Medicine: Breaking the Chain
The birth of twins at Hadassah who do not carry their mother’s mutated BRCA gene is not only a medical breakthrough, it offers hope for those who carry a genetic misprint.
Long before genetic counseling was available, Irish playwright George Bernard Shaw acidly homed in on one of genetics’ major pitfalls.
Crossing the Atlantic early last century aboard the same ship as a vacuous movie star, he endured four days of her empty chatter, until she gushed: “Mr. Shaw, what a wonderful thing it would be for us to marry! Think of the children we would have. Why, with my beauty and your brains, they would conquer the world!”
“Indeed, Madam,” replied Shaw. “But what if they were to inherit mybeauty and your brains?”
While the genes for brains and beauty have remained elusive (and largely unsought) in the decades since this reported exchange, the genetic misprints responsible for a large and growing number of crippling disorders have been identified. In the wake of this identification, screening techniques have been developed that recognize pernicious genes in fetuses and, more recently, even in embryos.
These are the advances that enabled the birth of full-term twins at the Hadassah–Hebrew University Medical Center in Ein Kerem last June with no more than an average risk of getting breast cancer, although their mother carries a mutated BRCA2 gene. As 3-day-old embryos, the boy and girl were tested at Hadassah, then implanted into their mother after they were found free of the mutated gene. Their mother, a 38-year-old Jerusalemite, has an 80-percent risk of developing cancer. This is the first time anywhere that the mutated BRCA2 transmission chain has been deliberately snapped.
“I watched my mother and great- uncle each lose their battle against breast cancer,” says the new mother, who asked to be known as Esther (“In honor of Hadassah,” she says, smiling). “For myself, I plan to have my ovaries and my breasts removed after having another baby. I’ll do so knowing I’ve ensured that my children won’t face this hideous choice I’ve had to make….”
Esther, like her mother and grandfather before her, carries a mutation located on chromosome 13, a large gene that, in its healthy form, is a tumor suppressor. This genetic alteration not only increases her chances of developing breast cancer but also raises her risk of ovarian cancer from about 1 to 25 percent.
“Esther was, in any case, an IVF candidate for reasons of mechanical infertility,” explains Dr. Neri Laufer, head of the Department of Obstetrics and Gynecology at Hadassah. “Because of her age, she requested that her embryos be screened for Down syndrome. With her family history, she also asked that we look for the BRCA2 mutation.”
In September 2007, following hormone treatment that boosted the number of ripened ova, egg cells were taken from Esther’s ovaries and fertilized in the laboratory with her husband’s sperm, using in vitro fertilization.
“Three days later, we found seven viable embryos, each having grown to around eight cells,” says Dr. Michal Sagi, senior genetic counselor and head of Hadassah’s Oncogenetic Counseling Clinic, part of the medical center’s human genetics department headed by Dr. Judith Melki. “They were ready for PGD [pre-implantation genetic diagnosis]. We drew two cells from each embryo.”
Within 24 hours, the results were in. “Three of the seven embryos carried the BRCA2 mutation and were discarded,” says Nomi Weinberg, a technician in the human genetics department’s molecular laboratory, headed by Dr. Dvorah Abeliovich. “Of the remaining four, three were conclusively diagnosed as diploids—that is, free of Down syndrome.”
From the original seven, therefore, three embryos had the right number of chromosomes and were free of the defective gene. “We implanted two of these, which resulted in a twin pregnancy,” says Dr. Laufer. “Esther had a largely uneventful pregnancy, and her son and daughter were born here at Hadassah nine months later.”
Only a handful of other centers worldwide have used these advanced molecular techniques to try to produce mutation-free babies in mutated-BRCA carriers. None, other than Hadassah, has analyzed embryos for both this gene and for Down syndrome. This, says Dr. Laufer, “makes it a significant achievement for us and adds a whole tier of new possibilities for [an older] woman who wishes to conceive.”
“I’ve saved my children from an ongoing struggle,” Esther told The Jerusalem Post in her seventh month of pregnancy. “I feel I’ve given them a gift and done the maximum to ensure they’ll be healthy. I’ve broken the very unpleasant chain of this mutant gene in my descendants.”
