Stem cell stories that caught our eye: Immune therapy for HIV, nerves grown on diamonds and how stem cells talk

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Trendy CAR T therapy tried on HIV.  The hottest trend in cancer therapy today is using CAR-T cells to attack and rid the body of cancer. Technically called chimeric antigen receptors the technology basically provides our own immune system with directions to cancer cells and keys to get inside them and destroy them. A CIRM-funded team at the University of California, Los Angeles, has now tried that same scheme with HIV.

Jerome Zack (left) and Scott Kitchen, found that the technique decreased HIV levels in mice by 80 to 95 percent.

Jerome Zack (left) and Scott Kitchen, found that the technique decreased HIV levels in mice by 80 to 95 percent.

The researchers worked with mice bred to have a human immune system so that HIV affects them similarly to humans. They harvested their blood-forming stem cells and inserted a CAR that recognized HIV. After giving the stem cells back to the mice they produced T cells capable of seeking out and destroying about 90 percent of the virus. The technique has a ways to go, but the study’s lead author noted their ultimate goal in a University press release picked up by HealthCanal:

“We hope this approach could one day allow HIV-positive individuals to reduce or even stop their current HIV drug regimen and clear the virus from the body altogether,” said Scott Kitchen. “We also think this approach could possibly be extended to other diseases.”

Nerves grown on diamonds. Diamonds are so chemically non-reactive our bodies would not recognize them as foreign. But they can also be made to conduct electricity, which could make nerves grown on their surface able to be turned on and off with electrical impulses. When developing cell therapy for several neurologic diseases the ability to control the activity of replacement cells could be critical to success—making new research by a team in Britain and Ireland intriguing, if very preliminary.

They doped diamonds with boron to make them able to conduct electricity and then used them as a surface for growing nerve stem cells that could later be turned into nerves. They then succeeded in growing nerves long term on the diamonds.

“We still have a lot more fundamental studies of the neuron/diamond interface to perform,” said Paul May of the University of Bristol. “[But] the long term possibilities for this work are exciting.  Long-lifetime diamond bio-implants may offer treatments for Parkinson’s, Alzheimer’s, stroke or even epilepsy.”

Materials Today wrote a piece explaining the work.

Some stem cells talk over “land lines.” Most cellular communication works through chemical signals that get dispatched by one cell and received by others. It turns out that some types of stem cells communicate by sending out tiny nanotubes, sort of a cellular land line.

A team at the University of Michigan and the University of Texas Southwestern Medical Center found the new form of communication working with fruit flies. Yukiko Yamashita, a senior author of the paper from Michigan explained why it is so important to get a better understanding of cell-to-cell communication in a university press release picked up by ScienceNewsline:

“There are trillions of cells in the human body, but nowhere near that number of signaling pathways. There’s a lot we don’t know about how the right cells get just the right messages to the right recipients at the right time.”

In a classic example of the beauty of young minds in science, prior images of these stem cells had shown the nanotubes, but they had been overlooked until a graduate student asked what they were.

Phase 3 melanoma trial explained. When a new therapy gets into its third and final phase of testing it is make or break for the company developing the therapy and for patients who hope it will become broadly available. CIRM recently provided funding to our first phase three clinical trial, one aimed at metastatic melanoma being conducted by Caladrius Biosciences.

The CEO of the company, David Mazzo, gave an interview with The New Economy this week that does a nice job of explaining the goal of the therapy and how it is different from other therapies currently used or being developed. The therapy’s main difference is its ability to target the cancer-inducing cells thought to responsible for the spread of the disease.

Stem cell stories that caught our eye: Parkinson’s in a dish, synthetic blood, tracking Huntington’s and cloning

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

3D nerve model for Parkinson’s. The wave of successes in making more complex tissues in three dimensional lab cultures continues this week with a team in Luxembourg creating nerves from stem cells derived from Parkinson’s patients that assembled into complex connections in the lab.

