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The On and Off of Epigenetic Science

Peter Jones is already a preeminent leader in epigenetics, a new approach to combating cancer, inherited diseases and aging.

by Monika Guttman

As director of the USC/Norris Comprehensive Cancer Center for the past 14 years, Peter Jones, Ph.D., has become a familiar face on the USC Health Sciences Campus and around the world, a seasoned leader in the fight against the most sobering diseases of modern times. Whether serving as president of the prestigious American Association for Cancer Research, supporting the work of young cancer researchers struggling against federal budget cuts or simply directing the cadre of USC/Norris researchers and clinicians, Jones leads boldly where few have gone before.

The even better news—especially for people with cancer—is that Jones leads boldly in the laboratory as well. He is titled Distinguished Professor of Urology and Biochemistry and Molecular Biology at the Keck School of Medicine of the University of Southern California, and the H. Leslie Hoffman and Elaine S. Hoffman Chair in Cancer Research. But beyond titles, he is renowned for his studies on the molecular biology of cancer, including the basic mechanisms of DNA methylation and its role in cancer and differentiation.

It is the laboratory research, in fact, that has put Jones squarely at the forefront of an entirely new approach to the treatment of aging, inherited diseases and cancer.

Gene packaging

To dispel the belief that the only way to treat cancer and other diseases is by fixing or replacing damaged genes, scientists are focusing on the field of epigenetics—the study of changes in gene silencing that occurs without changes in the genes themselves. So cancer, for example, is not due just to the DNA, passed along from parents with all its various mutations and recombinations. Instead, the genes may be affected by something else in the environment.

That “something else” is the epigenome, a series of chemicals that attach to DNA and work like traffic cops, getting those inherited genes to start and stop without actually changing the fundamental genetic information. The epigenome tells a cell to develop into a liver cell or a skin cell or to stop the cell death that might prevent uncontrolled growth, which is the hallmark of cancer.

“An epigenome packages the genome in different kinds of cells, in differentiated cells,” explains Jones. “You’re born with the same identical genes in all your cells. But how they are packaged determines how the cell knows what it should be. The same genome can give rise to an eye or a heart or a liver because the cell knows what it is to become.”

It turns out, he says, that incorrect packaging can cause cancer—and probably many other diseases. “So the question is how is this controlled and how is this altered during disease states and during normal aging and cancer?”

DNA methylation

Jones was among the first researchers to discover how epigenetic packaging works. In 1980, when he was working as a researcher at USC-affiliated Childrens Hospital Los Angeles, Jones studied the drug 5-azacytidine as a potential chemotherapy agent. Almost by accident, he found it could induce profound changes in gene expression, while also being a powerful inhibitor of DNA methylation.

Methylation, the addition of a group of specific chemicals to a stretch of DNA, can lock or silence that gene. If methylation silences a gene that normally would control cell growth or cell suicide, then the cell will grow unchecked and possibly turn into cancer. Jones and his colleagues not only discovered the role of methylation, they found its effects could be reversed.

That meant one huge step for cancer treatment—5-azacytidine is now used to treat a pre-leukemia bone-marrow disorder. It was also a leap for the field of epigenetics, because for the first time, researchers saw methylation as an identifiable expression of the epigenome.

The finding “has tremendous implications,” notes Jones. “For example, you can use epigenetics for early detection because you can detect these DNA changes in methylation accurately in small amounts of raw material, a signal of the beginning of cancer or other disease.”

Epigenetic uses

Epigenetics can also play a role in cancer prevention, “because we are finding how things like diet or environment affect the epigenome. So not only will you know what not to do or eat, but maybe you can deliberately prevent cancer by altering the epigenome.”

Jones also sees the application of epigenetics to combat disorders caused by aging, providing the opportunity to turn on genes shut down by the aging process.

Epigenetics is also at the heart of much of the hope for stem cell therapy. “As a cell divides, it assumes different epigenetic states. In other words, it packages its genes differently,” he says.

“So in the stem cell that’s going to give rise to skin, the epigenome is packaged in a certain way, which is different from the way its packaged in the cells that will give rise to blood cells,” he explains. “So if we understand how the epigenome repackages the DNA to create a particular type of cell and we could manipulate this, then the potential is there to take a stem cell and make it into a cell that’s able to give rise to any tissue you’d like.”

