A common consequence of the evolutionary process in many species is extensive genetic diversity. As has become apparent in recent studies (Tennessen et al., Science 2012; Nelson et al., Science 2012), the growth of the human population coupled with what is believed to be reduced selective pressure, presumably in part due to the life-promoting and life-saving effects of modern medical interventions, has facilitated a truly impressive range of rare variants in human genomes. Some of these rare variants are expected to be associated with predispositions to various diseases and medical conditions. Hence, as a consequence of human evolution the need for personalized medicine arises.
It is in this context that a recent study (Chen et al. Cell 2012) by Michael Snyder, the chairman of the Stanford Genetics Department, and his colleagues is of special interest. It is a technological tour de force and tour de self applied to blood samples from Snyder himself and in which Snyder and his associates combine multiple systematic high-throughput types of analysis (genomics, transcriptomics, proteomics, metabolomics, and more) i.e., as the authors’ preferred jargon would have it, a multi-dimensional integrated personal omics profile (iPOP). This analysis revealed a genetic variant predisposing to type 2 diabetes mellitus that led Snyder to screen for type 2 diabetes which subsequently developed. The authors claim that therefore this approach is a guide to the personalized medicine of the future. In what follows, I evaluate these claims, informed in part by my personal experience with an infrequently-recognized form of personalized medicine that has been in operation for no less than 15 or so years and possibly much longer depending on how precisely the concept is defined. I emphasize at the start that I support a role for personalized medical care in several senses not limited to the purely genetic but note that this approach, the substantial hype notwithstanding, nevertheless faces challenges and limitations.
The specific type of personalized medicine with which I am associated is clinical histocompatibility testing. I direct a laboratory, one of about 150-200 in the United States, that performs genetic and immunological testing to guide the selection of pairs of donors and recipients for various types of transplants involving either solid organs (such as kidneys, pancreases, livers, hearts, and lungs) or blood or bone marrow containing hematopoietic stem cells as well as other more differentiated cell types. In this capacity, we provide to transplant surgeons or physicians information about potential transplant recipients and donors that is unique to the individual transplant participant (recipient or donor) so that the best pairings of donor and recipient can be selected. Thus, unique genetic and immunological attributes inform the treatment of transplant patients. Such personalized medicine has been in widespread operation since the 1960’s and with the input of DNA-based genotypic information since the mid-to-late 1990’s.
While our improved our ability to precisely define the genotypes at key loci, i.e. our ability to determine the identities of the most relevant alleles, definitely has improved average graft and patient survival and average quality of life over the past twenty-five years, it is also clear that the genetic relationship between recipient and donor is only one factor in optimizing clinical transplantation outcomes. The immunological histories of the recipients and donors can be important, as can a number of other factors such as inter-current infections or other medical problems or conditions, and uncontrollable factors such as age. Thus, genetics is not all-powerful in this setting and as some geneticists have put it, phenotype trumps genotype.
The sort of analysis performed on the blood samples from Michael Snyder and his mother are orders of magnitude more information-rich than the test results referred to in the preceding two paragraphs. Nevertheless, some of the limitations are similar. There is always risk of both false positive and false negative results. The likelihood of one or more false positives or negatives will of course rise with the number of independent tests performed. This caveat applies not only to DNA sequencing errors, which can be difficult to identify in the context of whole genome sequencing, but to every assay for every analyte assessed. Thus, even aside from financial considerations, there is reason to be cautious about pursuing clinical application for an approach that involves measurements on as many as ~100,000 molecular analytes in cells or blood or other body fluids. Quality control will be a major issue for any clinical application of these technologies.
Chen et al. conclude: “Our study indicates that disease risk can be assessed from a genome sequence and illustrates how traits associated with disease can be monitored to identify varying physiological stages.” But consider the identification of genetic variants in his genome that influence the likelihood of type 2 diabetes mellitus. Snyder takes his subsequent development of what was diagnosed as type 2 diabetes as confirmation of the value of the genomic information, but we do not know how likely it is that others with his combination of predisposing variants would actually develop the disease. After all, if Snyder, 54 years old at the initiation of the study, had known of these genomic variants in his twenties, assuming the technology had made it possible, it would have required waiting thirty years for the ‘prediction’ of disease to reach fruition. Would Snyder have become diabetic if he had not suffered the particular virus infection, with respiratory syncytial virus, which appeared to be associated with his initial loss of normal glucose control soon after the infection?
