Is nature or nurture more important?
The question may sound trite applied to any aspect of genetics, including genetic medicine, but it’s an important question. Diseases and responses to various therapies depend strongly on both one’s genetic makeup and a host of environmental factors. Since the discovery of the DNA double helix in the 1950s, and especially since the first cloning of genes, resulting in GMO insulin, in the 1980s, genetics has played an increasingly important role in clinical medicine. Insulin produced through genetic engineering is just one of several products used routinely to save millions of lives. Increasingly, personal genomes play a central role in the diagnosis of diseases and selection of treatments.
When we think of genetic diagnosis, we think of tests that read and interpret the sequence of genetic building blocks called nucleotides. If you’re found have a certain variation in the nucleotide sequence for the BRCA1 or BRCA2 gene, for instance, then you have an elevated breast cancer risk. Similarly, when we think of gene therapy, we think of treatments that deliver pieces of DNA with a desired nucleotide sequence (for instance to cure cystic fibrosis, hemophilia or a host of other recessive diseases), the intentional deletion of genes, or what’s now on the horizon, editing of selected sections of a gene’s nucleotide sequence using sophisticated gene editing technology, such as CRISPR-Cas9.
But there’s an area of cell function that supplements genetics, and that’s epigenetics, which refers to a host of chemical phenomena affecting the expression of a genetic sequence—whether a gene is turned on or off, or, if switched on, is active in a given cell. Many biologists offer the analogy that your DNA is like the hard drive of a computer, while epigenetics is the software.
That’s very powerful and it’s the reason why pharmaceutical and biotechnology companies in recent years have been designing treatments to fight diseases by intervening in epigenetic processes. Basic and clinical research is currently booming. The market for epigenetic drugs is expected to grow by 20 percent over the next six years to close to $20 billion and the number of epigenetic targeting medical products (drugs, research and diagnostic kits, etc.) on the market is expected to triple by 2022. Drugs could emerge that target a variety of conditions most notably cancer. Yet there is still doubt as to how effective many of these treatments will be.
Epigenetic factors controlling gene activity include covalent modification, such as methylation (a methyl chemical group is added one of the four nucleotides: A,T,G, and C). Methylation is the most widely-studied epigenetic modulation, partly because it can be transmitted to successive generations. For instance, epigenome-wide association studies (EWAS, the epigenomic equivalent of genome-wide studies) show that methylation patterns change in certain genes, both in smokers and prenatally when the mother smokes, and that the new patterns show up in the next generation and even the next, placing future generations at increased risk for adult chronic diseases.
But expression of genes also is modulated by various types of small RNA molecules that function, either by binding to certain sequences on DNA, or by affecting pieces of messenger RNA (mRNA), which normally carry the sequence of a gene to a ribosome, where it is then translated into a protein, which affects the cell chemically. The winding of DNA in various degrees of tightness of around proteins called histones, also an epigenetic modification, because it determines how easily DNA sequences are accessed by enzymes that replicate them into more DNA, or transcribe them into RNA. Other epigenetic factors include entities called prions, which have been found to play a role in the pathophysiology of several diseases, including “mad cow disease” and its human variant Creutzfeldt-Jakob disease (CJD). Some have even hypothesized that prions could be involved in more common neurologic conditions, such as Alzheimer disease and Parkinson disease.
Moving epigenetics into the clinics
The idea of tapping into epigenetic workings of genes is a big deal now in the pharmaceutical industry. A conference held in March in southern California, hosted by GTCbio, was devoted entirely to the development of enzymes with epigenetic function for use as drugs in major diseases. Another such conference was held in New Orleans in April by the American Association for Cancer Research, and events such as these are on the rise.
This is an era when biotechnology is starting to catch up with dreams that researchers had several decades ago that medicine might advance through interventions at the level of genetic sequences. We see this in the emerging field of gene therapy and in new CRISPR gene editing technology that stands to make gene therapy work better, what I have called gene therapy 2.0. But there’s an idea now that manipulating sequences only might just be an early step.
“A more sophisticated, modern 21st century view of medical innovation recognizes that the most important medical innovation will involve epigenetics,” says Dr. Michael Fossel, president of the gene therapy company, Telocyte. “In this venue, CRISPR will be valuable, but is still too dull a tool to manipulate the thousands of precise interactions that we want to alter.”
Dovetailing with this idea, a host of drugs with epigenetic effects are currently on the market and in use in clinics, or in clinical trials, for a range of conditions including atherosclerosis (narrowing and clogging of arteries) and cancer. There are anticancer drugs that inhibit methylation, some fairly new such as RG108, and some old, such as 5-Azacytidine (Vidaza), which has been used since 1968 against certain cancers. There are drugs that inhibit the enzyme histone acetylase (HAT), which functions in the winding of DNA. There are even drugs that have been shown to affect methylation of the histone proteins themselves, and still others that affect other epigenetic factors.
But there is a caveat here that these drugs typically work through more than one mechanism and with many of these new treatments, it remains to be proven that the effect against disease is actually the result of the drug’s epigenetic action, rather than to some other mechanism, such as stimulation or blockage of a cell membrane receptor. Whether or not a drug is effective against a certain disease isn’t always straightforward to demonstrate. Just because a drug is known to have epigenetic action and has been shown to produce a benefit, it doesn’t necessarily follow that benefit is because of the epigenetic action.
As with drugs in general, quite often a drug is approved for clinical use, because it’s shown to be safe and effective, but the details of how and why it does what it does are worked out later, and there’s no reason to think that the era of epigenetics should not follow a similar pathway.
David Warmflash is an astrobiologist, physician and science writer. Follow @CosmicEvolution to read what he is saying on Twitter.