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Research, Science, Stanford News, Stem Cells

Researchers celebrate 25th anniversary of major stem cell discovery

Researchers celebrate 25th anniversary of major stem cell discovery

A new era of stem cell science began 25 years ago. At that time, Stanford researcher Irving Weissman, MD, and his colleagues announced in Science that they had purified hematopoietic stem cells from a mouse. This was the first “adult” (tissue specific) stem cell isolated in purified form from any species. In order to isolate the stem cells, the researchers had to identify the key cell-surface proteins that differentiated the stem cells from closely related cells and separate them from each other. They also had to develop new transplant models to show that the stem cells could produce every single type of blood an immune cell needed by the body.

Since then, researchers at Stanford and elsewhere have learned to identify and purify blood stem cells and other types of stem cells in humans, opening the door to creating stem cell therapies that researchers hope will be able to cure many intractable diseases. Today, we’re honoring this achievement as part of the observation of World Stem Cell Awareness Day.

Previously: Very small embryonic like stem cells may not exist, say Stanford researchers, Stanford’s Irving Weissman on the (lost?) promise of stem cells and Stanford study shows stem cell treatment improves survival of patients with metastatic breast cancer

Immunology, Research, Science, Stanford News, Videos

Ocean organism settles down, digests its proto-brain and loses its individuality

Ocean organism settles down, digests its proto-brain and loses its individuality

Last week, Science published a research report from Stanford scientists on the discovery of a single gene in a primitive marine organism that determines whether that organism recognizes wayward cells as being part of themselves or foreign. What’s interesting scientifically is that this is a very primitive immune system, and if we understand exactly how it works and how it evolved, we might learn something about how our own immune system recognizes foreign cells. It could eventually lead to new understanding about how to repel disease-causing organisms or how to successfully transplant organs.

That finding is impressive, but I also found myself fascinated by the strange organism they were studying: Botryllus schlosseri. This ocean-dwelling creature has two life stages. In the larval stage it swims about freely and has a primitive brain and notochord (like a proto-spinal cord). But eventually it attaches itself to a rock with other Botryllus organisms, dissolves its proto-brain, and buds off identical individuals to share life under a sheltering tunic. Domestic Botryllus bliss.

It gets stranger. These individual Botryllus organisms share a common circulatory system that pumps fluid through their colony. This circulating fluid carries cells from one individual to another. When two adjacent related colonies touch, they can fuse and form a joint circulatory system, allowing cells from one colony to implant themselves in the other. Circulating stem cells can then potentially replicate themselves throughout the fused colonies, replacing the cells of the recipient Botryllus until they are clones of the donor.

Luckily, they haven’t become advanced enough to engage in psychotherapy. No life cycle is long enough to work out those issues.

Research, Stanford News, Technology, Videos

Stanford computer scientist shows stem cell researchers the power of big data

Stanford computer scientist shows stem cell researchers the power of big data

Not long ago, Stanford computer scientist Debashis Sahoo, PhD, told investigators at the Stanford Institute for Stem Cell Biology and Regenerative Medicine that in a few seconds he could find many of the important stem cell genes that the researchers were used to finding only after spending millions of dollars and years in the lab. “We laughed and said, ‘That’s impossible,’” recalls Irving Weissman, MD, director of the institute, in a recent video. But Weissman went ahead and gave Sahoo information about two key genes – and within a few seconds, Sahoo had used his desktop computer to scour the world’s public gene databases, analyzed that information with the computer algorithm he had designed, and come up with over a dozen genes new genes that were involved in the development of certain kinds of cells. That search, Weissman estimates, saved his team a decade of work and about $2.5 million.

More details are shared in the video above. And as a reminder, big data – and the ways in which people like Sahoo are mining through vast amounts of publicly available information to further research and advance health care – is the focus of a Stanford/Oxford conference being held here later this month.

Previously: Atul Butte discusses why big data is a big deal in biomedicine and Mathematical technique used to identify bladder cancer marker

Cancer, Research, Stanford News, Stem Cells

Blood cancers shown to arise from mutations that accumulate in stem cells

Blood cancers shown to arise from mutations that accumulate in stem cells

How and why do some cells in our bodies become cancerous?  Can any cell become cancerous, or only certain kinds of cells? Those are longstanding questions with big implications for treating and preventing cancer.