The variable penetrance of many disease-associated alleles makes these questions highly relevant. In fact, it is noted in the study that both Snyder and his mother have a telomerase gene variant associated with aplastic anemia and neither individual has experienced this condition after a combined 137 years of life. In an interview with Snyder in another journal (Genome Biology, 2012), he explained that as a result of the study, he changed his diet and other aspects of his lifestyle, but of course, just getting the information from routine testing of his blood for glucose concentration could have prompted the same alterations in personal habits. In fact, even without personal medical information indicating that he was diabetic, Snyder could have adopted the same practices based solely on the widely available current recommendations for diet, exercise, and other lifestyle characteristics.
The study of Snyder and colleagues, which is indeed the systematic study of Snyder, is extraordinarily impressive as a demonstration of the potential of the latest high-throughput technology to provide massive molecular detail, at a single point in time and longitudinally, on an individual patient. How precisely and completely it will serve as a guide for the future of personalized medicine remains to be seen. As Snyder notes in the interview, there were additional modalities of analysis that could be deployed, such as but not limited to methylomics (the totality of covalent modifications of genomic DNA and histones) and exposomics (the totality of chemical exposures). I remain skeptical that the wholesale application of these various types of assessment will be cost effective or affordable in most instances unless per test costs decrease rather dramatically, which of course remains possible. However, it is likely that more selective implementation of these methods prompted by particular clinical scenarios offers the prospect of usefully personalized medical care of enhanced effectiveness. Studies aimed at refining the uses of these methods for clinical purposes should occupy numerous investigators for some time to come.
References
Tennessen JA, Bigham AW, O’Connor TD, Fu W, Kenny EE, Gravel S, McGee S, Do R, Liu X, Jun G, Kang HM, Jordan D, Leal SM, Gabriel S, Rieder MJ,
Abecasis G, Altshuler D, Nickerson DA, Boerwinkle E, Sunyaev S, Bustamante CD, Bamshad MJ, Akey JM; Broad GO; Seattle GO; NHLBI Exome Sequencing
Project. Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science. 2012 Jul 6;337(6090):64-9.
Epub 2012 May 17. PubMed PMID: 22604720.
Nelson MR, Wegmann D, Ehm MG, Kessner D, St Jean P, Verzilli C, Shen J, Tang Z, Bacanu SA, Fraser D, Warren L, Aponte J, Zawistowski M, Liu X, Zhang H, Zhang Y, Li J, Li Y, Li L, Woollard P, Topp S, Hall MD, Nangle K, Wang J, Abecasis G,Cardon LR, Zöllner S, Whittaker JC, Chissoe SL, Novembre J, Mooser V. An abundance of rare functional variants in 202 drug target genes sequenced in 14,002 people. Science. 2012 Jul 6;337(6090):100-4. Epub 2012 May 17. PubMed PMID: 22604722.
Chen R, Mias GI, Li-Pook-Than J, Jiang L, Lam HY, Chen R, Miriami E, Karczewski KJ, Hariharan M, Dewey FE, Cheng Y, Clark MJ, Im H, Habegger L, Balasubramanian S, O’Huallachain M, Dudley JT, Hillenmeyer S, Haraksingh R, Sharon D, Euskirchen G, Lacroute P, Bettinger K, Boyle AP, Kasowski M, Grubert F, Seki S, Garcia M, Whirl-Carrillo M, Gallardo M, Blasco MA, Greenberg PL, Snyder P, Klein TE, Altman RB, Butte AJ, Ashley EA, Gerstein M, Nadeau KC, Tang H, Snyder M. Personal omics profiling reveals dynamic molecular and medical phenotypes. Cell. 2012 Mar 16;148(6):1293-307. PubMed PMID: 22424236; PubMed Central PMCID: PMC3341616.
Genome Biology. 2012, 13:147 doi:10.1186/gb-2012-13-3-147.
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RE: What an excellent review of A case of Personalized Medicine in Type 2 Diabetes Mellitus!?
