Dr. Fride Leaves Us

Ester Fride, the Israeli scientist who showed that a newborn mammal cannot suckle and survive without a functional cannabinoid messaging system, died on New Year’s Day at the age of 56. The cause was lung cancer, diagnosed in July, 2008.

Ester was born in 1953, in Amsterdam. Her parents were Holocaust survivors, refugees from Germany. An ardent Zionist, she moved to Israel at age 19. Her family followed.

After getting a PhD in neurobiology from the medical school at Hebrew University of Jerusalem, Fride did research in the U.S. at Johns Hopkins and the National Institutes of Health on how prenatal stress affects the infant’s brain. In 1990 she returned to Israel and began work in the lab of Raphael Mechoulam, whose focus was on cannabinoids and their mechanism of action. Receptors activated by plant- and synthetic cannabinoids had recently been identified — the CB1 receptor in the brain and central nervous system, the CB2 receptor in the immune system — and the search was on for the body’s endogenous (“endo-“) cannabinoids to which these receptors normally respond.

The Mechoulam lab identified one such compound, Arachidonyl Ethanolamide, which was dubbed “anandamide,” in 1992. Another, 2-Arachydonyl Glycerol (2-AG) was discovered in 1995. Fride took part in numerous studies with Mechoulam and was co-author on his landmark 1993 paper describing the pharmacological activity of anandamide. She was also involved in the identification of a third endocannabinoid, 2-Arachidonyl Glyceryl ether, which turned out to be of minor importance.

In 1998 Fride was co-author on a paper by Shimon Ben-Shabat and Mechoulam describing the “entourage effect” that results in 2-AG binding to the CB1 receptor more readily when certain other inactive molecules are nearby.

The studies for which Fride is best known were undertaken at the College of Judea and Samaria in Ariel, where the Departments of Behavioral Sciences and Molecular Biology gave her a lab of her own to direct in 2001. Knowing that cannabinoid receptors are present from the time of gestation and abound in the fetal brain, and that endocannabinoids are present in milk, Fride hypothesized that the endocannabinoid system plays a key role in the nursing process.

She injected newborn mouse pups with an “antagonist” drug that binds to the CB1 receptor (preventing the endocannabinoids from doing so), and compared their development to a control group of pups. The controls gained weight normally, but the pups with blocked CB1 receptors failed to suckle (even though the mothers encouraged them with licking behavior) and starved to death within a week.

Fride et al determined that a baby’s 2-AG production spikes as it is being pushed out into the world, and falls off about 24 hours after birth. This correlated with their finding that injecting the antagonist drug 24 hours after birth resulted in only 50% mortality. Injecting the antagonist on the fifth day of a mouse pup’s life had no effect (the pups having learned by then how to control their mouth muscles).

Fride also experimented with “knockout” mice that had been bred to lack CB1 receptors and were unable to suckle at birth. When injected with THC promptly after birth, the knockout pups were able to suckle and developed normally.

“The medical implications of these novel developments are far-reaching,” Fride wrote in the European Journal of Pharmacology in 2004, “and suggest a promising future for cannabinoids in pediatric medicine for conditions including ‘non-organic failure-to-thrive’ and cystic fibrosis.”

Over the course of her career Fride was lead- or co-author on more than 40 papers. In recent years Fride did several studies involving Rimonabant, the CB1-antagonist drug that Sanofi-Aventis hoped to market for weight loss — the same drug that caused failure to thrive in her mouse pups. (Fride found that Rimonabant blocked the weight gain commonly caused by SSRI anti-depressants.) European regulators withdrew marketing approval after Rimonabant use was linked to an increased tendency to commit suicide.

Fride also took part in studies of a compound produced by the tree that is the source of Frankincense (Boswellia serrata). The compound — Incensole acetate, as in “incense” — was found to have anti-anxiety and anti-inflammatory properties.

Fride is survived by two children who are now young adults. A brother died of cystic fibrosis, a hereditary illness that claimed several other family members.

The future of Fride’s lab is uncertain. She was supervising Shimon Rabichev’s research into the role of the endocannabinoid system in schizophrenia; Michal Schechter’s study of how the EC system affects maternal behavior and attachment; and Hodaya Dahan’s efforts to elucidate the mechanism by which the endocannabinoid system mediates suckling behavior (and how to Induce appetite in cases of failure to thrive). Their findings must now be written up under the supervision of another scientist. Can one be recruited whose expertise is as broad as Ester Fride’s? The young scientists are worried about the future as they mourn the loss of their captain.

“She was the best teacher and a very democratic person,” says Dahan, who worked with Fride for seven years and will help the family produce a website in her honor when the traditional week of mourning is over.

Rosie and I rarely talk politics with the Israeli friends we’ve made at cannabinoid research conferences. We just express hopes for peace and leave it at that. But yesterday I asked Hodaya Dahan to fill me in — had Ester, who arrived in Israel as a 19-year-old Zionist, changed her outlook over the years? Hodaya said (over a grainy phone line in a Russian-Israeli-Bronx accent) that Ester was... “you have a word for it in America...” I thought I heard her say “secular” and repeated, helpfully: “Secular! Of course — Ester was secular.” “No,” said Hodaya, “Settler. She was settler.”

I’d known that “Judea and Samaria” was a term for the West Bank — “the occupied territories” — but I hadn’t thought of Dr. Fride’s running a lab there as a political act.

She was also an athlete, said Hodaya, a marathon runner. Which — like her incredible beauty — made her death at 56 seem even more unfair.