A New Field Could Hold the Key to Treating Both Cancer and Aging
How exactly does your DNA make you who you are?
It's because of epigenetics that identical twins can actually look different and develop different diseases.
Just as software developers don't write apps out of ones and zeros, the interesting parts of the human genome aren't written merely in As, Ts, Cs and Gs. Yes, these are the fundamental letters that make up our DNA and encode the proteins that make our cells function, but the story doesn't end there.
Our cells possess amazing abilities, like eating invading bacteria or patching over a wound, and these abilities require the coordinated action of hundreds, if not thousands, of proteins. Epigenetics, the study of gene expression, examines how multiple genes work at once to make these biological processes happen.
It's because of epigenetics that identical twins – who possess identical DNA -- can actually look different and develop different diseases. Their environments may influence the expression of their genes in unique ways. For example, a research study in mice found that maternal exposure to a chemical called bisphenol A (BPA) resulted in drastic differences between genetically identical offspring. BPA exposure increased the likelihood that a certain gene was turned on, which led to the birth of yellow mice who were prone to obesity. Their genetically identical siblings who were not exposed to BPA were thinner and born with brown fur.
These three mice are genetically identical. Epigenetic differences, however, result in vastly different phenotypes.
(© 1994 Nature Publishing Group, Duhl, D.)
This famous mouse experiment is just one example of how epigenetics may transform medicine in the coming years. By studying the way genes are turned on and off, and maybe even making those changes ourselves, scientists are beginning to approach diseases like cancer in a completely new way.
With few exceptions, most of the 1 trillion cells that make up your body contain the same DNA instructions as all the others. How does each cell in your body know what it is and what it has to do? One of the answers appears to lie in epigenetic regulation. Just as everyone at a company may have access to all the same files on the office Dropbox, the accountants will put different files on their desktop than the lawyers do.
Our cells prioritize DNA sequences in the same way, even storing entire chromosomes that aren't needed along the wall of the nucleus, while keeping important pieces of DNA in the center, where it is most accessible to be read and used. One of the ways our cells prioritize certain DNA sequences is through methylation, a process that inactivates large regions of genes without editing the underlying "file" itself.
As we learn more about epigenetics, we gain more opportunities to develop therapeutics for a broad range of human conditions, from cancer to metabolic disorders. Though there have not been any clinical applications of epigenetics to immune or metabolic diseases yet, cancer is one of the leading areas, with promising initial successes.
One of the challenges of cancer treatments is that different patients may respond positively or negatively to the same treatment. With knowledge of epigenetics, however, doctors could conduct diagnostic tests to identify a patient's specific epigenetic profile and determine the best treatment for him or her. Already, commercial kits are available that help doctors screen glioma patients for an epigenetic biomarker called MGMT, because patients with this biomarker have shown high rates of success with certain kinds of treatments.
Other epigenetic advances go beyond personalized screening to treatments targeting the mechanism of disease. Some epigenetic drugs turn on genes that help suppress tumors, while others turn on genes that reveal the identity of tumor cells to the immune system, allowing it to attack cancerous cells.
Direct, targeted control of your epigenome could allow doctors to reprogram cancerous or aging cells.
The study of epigenetics has also been fundamental to the field of aging research. The older you get, the more methylation marks your DNA carries, and this has led to the distinction between biological aging, or the state of your cells, and chronological aging, or how old you actually are.
Just as our DNA can get miscopied and accumulate mutations, errors in DNA methylation can lead to so-called "epimutations". One of the big hypotheses in aging research today is that the accumulation of these random epimutations over time is responsible for what we perceive as aging.
Studies thus far have been correlative - looking at several hundred sites of epigenetic modifications in a person's cell, scientists can now roughly discern the age of that person. The next set of advances in the field will come from learning what these epigenetic changes individually do by themselves, and if certain methylations are correlated with cellular aging. General diagnostic terms like "aging" could be replaced with "abnormal methylation at these specific locations," which would also open the door to new therapeutic targets.
Direct, targeted control of your epigenome could allow doctors to reprogram cancerous or aging cells. While this type of genetic surgery is not feasible just yet, current research is bringing that possibility closer. The Cas9 protein of genome-editing CRISPR/Cas9 fame has been fused with epigenome modifying enzymes to target epigenetic modifications to specific DNA sequences.
A therapeutic of this type could theoretically undo a harmful DNA methylation, but would also be competing with the cell's native machinery responsible for controlling this process. One potential approach around this problem involves making beneficial synthetic changes to the epigenome that our cells do not have the capacity to undo.
