Profile of Peter A. Jones

Van Andel Research Institute chief scientific officer Peter A. Jones, who was born in Cape Town, South Africa, recalls a challenge he received after traveling to Los Angeles in 1973. “Shortly after I arrived in the [United States], I met Charles Heidelberger, who was a giant in cancer research and a member of the National Academy of Sciences. He encouraged me, challenged me, and set a goal that took me more than 40 years to achieve—namely to be elected myself.”

Portrait of Peter Jones. Photo courtesy of Van Andel Research Institute.

Jones’ election to the National Academy of Sciences in 2016 honors his accomplishments in the field of epigenetics, which concerns chemical changes made to DNA that can switch genes on and off but do not alter the genetic code. He helped to show that epigenetic changes can cooperate with mutations to cause cancer. Jones and his colleagues have since investigated several potential cancer treatments, including a vitamin C-based therapy that may boost the effectiveness of a drug targeting myelodysplastic syndrome, a cancer in which bone marrow produces abnormal myeloblasts.

Formative Years in Zimbabwe

Jones’ family moved to Rhodesia (now Zimbabwe) when he was a child. “I was the first and only one of my 30 cousins to go to college because my parents were so convinced that I could do it, and I became obsessed by chemistry when I was about 14,” he says. His interest in science grew at St. George’s College, where Jones graduated in 1964 before attending the University College of Rhodesia. There, he met Arthur Hawtrey, who established the university’s Department of Biochemistry in challenging political times. “He was a charismatic scientist who inspired me immensely by his intuition and passion for science, and he cemented my love for molecular biology,” Jones says.

Joseph Taderera was another early mentor. “Joe had trained with Robert Auerbach, a pioneer in research on blood vessel formation and cell differentiation, and Howard Temin, a Nobel Prize-winning geneticist and virologist, in Madison, Wisconsin, and he taught me tissue culture and how to dream big,” Jones says. “The fact that we grew mammalian cells and conducted carcinogenesis experiments in the middle of Africa, where the next closest university was 500 miles away, was a testament to his resourcefulness and tenacity.” Jones earned a bachelor’s degree with first class honors in 1969. He then obtained a doctorate from the University of London. Jones’ thesis reported biochemical studies on chemical carcinogens in mammalian systems.

Unexpected Discovery

Jones wished to live and work in the United States, as he had extensively read about the country at the American Library attached to the US Embassy in Rhodesia. An opportunity came in 1973 when Jones received a National Institutes of Health fellowship that enabled him to obtain his postdoctoral training at the Division of Hematology-Oncology at the Children’s Hospital of Los Angeles. There, he worked with Bill Benedict, who is now a professor in the Division of Cancer Medicine at the University of Texas. Following his postdoctoral studies, Jones returned to South Africa to serve as chief research officer of the medical school at Tygerberg, but returned to California in 1977 after accepting an assistant professorship in pediatrics and biochemistry at the University of Southern California School of Medicine. There, Jones later became an associate (1981), professor (1985), distinguished professor (1999), and the holder of the Mark A., J. Ruth, and Stillman F. Sawyer Chair in Cancer Research (2012). He served as director of the USC Norris Comprehensive Cancer Center from 1993–2011.

Epigenetics was a nascent field when Jones and his team made an unexpected discovery in 1978 while studying the myelodysplastic syndrome drug 5-Aza-CdR. “Immortalized mouse embryo cells changed into contracting striated muscle several days after a brief treatment with micromolar concentrations of 5-Aza-CdR”(1), Jones says. “Since the drug had induced a profound and heritable reprogramming of the cells, it seemed important to figure out a mechanism of action.” Biochemist and molecular biologist Robert Stellwagen, also at the University of Southern California, suggested that Jones should investigate whether inhibition of DNA cytosine methylation caused the cellular reprogramming. DNA methylation refers to the addition of methyl groups to a gene. The modifications have the ability to silence genes, such as those that control either cellular growth or apoptosis, and may cause cells to grow unchecked and cause cancer. Jones and his first graduate student, Shirley Taylor, determined that DNA cytosine methylation was, as Stellwagen had suspected, responsible for the reprograming of the embryo cells (2). Jones says that within a short period, “We linked differentiation, gene expression, and DNA methylation for the first time.”