Nonetheless, with the increasingly-rapid advents of the high-throughput genomic technologies (GT) and a myriad of other molecular analytic methodologies, computer-electronics, digital informatics, and biomedical nanotechnologies, the personalized medicine (PM) in and for any given diseases, is here to stay — and — to proliferate in popularity, in disease-specific treatment-specialties, and in demand, in both the evermore advanced, research and development (R&D) clinics and labs worldwide, into the 21st century and beyond!?
These observations and assessments of the rigorous treatment-oriented R&D pursuits and practices in PM specialties — especially focusing on the biomedical and oncological healthcare issues — have had been recently reviewed here: “The future of cancer therapy? — RE: YES: The future of cancer therapy is The individualized therapy — just as One that has been executed strategically and preemptively in the Wartman case, as reported in the biomedical literature and public media above!?” (SciencebasedMedicineUSA; September 1, 2012).
Meantime, I would fully concur with Neil Greenspan’s nice review article (of the historical development of biomedicine) that “Such personalized medicine has been in widespread operation [especially in the tissue and/or organ transplantations and histocompatibility tests and practices] since the 1960’s and [such PM-translated modalities have also been evermore specialized, focused, targeted, and refined extensively] with the input of DNA-based genotypic information since the mid-to-late 1990’s [especially in and for other disease-specific R&D pursuits and practices, as well].” — Whereas the PM initiatives and concepts in and for any fully-strategized treatment modalities (from bedside to benchtop, and vice versa) of an elaborated, individualized cancer therapy (ICT) were first conceptualized, introduced, and pursued in both the academic and industrial healthcare complex settings, as well as in the evermore advanced, active, and creative R&D clinical and laboratory setups and/or startups worldwide, since the 1980s: at which time when the concomitant biotechnology, genetics, stem-cell and tissue engineering revolution has had also begun to take roots and spread, in both the academic-industrial R&D healthcare complex arenas worldwide, thus giving rise to the presently and intensively pursuits of GT-based and PM-translated treatment modalities in and for any given diseases of today; and of tomorrow, as well!?
As such, and more specifically, in the current GT-era of the 21st century and beyond, the pre-1980s misconceptions of the prevalent neo-Darwinist, bio-reductionist, or pseudo-geneticist adage that “genetics is not all-powerful in this [grossly-misinterpreted disease-specific or organic expression or transformation, manifestation, characterization, and identification process analytic] setting and as some [neo-Darwinist-biased or pseudo] geneticists have put it, phenotype trumps genotype” rhetoric or the bio-reductionism turned dogma in biology and humanity — can — No longer be true (or scientifically justifiable) than the sophists, bio-reductionists, pseudo-geneticists (or the late19th-century eugenicists) who had proclaimed that “genes is our destiny” or “genes predestines human nature and behavior” or “genes holds culture on a leash” etc, as those preeminent neo-Darwinist, bio-reductionist, sophist, and pseudo-geneticist slogans alike, that have had been commonly propagated, saturated, and punctuated in our pop-science and/or pseudoscience or bio-reductionist lexicon and literature worldwide, since the 1970s past; and even nowadays (see my recent review of PM specialties in ICT above; and also the doubly-asterisked [**] footnote below)!?
Whereas from any disease — or pathogenic or carcinogenic or embryonic — developmental perspective (but not from the evermore elusive or alternative explanatory or evolutionary biomedical reductionist perspective): The disease-specific or its biochemically-inflicted manifestation could show up at any points, links, or nexuses in time and space, in any organism or disease-specific or its subsequent phenotypic developmental expression and growth, and/or transformation, processes; especially arising anywhere along its genotypic (or molecular) to its phenotypic (cellular, tissue, organ, or fetal) development, organization, expression, and growth pathways and/or biochemical links — or even other physiological interruptions that may be arisen from and/or along the biochemically-inflicted pathways or links; in and among and/or along an organism’s vast networks or nexuses of its biochemical, active, and interactive dynamics: All are within its one lifetime, of course — or — No such phenotypic or disease-specific manifestations shall develop, express, or grow, at all; especially in and for some Very lucky, but rare or naturally-immune organisms on Earth — and — All these biochemical and cellular growth and developmental expressions (with or without concurrent inflictions) will elementally and eventually depend on their disease-specific or malignancy or embryo’s immediate, vast, biochemically and physiologically-active, interactive, and environmental conditions and factors; especially factors including foodstuffs, microbes, air, viral or other biochemical or nutritional elements, particles, pollutants, and/or even parasites, etc, that may be at opportune-times present within the same disease or cancerous or organism growth and developmental time and space milieu: such as, in the womb, and/or in any other organ-sites or tissue-types, in our body; and in our brain* as well!?