Nerve cells made from skin cells. Credit: Luxembourg Centre for Systems Biomedicine (LCSB), 2015

Nerve cells made from skin cells. Credit: Luxembourg Centre for Systems Biomedicine (LCSB), 2015

The name of the journal where the group published their results, Lab on a Chip, says a lot about where the field is going. While many have grown the dopamine-producing nerves lost in Parkinson’s disease in two dimensional cultures, the new technique better replicates the disease state and does it about 10-fold cheaper because the 3D bioreactors used can be automated and use less of the reagents needed to grow the cells and to tell them to become the right nerves.

They started with skin samples from patients and reprogrammed them into iPS-type stem cells. After those cells are placed in the vessel, they are matured into 90 percent pure dopamine-nerves. At that point they are ideal for testing potential drugs for any impact on the disease. The senior researcher, Ronan Fleming, explained the benefit in a press release from the University of Luxembourg, picked up by ScienceDaily:

“In drug development, dozens of chemical substances can therefore be tested for possible therapeutic effects in a single step. Because we use far smaller amounts of substances than in conventional cell culture systems, the costs drop to about one tenth the usual.”

Synthetic blood from stem cells. Making synthetic blood, particularly for people with rare blood types for which there are few donors, has long been a goal of science. Now, the British National Health Service (NHS) says it expects to begin giving patients at least one component of lab-made blood—red cells—by 2017.

Starting with adult stem cells grown in just the right solution they hope to produce large quantities of red blood cells. Initially they plan to give only small quantities to healthy individuals with rare blood types to compare them to donor blood.

“These trials will compare manufactured cells with donated blood,” said Nick Warkins of the NHS. “The intention is not to replace blood donation but provide specialist treatment for specific patient groups.”

The story got wide pick up in the British press including in the Daily Mail and in several web portals including Rocket News.

Tracking Huntington’s spread in the brain. A CIRM-funded team at the University of California, Irvine, has developed a way to track the spread of the mutant protein responsible for progression of Huntington’s disease. They were able to accurately detect the mutant protein in cerebrospinal fluid and distinguish between people who carried the mutation but were pre-symptomatic from those that had advanced disease.

The protein appears to be released by diseased cells and migrates to other cells, seeding additional damage there. Measuring levels of the protein should allow physicians to monitor progression of the disease ahead of symptoms.

“Determining if a treatment modifies the course of a neurodegenerative disease like Huntington’s or Alzheimer’s may take years of clinical observation,” said study leader Dr. Steven Potkin. “This assay that reflects a pathological process can play a key role in more rapidly developing an effective treatment. Blocking the cell-to-cell seeding process itself may turn out to be an effective treatment strategy.”

Medical News Today wrote up the research that the team published in the journal Molecular Psychiatry.

Good overview of cloning. Writing for Medical Daily, Dana Dovey has produced a good overview of the history of cloning, and more important, the reasons why reproductive cloning of human is not likely to happen any time soon.

She describes the important role a number of variations on cloning play in scientific research, and the potential to create personalized cells for patients through a process known as therapeutic cloning. But she also describes the many problems with reproductive cloning as it is practiced in animals. It is very inefficient with dozens of eggs failing to mature and often results in animals that have flaws. She quotes Robert Lanza of Advanced Cell Technologies (now Ocata Therapeutics):

“It’s like sending your baby up in a rocket knowing there’s a 50-50 chance it’s going to blow up. It’s grossly unethical.”


Hed: Stem cell stories that caught our eye: the why’s of heart failure, harnessing stem cells’ repair kits and growing organs

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Stem cell model sheds light on heat failure. Pretty much everyone who has heart failure due to cardiomyopathy—where the heart muscle doesn’t work as effectively as it should—or has a condition that could lead there, is taking a beta blocker. The beta-andrenergic pathway, a key molecular pathway in the heart, dysfunctions in patients with cardiomyopathy and we have never known exactly why. We just know these drugs help.

Now, a team at Stanford led by Joseph Wu has used skin samples from patients and normal subjects to create reprogrammed iPS type stem cells, grown them into heart muscle, and compared them at a very fine-tuned molecular level.