Expectations ahead

For now, the field of epigenetics “is like where genetics was 20 years ago,” says Jones. “People have been studying these processes one gene at a time. Now it’s time to ramp it up, to move from one gene at a time to all of the genome at one time, studying all the cells to figure out how the whole thing fits together and works.”

Again, Jones is leading the effort, spearheading the International Alliance for the Human Epigenome and Disease (AHEAD) project. He is leading a task force to make the AHEAD project a reality within the next year. “We’re at a point where we could be doing a lot more with this information, if only we had the blueprint.”

The blueprint mapping of the epigenome is already underway, involving an international group of 40 top cancer scientists, led by Jones and Robert Martienssen, Ph.D., professor, Cold Spring Harbor Laboratory in New York. It began with the proposal, “A Blueprint for a Human Epigenome Project,” published in the December 15, 2005, issue of the journal Cancer Research. The report spells out the needs, guidelines and expectations of a Human Epigenome Project, and describes the developing technologies that make the project currently feasible.

The authors stated: “The goal of the Human Epigenome Project is to identify all the chemical changes and relationships...that provide function to the DNA code, which will allow a fuller understanding of normal development, aging, abnormal gene control in cancer and other diseases, as well as the role of the environment in human health.”

“A coordinated, large-scale Human Epigenomic Project would pave the way for unforeseen breakthroughs in understanding normal and disease states,” Jones says.

Epigenome Center

Jones says USC will continue to be at the forefront with the Epigenome Center in the new Harlyne J. Norris Research Tower that will open later this year. Because he was a forerunner of epigenetic research, Jones early on recognized the importance of the field and began recruiting researchers who will eventually make up the Epigenome Center.

“We’ve already recruited several new faculty, including Judd Rice and Woojin An. We have many researchers working on epigenetic science here at USC such as Peter Laird, who has a grant that’s jointly funded by the National Institute of Genome Research and the National Cancer Institute to sequence literally hundreds and thousands of cancers to find the commonality of genomic alterations.”

Jones recognizes that epigenetics will bring not only substantial contributions to human disease, but also many surprises. He has no qualms about what lies ahead: “We’re not starting from scratch. We have a reputation in this field. We’re not trying to do something we’ve never done before. We actually are the leaders in this field. This is central to our goals here.”

 

TOWERING ABOVE THE REST When the Harlyne J. Norris Research Tower opens in April, the 10-story building will feature the most cutting-edge research space, ultra-functional laboratories, state-of-the-art education rooms, and even some one-of-a-kind technology. It will also bring to life the USC Epigenome Center, one of the first-ever centers devoted exclusively to the study of epigenetics. Epigenetics is the study of heritable changes in genome function that occur without a change in DNA sequence. The epigenome is a vast code that is rapidly being shown to play a direct role in human health. From the Greek epi, meaning "in addition to," the epigenome consists of chemical "amendments" that dangle like charms on a bracelet from the linear string of letters that spell out the genetic code. Scientists are studying how these chemicals switch a gene on or off, allowing a disease to commence or aging to occur. “We have an explosion of interest in the field, and a lot of the earliest work was done right here,” notes Peter Jones, Ph.D., director of the USC/Norris Comprehensive Cancer Center. “So we are already recognized as being a center of excellence in this field. The USC Epigenome Center will build on home-grown strengths.” An entire floor of the new Norris Research Tower will be devoted to the Epigenome Center, says Jones, which will provide enough space to “really develop new knowledge.” Many of the USC scientists who already work in epigenetics will move into the space, along with recently recruited researchers who work with technology that reveal the “packaging,” as Jones puts it, that comprises the epigenome. The goal, he says, is to be capable of doing high throughput analysis of different kinds of epigenetic models—finding patterns of DNA methylation, for example, or histone modification that define how specific genes switch on or off for a particular disease. “The Epigenome Center will allow USC investigators to access screening of epigenetic processes. For example, researchers who study aging, epidemiology, stem cells or neurobiology will have direct access to this as a core facility. It will have the equipment and ability to do these analyses on a big scale.” As one of the first facilities focused exclusively on epigenomics, Jones expects the new Epigenome Center will play an integral role in the international epigenome project he is spearheading. “It won’t be just a service provider; it will help scientists around the world develop new ways of approaching treatment and prevention of disease.”