In the case of leukemias, Stanford researchers finally have an answer to the first question: Mutations accumulate slowly in blood stem cells, the cells that produce all the cells of the blood and immune system. This had been a controversial theory of some experts, and the team proved it correct by comparing mutations found in leukemia cells with mutations found in blood stem cells from the same patient. As I explain in a release today:

When the researchers compared mutations in these seemingly normal blood stem cells with the leukemia cells, they could reconstruct exactly which mutations led to the leukemia, and the order in which the mutations arose. They did this by looking for blood-forming stem cells with a single mutation, which they knew must be the first, then finding other stem cells with that first mutation plus one other, which they could then identify as the second. They continued to do this until they found examples of stem cells at each stage of mutation accumulation, leading up to the full set of mutations found in the actual leukemia cell.

Individual mutations can occur in mature blood and immune cells too, but these cells will die off naturally before they get the whole set of mutations needed to cause cancer. Only the stem cells, which last a lifetime, are around long enough to accumulate all the mutations.

This information is important for treating leukemia (and perhaps other cancers, if the same pattern applies). Leukemia can initially be treated with chemotherapy to kill the cancer cells, but patients will often relapse – the cancer comes back, often more deadly than before. One possibility is that relapse occurs because a few leukemia cells survived the chemotherapy, in which case the solution might be increase the potency of the chemotherapy. But if relapse occurs because the stem cells are creating new leukemia cells, then it really won’t matter how effective chemotherapy is because the mutated stem cells are acting as a reservoir for the disease. Co-principal author Ravi Majeti, MD, PhD, said this area will be the focus of the next phase of the team’s research.

This study appears in Science Translational Medicine.

Previously: Leukemia prognosis and cancer stem cells

Cardiovascular Medicine, Image of the Week, Stanford News

Image of the Week: “Heart cells”

Image of the Week: "Heart cells"

As I reported in this week’s issue of Inside Stanford Medicine, Scott Metzler, PhD, is a researcher who not only studies the early development of the heart, but also suffers from a serious heart defect called Tetralogy of Fallot. Since hearts are a leitmotif of Metzler’s life, it seems appropriate that heart-shaped images, like this one, recently popped up under his microscope.

Metzler has been studying the action of apelin, a protein that seems to offer some protection against heart disease. Metzler observed that when heart muscle cells are exposed to apelin, the protein clusters at one point on the cell and pulls that spot down toward the center of the cell, making that spot pucker. In the microscope, from the side, these cells start to look like little hearts.

Photo courtesy of Scott Metzler

Medicine and Society, Technology

Medicine is about to be “Schumpetered” – and go through its biggest shake-up in history

Medicine is about to be “Schumpetered" - and go through its biggest shake-up in history

Eric Topol, MD, director of the Scripps Translational Science Institute in La Jolla, Calif., was at the Stanford Cardiovascular Institute talking yesterday about the transformative power of digital technology and social networks in medicine. He noted that economist Joseph Schumpeter described more than 50 years ago how old ways of doing things are destroyed as new technologies take over. “Medicine is about to go through the biggest shake-up in history,” Topol predicted. “We are about to get Schumpetered.”

Displaying a graph of people’s increasing interaction with digital devices, he talked about the rise of the iPod, the Blackberry phone, the iPhone and now social networking, and the accelerating changes they have made in how we live our lives. Add those devices to the increasing amount of digital information available about our biological and physiological states, and “we are about to hit the inflection point” in how all medicine is done.

Topol foresees a world in which people will know an enormous amount about their own genes, biochemistry and physiological state, and have the ability to monitor changes in real time and transmit that information to physicians far away. There are already wireless devices that record and transmit information about blood pressure, heart rate, physical activity and sleep state. Doctors can carry an echocardiogram device in their pockets. Very soon, Topol said, we’ll have inexpensive implanted sensors that will be able to spot cancer cells floating in the bloodstream or spot a developing heart attack, giving us enough warning to do something about it.

The new technology will enable many patients to be at home instead of in the hospital because they can be monitored from afar. “Why do we need hospitals except for intensive care visits?” Topol asked. “Why do we need clinics when we can do it wirelessly?”

Putting these information technologies to work will also finally allow medicine to move from a populations-based approach to individualized medicine. As an example, Topol cited the case of Nicholas Volker, who at three years old had undergone more than 100 operations because a mystery illness was eating away at his digestive tract. As a last resort, doctors sequenced his whole genome and found one gene mutation that was causing the problem. A stem cell transplantation from cord blood cured him.

