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.