A look at epigenetics
Dr. Ken Eilertsen is an associate professor in the Epigenetics and Nuclear Reprogramming Lab at LSU's Pennington Biomedical Research Center. He shared with us about his work, the importance of this field of study, and the key role that epigenetics plays in the diagnosis and treatment of disease.
Q: You study epigenetics and nuclear reprogramming - tell us about those topics and your scientific focus.
Epigenetics is the study of stably heritable traits that are not attributed to changes in DNA sequence. The Greek prefix epi- (Greek: over, outside of, around) in epigenetics implies features that are "on top of" or "in addition to" the traditional genetic basis of inheritance. Epigenetic changes affect gene activity. An example of epigenetic change in biology is the process of cellular differentiation. When a single fertilized egg cell divides, and daughter cells continue to divide, the resulting cells change into all of the different cell types in an organism, including neurons, muscle cells, blood cells and so on, by activating some genes while inhibiting expression of others. The progression from a single fertilized egg cell to a functioning tissue type is due to epigenetic factors that cause the organism's genes to behave in a specific manner.
Reprogramming refers to erasure and remodeling of epigenetic factors during mammalian development or in cell culture. An example is the creation of livestock clones. Clones are genetically identical organisms that are produced using the process of somatic cell nuclear transfer. During this process, the nucleus from a skin cell can be reprogrammed by an egg cell (oocyte) so that a new organism can be created.
Scientific focus: My early career focused on epigenetic reprogramming to produce livestock including cattle, pigs and sheep and to produce pluripotent stem cells from adult cells. Pluripotent stem cells generated from adult skin cells for example behave similarly to an embryonic stem cell with the ability to become any tissue type in an organism. (Pluripotent stem cells generated in a petri dish lack the ethical issues associated with embryonic stem cells.) In order to improve the process of reprogramming I began to look for chemical compounds that could alter the function of epigenetic factors. There are literally hundreds of epigenetic factors that could be altered yet there were very few chemical compounds that were known, and those that had been identified had poor efficacy or were highly toxic. It became clear to me that there was a need to identify more of these types of compounds as a potential new class of drugs to treat diseases. Currently my efforts are focused on developing compounds to inhibit two epigenetic factors: and enzyme referred to as G9a and another enzyme referred to as DNMT1. Both of these enzymes are recognized as drivers of a variety of cancers.
Q: Your work is important. Help our readers understand why.
Epigenetics and reprogramming have many and varied potential medical applications. Epigenetics may help explain mechanisms of cancer origins, heart disease, mental illness, Alzheimer's disease, obesity, type 2 diabetes and a host of other diseases. Some researchers think epigenetics may have a greater role in disease than genetics.
Q: Ultimately, what is the goal of your work?
The long term goal for the compounds directed at inhibiting G9a is to develop a therapeutic for patients diagnosed with Triple Negative Breast Cancer (TNBC). The compounds being developed to inhibit DNMT1 are aimed at developing a treatment for Acute Myeloid Leukemia (AML) in the elderly. Both TNBC and AML are diseases with poor prognosis and high unmet needs in terms of therapeutics.
Q: What challenges do you face in the course of your research and how do you work to overcome them?
Epigenetics and reprogramming are still considered to be emerging fields and with that a lot of hype, overstatement, and overpromise can be attached. In addition, a lot of misunderstanding and misconception is generated, especially among folks not deeply ingrained in this sort of work. One thing I do is accept invitations to speak at all sorts of gatherings with all sorts of groups - from school PTAs to science clubs - to try and talk with folks about these scientific fields, what health opportunities they may provide, and the challenges and risks that are very real, including ethical implications that are associated with this area of scientific research.
In addition, though we're working on it, Louisiana does not currently have strong drug discovery and development efforts. We lack the infrastructure for local collaborations that provide complementary expertise in developing new drugs. Thus, right now most of my scientific collaborations are long distance with people in the northeast or the west coast.
Q: How did you end up studying epigenetics? Was that always the plan?
It was never my plan to study epigenetics. I was well past graduate school and postdoc training in other fields when I recognized a problem: there was a lack of recognized /characterized chemical compounds that could specifically modify epigenetic factors. It became clear that this also represented a potentially new class of pharmaceuticals that could have therapeutic importance.
Q: Does your work impact the way you live on a day-to-day basis? (Such as health habits, etc.)
Yes. There is increasing evidence that several lifestyle factors such as diet, obesity, physical activity, tobacco use, alcohol consumption, environmental pollutants, psychological stress and even working night shifts can modify epigenetics that affect human health. Perhaps more alarming is evidence that lifestyle factors can induce epigenetic changes that can be passed down to subsequent generations. The importance of living a healthy lifestyle goes beyond me as an individual but also has implications for my children and their children.
Q: What do you foresee for the future of epigenetics?
I think the future of epigenetics is going to be the development of new diagnostic tests and treatments for a large variety of diseases. Currently cancer is the best model that exists to develop targeted epigenetic based therapies and there are several biotech companies that are beginning to move some drug candidates into and through clinical trials. However, I don't believe epigenetic-based therapeutics will be limited to cancers. I predict that epigenetic-based therapies will also be developed for chronic diseases including obesity and type 2 diabetes. For example, a recent publication in Nature Medicine by a group interested in Prader-Willi Syndrome (PWS) reported that inhibiting G9a improved survival of a mouse model of PWS. One of the features of PWS is childhood onset obesity and, interestingly, G9a - the same enzyme we are targeting to treat TNBC-- appears to be an important component of PWS and a possible therapeutic avenue.
For more information on how you can support this and other projects at LSU’s Pennington Biomedical Research Center, visit www.pbrf.org.