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Power in the blood |
| TheAllINeed.com/NC&T/WI/ |
"Imagine," says the Harvard Medical School researcher, "if a spaceship landed right in the middle of Boston and a bunch of extraterrestrials started listening in on the whole stem cell debate. They'd probably think that stem cell research is some new and exotic thing. But nothing could be farther from the truth. The idea of using stem cells for therapy is old."
In particular, adult blood stem cells taken from the bone marrow, also called hematopoietic stem cells (or HSCs), have been used therapeutically since the 1960s, saving the lives of tens of thousands of people.
But if our alien visitors are confused, it's understandable. Information about the abilities, and liabilities, of embryonic and adult stem cells has become entirely muddled.
Take, for example, news that came from the University of Minnesota in 2002. Here, researchers led by biologist Catherine Verfaillie published findings that suggested that a certain class of stem cells in the bone marrow, just like their embryonic counterparts, could create a variety of different tissues. These cells, she reported, could form brain, lung, heart, kidney and intestine tissues.
The implications were huge. Embryonic stem cells exist for only a few days in a very early stage after an egg is fertilized. But adult stem cells are sprinkled throughout our tissues and organs, continuously giving rise to new cells.
 | | Beginning with the fertilized egg, a cascade of cell differentiation (shown in simplified form) ends up with a fully specialized blood cell (Photo: Whitehead I) |
"There are studies out there showing that you can take blood stem cells and get them to do X, Y and Z," says Harvard Medical Researcher Stuart Orkin. "However, no one can reproduce these studies. Or some of them just aren't believable. People cite things to prove their preconceived notions."
Up until this point, while scientists touted embryonic stem cells as having endless potential to form nearly any kind of tissue in the body, adult stem cells were accorded a single fate on the biological ladder, never to form any tissue other than that from which they came.
But Verfaillie's findings indicated that adult stem cells might be just as therapeutically useful as their embryonic grandparents. And with no ethical baggage.
"This was probably the biggest thing in adult stem cell development to come along in years," says Whitehead Fellow Fernando Camargo, then a graduate student at Baylor College of Medicine. "Still, there were some red flags."
The Minnesota findings showed that mice and rats who had received transplants from cultured stem cells derived from the bone marrow seemed to have cells that genetically matched the donor's in other tissues, such as liver and muscle. It logically followed then that when these mice received the bone marrow transplant, HSCs made their way into these tissues, listened to their unique signals, and then ripened into liver or muscle cells.
But not everything added up. For example, whether a mouse received a single HSC or 1,000 HSCs from a donor, the number of donor-matching cells ending up in other tissue never changed. "That was illogical," says Camargo. "If these blood stem cells really were giving rise to other tissue, we should have seen an exponential increase based on the size of the transplant." In fact, even when blood stem cells were directly injected into liver or muscle, there was still no increase in new cells matching the donor's.
Camargo was one of a handful of scientists to discover that these HSCs instead were creating mature blood cells that then fused with cells in the liver. In fact, Camargo was the lead author on the Nature Medicine paper that identified macrophages as the fusing culprits.
Today, plasticity of adult stem cells has been largely discredited. Few scientists seriously pursue it (although some, like Stanford's Helen Blau, are investigating whether fusion itself might have therapeutic value).
The debate roars on, particularly with opponents of embryonic stem cell research. The notion that HSCs can treat everything from liver disease to heart disease to Parkinson's continues to pop up wherever the debate gets most heated.
While the truth is far more sobering, new findings from Whitehead researchers may help to render HSCs far more therapeutically potent than they've been thus far, giving us the ability to treat disease with more precision while sparing patients many brutal side effects.
Many groups opposed to embryonic stem cell research have made grand claims about adult stem cells, declaring that they can effectively treat brain cancer, neurodegenerative diseases, heart disease, and spinal cord injury, to name a few.
"There are studies out there showing that you can take blood stem cells and get them to do X, Y and Z," says Orkin. "However, no one can reproduce these studies. Or some of them just aren't believable. People cite things to prove their preconceived notions."
The blood system, however, is one area where adult stem cells can boast an unambiguous track record of success.
"We've made a lot of advances over the years using adult stem cells for treating blood-related disease," notes Camargo, who sees plenty of opportunities ahead.
Orkin, for example, has demonstrated that the genes programming blood cell development are the same ones mutated in leukemias. His lab is investigating how the basic machinery of blood cells interfaces with blood cancers. Camargo is interested in the molecular mechanisms that enable blood stem cells to maintain their "stemness."
"If you ask us to draw up a list of every gene that's essential to a hematopoietic stem cell, right now it would be a very short list," he says. He's conducting large-scale screenings of these cells using techniques such as microarrays and RNA interference in order to find the key molecular players. His hope is that with such knowledge, scientists can fine-tune these cells for more targeted therapies.
It's likely that this will happen with blood stem cells long before it happens with any other kind of stem cell.
"We've had deep knowledge of the blood system for over 100 years," says John Dick, director of the University of Toronto's Program in Stem Cell Biology. "And we've understood the major developmental lineages of HSCs since the mid-'70s. Compare that to the liver. Biologists are still arguing over what exactly a liver stem cell looks like."