Epigenetic and MicroRNA Events in Cancer

Since that seminal report in 1980, Jones has dedicated much of his work to elucidating the links between epigenetic processes and cancer. A 2002 review, coauthored by Jones and Stephen Baylin of the Johns Hopkins University, discusses how epigenetic events are associated with molecular alterations that might cause the altered gene expression in cancer (3). The authors highlight aberrant promoter hypermethylation, which is an increase in the epigenetic methylation of cytosine residues in DNA. Such changes may lead to inappropriate gene silencing and could therefore affect virtually every step in tumor progression.

Epigenetic processes can involve microRNAs, small molecules that regulate the expression of genes in growth, proliferation, development, and apoptosis. In 2006 Jones and his team treated human cancer cells with the drugs 5-aza-2′-deoxycytidine and 4-phenylbutyric acid. After treatment, the cells down-regulated the protein-coding gene BCL6, which has been linked to certain cancers (4). The authors wrote, “These results suggest that DNA demethylation and histone deacetylase inhibition can activate expression of miRNAs that may act as tumor suppressors.” Histone deacetylases are a class of enzymes that remove an acetyl group from histones, thereby influencing gene transcription. The following year, the University of Southern California’s Keck School of Medicine received a $10 million gift from the Kenneth T. and Eileen L. Norris Foundation that, with other support, enabled Jones and his team to launch the University of Southern California’s Epigenome Center, one of the nation’s first research facilities devoted to the study of epigenetics. For this and other achievements, Jones received the Cancer Association of South Africa’s Oettlé Award in 2008 and, with Baylin, the Landon Award from the American Association for Cancer Research in 2009. Two years later, Baylin and Jones also received the Medal of Honor from the American Cancer Society.

Soon, Jones and his team analyzed polycomb-group genes, which can remodel chromatin such that epigenetic silencing of genes takes place. Jones and his colleagues found that when polycomb-group genes are repressed, they have permissive enhancers that can initiate cellular reprogramming (5). The discovery suggests that the genes may provide an avenue for the initiation of cell-fate reprogramming associated with many processes, including cancer and aging.

Investigation of New Cancer Therapies

In 2014 Jones accepted the position of chief scientific officer at Van Andel Research Institute (VARI) in Grand Rapids, Michigan. Shortly after joining VARI, Jones and his team collaborated with Daniel De Carvalho, a former postdoctoral fellow, to unravel the antitumor mechanisms of DNA-demethylating agents (6). Jones and his colleagues found that these agents target colorectal cancer cells by inducing viral mimicry. The research identifies a molecular recognition pathway as a potentially druggable target against colon cancer, which is the third most commonly diagnosed cancer in the United States.

Jones’ Inaugural Article (7) outlines a method that may improve the effectiveness of the standard epigenetic treatment for myelodysplastic syndrome and acute myeloid leukemia. The researchers discovered that combining vitamin C with 5-Aza-CdR improved the therapy’s ability to combat the cancers in a cell line. Jones says, “I have been working with 5-Aza-CdR and studying its effects on gene expression for 40 years. I last worked on vitamin C in 1980 when we found that it could prevent the oncogenic transformation of immortalized mouse embryo cells. The problem was that we had no hypothesis for its mechanism of action.” In 2013, Anjana Rao of the La Jolla Institute for Allergy and Immunology and Sanford Consortium for Regenerative Medicine and colleagues showed that vitamin C is a cofactor for TET enzymes that can induce demethylation of DNA (8). Building on that discovery, Jones and his team combined vitamin C and the drug azacitidine to see if they could increase the latter’s ability to induce the expression of human endogenous retroviruses that are kept silent by DNA methylation in normal and cancer cells (7). They successfully did so, and a pilot clinical trial is now underway.

Jones, who is also the principal investigator with Stephen Baylin of the recently established VARI-Stand Up to Cancer, Epigenetics Dream Team, continues to maintain a busy leadership and international lecture schedule in addition to his time in the laboratory. Jones says, “I remain fascinated by the role of DNA methylation in shaping and controlling the epigenome, which I have worked on for a long time. I would really like to increase the responses of patients to epigenetic therapy and to work out why they respond to these agents in the clinic.”