[*In cases involving our distressed or disordered brain: that would be concerning the PM specialty as one that has had been systematically and continuously researched, evaluated, and prescribed in our modern neuropsychiatry of today and beyond; as one (long argument and refutation of the neo-Darwinist or pseudo-geneticist presumptive and/or alternative or elusive proclamation of “evolutionary calculus” or “evolutionary geneticism” of our mental depression) that has had extensively presented here: “The Evolutionary Calculus of Depression — RE: Let’s not dictate Psychiatry by neo-Darwinism — Evolutionary geneticism vs. Clinical diagnosis, alleviation, of Depression (distresses mental, spiritual, or otherwise)!?” (PsychiatricTimesUSA; June 3, 2010).]
Thus, as one that has had been analyzed in the Snyder case above (primarily concerning the PM modality being applied in a developmental stage of type 2 diabetes mellitus case): The extraordinary observation and conclusion of the predisposed genomics evaluation that “both Snyder and his mother have a telomerase gene variant associated with aplastic anemia and neither individual has experienced this condition after a combined 137 years of life” — exceptional as this specific telomerase gene detection may appear; while without subsequent disease manifestations within their successive lifetimes — from their Each idiosyncratic, auto-biogenetic, and/or pathogenic developmental perspective: It was no surprise, at all. Nor it be further misperceived or thus prescribed as a case of a “missed (or pseudo-geneticism predestined phenotype aplastic anemia) destiny” or of the evolutionary neo-Darwinist, bio-reductionist, and sophist proclamations alike, especially in their overt zealously-subscribed slogan that “genotype predestines phenotype” rhetoric or their bio-reductionist dogma of the 1970s past!? — And even today, as one neo-Darwinist evolutionary geneticism: or the eugenicist misconception of the pseudo-genetics of “natural selectionism” or their “genes predestines human nature, survival condition, behaviorism, intelligence, culture, values, etc” fallacies past, that I duly pointed out, analyzed, and refuted above (see also the doubly-asterisked [**] footnote below)!?
Consequently, the Snyder mother and son case of their successively-inherited genotypic predisposition to their (could be) associated phenotypic expression of aplastic anemia prognosis — might — have had been biochemically masked, or protected, or silenced by other dietary (or nutritional) and/or other physiological factors as well; especially regulatory factors associated with their successively-inherited epigenetics, and/or other vital elements that may be associated with their innate metabolomics, proteomics, transcriptomics, microbiomics, etc — or even their presumably or uniquely-inherited “regulatory genomics”** as well!?
[**The recently-discovered “regulatory genomics” — by the human genome ENCODE (Encyclopedia of DNA Elements) project — is the “non-expressive sequences” of our cellular DNA; as one that has had since the 1970s been proclaimed by the all too over-zealous neo-Darwinists, bio-reductionists, sophists, and pseudo-geneticists alike, as their “evolutionary junk sequences” of DNA — or as one of their all too well proclaimed of their bio-reductionist pseudoscience metaphors, analogies, and/or rhetoric that the “junk DNA” is likened to the “evolutionary vestigial appendix” rhetoric of our human gastrointestinal phylogeny and physiology thesis — or the evolutionary dogma or evolutionism in their so-called pop-science or “evolutionary biology” or “reductionism in biology and humanity” par excellence rhetoric — or even more accurately — their evermore elusive but forever descriptive or theoretically-explanatory power of their “evolutionary biologism” or “evolutionism” or “natural selectionism” or “evolutionary geneticism” in their neo-Darwinist pseudoscience lexicon and literature, worldwide; literature which has had since the 1940s been dictated and/or misguided by their so-called “Modern Synthesis” (or MS of neo-Darwinism, of course) or more specifically: Their mostly unscientific nor critical “Gross Superimposition” of the naturalist cum geologist (not a geneticist nor eugenicist) Charles Darwin’s (1809-82) “naturalism or natural selectionist theory of Evolution” (1859) — over — the botanist trained experimentalist Gregor Mendel’s (1822-84) “organic heredity or inheritance development and growth theory of Genetics” (1865); especially since the rediscovery of Mendel’s seminal works (1856-63) at the dawn of the 20th century past!?