As early as the late 1800s, thanks in large part to the Russian biologist Alexander Maximov, scientists knew much about all the different lineages of blood cells. (There are about 12 blood cell lineages, compared to only three cell lineages in brain tissue.) Interest soared in the mid-20th century, when scientists discovered just how vulnerable the blood system was to atomic radiation. By the 1940s the concept of bone marrow transplantation had worked its way into the biomedical world. Bone marrow trials began in the 1950s. But nearly all the patients died.
Canadian researchers James Till and Earnest McCulloch at the Ontario Cancer Institute in Toronto finally identified and characterized the first blood stem cell in the early 1960s (work that has dubbed them the "fathers of stem cell research"). Discovering the proteins that enable HSCs to differentiate and mature, Till and McCulloch made it possible to quantitatively analyze a single hematopoietic stem cell. That revolutionized the success of bone marrow transplants.
Then, in the mid-1980s, Irving Weissman of Stanford University developed methods for purifying HSCs using monoclonal antibodies (antibodies created in mass quantities from a single immune system cell).
"Even in the last five years we've come such a long way in understanding the molecular mechanisms that regulate and maintain blood stem cells," says Camargo.
This fine-grained understanding of the blood system and its stem cells has created a multi-billion-dollar therapeutic industry. Blood is one of the most highly characterized and best-understood tissues in the human body.
That doesn't mean that we can make it do what we want. "We've gotten very good at taking blood cells out of one person and transplanting them directly into another person," says Dick. "But if you want to do something with those cells in culture before transplanting them back, like expand them, we're still met largely with failure."
If there's one thing that Whitehead Member Harvey Lodish has learned over the last few decades, it's that hematopoietic stem cells are finicky.
"Our goal is to take these cells out of their natural environment and get them to do in the lab what we want them to do," says Lodish. "The tricky part is, these stem cells hate being taken out of their natural environment."
Quite simply, HSCs are happy in the bone marrow. Normally, when you place HSCs in a dish that tries to mimic that environment, they either die, or immediately mature into red and white blood cells.
Scientists would love to maintain HSCs in their stem cell state, multiply their number by 10 or 100, and then transplant them into the patient. "There just simply aren't enough of them in the bone marrow," explains Lodish. "The more stem cells you transplant, the more successful the procedure will be. Even in cord blood, the amount of stem cells just isn't adequate for treating an adult."
Because of these limitations, bone marrow transplants take a huge toll on patients. For a typical transplant procedure, a patient is first irradiated, which destroys all his or her own diseased bone marrow. A sample of donor marrow is then transplanted into the patient, where it eventually repopulates him or her with healthy blood stem cells.
Unfortunately, because families in the U.S. are getting smaller, only about one-third of the population has related donors. So physicians painstakingly try to match donors with patients so as to minimize immune system rejection. Sometimes after a transplant patients need to take immunosuppressant drugs for months. Other times, they do so for the rest of their lives.
One way to ease immune system rejection is to remove all the T cells from the donor marrow prior to the transplant. (T cells are a kind of white blood cell and are often the first to be recognized as foreign.) And although this effectively deals with the immune rejection, removing the T cells decreases the therapeutic potency of the transplant. In order to increase the potency, you need to increase the number of stem cells coming from the donor. But at the moment, we can't.
It's a catch-22: We can give either an effective transplant with immune system complications, or a less-effective transplant without these complications.
"Almost every roadblock we come to with blood stem cells comes down to our inability to multiply them in the lab," says Lodish.
Over the years many labs have reported success in this area, only to find that these purported advancements have been false leads. But in 2003, Lodish's lab stumbled upon what might just be the answer.
Chengcheng Zhang, a postdoctoral researcher, was studying fetal tissue in mice when he discovered a new population of cells that, in the natural environment, appeared to have a preserving effect on HSCs. When he isolated the stem cells and placed them in a lab dish by themselves, they died. When he mixed in these newly discovered cells, the stem cells thrived. But how did these cells manage to sustain the stem cells so dramatically?
Zhang reasoned that they might be secreting certain proteins that sustained the stem cells. Using a series of microarray platforms, Zhang located a number of such proteins.
In the fall of 2003 and early 2005, Zhang reported in the journal Blood that one of these proteins called IGF-2, when added to a solution of HSCs, increased their number eightfold. Later he discovered that two more growth factor proteins, angpt12 and angpt13, when combined with IGF-2 into a cocktail, caused a 30-fold increase. These results were reported in Nature Medicine.
Lodish is cautiously optimistic. "If these results, which occurred in mice, are repeated with human cells, this will have huge implications for not only bone marrow transplants but for cord blood transplants, for gene therapy and especially for basic research," he says. His lab now is collaborating with researchers at Lund University in Sweden to repeat these results with human cells.
As Lodish and colleagues continue exploring ways to multiply these slippery cells, others are still trying to discover if HSCs have therapeutic reach beyond blood.
For now, trying to get adult stem cells to behave more like their embryonic cousins appears doomed to failure. When a bigger payoff arrives from these highly specialized cells, it most likely will come from getting them to do what they already do best.
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