preferred and what is intentionally avoided. We may well see the basic phenomenon of the Tragedy of the Commons move from a more traditional place in the shared access to aquatic biodiversity to the collective gene pool of our species and the allelic variety present. In fact, some might advocate for what I could only term an organized allelicide which could theoretically remove a strictly Mendelian disease from the human gene pool in a single reproductive generation. Yet while diversity drops in some areas, it can be greatly enhanced in others.

Even an optimist like Gregory Stock must acknowledge that such a transition will not be glorious in all aspects, saying, “Humanity is moving out of its childhood and into a gawky, stumbling adolescence in which it must learn not only to acknowledge its immense new powers, but to figure out how to use them wisely.”[12] Careless use of these technologies has of course led many to predict a torrent of problems arising from indiscretion: not least among these are a gender imbalance in society, discrimination and arrogance borne of genetic elitism, fundamental changes in parent-child relationships, and various unintended biological tragedies from meddling with the unknown. This essay does not attempt to assert that problems will not arise, only that such actions will be taken. There are often unexpected tragedies from any emerging technologies, as we saw the initial success of gene therapy for X-SCID tainted with the occasional tragedy of inducing leukemia. But the occasional tragedy will not stop it; we will learn from our mistakes and continue to “upgrade” our genomes.

Our biodiversity has never been static, and there is no evolutionary reason to imagine that the human gene pool represents a state of culmination upon which improvements cannot be made. How much of the opposition to germline engineering is simply a status-quo bias, based only on intuitive perceptions of what is “normal” and “natural”? It is not unreasonable to assume that a portion of that status quo bias will dissipate with the proliferation of those procedures which are already allowed. Advancements in biomedical technology will most likely make for a more inclusive list of what is deemed acceptable. Increased availability and usage will most likely change perceptions of what is “normal”, and somewhere down the line, new decisions about germline engineering will be made by generations comprised of individuals who were, more often than not, conceived in a laboratory. In a paper titled “Daedalus of Science and the Future”, J.B.S. Haldane wrote of advances in biology being initially regarded as indecent and unnatural, but that, “The biological invention then tends to begin as a perversion and end as a ritual supported by unquestioned beliefs and prejudices.” [13] And this may well be prophetic even for human reproduction, which may routinely take place in the laboratory for greater efficiency and safety in the future. But not to worry, sexual intercourse will not disappear, it will remain behind to serve other… vestigial purposes. Although the graph in Figure 3 shows more support for PGD among men than women, it might well be career-oriented women, wishing to start a family at a later stage in life, who will push reproduction into the laboratory with more frequency.
Even now, opponents of this technology, or those calling for stricter controls, recognize the extreme possibilities. Bioluminescent skin, which has been created in a host of transgenic animals, including the germ line of primates [14], has become a talking point to highlight absurd and seemingly heretical notions of how we might modify ourselves.

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Figure 5: A transgenic marmoset (Callithrix jacchus) expressing Green Fluorescent Protein

It would not surprise me in the least if a small group of fervent advocates for unrestricted procreative liberties stands up to say, “Why can’t I make my skin glow if I so choose?” But the envelope will not be pushed by tinkering for frivolous or ostentatious displays of genetic liberty; instead it will be pushed the furthest by manipulations where the desired outcome is of obvious benefit. Where it is allowed and available, the choices will be made by individuals, but the net outcome can be viewed at the population level.
And now to enter the realm of the truly speculative, to push the boundaries based on assumption that advances in the holistic approach of systems biology, genomics, and proteomics will become informative enough to offer some guidance in dealing with pleiotropy, polygenic traits, and more clear and comfortable answers in the "nature-nurture" debate. It will be a difficult road, but with the pace of biomedical technologies is it inconceivable that we may in the future confidently make informed decisions about traits as complex as intelligence? We could perhaps even add a part to our brains, already named an “exocortex” by some futurists, to process and store vast amounts of information. Might we adapt our biology to be more easily integrated with technology? Might we give ourselves the ability to manufacture bacteriophages to augment our immune response, or produce the same type of endogenous antibiotics found in crocodilian blood? Might we extend our lifespan, stave off the effects of aging, keep our minds sharper and our bodies more capable? Is the limb regeneration seen in the axolotl an ability we could give to ourselves? We could conceivably work to optimize our biochemistry, give ourselves sensory capacities that we currently lack, improve upon the strength of our muscular and skeletal systems, and make our skin more durable. Will we rid ourselves of genetic components of asthma, diabetes, heart disease, and cancer? Perhaps we could even go so far as to encrypt our genome so that our cellular machinery cannot be hijacked by viruses. Some day we might be able to use computers to move beyond the “copy-paste” version of genetic engineering, and design a functional protein de novo, one that has no natural homologue, and then string together the nucleotides that will create it. Perhaps our cells could be engineered to contain microscopic biochemical “doctors” to diagnose, signal, and even treat pathologies as they develop. If our species is to colonize the galaxy, can we alter ourselves to allow efficient cryopreservation to withstand the journey? With increased years of healthy longevity and the elimination of many diseases, we could be productive with a much greater percentage of our lives. With the associated economic costs of so many treatments vanished, how much more of our resources, both human and material, might be devoted to other ventures? With the limits of human capacity no longer set purely by natural inheritance, but supplemented by our own choice, the very nature of what it means to be a human may have to be radically and continually altered to account for the actual fundamental changes that occur as our species crosses the threshold into participatory evolution.

WORKS CITED:

[1] Silver, Lee M. Challenging Nature: The Clash Between Biotechnology and Spirituality. Ecco/Harper Collins, 2006. Print

[2] Juan Enriquez TED Talk http://www.ted.com/talks/lang/eng/juan_ ... ience.html

[3] Thrasher, et al. Gene therapy: X-SCID transgene leukaemogenicity. Nature. 2006 Apr 27.

[4] Green, Ronald M. Babies by Design: The Ethics of Genetic Choice. New Haven and London. Yale University Press, 2007. Print.

[5] Sato, et al. In vitro production of functional sperm in cultured neonatal mouse testes. Nature. 2001 Mar 24.

[6] Image from Institute for Reproductive Health, Cincinnati OH.

[7] Human Fertilisation and Embryology Authority Website: http://www.hfea.gov.uk/756.html

[8] Harrington, et al. Formation of de novo centromeres and construction of first-generation human artificial microchromosomes. Nature Genetics. 15, 345 - 355 (1997)

[9] Hudson, Kathy L. Preimplantation genetic diagnosis: public policy and public attitudes. The Genetics and Public Policy Center, Berman Bioethics Institute, The Johns Hopkins University, Washington, DC

[10] World Anti-Doping Agency Website:
http://www.wada-ama.org/en/About-WADA/H ... ti-Doping/

[11] Brockman, John, ed. Richard Dawkins: Son of Moore’s Law. New York: Vintage Books, 2002. Print.

[12] Stock, Gregory. Redesigning Humans: Choosing our Genes, Changing our Future. Boston and New York: Houghton Mifflin Company, 2003. Print.

[13] Haldane, J.B.S. Daedalus of Science and the Future A paper read to the Heretics, Cambridge on February 4th, 1923. Sir William Dunn Reader in Biochemistry. Cambridge University. New York. E. P. Dutton & Company. 681 Fifthe Avenue.
Available at http://www.3nw.com/energy/h2/daedalus.pdf

[14] Stein, Rob. “Monkeys first to inherit genetic modifications.” Washington Post 28 May 2009.