Hadassah breaks chain of BRCA mutation

World first in Hadassah: Healthy fetuses from embryos "sampled" to prevent adult-onset disease.

doctor woman 224.88 (photo credit: Judy Siegel)
doctor woman 224.88
(photo credit: Judy Siegel)
A 38-year-old Jerusalemite whose cells carry defective BRCA2 genes is apparently the first woman in the world in an advanced state of pregnancy with fetuses that were screened for the mutation as three-day-old embryos and selected for implantation when shown to be healthy. Without the screening, the significantly higher risks for breast and ovarian cancer in females and slightly higher risk of prostate and breast cancer in males could have produced a malignant tumor in her children after they reached adulthood. The breakthrough in-vitro fertilization plus pre-implantation genetic diagnosis (PGD) of fraternal twins - performed at Hadassah-University Medical Center in Jerusalem's Ein Kerem - offers hope to many defective-gene carrier couples around the world of having children free of their mutation. The woman, who is due to deliver a healthy daughter and son in 13 weeks, had to undergo IVF in any case because of "mechanical infertility" in which her husband's sperm could not pass through the Fallopian tubes into her uterus. She is very familiar with the curse of genetically transmitted breast cancer, as her mother - who also carries the defective gene - contracted it at the age of 55, a great-uncle developed breast cancer and many other female relatives are carriers or have had the tumor. The IVF/PGD procedure - in which embryos were created by shooting a single sperm into ripened ova and two cells were taken from three-day-old embryos to examine their genes and chromosomes - was performed by Prof. Neri Laufer, a world-famous fertility expert and chairman of the medical center's obstetrics and gynecology department, and colleagues, together with Dr. Michal Sagi and colleagues at Hadassah's human genetics department. The human genetics department performed the genetic tests and provided counseling. While the gynecology department and the genetics department cooperated on the PGD project, the embryos were also screened for the number of chromosomes in the cells, as due to her age, the patient was at higher risk for babies with Down's Syndrome. The Hadassah staff members were "very patient, taking personal feelings into consideration and very caring," she said. The attractive and smiling woman, who prefers to call herself "Esther," married two years ago and learned she suffered from infertility. "I have saved my children from an ongoing struggle," she told The Jerusalem Post in Laufer's office on Sunday. "I feel I have given them a gift and done the maximum to ensure they will be healthy. I have broken the very unpleasant chain of mutant genes. Every mother wants her children to have the best chance for health; I am especially relieved that I will not have to worry my daughter." "We have not found any case here or abroad in which these advanced molecular techniques produced healthy advanced pregnancies in BRCA carriers," said Sagi, who said the important message of the breakthrough was that women should be informed of the option. "One in 40 Israeli women is a BRCA mutation carrier. For those who want to get pregnant, this technique is the most optimistic news they can hear, as they don't have to pass the risk down to their children," the geneticist said. Asked how they were the first to perform the procedure, Laufer and Sagi said that other centers abroad may have tried to carry it out and not succeeded or produced embryos that did not reach an advanced stage of gestation. Most women diagnosed as BRCA mutation carriers have already completed their families and are not thinking about the risk of passing on the defect to unborn children. Six couples have asked Hadassah about undergoing the procedure, and one couple is in the early stages of pregnancy with a healthy embryo. Esther said she hoped to have more children via the innovative technique and that when she has finished having kids, she planned to have a prophylactic oophorectomy (voluntary removal of her ovaries) and double mastectomy (surgical removal of her breasts) to lower her own risk. Carrying the defective gene increases the risk of having breast cancer by 50 percent to 80% and that of contracting ovarian cancer by 25% to 40%. Nevertheless, the majority of breast cancer cases are not connected to inherited mutations but rather to environmental and other factors. A very Orthodox woman who covers her hair with a wig, Esther and her husband consulted with numerous rabbis here and abroad. The rabbis unanimously approved the procedure after saying that embryos only a few days old and swimming in a Petri dish are not considered human life but only cells, and that producing disease-free babies with a healthy future was not only permitted but preferred in her situation. There are several Israeli medical centers besides Hadassah that perform the inexpensive screening for mutant BRCA. "I know all about breast cancer," Esther said, having seen her mother get it, be anxious, undergo a double mastectomy and having to have tests twice a year. "She contracted the mutation from my grandfather. As her family are Holocaust survivors, it's impossible to know how many would have had the disease if they had not been murdered in Europe." When the twins are old enough, she will tell them how they were conceived and why they were selected from among 10 embryos produced by IVF; four had too many chromosomes (which were discarded); three carried BRCA2 (and were put in permanent storage); and three were free of the defective gene and had the correct number of chromosomes. Two of the healthy ones were inserted, and both implanted themselves in her womb. Laufer and Sagi noted that PGD has been performed in the past to identify embryos that are doomed to suffer from single-gene disorders with immediate effects in all cases, but not those that carried a BRCA1 or BRCA2 gene, which if the cancer appears, can cause great suffering and even death. The genetic form of Creutzfeldt-Jakob disease, a fatal brain disorder that runs mainly in Libyan Jewish families, is caused by a single defective gene, and IVF/PGD could be relevant for selecting mutation-free embryos. However, Parkinson's disease, which is not due to a single gene, is not. "Breast cancer is mostly a disease of middle age," said Sagi. "Many women who are BRCA mutation carriers - and even some of our doctors - are unaware that the defect can be detected in embryos. "To be a carrier is to live in fear. Some might argue that there is a moral problem in selecting among embryos that carry a defective gene that does not bear a 100% risk of disease and does not appear immediately, but we believe the couples should be the ones to decide, and there is no halachic problem," he said. Catholics and fundamentalist Protestants who oppose selection of embryos from IVF and discarding those that carry disease would object to PGD as well. If a woman BRCA gene carrier free of fertility problems that require IVF came to Hadassah and asked to undergo the technique, "we would have to have long deliberations, as IVF itself - with high exposure to hormones - poses a risk of cancer as well," said Sagi. Laufer's department is ready to offer the treatment to women like Esther here and from abroad if they are suitable. Dr. Mordechai Halperin - a gynecologist and expert in Jewish medical ethics - congratulated the Hadassah team on producing the healthy embryos and the pregnancy with the technique. "The great sage Rabbi Shlomo Zalman Auerbach and other rabbinical arbiters have clearly approved non-natural conception to prevent diseases in a couple's offspring. They saw no difference whether the procedures prevented a disease that would appear immediately or later. If IVF and PGD produced only male embryos that were BRCA mutation carriers, whether to implant them or try another cycle of IVF depends on medical conditions. But because there is some risk from the hormones in IVF, one cannot ask to undergo this solely for non-medical reasons, such as choosing the embryo by its sex," Halperin said. He added that even if a BRCA carrier did not need IVF to conceive, she was allowed to do so to have healthy offspring.