History of Epigenetics
In the early 1940s, Dr. Waddington, an embryologist, put forth a radical idea for its era. Most embryologists did not believe genes were important in human development; rather, they contended that genes played a minor role, controlling inconsequential details like eye color. Dr. Waddington disagreed and introduced the concept of genes and their regulation via an epigenetic landscape, as controlling cell fate and how cells become specialized.
Johns Hopkins and Epigenetics
The epigenetic landscape that Dr. Waddington first referred to more than a half century ago is just now beginning to be understood, particularly how it applies to cancer.
Findings by Andrew Feinberg, M.D., M.P.H., now director of the Johns Hopkins Center for Epigenetics, and Kimmel Cancer Center epigenetics expert Stephen Baylin, M.D., were trailblazers in this area of science, helping to garner attention for the field.
Dr. Feinberg described a global demethylation of the cancer genome. To try to better understand how epigenetics contributed to disease, he dug deeper into the role of normal epigenetic controls in cell behavior. In normal human development, when the sperm and egg come together and form that first cell, how that one cell divides and determines what its fate will be to eventually form a complete human body, Dr. Feinberg showed, is controlled through epigenetic mechanisms. Gene expression is what makes a cell behave the way it behaves, but how a cell figures out what proteins to express is controlled through epigenetics.
Dr. Feinberg suspected that this process was somehow getting hijacked in cancer. Corruption of the mechanisms that makes an undifferentiated cell know to become a liver cell could be at the root of the transformation of that same liver cell into a cancer cell.
“In cancer, cells are confused about their own identity,” says Dr. Feinberg. “I think epigenetic instability may be a general, universal feature of solid tumors—not necessarily genes getting turned off or genes getting turned on, but genes getting randomized until a preference for the cancer cell results.”
Dr. Baylin’s focus was on the hyper- or over-methylation of cancer genes, mainly tumor suppressor genes. The process turned off gene expression, and what’s more it provided a therapeutic target. Drugs that blocked methylation of the gene could, in principle, turn the gene back on. This work began to inspire the research of young investigators entering the cancer field.
More Science Emerges
Kimmel Cancer Center Director William Nelson, M.D., Ph.D., was one of them. He did not set out to become an epigenetics researcher. In the early 1990s, he was beginning his career as a prostate cancer clinician and scientist when his research on cancer drug resistance led him to what remains today as one of the most classic examples of gene silencing through hypermethylation driving the development of cancer.
Drs. Baylin and Herman already had introduced a scenario in which tumor suppressor genes could be rendered inactive through the epigenetic process of hypermethylation, but they had not yet uncovered a good real life example of it they could point to.
When Dr. Nelson’s research led him to a gene called GSTP1, which he found was recognizably and verifiably hypermethylated in prostate cancer, still, the scientific world, except for a few, remained unconvinced of this purported epigenetic involvement in cancer. Dr. Nelson struggled to get his research published.
In some ways, Dr. Nelson believes it may have been the early detractors that helped propel the field forward.
“It created a higher level of rigor among those of us who believed,” says Dr. Nelson. They set out to prove what they were convinced—what their research was showing them—that epigenetics played a key role in cancer initiation and progression.
It is this collegiality that maintained the momentum of epigenetics research at the Kimmel Cancer Center despite an inhospitable environment among the greater cancer research community.
Drs. Baylin and Herman built a tool that allowed scientists to look laterally at many genes across many cancers and establish a pattern of silencing through gene methylation. These hypermethylated genes were the subjects of promising innovation in the form of biomarker tests that could tease out aggressive cancers from more indolent forms and provide new targets for novel treatment strategies. The origination of personalized cancer medicine was at hand.
Dr. Nelson’s colleagues describe him as a problem solver with an uncanny ability to see complex problems in a straightforward and logical way, and he saw an unmet medical need for men at risk of prostate cancer in his epigenetic discovery. In a disease where overtreatment is a major problem, Dr. Nelson’s discovery was used to create the first, noninvasive, epigenetic-based test for the disease.
The GSTP1 gene is only hypermethylated in cancer. The epigenetic marker is not found in any normal cell, says Dr. Nelson. As a result, it is being translated into a simple urine test. It is most useful for men who are suspected to have prostate cancer because of an abnormal exam or rising PSA (prostate specific antigen) levels, despite a negative biopsy. Prostate biopsies miss about 25 percent of cancers, and the test helps address this uncertainty. If the urine test is positive, it predicts the presence of prostate cancer with almost 100 percent certainty. If results are negative, it confirms the biopsy results with less than a five percent error rate.
Dr. Nelson is now collaborating with epigenetics expert Vasan Yegnasubramanian, M.D., Ph.D., to further refine the technology for use as a general prostate cancer screening test and as a tool to identify men who may have lower risk forms of the disease and could safely forgo treatment. Conversely, such a test, given the right epigenetic markers, could distinguish men who have more aggressive forms of the cancer who would benefit from treatment.
The promising work of this group of researchers was at last gaining acceptance for the field of epigenetics.
Laying the groundwork for the Epigenetic Dream Team
When Stephen Baylin, M.D., first began his research some three decades earlier, the term epigenetics did not exist. Now, he is viewed as the leader in the field, and his research in epigenetics is the most frequently cited in the established and rapidly growing specialty.
The pioneering work of Dr. Baylin and team in this emerging field of epigenetics, coupled with breakthroughs in cancer genetics made by scientists with Johns Hopkins’ Ludwig Center, resulted in the Johns Hopkins Kimmel Cancer Center being dubbed in media reports a “cancer research powerhouse.”
But accolades and laboratory success have never been what the Kimmel Cancer Center is about. Translational science—the ability to transfer laboratory knowledge to the benefit of patients—was the goal. The most exciting aspect for Dr. Baylin was that his life’s work was about to become a treatment for cancer. The perseverance and innovative thinking by Dr. Baylin and others had laid the groundwork for an Epigenetic Dream Team.