In the midst of a combined clinical and postdoctoral fellowship in the lab of Prof. Brendan Lee in Baylor College of Medicine, in Texas, Dr. Ayelet Erez encountered a case that would set her on her present research path: A child was admitted to the hospital with high blood pressure that did not respond to treatment. That child suffered from a genetic disease; his body lacked an enzyme responsible for the production of a particular amino acid, called arginine. But the connection between the missing enzyme, known for short as ASL, and the symptoms of the disease was a riddle that left the doctors helpless. What took place next illustrates what can happen when science and medicine get together: Erez, who was on a double medical and research track, combined her knowledge from both fields to create a mouse model of the disease.
That is how she discovered a previously unknown function for this enzyme: It is structurally required for the production of nitrous oxide (NO), a biological messenger that plays a role, among other things, in dilating blood vessels and the functioning of the nervous system. She showed that the child’s symptoms were caused by low NO levels in his body – the result of the lack of ASL enzymes. In this case, the path from lab bench to bedside was a short one: The child was treated with a drug supplement containing NO. His blood pressure returned to normal and has remained so until now – for more than three years – and his cognitive abilities eventually began to improve as well. Erez received the William K. Bowes Jr. Award in Medical Genetics, awarded by Harvard Medical School, for this work. “The combination of clinical experience and research enabled me to succeed,” she says, “and it gave me a lot of personal satisfaction – as a doctor, a scientist and a mother.”
Nitrous oxide research goes back to 1846, the year an Italian chemist invented the explosive nitroglycerin. One hundred years later, Ferid Murad, Louis J. Ignarro and Robert F. Furchgott, who received the 1998 Nobel Prize in Medicine for their work, discovered that the body can break down nitroglycerin into NO molecules and that this substance dilates the blood vessels. Since then, mounting evidence points to an important role for this molecule in maintaining blood vessel and nervous system health, but both the mechanisms by which it works and those that regulate its activities have remained unknown. Among the obstacles to research in this area is the fact that three different enzymes are known to produce NO. Results of experimental attempts to genetically manipulate these enzymes, in order to create disease models, for instance, have been inconclusive.
Erez’s solution to this problem is to focus on an earlier stage in the NO metabolic pathway – in which the enzyme she researched at Baylor comes into play. ASL is responsible for arginine production; this amino acid is the raw material that all three NO enzymes process to produce nitrous oxide. Erez later discovered that ASL is also vital for the assembly of the protein complexes needed to produce NO – a role that ranks it as a top regulatory factor for controlling crucial NO levels in the body.
Now, in her Weizmann Institute lab, Erez plans, among other things, to delve deeper into the workings of the ASL enzyme, as well as the metabolic cycles of arginine and NO. The diseases in which disruptions in these metabolic pathways figure include degenerative nerve diseases, kidney failure and cancer, and Erez hopes her findings will contribute to the development of new ways to treat them.
Relevance for real patients
Once a week, Erez forgoes her lab work in the Institute’s Biological Regulation Department to go to the Chaim Sheba Medical Center, in Ramat Gan (near Tel Aviv). There, she spends half a day working in pediatric genetics with families of children whose cancer has a genetic origin. Her work there ties in with another kind of metabolic process she intends to investigate: that which turns a healthy cell into a cancerous one. She believes that by taking both clinical and scientific approaches to fighting disease, the two will end up complementing and strengthening one another. To further this strategy, she and Dr. Eran Elinav of the Immunology Department have started organizing on-campus meetings between researchers and clinical physicians to discuss different topics. “As an MD-Ph.D., my starting and ending point is always the human being; it is important to me that my research questions have relevance for real patients. At the end of the day, over and above the satisfaction of my scientific curiosity, is the fulfillment that comes from understanding a disease mechanism and optimizing its therapy.”
Dr. Ayelet Erez was born in Haifa and completed her medical studies at the Technion there. She undertook a residency in pediatrics at Chaim Sheba Medical Center and her doctoral research in cancer genetics was completed at Tel Aviv University while she worked in a pediatric clinic. Her postdoctoral research was conducted at Baylor College of Medicine, in Houston, Texas – a school that allowed her to pursue a medical sub-specialization in clinical genetics along with her postdoctoral work. In 2012, she joined the Weizmann Institute’s Biological Regulation Department.
Erez, her husband, who is a veterinarian, and their two daughters, live on Moshav Bnei Zion, north of Tel Aviv.
Dr. Ayelet Erez's research is supported by the Adelis Foundation; Joseph Piko Baruch, Israel; the Dukler Fund for Cancer Research; the Paul Sparr Foundation; and the estate of Fannie Sherr. Dr. Erez is the incumbent of the Leah Omenn Career Development Chair.