Dr. Fornace's laboratory is recognized for dissecting the response of mammalian cells to stresses within a cell's environment - everything from the impact of ionizing radiation to toxic substances - that lead to the development of cancer and other diseases. As Dr. Fornace has shown, this happens when stress-related signals inside the cell alter expression of multiple genes involved in cell-cycle control, programmed cell death, and DNA damage processing.

According to ISI Thompson Scientific, Dr. Fornace is one of the most highly cited researchers in the field of molecular biology and molecular oncology, and has published more than 250 papers and serves on the editorial boards of eight journals, including Cancer Research, DNA Repair, and Molecular Cancer Research. He also holds eight patents for technologies therapeutic targets and therapeutic models for treatment and prevention of cancer.

"Cancer still is a rare event," explains Dr. Fornace, "And what we're focusing on is the stress signaling pathways and the regulatory mechanisms that prevent the development of cancer."

Prior to joining Harvard, where he served as director of the John B. Little Center for the Radiation Sciences and Environmental Health, he was a senior investigator at the National Cancer Institute. From 1997 onward, he served as chief of the Gene Response Section. Board certified in anatomic pathology, Dr. Fornace has served in the United States Public Health Service as both an active duty surgeon and reservist for over 30 years.

Understanding Stress at the Molecular Level

When healthy cells are subjected to stressful conditions - like sunburn, injury, or radiation - protective mechanisms kick into gear. Dr. Fornace studies the pathways involved in this molecular salve.

In the 1980s, little was known about how cells responded to these stressful conditions. It was even unclear whether genes were turned on as a response to cellular stress because the state of the art technologies at that time could not detect the small changes in gene expression that we now know occur. By 1990, Dr. Fornace had published multiple papers in high impact journals on just this topic using a new assay that he developed for just this purpose. Using these techniques, he has found that key genes that control growth, such as the well-known tumor suppressor genes p53 and RB, play central roles in some of these stress response signaling pathways.

Dr. Fornace is also well-known for the discovery and cloning of the Gadd (growth arrest and DNA damage inducible) genes and his laboratory was the first to demonstrate that the p53 tumor suppressor can turn "on" a stress gene, which in this case was Gadd45a. This gene has numerous functions â€“ it protects the skin against cancer, helps regulate another key oncogene, and plays a critical protective role in the human immune system.

Dr. Fornace's research into cell trauma was recently funded by a $1.4 million grant from the National Aeronautics and Space Administration. Lauded by Senator Edward Kennedy of Massachusetts, this research is the first of its kind to investigate the health risks of astronauts who are exposed to various types of radioactive particles. Specifically, he will be looking at the role of a single known tumor suppressor gene, which has been implicated in early phase progression of colon and other gastrointestinal cancers.

A Deeper Look: When Protective Mechanisms Go Haywire

Another type of stress that is especially important to cancer researchers is oncogenic stress. That is, how does a cell respond when the genes that keep a cancer from forming become mutated?

Environmental stresses such as UV, x-rays, and radiation can cause DNA damage that activates oncogenes. This is the first step in the malignant transformation whereby normal healthy cells become cancerous. These environmental stresses are a near-constant bombardment on our bodies.

Growing up with a mother who was a physicist on the Manhattan Project and a father who was a physician, Dr. Fornace seems to have chosen the perfect field. He graduated in 1972 from a five-year combined undergraduate and medical program at Jefferson Medical College with the intention of using his degree to conduct research.

His first post-doctoral research fellowship landed him in the field of DNA damage and repair looking at the agents used in cancer treatment. When his mother was diagnosed in 1975 with chronic myelogenous leukemia, or CML, Dr. Fornace only rededicated himself to his chosen field of study.

"The reason cells don't become malignant more often is that we have a complex pathway of protective mechanisms that can be triggered," explains Dr. Fornace. "They will either tell cells to die, or to senesce and stop growing. That pushes a lot of cells that may be on the way to becoming malignant out of the cell cycle and removes them from the population."

