Dr. Ohad Birk, head of the Genetics Institute at Soroka Medical Center and The Morris Kahn Lab of Human Genetics at Ben-Gurion University of the Negev, is a connector. Though he may not technically fit Malcolm Gladwell’s pop-culture definition of the term, he has still played the pivotal role in bringing key people together to solve a difficult genetics puzzle. Through the right collaborations with patients and scientists, he has been able to better understand the causes of and work toward the cure for a devastating disease found among Jews of Iraqi and Moroccan descent.
Progressive Cerebro-Cerebellar Atrophy (PCCA) is a disease characterized by the progressive wasting away of cells throughout the brain, causing psychomotor retardation which is severe by 1 to 2 years of age. Children with the disease appear normal at birth, but soon develop spasticity (stiffness of the body, especially in the arms and legs), and most of them also have epilepsy. Individuals with PCCA can live up to two decades.
Birk has done a great deal of genetic disease research among the populations found in the southern part of Israel, especially the Bedouin who have a 60 to 65 percent rate of endogamy (marriage within a tribe or among cousins). He and his team at BGU have identified the genetic basis for 15 different diseases found mostly among the Bedouin, which has led to the Israeli government’s provision of free carrier testing to this population.
The doctor recently told journalists visiting BGU from the United States that four years ago he began a study among the mostly non-Ashkenazi Jewish population of the Negev region, when children from Moroccan and Iraqi families were presenting with PCCA. He could not find the gene causing this disease in the Moroccan families with an affected child, but he did find it in the Iraqi families. He then looked at “mixed” families in which one parent was of Moroccan descent and the other was of Iraqi descent, and he discovered that each parent carried the bad gene, but with slightly different mutations.
Birk checked how common these mutations were among these ethnic groups by taking 300 samples from each, and he found that one in 40 Moroccan Jews and one in 40 Iraqi Jews are carriers of the mutated gene causing PCCA. “This is significant, given that there are about 1 million North African and Iraqi Jews in the world,” Birk said. “I’m now getting e-mails from around the world from these families with children with the disease.”
However, Birk and his colleagues at BGU were not able to solve the genetic mystery behind PCCA alone. Birk’s reaching out to Dr. Dieter Soll, Sterling Professor of Molecular Biophysics and Biochemistry at Yale University, was key to solving the PCCA genetic puzzle on the molecular level. “This was a perfect example of the [global] collaborations that happen in medicine today,” noted Soll, who had never personally met Birk, but had heard of him through a friend who knew Birk from some work he had done at NIH.
“Ohad is a human geneticist. He wants to correlate defective genes with a known phenotype. If you have enough DNA samples [usually from an inbred population] — which are easy to sequence nowadays — you come up with some regularities,” Soll explained. “It helps you find your needle in a haystack.”
“So, one day I got a call from Ohad asking me to collaborate,” Soll continued. Birk knew that it was Soll who had originally discovered the chemical basis for the genetic mutation involved. “Soll was a chemist in want of a genetic metabolic disorder until Ohad Birk came along,” said Dr. Harry Ostrer, director of Human Genetics and Professor of Pediatrics and Pathology at New York University Langone Medical Center. “Had Ohad discovered a different gene, it would not have been me whom he called,” Soll concurred.
Genetic codes are generally made up of 20 amino acids; however 25 of the 30,000 genes in the human genome utilize a 21st amino acid called selenocysteine (SEC), which requires the element selenium as a nutrient. “Three to four years ago, we discovered how an enzyme brings selenium into the body through an RNA dependent process involving SEC,” Soll said. The mutations in the gene that Birk discovered among the Moroccan and Iraqi parents of children with PCCA leads to the production of an enzyme that is not active. Because it is not active, SEC is not made for those 25 proteins.
“We are also trying to develop medical solutions to the disease,” Birk reported. It seems that giving the children selenium or introducing the amino acid into their bodies does not work. “But based on knowing the mechanism involved in the mutation, you can start thinking about other possible solutions,” he said hopefully.
Birk estimates that there are at least 200 cases of PCCA caused by this genetic mutation in Israel. Not long after Birk, Soll and their collaborators solved the PCCA genetic puzzle, parents in Israel were already able to have their embryos tested at Birk’s lab for the disease either in utero by chorionic villus sampling (CVS), or by pre-implantation in-vitro testing. As of May 1, the parents themselves are now also able to be screened for carrier status by a simple blood test.
As a search for a medical solution to the disease proceeds, “the main thing now is prevention,” Birk emphasized. According to the GeneTests Web site (a publicly funded medical genetics information resource developed for physicians, other healthcare providers and researchers), available at no cost to all interested persons at www.ncbi.nlm.nih.gov/sites/GeneTests/, there is no testing available in the United States for the PCCA-causing genetic mutation. Individuals with children who have been diagnosed with PCCA or who are concerned that they themselves might be carriers, should seek genetic counseling and connect with Birk’s lab at BGU.