Some patients have a mutation in a protein called TNNT2 in heart muscle fibers, which regulates muscle contraction. So, one thing they looked at was the impact of that mutation. Wu’s team followed the actions triggered by this mutation and found they lead to the beta-andrenergic pathway. Wu explained the value he sees in this fundamental understanding of the disease in a Stanford press release:

“As a cardiologist, I feel this basic research study is very clinically relevant. The beta-andrenergic pathway is a major pharmaceutical target for many cardiac conditions. This study confirms that iPS-cell-derived cardiomyocytes can help us understand biologically important pathways at a molecular level, which can aid in drug screening.”

CIRM did not fund this project but we do fund other projects in Wu’s lab including one to advance the use of iPS cells as models of heart disease, one using tissue engineering to repair damaged areas of the heart and one using embryonic stem cells to generate new heart muscle.

Harnessing stem cells’ repair kits. Stem cells repair tissue in multiple ways, but primarily by maturing into cells that replace damaged ones or by excreting various chemicals that give marching orders to neighboring cells to get busy and make the repairs. Those chemicals, collectively called paracrine factors, get excreted by the stem cells in vessels known as exosomes. So, a team at Temple University in Philadelphia decided to try injecting just the exosomes, rather than whole stem cells to repair heart damage. It seemed to work pretty well in mice.

Stem cells release exosomes, tiny vessels that act as repair kits.

Stem cells release exosomes, tiny vessels that act as repair kits.

After treatment with the exosomes, mice with induced heart attacks showed fewer heart cells dying, less scar tissue, more development of new blood vessels and a stronger heart function. The head of the Temple team, Raj Kishore, described the result in a university press release distributed by EuekaAlert:

“You can robustly increase the heart’s ability to repair itself without using the stem cells themselves. Our work shows a unique way to regenerate the heart using secreted vesicles from embryonic stem cells.”

The team went on to isolate a specific regulatory chemical that was among the most abundant in the exosomes. That compound, a type of RNA, produced much of the same results when administered by itself to the mice—intriguing results for further study.

Good primer on using stem cells to grow organs. The Wisconsin State Journal ran a nice primer in both video and prose about what would theoretically go into building a replacement organ from stem cells and some of the basic stem cell principals involved. The piece is part of a series the paper produces with the Morgridge Institute at the University of Wisconsin. This one features an interview with Michael Treiman of Epic Systems:

“The biggest challenge right now is that we can push a stem cell to be a particular type of cell, but in a tissue there’s multiple cells. And an organ like your heart or brain isn’t just made of one cell type; it’s made of many cell types working together.”

Stem cell stories that caught our eye: Parkinson’s trial revived, aspirin kills cancer stem cells and a stem cell role in mother-child obesity

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Parkinson’s clinical trials back on track.
After nearly 20 years of being stuck on the clinical trial “bookshelf”, an international team from Cambridge, UK revived a cell therapy for Parkinson’s disease.

In an announcement picked up this week by the Genetic Literacy Project, the team reported they had treated their first patient. Specifically, fetal brain cells were injected into the brain of a man in his mid-50’s with the disease.

Neurons derived from human embryonic stem cells

A fluorescent microscopic image of numerous dopaminergic neurons (the type of neurons that are degenerated in Parkinson’s disease patients) generated from human embryonic stem cells. Image courtesy of the Xianmin Zeng lab at the Buck Institute for Age Research.

In Parkinson’s, nerve cells controlling movement die for poorly understood reasons. An accumulation of data through the 60’s and 70’s suggested transplantation of fetal brain cells into the Parkinson’s brain would replace the lost nerve cells and restore movement control. After initial promising results in the 80’s and 90’s, larger clinical trials showed no significant benefit and even led to a worsening of symptoms in some patients.

Due to these outcomes, the research community shelved the approach. Insights gained in the interim pointed to more ideal brain injection sites in order to help avoid side effects. Also, follow up on patients beyond the two-year run of those early trials suggested that positive effects of the cell therapy may not emerge for at least three to five years. So this latest trial will run longer to capture this time window.

One remaining snag for this therapeutic strategy is the limited number of available cells for each transplant. So in the meantime, scientists including some of our grantees are working hard at getting embryonic stem cell- or iPS cell-based therapies to the clinic. Since stem cells divide indefinitely, this approach could provide an off-the-shelf, limitless supply of the nerve cells. Stay tuned.