Dr. Fornace studies these protective mechanisms in order to better understand the malignant transformation. Specifically, his team studies the downstream components of the pathways which control the cell's response by turning on or off the protective mechanisms.

"In the case of cancer, some of these protective mechanisms have to be overwhelmed so that cells can become malignant. There may be ways to reverse this and one thing that we've been working on is a protein called the Wip1 phosphatase, which appears to be a normal negative feedback regulator of some of these protective mechanisms."

Wip1 is an oncogene that selectively regulates cellular processes. Wip1 turns off the protective pathways, a function which is important in healthy cells. For example, when a sunburn heals, skin cells that were only peripherally damaged are repaired and Wip1 can be activated to return them to the normal cell cycle. But because the protein occupies a key position in the pathways that regulate response to stress, its activity is often altered in cancers. In fact, the molecule is over-expressed in many cancer cell lines, which turns off the protection pathways allowing oncogenesis to proceed.

 "You have the classic example in primary cells that if you put an oncogene in, it doesn't usually transform them. You usually have to put in two oncogenes to overcome the mechanisms blocking various malignant pathways," said Dr. Fornace.

Wip1 can help cells with other activated oncogenes overcome the protection, and this makes it an important molecule for cancer researchers to study. In one study, he created cancer-resistant mice by knocking out the gene for Wip1. Since the protein was not present to overcome the protective pathways, the malignant transformation could not take place.

Dr. Fornace sees great potential for Wip1 as a therapeutic. Relying on the principle of "oncogene addition" – that cancer cells require activated oncogenes to survive – he has found an inhibitor of Wip1 that will reversing the effects of the over-expressed the protein. Once its activity is blocked, the cancer cannot survive because the protection pathways will kick back in and kill or sequester the abnormal cells.

Looking further into the future, Dr. Fornace believes that his work with Wip1 could lead to mechanisms for prevention and increasing the sensitivity of tumors to conventional chemotherapy agents.

Tackling Stress Response On the "-Omic" Scale

At the same time as Dr. Fornace works to develop applications based on a single molecule's role in the progression of cancer, he is also using a wide-angle lens to monitor stress responses at the genome-wide level. In fact, another first from his laboratory occurred in 1999 when he was the first to publish findings on stress response using the gene array technologies.

With support from the NIH and the Department of Energy's Low-Dose Radiation Research Program, Dr. Fornace and his laboratory team have developed a system to monitor for stress responses at the genome-wide level. In studies of cells that have been exposed to ionizing radiation, they have identified new p53-regulated genes and also dose-rate gene responses. These and other studies have implications for homeland security monitoring of exposure to toxic agents, as well as for toxicological assessment of new pharmaceutical agents.

For example, by understanding the genome-wide response to stresses like radiation or chemical toxins, Dr. Fornace will be able to develop biomarkers to detect exposure. He is specifically looking for markers in both gene expression and metabolites which could be detected in easily obtainable samples like urine, saliva, sweat, and blood. With this kind of test available, emergency response personnel would be able to identify and triage patients who received significant exposure.

These metabolomic approaches to understanding responses to stress, which look at the specific by-products that result from cancer treatment or after exposure to other toxicants, are the second component of his wide-angle omic studies. He has been working with medicinal chemist Milton Brown, MD, PhD, to develop these tests. Dr. Brown's laboratory will synthesize the metabolites identified by Dr. Fornace and his team, providing materials for developing new tests.

To Dr. Fornace the value of this work is clear: "In the Chernobyl accident, there were reports of many people vomiting. Now, this is a side effect of exposure to a high dose of radiation. But there are many other reasons why someone could be vomiting, especially after a traumatic incident. By screening all those people who may have been exposed, and finding patients who truly received high dose exposures, we can lessen the impact of an event. There is currently no gold standard for doing this."

Published: 7/25/09
By Allison Whitney
Adapted from "Stressing Cells" published in Georgetown Medicine Spring 2007