If the human genome is the static hardware of our cells, the epigenome is like the software, encoding for the cells’ identity and behavior, according to Ari M. Melnick, Medicine/Pharmacology, Weill Cornell Medicine. The epigenome, in other words, tells the genome what to do, using chemical modifications to the DNA and the proteins that associate with the DNA. It has exquisite control over what genes are expressed, what variants of those genes are expressed, and how much expression there is. “All of that is what gives each cell type its unique characteristics,” Melnick says.
The differentiation of normal, healthy cells depends on this epigenetic programming, but the same is true for tumors. “Tumors manifest all of their phenotypes through the same mechanisms that normal cells do,” Melnick says. “One of the exciting aspects of this is that if you can gain sufficient understanding of those mechanisms, reading the cell’s epigenome can point you towards the vast numbers of regulators and factors that actually introduce, control, and drive that coding for malignancy.”
Over 3,000 proteins are involved in coordinating the changes that make up the epigenetic code. The incredible complexity is a challenge, but its plasticity is an opportunity. “The genome that you have is the genome that you have,” Melnick says. “But the epigenome is constantly being erased and rewritten. If you understand how tumor phenotypes are epigenetically encoded, you can actually reverse it.”
Malignancy—Understanding What Genes Are Expressed and How
Melnick has worked primarily on cancers that arise from the immune system and the blood: lymphomas and leukemias. Over the years, he and his team have defined the mechanisms of the most frequent mutations that lead normal immune cells to transform into lymphoma.
Most of the mutations are in proteins that modify histones, which are the proteins that the DNA is wrapped around, often represented as packages of round beads bound together by strands of DNA. Free-floating proteins, called histone writers and erasers, make chemical modifications to the histone beads. The histone writer might add a chemical to the histone, while the eraser will take it away. These additions and deletions then change what genes are expressed and how.
One of Melnick’s most important breakthroughs has been in understanding how the balance of the histone writers and erasers contributes to malignancy. “In healthy cells, it’s like a see-saw,” Melnick says. “They’re balancing each other out.” But when a genetic mutation in the immune cells reduces the number of histone writers, the histone erasers dominate, which ultimately changes how the DNA is expressed, driving malignancy.
Now that this is understood, drugs can be used to target those erasers. “Lymphomas become addicted to the unopposed erasers, and when you hit the erasers, boom, lymphomas with those mutations in the writers are very powerfully affected,” Melnick says.
This goes against previous assumptions and suggests a new paradigm in cancer treatment. “Normally people think of tumor suppressors, like the histone writers, as something you can’t target, because they’re already gone, the tumor is already deleting them,” Melnick says. “But the loss of a tumor suppressor actually creates an oncogene, a gene that can transform a normal cell to a tumor cell. If you can then hit those erasers therapeutically, you’ll essentially mitigate or remove the effect of that lost tumor suppressor from those tumors. You restore balance to these lymphoma cells, and when you do that they are really potently suppressed.”
Tumor Mutations: A Relentless Complexity
If you look at the genomes in leukemia cells, you can trace a kind of mutation tree, with the inciting mutation at the top, which all the cells share. Then the cell lines branch out in different directions due to new mutations. So the tumor does not consist of clones of the same cell but a compilation of different clones.
“This notion in precision medicine, of hitting a particular mutation, is potentially problematic,” Melnick says. “It really just means hitting one clone and not the whole tumor.”
If the clonal composition of tumors is more complicated than researchers originally thought, taking into account the epigenetic variation of these clones makes the tumor’s composition beyond complex. “The number of mutations in the genome is dwarfed by the extensive alterations in the epigenome,” Melnick says. “Years ago we postulated that clonality in tumors is much more extensive than we realized.”
In 2011, Melnick’s group confirmed this hypothesis—finding that in tumor cell populations, different individual cells have different software settings or epigenetic heterogeneity. This makes targeting the tumors, or even understanding their make-up, much more difficult. Melnick’s group went on to show that there’s a clinical consequence to this heterogeneity. Patients who have greater degrees of epigenetic heterogeneity do much worse clinically. With a larger number of possible cell phenotypes, the tumors have more options to choose from in order to survive.
“We know that, for example, when patients are treated with chemotherapy, the tumors can select one of the epigenetic clonal states that’s favorable, that can survive the therapy,” Melnick says. “This kind of epigenetic evolution is independent of the genetic mutations in the tumors.”
This ability of the tumors—to use the epigenome to essentially evolve—sounds like very bad news, but the plasticity of the epigenome also makes these states reversible. “We have emerging data showing that we can use drugs that block some of the enzymes involved to reduce the epigenetic clonality,” Melnick says. With lower degrees of heterogeneity, the tumors then become more sensitive to chemotherapy. Two Phase III clinical trials are just beginning to test these kinds of drugs in patients.
Along with emerging immunotherapies and genetic approaches, exploiting the epigenetic programming gives researchers and clinicians another tool in a multi-faceted approach to cancer treatment. “It’s going to be the rational combination of these approaches that will yield the definitive medical approach for controlling cancer,” Melnick says.
“That’s one of the rewards. The science has helped her to be free of this disease. It was very rewarding and powerful to see.”
Melnick also predicts that someday chemotherapy won’t be needed. “The reason we use chemotherapy is because we don’t understand how cells work,” he says. “Ten years ago, we were at .001 percent understanding, and now we’re maybe at one percent. But we can start to visualize that we’ll be able to control this in a more rational matter, without cytotoxic drugs or nonspecific killing.”
Targeting the epigenome is already yielding clinical results. Melnick even met a patient from one of the lab’s clinical trials who had been essentially cured of her tumor. “That’s one of the rewards. The science has helped her to be free of this disease,” he says. “It was very rewarding and powerful to see.”
The Epigenome, Key to How Cells Work
The importance of the epigenome is now accepted by the mainstream scientific community, but when Melnick began his lab in 2002, people thought it was science fiction. “You really had to work out in the hinterlands and find money from untraditional sources,” he says. “But I was just convinced that the epigenome was the essential program, the blueprint for how cells work.”
In 2010, Melnick’s lab published the first-ever, large-scale epigenome mapping in cancer, showing the extent to which the epigenome programs cells. After that, the community started to catch up, and Melnick now collaborates with researchers from around the globe, kindred spirits who come together to tackle complex problems. “I go all over the world and meet people, and it’s like I always knew them,” he says. “From every continent and culture and language, and we all have the same fascination, the same capacity to wonder. It’s this openness and interactivity that make, in my view, for the best science.”
In addition to helping people and working with them, Melnick says the other main reward is just figuring out how things work. “Nature is stranger than the human mind can really fully grasp. It’s chaos and probability and magnificent accumulation of small little things that come together to give the appearance of order where there really is very little order,” he says. “That aspect of discovery, the strangeness, and the constant amazement, is exciting and intoxicating.”