Targeting cancer stem cells with the Wonder Drug.
Aspirin: it’s the wonder drug that may turn out to be even more wonderful.

Ball and stick model of aspirin, the wonder drug: relieves pain and prevents cancer

Ball and stick model of aspirin, the wonder drug: relieves pain and prevents cancer

Famous for relieving pain and preventing heart attacks, aspirin may add breast cancer-killer to its resume. This week a cancer research team at the Kansas City (Mo.) Veteran Affairs Medical Center published experiments picked up by Eureka Alert showing a daily dose of aspirin could put the brakes on breast cancer.

The analysis attributed this anti-cancer effect to aspirin’s capacity to reduce the growth of cancer stem cells. These cells make up a tiny portion of a tumor but if chemotherapy or radiation treatment leaves any behind, it’s thought the cells’ stem cell-like ability for unlimited growth drives cancer relapse and spread (metastasis).

In the study, mice with tumors given a daily low dose of aspirin for 15 days had, on average, tumors nearly 50% smaller than the aspirin-free mice. In another set of experiments, the team showed aspirin could prevent tumors as well. Mice were given aspirin for 10 days before exposing them to cancer cells. After another 15 days, the aspirin treated animals had significantly less tumor growth compared to an untreated group.

Senior author Sushanta Banerjee stands behind these findings: he’s been taking an aspirin a day for three years but stresses that you should consult with your doctor before trying it yourself.

A stem cell link to the passing on of obesity from mom to child?
It’s been observed that children of obese moms have a high risk for obesity and diabetes. You might conclude that genetics are the culprit as well as lifestyle habits passed down from parent to child. But research published this week by researchers at the University of Colorado School of Medicine suggests another mechanism: they conclude the mere presence of the growing embryo in the uterus of an obese mother may instruct the child’s cells to take on more fat.

The team’s reasoning is based on an analysis of umbilical cord blood stem cells collected from babies born to 12 obese mothers and 12 normal weight mothers. In the lab, the stem cells were specialized into fat and muscle cells. The cells from babies of obese mothers showed increased fat accumulation and a lower production of proteins important for uptake of blood sugar (a state that could eventually tip the scales towards diabetes).

Certainly it’s a leap to link the property of cells in a dish to the eventual health of a child. But the results are intriguing enough that the researchers intend to follow the children as they get older to look for more connections between the state of the kids’ stem cells and their health profile.

Stem cell stories that caught our eye: regenerating limbs on scaffolds, self regeneration via a drug, mood stem cells, CRISPR

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Regenerating a limb, or at least part of it. Many teams have generated organs or parts of organs in animals by starting with a dead one. They literally wash away all the cells from the donor organ using a detergent so that they are left with a framework of the cells’ connective tissue. Then they seed that scaffold with stem cells or other cells to grow a new organ. A team at Massachusetts General Hospital has now used the same process to generate at least part of a rat limb.

The news cells growing on the donor limb scaffold in a bioreactor

The news cells growing on the donor limb scaffold in a bioreactor

It took a week to get the tiny little leg fully cleaned up and then another two weeks for the seeded cells to repopulate the scaffold left behind. That cellular matrix seems to send signals to the seeded cells on what type of tissue to become and how to arrange themselves. The team succeeded in creating an artificial limb with muscle cells aligned into appropriate fibers and blood vessels in the right places to keep them nourished. The researchers published their work in the journal Biomaterials and the website Next Big Future wrote up the procedure and provided some context on the limitations of current prosthetic limbs. The author also notes that the researchers have a lot more work to do, notably to prove they can get nerves to grow and connect at the point of transplantation to the “patient” animal. Discover also wrote a version of the story.