PGD, which was developed in Britain in the mid-1980s as an alternative to prenatal diagnosis, has, until now, been used to identify embryos afflicted with single-gene disorders that cause severe childhood diseases. Among them are Duchenne’s muscular dystrophy, Tay-Sachs disease, cystic fibrosis, beta-thalassemia, sickle cell anemia, fragile X syndrome and hemophilia A. PGD is also performed at Hadassah for adult-onset genetic disorders, such as Huntington’s chorea and the fatal brain disorder, Creutzfeldt-Jakob disease, found mainly in Libyan Jewish families. There have been fears that PGD will be used to create so-called designer babies, but these worries have been largely unrealized.
“As long as we know the culprit gene, we can do PGD within 24 hours,” says Dr. Sagi. “And we do—about two or three times a week.”
Selecting against breast cancer is, however, more ethically complex than sidestepping disabling and fatal diseases of childhood.
“There are two main arguments against it being appropriate,” she says. “First is that breast cancer is usually a late-onset disease with individuals generally remaining healthy until middle age. Second is that, while an 80-percent predisposition to a disease is very high, there is not a 100-percent certainty that the disease will develop. And even when it does, it can sometimes be controlled by early diagnosis and treatment.”
The compelling counterargument, she says, is that living with the knowledge of a very high probability of developing a devastating cancer can mean a life spent in fear, ever-watchful for the first symptoms. Measures to prevent the cancer, such as elective surgeries, seem too drastic.
“One in every 40 Ashkenazic women carries the BRCA1 or BRCA2 mutations,” says Dr. Sagi. “This frequency is very much higher than among non-Ashkenazim, although we have identified specific BRCA mutations among Jews from Iraq and Yemen.”
Those carrying or suspecting they carry a mutation in one of the BRCA genes constitute a substantial part of the population seeking guidance at Hadassah’s Oncogenetic Counseling Clinic. Opened in 1995 at the Hadassah Hospital in Ein Kerem, the clinic has counseled more than 4,000 people. The majority are looking for advice because of personal or family histories of breast, ovarian, uterine and colorectal cancers, the malignancies with which several genes are known to be associated.
“While not all cancers are genetically transmitted, some of the most deadly are, and we discuss this with every client prior to genetic testing,” says Dr. Sagi. “Testing can, of course, in itself have an important medical impact. Women who test positive become candidates for extensive early-detection screening and preventive surgeries. On the other hand, as we’re very well aware, a positive result can lead to anxiety, depression and anger; it can impact on social relationships and finances.
“Our role is to explain all the options and their implications without pushing any of them,” she adds. “To those with so poor a family history of cancer that they consider not having children in order to avoid passing on the gene, we [discuss] prenatal testing and embryo screening.”
Hadassah’s target population for screening embryos for the mutated BRCA gene are women like Esther who are, in any case, undergoing IVF.
“We don’t know how many women would opt for assisted reproduction if they could conceive normally,” says Dr. Sagi.
Despite the significant emotional stress of IVF and its high hormone doses, the procedure does bestow one significant advantage for women choosing to snap the chain of mutated genes. “When screening is performed prenatally, the choice of not having an affected baby means terminating a pregnancy,” says Dr. Sagi. “But when screening is done as PGD, affected embryos are not implanted and the pregnancy is never started. Not only does this make an enormous difference to a woman’s physical health and well-being, it also sidesteps what is, for many, a stark ethical stumbling block.”
“I wouldn’t terminate a pregnancy unless my life were in danger,” says Esther, who is Orthodox.
She and her husband consulted rabbis in and outside Israel before going ahead with PGD. The sages concurred that the soul enters the embryo on its 40th day. Therefore, days-old embryos, comprising a few cells, are not considered human beings under Jewish law.
This is in total contrast to the status of a 9-week-old fetus, the earliest that prenatal diagnosis can be performed; it would be halakhically problematic to terminate the pregnancy at this stage of development. Producing mutation-free babies with a healthy future was not only permitted in Esther’s situation, but actually preferred.
Six more couples who carry the BRCA mutation and underwent IVF also asked Hadassah to check their embryos for the breast cancer gene before implantation. One gave birth in September. The other five are in earlier stages of pregnancy.
PGD, with its potential to screen for nonmedical factors—from eye color to intelligence—and so create designer babies, is regarded with suspicion by some. But if designer babies are understood to be children free from devastating inherited disease, it is a technology to embrace.