Possible new treatment approach suggested by Arab-Israeli pediatrician’s discovery of how interrupted sleep speeds the spread of cancer.

By Blum
Dr. Fahed Hakim.

Dr. Fahed Hakim.

Dr. Fahed Hakim laughs while admitting that he is remiss at taking his own advice about getting a good night’s sleep. As is the case with so many of us, his grueling work schedule, coupled with a full family life, takes its toll on his ability to get sufficient shut-eye.

But Hakim, a pediatrician and pediatric pulmonologist at the Rambam Medical Center in Haifa, as well as a private practitioner in Nazareth, spends his waking hours efficiently and wisely. Sleep research he conducted during a two-year stint at the University of Chicago Comer Children’s Hospital led to a discovery that is causing genuine excitement in the scientific community.

“We found a new pathway that could drive medication in cancer treatment,” Hakim tells ISRAEL21c at his office in Rambam.

The connection between health problems and fragmented sleep is already known, says Hakim. For example, children who don’t get enough sleep exhibit memory and cognition difficulties, and have a greater tendency to attention deficit disorder. Hakim wanted to know why.
His groundbreaking study on the effect of interrupted sleep on tumor growth was published in the January 2014 issue of the Journal of Cancer Research.
Sleep less, eat more
Hakim, 40, is a Christian Arab-Israeli who was born, raised and still lives in Nazareth. He is a married to a dentist, also from Nazareth, whom he began dating when the two were students at the Hebrew University in Jerusalem. The couple has two sons, 11 and 7.
His father, a civil engineer, pushed him to excel in his studies. Hakim participated in several educational programs and summer camps in Israel for gifted children. He completed his degree in medicine in 2000, and has worked at Rambam ever since.
In 2010, Hakim received a joint American Physicians Fellowship/Israel Medical Association Fellowship grant that took him and his family to Chicago.
The first topic he examined there, under the tutelage of pediatrics chairman David Gozal, was the correlation between poor sleep and conditions such as hypertension and metabolic syndrome (obesity).
Rambam Medical Center, Haifa.
Rambam Medical Center, Haifa.
“People with sleep disorders tend to eat much more,” says Hakim. “This creates a vicious cycle, because they keep gaining weight, and if they become obese, they are prone to sleep apnea.”
More waking hours mean more trips to the fridge because brain receptors for the appetite-suppressing hormone leptin cease working in people whose sleep is fragmented.
Hakim’s first year in Gozal’s lab was devoted to this issue. His second was spent researching the connection between fragmented sleep and cancer.
Sleepless mice
“We knew from epidemiological studies that people whose Circadian rhythm is disrupted – like night-shift workers – have a higher incidence of cancer,” says Hakim.
“We also knew that sleep apnea sufferers, who snore and wake up dozens of times a night, have a higher tendency to cancer. In other words, the more hypoxic a person is – the lower the levels of his oxygen – the more he is disposed to cancer. Studies on this emerged just when we began to think about our next research project. So we decided to ask how it happens and why.”
Hakim and his research team experimented on two groups of mice. The control group was allowed to sleep normally. The other group was wakened repeatedly. After a week, cancerous tumor cells were injected into all the mice.
Within four weeks, the volume of the tumors – as well as the amount of cancer cells — in the mice whose sleep had been interrupted was double that in the mice that slept soundly.
And the tumors in the sleep-disrupted mice were more invasive; they spread into the adjacent tissue, muscles and bones. The tumors in the mice that had slept better, meanwhile, were better contained.
“To understand why, we looked at the tumor micro-environment,” says Hakim.
“When you have an invader in your body, your immune system tries to attack it. The cells that eat invaders, like bacteria, are called microphages. Tumor cells have two kinds of macrophages — M-1 and M-2. M-1 helps the immune system; M-2 helps the invader. In the sleep-fragmented mice, instead of having more M-1 cells to help the immune system fight the tumors, the M-2 cells came out to help the tumors.”
Take sleep seriously
Hakim’s team discovered that these M-2s were sitting on the edges of the tumors and calling other macrophages to the area by sending messages to the TLR4 receptor – a protein that activates the immune system.
“What we found was that the TLR4 in the sleep-deprived mice was highly activated,” Hakim says. “So we decided to knock out the TLR4. And we discovered that the tumors in the mice in which we knocked out the TLR4 did not grow as quickly.”
It is this discovery – which suggests pharmaceutical possibilities – that has the scientific community buzzing.
For the rest of us, the take-home message is that we need to take sleep seriously.
“Sleep fragmentation is widespread, even among healthy people, but it has negative long-term effects,” Hakim says. “Thomas Edison did not realize when he invented the light bulb that this would mean we would never be in complete darkness.”
Hakim stresses the importance of preparing properly for sleep. “Sleep is not the default of being awake; you don’t just unplug yourself and go to sleep. It is something that requires taking a kind of action, such as creating the right atmosphere before getting into bed. Calming down by reading or taking a shower or whatever works for you.”