Getting the body to regenerate itself. A strain of mice discovered 20 years ago has led a multi-institution team to a possible way to get the body to regenerate damaged tissue, something the mouse discovered two decades ago can do and other mammals cannot. The researchers found that those mice have one chemical pathway, HIF-1a, that is active in the adult mice but is normally only active in the developing embryo. When they pushed that chemical path to work in normal mice those mice, too, gained the power to regenerate tissue. Ellen Heber-Katz from the Lankenau Institute for Medical Research outside of Philadelphia was quoted in the institute’s press release on Health Medicine Network.

“We discovered that the HIF-1a pathway–an oxygen regulatory pathway predominantly used early in evolution but still used during embryonic development–can act to trigger healthy regrowth of lost or damaged tissue in mice, opening up new possibilities for mammalian tissue regeneration.”

Heber-Katz led the team that included researchers from the company Allergan and the University of California, Berkeley. In order to activate the HIF-1a pathway they basically took the natural brakes off it. Another cellular chemical, PHD normally inhibits the action of HIF-1a in adults. The researcher turned the table on PHD and inhibited it instead. The result, after three injections of the PHD inhibitor over five days the mice who had a hole punched in their ear healed over the hole complete with cartilage and new hair.

Regulating memory and mood. It turns out your brain’s hippocampus, the section responsible for both memory and mood, has not one type of stem cell replenishing nerves, but two. And those two types of stem cells give rise to different types of nerves, which may account for the highly varied function of this part of the brain. Researchers at the University of Queensland in Australia isolated the two types of stem cells and then let them grow into nerves but the nerves from each expressed different genes, which means they have different functions. The lead researcher on the study, Dhanisha Jhaveri, discussed the findings in a press release picked up by Science Daily:

“The two cell groups are located in different regions of the hippocampus, which suggests that distinct areas within the hippocampus control spatial learning versus mood.”

The research provides fodder for future work looking into the treatment of learning and mood disorders. Review of the now celebrity tool, CRISPR. I don’t think I have ever seen so much ink and so many electrons spilled over a science tool as I have seen for CRISPR, particularly for one few scientists can tell you what the acronym stands for: Clustered Regularly Interspaced Short Palindromic Repeats. It is basically a fluke in the genes of several bacteria in which some of the base pairs that make up their DNA get repeated at regular intervals. Their configuration confers the ability for CRISPR segments to be used to disrupt or change specific genes in other organisms. Heidi Ledford writing for Nature in the journal’s news section provides a great wrap-up of what the technology is and what it can do, but also provides some caveats about its efficiency, accuracy, ethical concerns, and occasionally just not understanding how it works. The Nature team provides some valuable infographics showing the history of the science and on the rapid adoption of the technology as shown in publications, patents and funding. They also published an infographic on using CRISPR for “gene drive,” a way to push a modified trait through a population quickly, such as a mutation that could stop mosquitos from transmitting malaria. This potential drives much of the concern about misuse of the tool. But scientists quoted in the piece also provide more mundane reasons for moving slowly in thinking about using the therapy for patients. One of those is that it can sometime cause a high rate of “off-target” gene edits; simply put, cutting DNA in the wrong place. But as a research tool, there is no doubt it has revolutionized the field of gene modification. It is so much faster and so much cheaper than earlier gene editing tools; it is now possible for almost any lab to do this work. The piece starts out with an anecdote from CIRM-grantee Bruce Conklin of the Gladstone Institutes, talking about how it completely changed the way his lab works.

“It was a student’s entire thesis to change one gene,” Conklin said, adding “CRISPR is turning everything on its head.”

Stem cell stories that caught our eye: Spinal cord injury, secret of creating complex tissue, mini brains in a dish and funding

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Monkey trial provides some hope for spinal cord injury. Stem cell treatments have made many mice and rats walk again after spinal cord injury, but moving from those rodents to human has been a slow process. Their immune systems and nervous systems are very different from ours. So, it was good to read this week that a team at Japan’s Keio University reported success in monkeys with systems much more like ours.

The experiment was “controlled.” They compared treated and non-treated animals and saw a significant difference in mobility between the two groups. Bloomberg picked up the release from the journal that published the work Stem Cells Translational Medicine, which quoted the study author Hideyuki Okano:

“An animal in the control group, for example, could not raise her hands up to head height at 12 weeks after injury when motor function almost plateaus. On the other hand, at the same point in time a transplanted animal was able to jump successfully and run so fast it was difficult for us to catch her. She could also grip a pen at 3 cm. above head-height.”