I, for one, am looking forward to these changes. I think they’ll result in a system in which we’re more connected to our health needs and more connected to people around us. And I think we’ll have generally better health care – as long as we don’t lose the personal connection to physicians.

Cancer, Research, Stanford News, Stem Cells

Cancer stem cell researchers are feeling the need for speed

Cancer stem cell researchers are feeling the need for speed

Stanford researchers just announced that by using a new antibody against a cell protein called CD47, along with an existing anti-cancer antibody, they were able to cure well over half of a group of mice with human non-Hodgkin’s lymphoma. (Their paper appears in the journal Cell.) This is particularly promising because there is an abundance of CD47 on many other human cancers – such as breast, bladder, skin, brain and lung cancer – and the potential benefit might be extended to these other malignancies.

I had been hearing about this result around the labs for a while, and when I learned in early August that the research would be published I was excited that we would soon be able to talk about it publicly. But that excitement was tempered by a sad counterpoint.

That same week I read in a local newspaper a story about a non-Hodgkins lymphoma patient, Vallejo, Calif. police sergeant Brian Carter. Carter, a 36-year old father of two young boys, had been diagnosed last year and had beaten back the cancer with chemotherapy. But the leukemia returned this year, stronger than before, and at the time I read the story, Carter was searching for a compatible donor for a bone marrow transplant. Happily, I’ve since learned that a matched donor had been found and his chances of successful treatment are good, but there are many people around the world in the same situation who won’t be so lucky.

I see the same mixed feelings all the time among cancer stem cell researchers. Many of the researchers are also physicians who treat patients, and they know existing cancer therapies are not effective enough for many – which is why they went into the lab in the first place. They’re excited to be making real progress, but at the same time they know research can only move so fast.

As for this promising research, science has not progressed to the point where people can be treated. But “we want to bring this to patients as quickly as we can,” MD/PhD student Mark Chao and co-first author of the release, said in a release. Plans are already in the works to create a human version of the anti-CD47 antibody and prepare for a clinical trial within a couple years, which is about as fast as the process can go.

Autoimmune Disease, HIV/AIDS, Stem Cells

Using stem cells to treat and cure immune diseases

Irving Weissman, MD, director of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine, along with graduate student Agnieszka Czechowicz, recently published a fascinating review article in the May issue of the journal Immunology and Allergy Clinics of North America. The piece lays out how a one-time treatment with blood (hematopoietic) stem cells could provide a lifelong cure for autoimmune disease like lupus, rheumatoid arthritis and type 1 diabetes, could possibly cure AIDS, and could eliminate the ongoing need for anti-rejection drugs by organ transplant recipients.

How? If the immune cells that cause the problems can be eliminated and replaced with new blood and immune stem cells, those cells will spawn immune cells that don’t attack the body’s own tissues. Scientists have also shown that, at least in one case, stem cell transplantation from someone naturally resistant to AIDS could cure the disease in someone already infected. And if doctors giving someone an organ transplant also give them blood stem cells that are from the organ donor, the recipient’s body won’t try to reject the new organ.

But most of these therapies remain in the future. The problem? The blood stem cells that are already in the body don’t like to give up their territory to newcomers. In order to get transplanted stem cells to take up residence in the bone marrow, doctors have to wipe out some or all of the existing blood stem cells. For years, physicians have done exactly that to treat leukemias, by administering radiation or toxic chemicals that kill both cancerous cells and blood stem cells, and then adding back bone marrow from an immunologically compatible donor. But to do this, the patient has to be brought to the edge of death. Between 10 and 20 percent of those who get bone marrow transplantation will die, and even if the patient survives, the therapy also damages other tissues. As long as other treatments exist for many of these diseases, using a therapy so dangerous and damaging is hard to justify.

The article notes, however, that as we understand more about how blood stem cells work, we are seeing a possible path to much safer treatments. Researchers now know about molecular signals that can get native stem cells to vacate their niches for transplanted stem cells. In the future, these or other signals may become the basis for safer stem cell transplantation and open the door to new therapies for difficult, chronic immunological diseases.

Cardiovascular Medicine, Stem Cells

The cruelty of fraudulent stem cell therapy

iStock_quackdoc.jpgUPDATE 01-30-10: In writing about what seems to be a clear case of medical abuse I did not note that there are legitimate scientists who continue to investigate the use of bone marrow cells as a vehicle for heart repair. My apologies to them. However, these therapies are still in the research stage and patients should only get them as part of a controlled clinical trial. The problem in differentiating research that is legitimate from that which isn’t only highlights the need for a certification system for stem cell treatments.