[**Furthermore, with the evermore rapid (GT-based and GT-driven) advents and advances in our contemporary biotechnology and genetic engineering revolution (BGER) since the 1980s, the Mendelian “heredity developmental genetics”(1865) has had since been rigorously revisited, reevaluated, reappraised, redirected, extended, expanded, differentiated, and delineated (especially: critically, scientifically, crucially, and foundationally) from the evermore sophist, reductionist, MS theory-based and/or driven “evolutionary rhetoric” of the bio-reductionist or pseudo-genetics of “evolutionary geneticism” (1976; see Richard Dawkins: “The Selfish Gene”) or the evermore elusive (for being pursued without any experimentally or empirically-tested hypotheses, at all; but merely pursued as their forever theoretically-descriptive or their so-called evolutionary explanatory power of rhetoric, that is) “evolutionary biology” or to be more literary exact “evolutionary biologism” (1975; see E O Wilson: “Sociobiology: The New Synthesis”) wherein they each and both have had since represented the 2 most extreme and most polar-opposite of their irrespective biogenetic-reductionist fallacies — especially in their concurrent neo-Darwinist “evolutionary biologism vs. evolutionary geneticism” debates across the Atlantic!? In fact, both unknowingly and uncritically, especially since the 1970s, all of their so-called “evolutionary theories” of neo-Darwinism, have had been (fundamentally, predominantly, uncritically, bio-reductively, pseudo-scientifically, and pseudo-genetically) theorized, anthropomorphized, extended, modeled, synthesized, and/or misled or dictated by the 1940s MS of neo-Darwinism past; especially in our concurrent pop-science or “evolutionary biology” lexicon and literature of today and beyond, worldwide!?
[**As such, not only the 1980s BGER has critically and correctively helped to scientifically focus, differentiate, and delineate the seminal scientific works of Mendel’s “developmental genetics” thesis (1856-63) — from — the concurrent neo-Darwinist “natural selectionism” or “evolutionary geneticism” or “evolutionism” or “evolutionary bio-reductionism” or “biologism” rhetoric (since the 1930s-40s); the 1980s BGER has also ushered in, and further helped to foundationally jumpstart, focus, initiate, consolidate, expand, differentiate, delineate, establish, and advance the currently GT-based and GT-driven biomedical R&D pursuits and practices, in and for any categorically-identifiable and manageable PM specialties, and their subsequent PM-translated disease-specific treatment-modalities, etc, into the 21st century and beyond!?]
Indeed, it would be more than just a simple case of “pure luck” and/or a simple wish of “best of health” to both the Snyder and his mother’s “disease-free” experiences and existences — above all — to their successively biogenetic inheritances, particularly in their apparently absence (or free) of their (prescribed GT-detected or genetically-predisposed) aplastic anemia condition and manifestation case above!? Last, but not least, I would fully concur with the conclusion of the above excellent review that “Studies aimed at refining the [cost-effective ways and means and] uses of these [GT-based] methods for clinical purposes should occupy numerous investigators [and/or more of the PM specialty reviewers and critics alike worldwide] for some time to come.” — Or perhaps, for some decades (if not another century) to come, into the 21st century and beyond (see my assessment and prediction of the PM modalities in the GT-based and GT-elaborated ICT above)!?
Best wishes, Mong 10/1/12usct3:47p; practical science-philosophy critic; author “Decoding Scientism” and “Consciousness & the Subconscious” (works in progress since July 2007), Gods, Genes, Conscience (iUniverse; 2006) and Gods, Genes, Conscience: Global Dialogues Now (blogging avidly since 2006).