But the work requires some caveats. They treated all animals at exactly 14-days post injury, a window considered optimal for having initial inflammation subside and scar tissue not yet formed. Also, the researchers inflicted bruises not more severe damage to the spinal cord. Most patients with spinal cord injury are chronic, long past the 14-day window, and have damage to their spinal cords more severe than these animals.

The researchers started with embryonic stem cells and matured them into nerve progenitor cells, which they injected into the monkeys. While this process can yield plentiful cells for therapy the researchers acknowledged that much more research is needed before they can help the vast majority of spinal cord injuries with more severe and older injuries. CIRM funds a clinical trial using cells derived from embryonic stem cells to treat more complex spinal injuries, but it is just getting underway.

Clues to creating complex tissues. These days getting stem cells to form a single type of tissue, nerve or skin for example, is almost routine, with the remaining hurdle being purity. But getting stem cells to form complex tissues with multiple types of cells, while done a few times, still gets folks attention. For the most part, this is because we don’t know the cell-to-cell interactions required to form complex tissues. A CIRM-funded team at the University of California, San Diego, thinks they have part of the answer.

They studied something called the neurovascular unit, made up of blood vessels, smooth muscle and nerves that regulate heart rate, blood flow and breathing, among other basic functions. Using a lab model they showed how the different cell types come together to form the vital regulatory tissue. San Diego Newscape posted a piece on the work, quoting the study’s senor author David Cheresh:

“This new model allows us to follow the fate of distinct cell types during development, as they work cooperatively, in a way that we can’t in intact embryos, individual cell lines or mouse models. And if we’re ever going to use stem cells to develop new organ systems, we need to know how different cell types come together to form complex and functional structures such as the neurovascular unit.”

And a brainy example.   Prior research has created small brain “organoids” that started with stem cells and self assembled in a lab dish to create layers of nerves and support cells, but the cells did not interact much like normal brain tissue. Now, a team at Stanford has developed “cortex-like spheroids” with different types of cells that talk to each other.

Nerves and supporting cells form layers and organize like in the developing brain

Nerves and supporting cells form layers and organize like in the developing brain

In the new cortex spheres the nerves are healthier with a better network of the natural supporting cells called glial cells. The cells form layers that interact with each other like in our brains as we are developing.

A program at the National Institutes of Health (NIH) focusing on using stem cells to create models of disease in the lab funded the work. Thomas Insel, Director of the NIH’s National Institute of Mental Health described the importance of the current work in a press release from the institute picked up by HealthCanal:


“There’s been amazing progress in this field over the past few years. The cortex spheroids grow to a state in which they express functional connectivity, allowing for modeling and understanding of mental illnesses. They do not even begin to approach the complexity of a whole human brain. But that is not exactly what we need to study disorders of brain circuitry.“

The release starts with a fun lede imagining the day when a patient tormented by mental illness could have a model of their disease grown in a dish and researchers could genetically engineer better brain circuits for the patient. Certainly not just around the corner, but not far fetched.

States economic gain from funding research. The very niched web cite Governing posted a piece that appears to be largely from a conference in Washington D.C. hosted by the Greater Phoenix Economic Council. It quotes several experts speaking about the opportunity for states to gain economic advantage by funding research.

The piece notes some well documented examples of federal government spending on research spawning industries—think Silicon Valley. Then it talks about some more recent state examples including the California initiative that created CIRM.

One speaker, Mark Muro of the Brookings Institute said that we are in a new era now and states may not be able to fund research through their general tax revenue. He said:

“It may be the state becoming part of a consortium or working with Fortune 500 companies, or going to voters with a general obligation bond vote. I think we’re heading for a new complexity.”

Since CIRM was created through a vote for bonds, guess we have to agree.