* * *

When someone e-mails the Stanford Institute for Stem Cell Biology and Regenerative Medicine, the note comes to me. So I get to see a lot of heartbreaking pleas for help from patients or family members. Sadly, although a few stem cell therapies (such as bone marrow transplantation) are available now and many are getting closer, most stem cell treatments – the miracle cures for multiple sclerosis, paralysis, Alzheimer’s disease, heart failure and many other conditions – remain in the future.

This morning I got a plea not for treatment, but for justice. The writer’s mother had been seen in Florida at a self-described stem cell clinic for a heart condition. The mother had been through multiple open heart surgeries and valve replacements. She had been in the hospital as recently as November, and was still so frail she could hardly walk herself to the restroom. Nonetheless, the clinic convinced her that they could treat her for $65,000, and in January she was taken to an “ill-equipped and poorly staffed” hospital in the Dominican Republic. The writer reports that his mother was dead within two hours of the treatment.

It’s hard to tell from the note, but most likely the stem cell “therapy” was an infusion of cells that may have come from bone marrow or other tissue. There used to be hope among some scientists that stem cells from bone marrow could colonize and repair heart tissue, but a few years ago Irving Weissman, MD (the director of Stanford Institute for Stem Cell Biology and Regenerative Medicine) and Robert Robbins, MD (the director of the Stanford Cardiovascular Institute) proved that this was not true. There are some promising studies going on at Stanford and elsewhere looking at the use of cardiac-specific stem cells to repair the heart, but these are not yet clinical treatments, and no responsible scientist now thinks that you can throw just any old stem cell into the heart and it will make anything better.

That hasn’t stopped companies around the world from claiming that they treat all sorts of disease with stem cells, for the right price. These companies are represented by doctors or nurses here, but the treatments are usually done overseas to avoid scrutiny by US authorities. Weissman is currently president of the International Society for Stem Cell Research (ISSCR), and one of his priorities is to establish a system that will review stem cell treatments so that patients and doctors can find out which are scientifically valid. Until that becomes a reality, however, desperate and vulnerable people are dealt another round of heartache, and the truly wonderful promise of stem cell therapy may be tarnished by quacks.

Photo from iStockphoto

Neuroscience, Pain

Tinnitus: the ear’s version of phantom limb?

iStock_tinnitusW200.jpgThe New York Times recently reported on a really interesting treatment for tinnitus, the irritating (and sometimes crazy-making) ringing in the ears that sometimes accompanies noise-related hearing loss. The article doesn’t mention it, but the treatment seems to me to have parallels to therapies for phantom limb pain, and reinforces new ideas about how the brain works.

The tinnitus treatment involves listening to music in which researchers have removed a one-octave frequency band centered around the frequency of the ringing. Those who listened to this “notched” music for 12 hours a week over the course of a year reported much improvement in their tinnitus.

In phantom limb syndrome, people who have lost a limb report that they still sense the limb’s presence, and often feel intense pain that they cannot get rid of. For instance, some people who have lost their hand report that they feel as if the missing hand is permanently and painfully clenched in a fist that they can’t relax. Neuroscientists think that the brain is used to sensory signals coming from the hand, and that when those signals suddenly cease, the brain supplies its own signals about what the hand is doing. A great article in the New Yorker described a similar phenomenon that causes endless itchiness.

A fairly new therapy for phantom limb pain uses a mirror to trick the brain into thinking it is getting signals from the missing hand: the patient is asked to imagine making the same motions with both hands, with the real hand making those motions in front of a mirror while the reflection seems to show the missing hand making the same motions (kind of like the old “levitating” trick). Regular sessions with the mirror seem to supply enough virtual input from the missing hand that the brain is able to reorganize and let go of its need for input.

It may be that a similar thing is happening with tinnitus: when input from some frequencies is missing due to hearing loss, the brain supplies its own input. With phantom limb syndrome, therapists are tricking the brain into thinking it is getting signals from the missing hand, whereas with tinnitus, therapists may be tricking the brain into thinking that the signals from the missing frequency are gone for a reason – the whole octave is missing. In both cases, supplying an artificial context for the missing signals may then allow the brain to stop supplying its own bothersome signal.

Photo by iStockphoto

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