Stem Cells

I was so happy to learn that Stanford stem cell researcher Marius Wernig, MD, (here describing his research as part of the California Institute for Regenerative Medicine’s recent Elevator Pitch competition) has been selected by the International Society for Stem Cell Research to receive its Outstanding Young Investigator of the year at the organization’s annual meeting in June in Boston.

My colleagues at CIRM beat me to the punch yesterday (Wernig is a CIRM grant recipient) with a nice blog post about the award.

I’ve written several times (here and elsewhere) about Wernig’s research as part of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine. Essentially, he’s shown that it’s possible to directly convert adult, terminally differentiated cells directly into other types of cells like neurons, without first having to force the cells through a stage called induced pluripotency. It’s exciting stuff.

Wernig, who was in a former life a composer of classical music, joins Stanford researcher Joanna Wysocka, PhD, in the ISSCR hall of fame. She won the award in 2010.

Previously: Stanford scientists turn human skin cells directly into neurons, skipping iPS stage, The end of iPS? Stanford scientists directly convert mouse skin cells to neural precursors and Stanford researcher wins Outstanding Young Investigator Award from international stem cell society.
Video courtesy of the California Institute for Regenerative Medicine

Really. Come on. Who isn’t interested in hair? Hair growth, hair loss, hair thickness, hair shape, hair location. I’d bet that everyone of us spends at least a minute or two each day thinking about (or, if you’re like me, futilely plucking and prodding at) the state of our locks.

Now Stanford researchers have delved deep into the cells surrounding our hair follicles to better understand what makes them grow and maintain hair. Perhaps not surprisingly, the answer lies in the stem cells (here, called ‘bulge cells’) within the follicle.

Specifically, research associate Yiqin Xiong, PhD, and associate professor of medicine Ching-Pin Chang, MD, PhD, have identified a signaling circuit that controls the cells’ activity. The research was published yesterday in Developmental Cell (subscription required). As Chang explained in an e-mail to me:

By promoting self-renewal of stem cells, this circuit maintains a healthy pool of bulge cells for repeated cycles of hair growth and regeneration. Each cycle of hair regeneration is initiated by the activation of this circuit in those bulge cells, and subsequent growth of the hair is sustained by the circuit in hair matrix cells. Besides hair regeneration, the circuit is triggered by skin injury to stimulate migration of the bulge cells to the wounded area to differentiate into epidermal cells, thereby regenerating epidermis over the wounded skin.

In the past, news about hair growth (and how to stimulate it) has been a trigger for a deluge of interest from media and individuals struggling with… (how shall we say it?) ‘hair problems.’ But the research has many implications beyond hair, or the lack thereof. For example, the presence or absence of hair follicles on the skin affect how the skin heals after a wound, and whether a scar remains. According to Chang:

This molecular circuit in the hair follicle can be targeted for therapeutic purposes. Because of its activity in hair regeneration, inhibition of this circuit can reduce hair growth in patients with excessive hairiness (hirsutism), whereas activation of this pathway can promote hair growth for people with baldness (alopecia). Also, for its activity during epidermal regeneration, activation of the circuit can facilitate wound healing for patients receiving surgery and for diabetic patients who have wounds that are difficult to treat. The activity of the circuit in both hair follicle and epidermal regeneration may have additional therapeutic benefit. Lack of hair follicles in a wounded area is a hallmark of scar formation. Targeting this pathway has the advantage of promoting both hair follicle formation and wound repair, thus reducing scar formation in the wound.

Interestingly, one of the key molecules, called Brg1, involved in this regulatory circuit has also been implicated in previous work from Chang’s lab in the enlargement of the heart and in fetal heart development. It’s apparent this story has many layers, some more than skin deep.

Previously: Examining the role of genetics in hair loss and Epigenetics: the hoops genes jump through,
Photo by Furryscaly

Hot on the heels of my Friday post about the elevator-pitch throwdown organized by the California Institute for Regenerative Medicine comes news that Stanford postdoc and clinical instructor Michael Rothenberg, PhD, was awarded third place in the organization’s “non-lead scientist” category. (Awards were given in two categories - non-lead scientist and lead scientist - to acknowledge the vast range of experience and training of the scientists who chose to compete. )

Rothenberg works in the laboratory of Michael Clarke, MD, at Stanford’s Institute for Stem Cell Biology and Regenerative Medicine, and he studies… well, why don’t I let him tell you himself? Watch the video above to see how winning science communication is done. And then check out a few more of the winners (links in the CIRM announcement).

