I am going to step away from traditional genetics for a post to discuss something that affects genetic expression but with which most people are generally unfamiliar: epigenetics. Epigenetics are heritable changes in gene expression not resulting from DNA changes. There are several mechanisms by which epigenetics take place, for instance DNA methylation is a process where a methyl group is added to an A or C rendering those base pairs inaccessible for gene activity. I will not delve into all the mechanisms, as that would make for an extremely long post, but rather take a little time to explain some of the effects as well as interesting recent epigenetic findings.

Epigenetics are important in development, as it is the process by which specific genes are turned off to create different tissues during embryogenesis. As epigenetically modified genes are turned off, it is also a source of disease that may resemble classical genetic diseases. Notable examples of this are Prader-Willi and Angelman syndromes. These two rare genetic diseases are actually the result of loss of genetic expression of the same region of chromosome 15, so one might ask how do you end up with two differing disorders; the answer lies in parental, sex specific epigenetic modification. The region contains genes differentially, epigenetically modified on paternally and maternally inherited chromosomes. Loss of the region inherited from the mother results in Angelman syndrome but inheritance from the father results in Prader-Willi syndrome. For a more in-depth look see http://www.nature.com/scitable/topicpage/imprinting-and-genetic-disease-angelman-prader-willi-923.

Lastly, epigenetic modifications may result from environmental influence. Environmental exposure, such as a person’s diet, can effect expression of their genes. Additionally, recent findings show that environment also affects epigenetic modification passed on to offspring. A Nature Communications publication in April found that a woman’s diet at the time of conception actually affects what genes will be epigenetically modified in her baby (http://www.technologynetworks.com/Genomics/news.aspx?ID=165262). While much research remains to understand the implications of these changes, significant changes in methylation levels were associated with differing nutrient levels and body mass index. These findings underpin the importance of further studying epigenetics as a mechanism to possibly explain some of the ‘nature vs. nurture’ debate.

Simply, pharmacogenomics associates the information in a person’s genome to how they react to various drug therapies. The idea, while not new, is finally within reach given the plummeting costs of genetic analyses. The idea being that pharmacogenomics will contribute to personalized medicine by utilizing a single test to determine the best treatment for an individual, prior to wasting time and money on non-viable options.

Until recently, only the most urgent circumstances, such as cancer, were considered worthwhile for genetic determination of treatment. Cancer, on the forefront of pharmacogenomics, is moving beyond genetic testing as a good idea and making it a necessity. With more than 30 anti-cancer drugs approved for specific gene mutations, genetic testing is becoming a first line diagnostic tool for treatment options. The information gathered from these tests steer what drugs to use and even what dosage to start with, which means getting patients what they need faster and with fewer side effects.

However, pharmacogenomics is not just for those with life threatening diseases; available research relates genetic information to everything from aspirin to Zocor, we just need cost effective testing. Partnerships between companies like Coriell Life Sciences (http://www.coriell.com/) and GeneWiz (http://www.genewiz.com/) endeavor to do just that, with products like PGxOne launched earlier this month (http://www.genewiz.com/public/PGxOne-pharmacogenomics-test.aspx). PGxOne offers a single test for all well-established genes associated with drug treatments. PGxOne provides treatment information for a diverse set of disorders, such as atrial fibrillation, autoimmune diseases, depression, malaria, and schizophrenia, making pharmacogenomics testing informative for a diverse set of individuals.

From a patient standpoint, this type of testing could reduce time and suffering from improper treatment. Financially, billions could be saved on paying for ineffective therapies and adverse reactions. Therefore, it is a win-win situation; all we need is implementation.

For decades, people have heard that gene therapy will someday replace treatment for many genetic diseases, but, thus far, the public has seen few of these claims come to fruition. However, Crispr (Clustered regularly interspaced palindromic repeats) may change all of that. Crispr is the bacterial equivalent of an immune system. It recognizes repetitive sequences in an attacking viral genome, and cuts its DNA, thereby destroying the virus. So essentially Crispr is a saw and guide system that specific DNA sequences act as the guides. Scientists can usurp these guides to utilize the saw for genetic manipulation. This is great news on the gene therapy front.

Most methods of gene therapy to date involve viral introduction of beneficial genes. This method is limited as introduction to the cell is inconsistent and it can only help individuals whose disease results from a lack of the proper gene product. It is useless for individuals with a dominant, harmful gene product, such as Huntington’s disease (http://en.wikipedia.org/wiki/Huntington%27s_disease). Crispr on the other hand introduces changes to your own DNA. This means damaging mutations could be turned off or corrected.