Also fueling this frontier is a new approach to understanding disease itself. Scientists and doctors are now moving beyond the "one defective gene = one disease" paradigm. Because lots of diseases are caused by multiple genes going haywire, epigenetic therapies could hold the key to new types of treatments by targeting multiple defective genes at once.
Scientists are still discovering which epigenetic modifications are responsible for particular diseases, and engineers are building new tools for epigenome editing. Given the proliferation of work in these fields within the last 10 years, we may see epigenetic therapeutics emerging within the next couple of decades.
When a patient is diagnosed with early-stage breast cancer, having surgery to remove the tumor is considered the standard of care. But what happens when a patient can’t have surgery?
Whether it’s due to high blood pressure, advanced age, heart issues, or other reasons, some breast cancer patients don’t qualify for a lumpectomy—one of the most common treatment options for early-stage breast cancer. A lumpectomy surgically removes the tumor while keeping the patient’s breast intact, while a mastectomy removes the entire breast and nearby lymph nodes.
Fortunately, a new technique called cryoablation is now available for breast cancer patients who either aren’t candidates for surgery or don’t feel comfortable undergoing a surgical procedure. With cryoablation, doctors use an ultrasound or CT scan to locate any tumors inside the patient’s breast. They then insert small, needle-like probes into the patient's breast which create an “ice ball” that surrounds the tumor and kills the cancer cells.
Cryoablation has been used for decades to treat cancers of the kidneys and liver—but only in the past few years have doctors been able to use the procedure to treat breast cancer patients. And while clinical trials have shown that cryoablation works for tumors smaller than 1.5 centimeters, a recent clinical trial at Memorial Sloan Kettering Cancer Center in New York has shown that it can work for larger tumors, too.
In this study, doctors performed cryoablation on patients whose tumors were, on average, 2.5 centimeters. The cryoablation procedure lasted for about 30 minutes, and patients were able to go home on the same day following treatment. Doctors then followed up with the patients after 16 months. In the follow-up, doctors found the recurrence rate for tumors after using cryoablation was only 10 percent.
For patients who don’t qualify for surgery, radiation and hormonal therapy is typically used to treat tumors. However, said Yolanda Brice, M.D., an interventional radiologist at Memorial Sloan Kettering Cancer Center, “when treated with only radiation and hormonal therapy, the tumors will eventually return.” Cryotherapy, Brice said, could be a more effective way to treat cancer for patients who can’t have surgery.
“The fact that we only saw a 10 percent recurrence rate in our study is incredibly promising,” she said.
Few things are more painful than a urinary tract infection (UTI). Common in men and women, these infections account for more than 8 million trips to the doctor each year and can cause an array of uncomfortable symptoms, from a burning feeling during urination to fever, vomiting, and chills. For an unlucky few, UTIs can be chronic—meaning that, despite treatment, they just keep coming back.
But new research, presented at the European Association of Urology (EAU) Congress in Paris this week, brings some hope to people who suffer from UTIs.
Clinicians from the Royal Berkshire Hospital presented the results of a long-term, nine-year clinical trial where 89 men and women who suffered from recurrent UTIs were given an oral vaccine called MV140, designed to prevent the infections. Every day for three months, the participants were given two sprays of the vaccine (flavored to taste like pineapple) and then followed over the course of nine years. Clinicians analyzed medical records and asked the study participants about symptoms to check whether any experienced UTIs or had any adverse reactions from taking the vaccine.
The results showed that across nine years, 48 of the participants (about 54%) remained completely infection-free. On average, the study participants remained infection free for 54.7 months—four and a half years.
“While we need to be pragmatic, this vaccine is a potential breakthrough in preventing UTIs and could offer a safe and effective alternative to conventional treatments,” said Gernot Bonita, Professor of Urology at the Alta Bro Medical Centre for Urology in Switzerland, who is also the EAU Chairman of Guidelines on Urological Infections.
The news comes as a relief not only for people who suffer chronic UTIs, but also to doctors who have seen an uptick in antibiotic-resistant UTIs in the past several years. Because UTIs usually require antibiotics, patients run the risk of developing a resistance to the antibiotics, making infections more difficult to treat. A preventative vaccine could mean less infections, less antibiotics, and less drug resistance overall.
“Many of our participants told us that having the vaccine restored their quality of life,” said Dr. Bob Yang, Consultant Urologist at the Royal Berkshire NHS Foundation Trust, who helped lead the research. “While we’re yet to look at the effect of this vaccine in different patient groups, this follow-up data suggests it could be a game-changer for UTI prevention if it’s offered widely, reducing the need for antibiotic treatments.”