Videos longer than 35 seconds lost points. All had to clearly explain in plain language what their CIRM-funded research was about. Humor helped, but it wasn’t necessary. And although the contest was lighthearted, the purpose was serious. From CIRM’s release:

The goal of the Elevator Pitch Challenge was to help researchers who get funding from the stem cell agency, the California Institute for Regenerative Medicine (CIRM), do a better job of communicating with the public. After all, we are a publicly funded agency and the money we use to fund research comes from the people of California, so it’s only reasonable to expect researchers to be able to explain the importance of what they do to Californians, and anyone else they might meet.

Congratulations Michael!

Previously: Learning and laughing: CIRM’s elevator pitch contest and A call to fix the “crisis of communication” in science

Stem cells in the laboratory lead a seemingly idyllic life, spending most of their time being gently sloshed around in a warm bath of yummy nutrients. But this pampered, directionless lifestyle presents a problem for scientists trying to understand how the cells organize themselves in the body. In “real life” it matters quite a lot who your neighbors are and from what direction the various messages and signals that guide cellular life originate. Until now, however, it’s been nearly impossible for scientists to study how such localized signals affect stem cells.

Now developmental biologist Roeland Nusse, PhD, and Shukry Habib, PhD, a research associate and Siebel Scholar, have devised an ingenious way to mimic localized signals by binding a signaling molecule (in this case, a protein called Wnt3a) to an inert microscopic bead. They then traced the actions of individual mouse embryonic stem cells bound to only one bead-meaning the cell was receiving the Wnt3a signal from only one location on its membrane. The research was published yesterday in Science (subscription required). From our release:

The effect of the localized signal was clear. In 75 percent of cases, the stem cell began to divide in a very specific orientation, with the plane of division occurring perpendicularly to the location of the incoming signal. In contrast, only 12 percent of cells exposed to beads bound to a control protein exhibited similar patterns of division.

Habib and his colleagues also found that the daughter cell closest to the Wnt3a signal expressed proteins showing it was maintaining its pluripotency, or ability to function as a stem cell like its parent. The one farthest from the signal, however, expressed proteins indicating that it was beginning to differentiate.

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I’m having WAY too much fun this morning reviewing entrants in the most recent competition sponsored by the California Institute for Regenerative Medicine. This contest pits scientists against one another as they battle not for funding, but for the title of the ‘best elevator pitch.’ The idea, as described here by the institute’s senior director of public communications Kevin McCormack and communications manager (and my friend!) Amy Adams, is to help researchers improve their ability to describe their lab work as articulately and quickly as possible.

Amy and Kevin have great fun parodying exactly how bad some scientists can be at explaining their work, while encouraging grantees to take their turn in front of the camera during a meeting earlier this month. (Amy’s white knuckle grip on her coffee cup while a researcher gabbles on about gliogenesis in infant monkeys made me laugh out loud.) You can see all the entrants on CIRM’s YouTube channel - including several from Stanford.

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This last winter has been a tough one for my small rural community. Every time I turned around, more people were sniffling and sneezing, coughing and feverish. We’ve all been just as likely to compare doctors’ recommendations as our children’s report cards, and more than one of my friends walked away from the physician with a prescription for a Z-pack: a five-day regimen of an antibiotic called Zithromax that’s effective in treating many common infections.

Last week, however, the Food and Drug Administration strengthened their warning about Zithromax: Mounting evidence has shown that the drug can be dangerous for people with certain preexisting heart conditions, or those who may be taking other drugs that affect the heart’s rhythm.

How could such a common medication carry such risks? It’s simple, explain Stanford scientists. The current methods of testing a prospective new drug’s heart safety profile depend primarily on the use of non-heart cells that are genetically modified to mimic some aspects of real ones. But they’re no substitute for the real thing. Unfortunately, the “real thing” is hard to get. After all, we’re not all lining up for heart biopsies so scientists can have a steady supply of material on which to test each drug.

Today cardiologist Joseph Wu, MD, PhD, medical student Andrew Lee, and postdocs Ping Liang, PhD, and Feng Lan, PhD, published some really exciting new work in the journal Circulation (subscription required) that presents an alternative. In short, the researchers collected painless skin samples from patients with one of three inherited cardiac conditions, as well as from healthy family members. They then used induced pluripotent stem, or iPS, cell technology to convert the skin cells in the laboratory into functioning heart cells that reflected each patient’s specific heart aliment. Finally, they tested the response of the cells to specific medications - some of which have been shown to be relatively safe for the heart and another that had been withdrawn from the market due to unexpected cardiotoxicity. As Lee explained in our release:

It’s clear that individual patients will respond uniquely to specific drugs. If you have a hereditary disease or a problem with your ion channels, you’re going to respond differently than members of the general population. Even companies relying on genetically normal human embryonic-stem-cell-derived cardiac cells won’t be able to see all these effects. But our ‘clinical trial in a dish’ with patient-specific iPS cells allows us to model this personalized response and identify high-risk groups who should not receive the drug.