Stem cell stories that caught our eye: sickle cell patient data, vaccine link to leukemia protection, faster cell analysis

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Good news from sickle cell clinical trial. It is always satisfying to report positive results from human clinical trials using stem cells even when we don’t fund the work. Bluebird Bio released the first data on a patient treated for sickle cell anemia using the same procedure the company had earlier used to get good outcomes for two patients with beta thalassemia.

Both diseases result from defects—though different defects—in the gene for hemoglobin, the protein our red blood cells use to carry needed oxygen. So, in both cases they use a modified, deactivated virus to carry a correct version of the gene into patients’ own blood-forming stem cells in the lab. They then re-infused those cells into the patients to provide a ready supply of cells able to make the needed protein.

In the sickle cell patient, after the transplant a third of his red cells were making the right protein and that was enough to wean him off blood transfusions that had been keeping him alive and prevented any further hospitalizations due to the disease. The company also announced that the two previously reported patients treated for beta thalassemia had continued to improve. Reuters ran a story on the new data.

CIRM funds a similar project about to begin treating patients for sickle cell disease (link to video), also using a viral vector but a somewhat different one, so it is reassuring to see viral gene carriers working without side effects.

Another reason to vaccinate, prevent leukemia. While it has been known for some time that infant vaccination seems to have driven down the rate of childhood leukemia, no one has known why. A CIRM-funded team at the University of California, San Francisco, thinks they have figured it out. Viral infections trigger inflammation and the production of enzymes in cells that cause genetic mutations that lead to the cancer.

They worked with Haemophilus influenza Type b (Hib) vaccine but suggest a similar mechanism probably applies to other viral infections, and correspondingly, protection from other vaccines. The senior author on the paper, Marcus Muschen, explained the process in a university press release posted at

“These experiments help explain why the incidence of leukemia has been dramatically reduced since the advent of regular vaccinations during infancy. Hib and other childhood infections can cause recurrent and vehement immune responses, which we have found could lead to leukemia, but infants that have received vaccines are largely protected and acquire long-term immunity through very mild immune reactions.”

Barcoding individual cells. Our skin cells all pretty much look the same, but in the palm of your hand there are actually several different types of cells, even a tiny scratch of the fingernail. As scientist work to better understand how cells function, and in particular how stem cells mature, they increasingly need to know precisely what genes are turned on in individual cells.

Both techniques use tiny channels to isolate individual cells and introduce beads with "bar codes."

Both techniques use tiny channels to isolate individual cells and introduce beads with “bar codes.”

Until recently, all this type of analysis blended up a bunch of cells and asked what is in the collective soup. And this did not get the fine-tuned answers today’s scientists are seeking. Numerous teams over the past couple years have reported on tools to get down to single-cell gene analysis. Now, two teams at Harvard have independently developed ways to make this easier. They both use a type of DNA barcode on tiny beads that gets incorporated into individual cells before analysis.

Allan Klein, part of one team based at the Harvard Medical School’s main campus, described why the work is needed in a detailed narrative story released by the school:

“Does a population of cells that we initially think is uniform actually have some substructure. What is the nature of an early developing stem cell? . . . How is [a cell’s] fate determined? “

Even Macosko who worked with the other team centered at the Broad Institute of Harvard and MIT, noted the considerable increase in ease and decrease in cost with the new methods compared to some of the early methods of single cell gene analysis:

“If you’re a biologist with an interesting question in mind, this approach could shine a light on the problem without bankrupting you. It finally makes gene expression profiling on a cell-by-cell level tractable and accessible. I think it’s something biologists in a lot of fields will want to use.”

The narrative provides a good example of what we called the “bump rate” when I was at Harvard Med. Good science often moves forward when scientists bump into each other, and with Harvard Medical faculty scattered at 17 affiliated hospitals and research institutes scattered across Boston and Cambridge we were always looking for ways to increase the bump rate with conferences and cross department events. Macosko and Klein found out they were both working on similar systems at a conference.

Stem cell stories that caught our eye: a new type of stem cell, stomach cancer and babies—stem cell assisted and gene altered

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

New type of stem cell easier to grow, more versatile. Both the professional scientific media and the lay science media devoted considerable ink and electrons this week to the announcement of a new type of stem cell—and not just any stem cell, a pluripotent one, so it is capable of making all our tissues. On first blush it appears to be easier to grow in the lab, possibly safer to use clinically, and potentially able to generate whole replacement organs.

