Epigenetics and Drug Discovery: The Missing Link?
In a recent post titled “Phenotype matters!”, Robert Plenge, Vice President and Head of the newly created Department of Genetics & Pharmacogenomics at Merck, begins with the premise that “for drug discovery…human genetics is a useful tool to uncover novel drug targets that are likely to have unambiguous promotable advantage.” From this premise Dr. Plenge promotes the idea that the most effective use of genetic studies of this kind is to “pick the right phenotype, one that is an appropriate surrogate for drug efficacy.”
As examples of the importance of phenotype in effective drug discovery, Plenge discusses type I diabetes and rheumatoid arthritis. For type I diabetes, Plenge observes that geneticists have identified a number of alleles associated with increased risk for this disease, “nearly all of which act on the immune system (see here).” Given the identification of these genetic components, Plenge writes, we would expect drug therapies that alter the immune system to prevent development of the disease. However, the primary treatments for type I diabetes focus on the administration of insulin “thus, the genetic pathways that lead to the development of type 1 diabetes (immune dysregulation) are different from the biological pathways that are relevant for treating type 1 diabetes once diagnosed (glucose homeostasis).” In contrast, “in patients with rheumatoid arthritis the immunological pathways that lead to the disease also seem to be related to the immunological pathways that contribute to symptoms in patients with established disease,” which pathways are the targets for effective drug therapies for rheumatoid arthritis.
Plenge uses these examples to pose the question: “Are the genetic pathways that lead to disease the same as the pathways that should be modulated to treat the disease?” And asks his readers to consider phenotypes such as asthma, heart failure and type 2 diabetes in the context of this question, arguing that some of these phenotypes are more relevant to drug discovery than others. Plenge then observes that one good way to answer his own question is “if prior genetic data link a clinical phenotype and an approved therapy, then this provides strong evidence that the clinical phenotype is relevant for drug discovery.” He then refers to the results of genome-wide association studies (GWASs) of psoriasis and osteoporosis as providing evidence of these as more relevant phenotypes, and of developmental diseases (e.g., autism and congenital heart defects) and degenerative diseases (e.g., Alzheimer’s) as examples of less relevant phenotypes. In regards to the latter, Plenge writes that while “genetics may uncover targets that, if pharmacologically modulated prior to disease onset, may prevent development of disease…it seems less likely that genetics will uncover targets that can be modulated once the disease is established.” Plenge does allow that as biological knowledge evolves such phenotypes may become more relevant in the future “as additional knowledge about biological pathways is learned,” but that for now efforts at drug discovery are best confined to these more relevant phenotypes as identified through genomics.
I concede to Dr. Plenge’s expertise in this area in terms of the current practices based on contemporary genetics. However, his emphasis on the importance of phenotype for drug discovery raises what I think is a critically important aspect which is missed by this conventional approach based solely on genetics and genomics: The role of epigenetics in the expression of these phenotypes.
I have already posted about what epigenetics adds—or could add—to such gene-focused searches for the genetic correlates of diseases and disorders. In this previous post I discuss how while GWASs can reveal the sequences of genes associated with certain phenotypes such as those mentioned by Dr. Plenge, GWASs [to my knowledge] do not reveal anything about the three-dimensional structure of genomes which can also have a significant effect on gene regulation and expression. This structure is both determined and manipulable through the epigenome (in particular, through the methylation/demethylation or acetylation/deacetylation of chromatin and histones) in response to a host of environmental conditions. Thus, my recommendation in this previous post is that including epigenetics with genomics will allow for the analysis of both the sequence and the structure, and should only enhance the diagnostic and predictive power of such processes.
The observations of Dr. Plenge introduce another wrinkle into this discussion about what epigenetics can add to genomics. It is interesting to me that the phenotypes Plenge identifies as “less relevant” are precisely those which are the focus of so much research in epigenetics (see here for an extensive list of Q&As with experts working in epigenetics in different areas). In other words, while the biological pathways of some phenotypes may be difficult to target with effective drug treatments using conventional gene-focused methods, these same pathways appear to be identifiable via epigenetics—in ways which are capable of addressing not just the symptoms of the disease phenotype but the actual biological sources of the phenotype, just as Dr. Plenge recommends.
For example, consider the phenotypes of impaired brain development, abnormal sexual differentiation and impaired immune function. Because these are developmental disorders, according to Dr. Plenge, once these diseases are established “it seems less likely that genetics will uncover targets that can be modulated,” which makes them “less relevant” for drug discovery via genomics.
However, research in both animals and humans has linked these same phenotypes, among many other effects, with ingestion of the synthetic chemical bisphenol A (BPA) through epigenetic effects. Because these phenotypes have been found to manifest through modifications of the epigenome, the biological pathways of the diseases themselves and not just their symptoms have been identified, just as recommended by Dr. Plenge. What is more, very specific treatments for such disease phenotypes have been found via epigenetics —as in this study which found that maternal dietary supplementation with methyl donors “negated the DNA hypomethylating effect of BPA.” Although this maternal supplementation does not ‘modulate the target’ once the disease is established, to paraphrase Dr. Plenge, prior [epi-]genetic data does link a clinical phenotype and an approved therapy, which “provides strong evidence that the clinical phenotype is relevant for drug discovery.”
Epigenetic pathways have also been found for other “less relevant” phenotypes explicitly mentioned by Dr. Plenge, such as autism. Significant attention is already being focused on the epigenetic aspects of autism – see germlineexposures.org and autismepigenetics.org – as potential avenues for the treatment and possibly the cure for autism. This identification of the pathways of these phenotypes and not just of the symptoms of the phenotypes should therefore, according to Dr. Plenge. move these disorders from the “less relevant” to the “more relevant” category in terms of developing targeted pharmaceutical therapies.
What is noteworthy, though, is that epigenetics—or even any consideration of epigenetic mechanisms—are not mentioned by Dr. Plenge. This oversight is understandable in one sense, in that no one can or should be expected to be a specialist about everything; in another sense, though, this oversight carries some rather significant implications for all those who currently suffer from disease phenotypes which are ‘less relevant’ via genomics, as well as for all those who will suffer from diseases such as “autism, congenital heart defects…late-stage Alzheimer’s disease, end-stage kidney disease,” to name only those phenotypes mentioned by Dr. Plenge. That such suffering could be alleviated by the seemingly simple combination of genomics with epigenetics seems incentive enough to pursue the unification of these two fields (as recommended here by Dr. Randy Jirtle).
Given the magnitude of the possible benefits of unification, that there is still such an unawareness or even outright hostility towards epigenetics by many geneticists is curious. Science-based doubts about the results of epigenetic research are understandable enough, and resolvable through science-based back-and-forth; the non-science based opprobrium directed towards epigenetics is not so understandable. Detailing the historical, political and philosophical reasons for this antipathy and even antagonism towards epigenetics is a primary focus of this blog, as discussed in posts too numerous to mention.
My intentions for writing this post and this blog are not as some diatribe against genetics or genomics; rather I see the benefits of both genomics and epigenetics, and would like to see the unification of both which would provide a more complete picture of ourselves and of our relationships to each other, and of our place in the world around us. Hopefully posts like this contribute to this project.
Is the unification of epigenetics and genomics possible? Is it probable? What would have to occur for this unification to take place? What are some of the ways this unification could take place? Or is genomics fine without epigenetics (and vice versa)?
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