The researchers found that the heart cells in the dish responded in much the same way to the medications as did human patients. They anticipate that this type of “clinical trial in a dish” may become a standard method of testing drugs for cardiotoxicity on healthy and diseased hearts. It may also allow researchers and clinicians to test the effect of combinations of drugs while limiting the risk to real patients. Although none of my antibiotic-toting friends have been harmed by Zithromax (and thank goodness, we all seem to be feeling a bit better!), who would argue with better, faster and safer testing of all drugs? According to Wu:

Our hope is that, instead of a physician using a patient as a guinea pig, trying one medication after another until something is found to be effective, this method will one day lead to personalized drug screening to find out exactly which medication is the best for you.

I’m really excited about this research, and in this use for iPS cells in general. We’ll likely be hearing more about this approach; earlier this week Wu, who co-directs the Stanford Cardiovascular Institute, received$1.44 million from the California Institute for Regenerative Medicine to collect tissue samples to create iPS cells from several hundred patients with idiopathic familial dilated cardiomyopathy - that is, members of families with a predisposition to develop enlarged and weakened hearts without an obvious cause.

Previously: Sudden cardiac death has a cellular cause, say Stanford researchers, New leaders in heart medicine at Stanford and Lab-made heart cells mimic common cardiac disease in Stanford study
Photo by kaibara87

Stem-cell therapy for damaged hearts is a brilliant idea whose time has not yet come. To date, human and animal trials - there have been quite a few - in which stem cells were injected into cardiac tissue to treat severe heart attacks or substantial heart failure have mostly produced poor results.

Stanford’s Sam Gambhir, PhD, MD, who heads the medical school’s Department of Radiology, thinks he knows part of the reason why, and he may have found a way around it.

At present, there’s no way to ensure against faulty initial placement, he told me in an interview about his study describing the proposed solution, just published in Science Translational Medicine. “You can use ultrasound to visualize the needle through which you deliver stem cells to the heart. But once those cells leave the needle, you’ve lost track of them.”

In my release about the work, I wrote:

As a result, key questions go unanswered: Did the cells actually get to the heart wall? If they did, did they stay there, or did they diffuse away from the heart? If they got there and remained there, for how long did they stay alive? Did they replicate and develop into heart tissue?

Gammbhir’s lab has figured out a way to “mark” stem cells before infusing them into the heart, rendering them visible to standard ultrasound as they’re squeezed out of the needle. The key was to invent an innovative imaging agent, in the form of nanoparticles whose diameters clustered just below one-third of a micron — less than one-three-thousandth the width of a human hair. The nanoparticles’ main ingredient, silica, shows up on ultrasound. The particles were also doped with the rare-earth element gadolinium, so they can also be observed using MRI.

It turns out that mesenchymal stem cells — a class of cells often used in heart-regeneration research because they can differentiate into beating heart cells and because they can sometimes be harvested directly from the patients themselves, avoiding possible immune-compatibility problems — were happy to gobble up the nanoparticles in a lab dish without losing any of their ability to survive, thrive, and replicate themselves.

When Gambhir and his associates infused these nanoparticle-loaded stem cells into the hearts of healthy mice, they were indeed able to monitor the cells via ultrasound after they left the needle tip, guide them to the targeted area of the heart wall, and still get a strong MRI signal from the cells two weeks later.

Stem-cell therapy for damaged hearts isn’t going to be cheap anytime soon. (A wild guess of, say, $50,000 per procedure is probably not too far off the mark.) But a one-time delivery, if it worked, could replace a lifetime of constant drug administration. Adding what Gambhir estimates might be another $2,500 a pop for the added imaging capability is likely to be hugely cost-effective, because it could greatly improve the odds of the procedure’s success.

Previously: Nanoparticles home in on human tumors growing in mice’s brains, increase accuracy of surgical removal, Nanomedicine moves ones step closer to reality and Developing a new molecular imaging system and technique for early disease detection
Photo by miguelb

Say you’re a human embryonic stem cell researcher (odds are, that at least some of the readers of this blog fit this description). If so, you’re familiar with the alphabet soup of regulations that govern this type of research in California and elsewhere. In particular, depending on the specifics of your proposed experiments, you may need to seek approval from your Institutional Review Board (the IRB), your Institutional Animal Care and Use Committee (the IACUC) and an Embryonic Stem Cell Research Oversight Committee, or ESCRO. That could change, however.