This may sound similar to systems developed using zinc finger nucleases (ZFN), some of which are already in clinical trials (http://www.nejm.org/doi/full/10.1056/NEJMoa1300662). However, the ZFN system requires a new protein for each targeted change. This is cumbersome and time consuming. Why? Well to go back to our woodworking example, researchers basically have to invent a new specialty saw for each project. Crispr only requires its guides to be placed on each new piece for it to work. Even better, you could place multiple guides and make more than one cut per attempt. This means people with multi-gene diseases could have a therapy that treats multiple issues in one foul swoop. So keep your eye out for Crispr, it could be the new saw in the doctors’ workshop.

For more information on Crispr see:

http://editasmedicine.com/index.php

When I talk to most people outside of the medical/pharma world, they have never heard of an orphan drug. The description brings a queer smile to their face, as they image some sort of little orphan Annie drug. However, unbenounced to most people, orphan drugs are likely future of the drug industry.

To begin, let us define exactly what an orphan drug is. The FDA states that an orphan drug is a product used for “the safe and effective treatment, diagnosis or prevention of rare diseases/disorders that affect fewer than 200,000 people in the U.S.” With over 317 million people in the U.S., a drug that affects less than 200 thousand seems insignificant, but looks can be deceiving. The U.S. population will start to see these drugs on their shelves in the next two decades via two ways.

The first is the use of drugs, initially approved for orphan status, repurposed to treat common disorders. Does this seem an unlikely drug discovery strategy? Actually common disorders have benefitted from rare genetic disorder research for a long time. For instance, Familial Hypercholesterolemia (FH) is a rare genetic disease characterized by high “bad cholesterol” levels. Studies of FH patients in the 1970s and 80s informed the discovery of statins (e.g. Lipitor), one of the most widely used class of drugs on the market.

Today, companies like Zafgen are taking advantage of orphan drug status to get approval of compounds they hope will treat the greater population. Zafgen’s beloranib treats obesity in individuals with Prader-Willi syndrome, a rare genetic disorder caused by a partial deletion of chromosome 15. Beloranib targets an important metabolic enzyme deficient in individuals with Prader-Willi syndrome and likely a subsection of individuals with severe obesity in the greater population. Therefore, beloranib’s approval by the FDA may bring a new drug to market with the potential of treating obesity in the common populace.

The second way orphan drugs will become a greater consideration is through personalized medicine. As genomics takes on a larger role in medical decisions, the ‘one drug, one disease’ model will no longer be relevant. Drugs will progress towards specific genetic populations, as revealed through an individual’s particular genetic background. So next time you hear the term ‘orphan drug’ keep an eye out, your medicine cabinet may be giving it a home very soon.

The ongoing battle for the $1000 genome may be coming to a close, but the larger question of what it all means for the average person remains. After years of boisterous claims about future DNA sequencing capabilities from companies like Ion Torrent and Pacific Biosciences, the genomics giant Illumina announced that with the release of its HiSeq X, the $1000 genome is now a reality (http://www.businessweek.com/articles/2014-01-14/illuminas-dna-supercomputer-ushers-in-the-1-000-human-genome). As a self proclaimed genomic junky, the idea of getting my hands on all of my genetic information for a mere 1k makes me a little giddy, but for the average person how is it really going to affect their daily life. Well in reality, with the state of genomic analyses, it probably will be years before your doctor opens your medical file and says, “John, I have the results from your genome analysis and I think it’s time to cut back on those simple carbohydrates and add more fiber to your diet. You have an increased risk of high triglycerides and colon cancer.”

Why you say? Well there is a lot more to understanding a person’s genome than just reading it. Imagine for a minute that you are a cook and a client gives you a cookbook and asks you to prepare a seven-course meal from it. You open the book to find that it is in a language you are only passingly familiar with and you have never heard of half of the ingredients. A cookbook is meaningless unless you can create something from it.

Additionally, translating our genomic ‘cookbook’ is only another step. If you want that book to be on everyone’s shelves, something they refer to often, than it has to be accessible and useful. That requires readily available data that doctors can access on what a particular genetic background means and what treatments will be the most useful, without having to do an extensive literature search for every single patient. This is the challenge facing genomics today.

In an era where scientific research is constantly fighting to maintain funding, the average person wants to see tangible results for their hard-earned dollar. If sequencing their genome cannot tell them how their genetic background will influence their health and what can be done about it, what difference does it make that they have access to it for $1000. Do not get me wrong, I emphasis that if the hype is true it is exciting news, and puts us another step closer to that elusive personalized medicine we await. However, there is a world of analysis, drug investigation, and doctoral education that stands between now and that reality. So thanks Illumina for giving us the next step in what the world needs to make our genome medically relevant. Now we need a company to release the $1000 genome analysis.