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Scientists Are Developing New Ways to Treat Disease With Cells, Not Drugs

Date (2018-09-17)

When Nichelle Obar learned she was pregnant with her second child last year, she never expected that her pregnancy, or her baby, would make history.

But when the 40-year-old food-and-beverage coordinator from Hawaii and her fiancé Christopher Constantino went to their 18-week ultrasound, they learned something was wrong. The heart was larger than it should have been, and there was evidence that fluid was starting to build up around the organ as well. Both were signs that the fetus was working extra hard to pump blood to its fast-growing body and that its heart was starting to fail.

Obar's doctor knew what could be causing it. Obar and Constantino are both carriers of a genetic blood disorder called alpha thalassemia, which can lead to dangerously low levels of red blood cells. Red blood cells carry hemoglobin, which binds to oxygen and transports it from the lungs to feed other cells–so fewer red blood cells means low levels of oxygen in cells throughout the body. Neither parent is affected by the condition, but depending on how their genes combined, their children could be.

When Obar was pregnant with their first child, Gabriel, the couple was told that if he had the disease, his prognosis would be grim. "The information we got was that most babies don't survive, and if they do survive to birth, they might not live for too long," Obar says. Gabriel was lucky. The DNA he inherited from his mom and dad did not endow his cells with enough of the mutation to make him sick.

But soon after that 18-week ultrasound, their second baby, a girl, was officially diagnosed with alpha thalassemia. "We were pretty devastated," Obar says. They did not have many options: their daughter would need blood transfusions in utero just to improve her chances of being born, and even if she survived to birth, she might need regular transfusions for the rest of her life, relying on a healthy donor's blood to make up for the low oxygen in her own.

Their genetic counselor did have one other suggestion, but it was a long shot. She had just learned about a study at the University of California, San Francisco (UCSF), testing a daring new way to potentially treat alpha thalassemia: a stem-cell transplant given to the baby in utero.

In utero stem-cell transplants had been tried before for the blood disorder but with limited success. Blood stem cells, which develop into all of the different types of blood cells, are extracted from a donor's bone marrow, processed in a lab and injected directly into the umbilical vein connecting the fetus to the mother's placenta. Ideally, the donor's healthy stem cells then start dividing and take over for the fetus' defective blood cells. But removing bone marrow can be risky in pregnant women, so past trials involving alpha thalassemia used stem cells from fathers, which were often rejected. This new trial challenged the ethical question: Was it worth the risk to the mother in order to possibly save the fetus? There was also a chance the transplant could harm Obar's daughter more than it helped. But on the basis of new studies suggesting that a developing fetus would tolerate a mother's transplanted cells better than a father's, Dr. Tippi Mackenzie, a professor of surgery at UCSF and the leader of the study, believed it was worth a shot.

Obar had concerns, but if the cells worked as they were expected to, it could give her daughter a chance at life, hopefully even a normal life free of her disease. She and Constantino decided to try it. Their daughter would be the first fetus in the world to receive stem cells from her mother in a carefully monitored clinical trial.

While blood stem cells from bone marrow have long been a cornerstone of treating blood cancers like leukemia and lymphoma, Mackenzie's trial extracting the cells from a pregnant woman to treat a developing fetus in utero is just one of several innovative uses of stem cells to treat a growing list of diseases with cells instead of drugs. And promising studies are inching more of these stem-cell-based treatments closer to finally being tested in people.

With stem cells like those found in bone marrow, scientists are taking advantage of what the body does naturally: generate itself anew. Many of the adult body's organs and tissues, including fat cells and blood, are equipped with their own stash of stem cells whose sole job is to regenerate cells and tissues when older ones are damaged or die off and which can be harvested for research and growth outside the body.

Some organs are not endowed with these large stem-cell reservoirs, however, most notably the brain and heart muscle. So more than two decades ago, scientists found another source of these flexible cells–in embryos that were donated for research from in vitro fertilization clinics. They learned how to grow these cells in the lab into any cells in the body. That opened the possibility that conditions like heart disease, diabetes or even psychiatric disorders might eventually be treated by replacing damaged tissues or organs with healthy ones, which could provide cures and treatments that didn't require drugs or surgery.

But using cells obtained from human embryos raised serious ethical questions; because extracting the embryonic stem cells required terminating what some felt was a living human being, for years federal law prevented scientists from using government funds to conduct research on these cells.

Beginning in 2006, scientists found a detour around this ethical roadblock. A Japanese team led by Shinya Yamanaka from Kyoto University showed it's possible to take a skin cell from any person, erase its life history as a skin cell and return it to the clean slate it had in the embryo–turning it essentially into an embryonic stem cell without the morally complicated provenance. Called induced pluripotent stem (iPS) cells, these malleable cells can be coaxed in a lab dish, with the right cocktail of factors, into becoming heart muscle, brain nerves or insulin-pumping pancreatic cells.

In the quest to try these treatments on patients, there have been false starts. In 2009, the FDA approved the first embryonic-stem-cell clinical trial, which involved transplanting nerve cells made from stem cells into paralyzed people to restore the function of spinal nerves. In initial tests with mice, however, the transplanted cells started to form concerning clumps, which were not tumors but raised enough alarms about the safety of the therapy that the FDA put the study on hold; after resuming the trial, the company conducting the research eventually decided to stop it.

Now, with more years of study and experience, scientists are preparing to test whether stem cells that transform into heart muscle could replace dead tissue after a heart attack, for example, or whether pancreatic cells that can't produce enough insulin might be replaced with new cells that can do the job in people with Type 1 diabetes. Researchers even hope to one day treat brain disorders like Parkinson's with new neurons made from stem cells that can replace the damaged motor nerves in the brain that lead to uncontrollable tremors.

"With stem cells we can now get to the root cause of a disease and start looking for cures rather than [treatment] patches," says Dr. Deepak Srivastava, director of the Roddenberry Stem Cell Center at the Gladstone Institutes and a professor at UCSF.

Not only can stem cells lead to new treatments for diseases where they can replace ailing cells, but they can also provide a critical new way to study conditions that have remained black boxes because scientists simply didn't have the luxury of studying live cells. Now labs across the country are incubating so-called mini-brains, made up of tens of thousands of brain cells grown from iPS cells, to serve as models for studying psychiatric disorders from autism to schizophrenia. Such knowledge could lead to new treatments in a field where therapies haven't been as widely successful as doctors hoped.

Putting the entire universe of stem-cell research together, from iPS cells to the new use of blood stem cells that Obar's daughter received from her mother, Mackenzie says, "it's an unbelievably exciting time to be in medicine, with all of these things exploding around us."

 

 

Source : time

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