Stanford bioethicist Hank Greely, JD, spoke out yesterday in an article in Nature exploring whether all these layers of approval are really still necessary. (Greely published a commentary on the topic in the January issue of the American Journal of Bioethics.) As the article explains, ESCROs were implemented when embryonic stem cell research was still in its infancy:

To encourage responsible practices, the US National Academies issued a report in 2005 calling for the establishment of stand-alone institutional oversight committees, and within two years, at least 25 so-called ‘embryonic stem cell research oversight committees’, or ESCROs, cropped up across the country. Most of these were created voluntarily, except in the few states—California and Connecticut, as well as New York if the research is performed with state funding—that made the practice mandatory. Now, however, with hESC research widely practiced and accepted, some experts are questioning whether stand-alone ESCROs are still needed.

“As that early period of figuring out ways to implement good ethical guidelines has shifted into the more normal science of applying those concerns, the need for ESCROs has gotten smaller,” says Henry Greely, a bioethicist at the Stanford Law School and chair of California’s Human Stem Cell Research Advisory Committee. “It’s not rocket science any more. A lot of [hESC research] is pretty routine, and it doesn’t necessarily need a unique institution to deal with it.”

Greely’s no newcomer to the ethical and legal issues surrounding embryonic stem cell research. He’s been a frequent commenter here on the topic. Not all experts agree with Greely in the case of the ESCROs, but it’s an interesting discussion. As he argues:

Ultimately, the decision to maintain ESCROs or not all comes down to a cost-benefit ratio, says Greely. Streamlining committee structures won’t bring “enormous benefits,” he admits, “but I don’t think they’re trivial benefits, and what are the benefits of continuing to have ESCROs after this breaking in and bureaucratization process has worked itself out? They’re not very big.”

“It’s not saying these guys have been failures and we should get rid of them,” he adds. “It’s almost saying, ‘These guys have been so successful that they worked themselves out of a job’—and that’s not a bad thing.”

Previously: Supreme Court decision on human embryonic stem cell case ends research uncertainty, and Stanford law professor on embryonic stem cell ruling
Photo by Max Braun

Describing complicated medical research in an easy-to-understand way isn’t the easiest thing in the world to do. It seems to come naturally to some people, though - like many of my colleagues and, as I recently discovered, UCSF graduate student Florie Charles. Charles, through her website Youreka Science, posts short, lay-friendly videos on scientific discoveries. In the one above, she describes a recent Stanford study, funded in part by California’s stem cell agency, on neural progenitor cells. (Think that sounds like complicated stuff? Just hit play.)

Previously: Brain Police: Stem cells’ fecund daughters also boss other cells around
Via California Institute for Regenerative Medicine

If you’re like me, you sometimes worry about your hearing. Certain tones of voices and noisy places can make it difficult to pick up every word in a crowded room. Although I don’t have a severe problem (yet), many people do. Now Stanford researcher and otolaryngologist Alan Cheng, MD, and his colleagues have published work (subscription required) that one day may help those with what’s been called “the invisible disability.” From my release:

Twenty percent of all Americans, and up to 33 percent of those ages 65-74, suffer from hearing loss. Hearing aids and, in severe cases, cochlear implants can be helpful for many people, but neither address the underlying cause: the loss of hair cells in the inner ear. Cheng and his colleagues identified a class of cells called tympanic border cells that can give rise to hair cells and the cells that support them during a phase of cochlear maturation right after birth.

Hair cells work by swaying in response to the vibrations in the air caused by sound - like seaweed in an ocean current. But when these cells are damaged, that’s that:

“It’s well known that, in mammals, these specialized sensory cells don’t regenerate after damage,” said Alan Cheng, MD, assistant professor of otolaryngology. (In contrast, birds and fish are much better equipped: They can regain their sensory cells after trauma caused by noise or certain drugs.) “Identifying the progenitor cells, and the cues that trigger them to become sensory cells, will allow us to better understand not just how the inner ear develops, but also how to devise new ways to treat hearing loss and deafness.”

Cheng, who is a member of the Stanford Initiative to Cure Hearing Loss, collaborated with Stanford developmental biologist Roel Nusse, PhD, to investigate which cells in the inner ear might be responsive to a developmental pathway called Wnt that drives the renewal and proliferation of many types of stem, or progenitor cells. Together they identified a Wnt-responsive population of cells in the inner ear called the tympanic border cells and showed that, when grown under proper conditions in the laboratory, they could become sensory and supporting cells.

Now the next step is learning whether and how these cells could be coaxed to jump into action in people with hearing loss, says Cheng.

Previously: Regenerating sensory hair cells to restore hearing to noise-damaged ears, Stanford researcher comments on the use of human embryonic stem cells to restore hearing, and Growing new inner-ear cells: a step toward a cure for deafness