The Stem Cell Fast Track
Fri, 01/30/2009
Staff Writer

In a city where so many cultures seek spiritual reawakening, scientists in Jerusalem are harvesting their own type of rebirth, as they develop more ways to save lives through the use of undifferentiated stem cells.

The laboratories of Israeli universities boast some of the newest advancements in molecular biology, and two potentially life-changing stem cell projects are unfolding at Hebrew University – Hadassah Medical School.

Fixing what was once thought to be irreversible, one of the teams is now capable of repairing neural birth defects, according to their leader Joseph Yanai, professor of biology at Hadassah Medical School and adjunct professor at Duke University Medical School. The second team, led by Hadassah professors Howard Cedar and Yehudit Bergman, says they are unraveling the mechanism that locks cells into differentiated tissue types and reverting them back to their stem cell origins, so that the cells are viable for future disease repair in multiple organs.

While neither team can predict when their discoveries will be implemented in human lives, both teams are impressed with the rapid progress.

“It’s developing fast,” Yanai said.

Neural and behavioral birth defects are more difficult to treat than other conditions such as Parkinson’s disease, where doctors understand exactly what’s going on and can target a specific location for cell transplantation, according to Yanai. For birth defects, the situation is not so clear. Neural birth defects are caused by agents vaguely called “teratogens,” which diffuse all over the brain through a mechanism that is still mysterious to scientists and can cause multiple defects, he explained.

But Yanai and his lab team may be on their way to solving this mystery, by inserting stem cells from the patient’s very own nervous system.

“We transplant neural stem cells — they’re in a more advanced stage,” he said, noting that while these cells are somewhat specified, they are also still a bit flexible. “They are already decided they are going to be brain cells, but they don’t know what kind of brain cells they are going to be.”

“They’re the little doctors — we send them to the brain, they run around in the brain. Find loci of the problem, site of the problem, find what type of problem,” he continued. “That’s why we were able to repair neural behavioral birth defects.”

Through chemical signals, the cells can locate the exact site of problem and differentiate into whatever type of neural cell that the brain needs, Yanai explained.

In his lab, Yanai and his team have been using mice and chickens as their subjects, by exposing pregnant mice to both heroin and the pesticide organophosphate, which caused imminent brain damage to their offspring.

“The addiction of heroin is very specific to fertility age and organophosphate because the developing organism is very sensitive to organophosphate,” Yanai said, noting that a newborn baby is 100 times more sensitive to organophosphate than is an adult.

Using their new technology, the doctors were able to successfully repair these preplanned birth defects once the animals matured, Yanai said. But they are also now able to transplant some neural stem cells into a chicken embryo.  

“Normally since the fetus is so young we are going for models that are more focused,” he said. “We have to go to a model which is specific where the damage is clear, where it is known.”

Yanai and his team are currently developing a method to be able to transplant the stem cells directly into blood vessels, and because the cells are from the patient’s own body, they will not face immunological rejection. 

“I solved three problems — friendlier administration, rejection and moral issues,” he said, explaining that now he will not have to face ethics disputes over embryonic stem cell usage. 

In the second Hebrew University team, doctors are also aiming to curb the ethics problem associated with embryonic stem cell extractions, by reverting already differentiated adult stem cells backwards, to their infantile form.

“One of the challenges today is to generate normal tissues for replacing abnormal damaged cells in a variety of different diseases, such as diabetes,” Bergman said. “Our findings will probably help in reprogramming adult cells to flexible embryonic cells, which could be, in turn, induced to differentiate to a specialized needed cell type.”

During embryonic development, all cells begin in a pluripotent stage and have the flexibility to do anything, Cedar explained. Very quickly, however, they enter differentiation and grow into a fixed, specific cell type.

“The way the programming is done, it’s very unidirectional,” Cedar said.

“Coming back is very difficult,” he continued, explaining that the human body system instinctively tries to remain stable. “If you can take any cell in the body and go backwards, then you can use that cell to make a different kind of tissue.”

And Cedar and his coworkers may have figured out a way.

The team has identified a “master regulatory” enzyme called G9a, which is responsible for shutting down cell pluripotency – the ability of cells to develop into more than one type of mature cell --when the embryonic cells are ready to begin differentiation, according to Cedar, whose research is financed by the Israel Cancer Research Fund.

“There’s a mechanism for turning off [the cell’s] ability to be flexible — when the cell starts differentiation that whole mechanism is turned off, and it’s turned off by this protein G9a,” he said. “If you can get rid of G9a, that will help you go backwards.”

Thus far, the doctors have accomplished this goal in lab mice only because of the illegality associated with human genetic testing, Cedar said. But eventually, they are hoping to be able to take a person’s very own blood cell, place it in a culture to perform the reversion process and then reprogram that cell as needed. As Yanai also explained, Cedar pointed to the efficiency of using cells from that very same patient, rather than borrowing from another person or from an embryo.

“When you put cells into the body from another person, the body responds. You have an immune response and that prevents any of this from working,” he said. “Every cell in the body has the same exact genetic material, but in every cell it’s programmed differently.”

By removing G9a from a patient’s own developed cells, doctors would be able to begin with a clean slate that is 100 percent compatible with the person’s immune system, Cedar explained. And in humans, he said, this could be a solution for so many life-threatening cancers and diseases. In diabetes, for example, rather than constantly injecting a person with insulin, doctors could perhaps reprogram nondescript blood cells to regenerate healthy, insulin-secreting pancreatic cells. Likewise for Parkinson’s patients, doctors could implant reprogrammed motor cells, he said.

But the question remains – when will these potentially life-renewing techniques be available to humans?

“The answer for almost everything in science is yes. One day we’ll do everything,” Yanai said. “There’s no limit at all. Then you will ask me, so when? Here I cannot answer.”

“The technology exists, but it’s just not at the stage where you can use it yet,” Cedar agreed. “But it will be soon — it’s progressing very rapidly.”