The newly found stem cells (shown in green) integrating into a mouse embryo.

The newly found stem cells (shown in green) integrating into a mouse embryo.

How a team at the Salk Institute made the discovery was perhaps best described in the institute’s press release picked up by HealthCanal. They sought to isolate stem cells from a developing embryo after the embryo had started to organize itself spatially into compartments that would later become different parts of the body. By doing this they found a type of stem cell that was on the cusp of maturing into specific tissue, but was still pluripotent. Using various genetic markers they verified that these new cells are indeed different from embryonic stem cells isolated at a particular time in development.

The Scientist did the best job of explaining why these cells might be better for research and why they might be safer clinically. They used outside experts, including Harvard stem cell guru George Daly and CIRM-grantee from the University of California, Davis, Paul Knoepfler, to explain why. Paul described the cells this way:

“[They] fit nicely into a broader concept that there are going to be ‘intermediate state’ stem cells that don’t fit so easily into binary, black-and-white ways of classifying [pluripotent cells].”

The Verge did the best job of describing the most far-reaching potential of the new cells. Unlike earlier types of human pluripotent cells, these human stem cells, when transplanted into a mouse embryo could differentiate into all three layers of tissue that give rise to the developing embryo. This ability to perform the full pluripotent repertoire in another species—creating so called chimeras—raises the possibility of growing full human replacement organs in animals, such as pigs. The publication quotes CIRM science officer Uta Grieshammer explaining the history of the work in the field that lead up to this latest finding.

Stem cells boost success in in vitro fertilization.  Veteran stem cell reporter and book author Alice Park wrote about a breakthrough in Time this week that could make it much easier for older women to become pregnant using in vitro fertilization. The new technique uses the premise that one reason older women’s eggs seem less likely to produce a viable embryo is they are tired—the mitochondria, the tiny organs that provide power to cells, just don’t have it in them to get the job done.

The first baby was born with the assistance of the new procedure in Canada last month. The process takes a small sample of the mother-to-be’s ovarian tissue, isolates egg stem cells from it, extracts the mitochondria from those immature cells and then injects them into the woman’s mature, but tired eggs. Park reports that eight women are currently pregnant using the technique. She quotes the president of the American Society of Reproductive Medicine on the potential of the procedure:

“We could be on the cusp of something incredibly important. Something that is really going to pan out to be revolutionary.”

But being the good reporter that she is, Park also quotes experts that note no one has done comparison studies to see if the process really is more successful than other techniques.

Why bug linked to ulcers may cause cancer. The discovery of the link between the bacteria H. pylori and stomach ulcers is one of my favorite tales of the scientific process. When Australian scientists Barry Marshall and Robin Warren first proposed the link in the early 1980s no one believed them. It took Marshall intentionally swallowing a batch of the bacteria, getting ulcers, treating the infection, and the ulcers resolving, before the skeptics let up. They went on to win the Nobel Prize in 1995 and an entire subsequent generation of surgeons no longer learned a standard procedure used for decades to repair stomach ulcers.

In the decades since, research has produced hints that undiagnosed H. pylori infection may also be linked to stomach cancer, but no one knew why. Now, a team at Stanford has fingered a likely path from bacteria to cancer. It turns out the bacteria interacts directly with stomach stem cells, causing them to divide more rapidly than normal.

They found this latest link through another interesting turn of scientific process. They did not feel like they could ethically take samples from healthy individuals’ stomachs, so they used tissue discarded after gastric bypass surgeries performed to treat obesity. In those samples they found that H. pylori clustered at the bottom of tiny glands where stomach stem cells reside. In samples positive for the bacteria, the stem cells were activated and dividing abnormally. HealthCanal picked up the university’s press release on the work.

Rational balanced discussion on gene-edited babies.   Wired produced the most thoughtful piece I have read on the controversy over creating gene-edited babies since the ruckus erupted April 18 when a group of Chinese scientists published a report that they had edited the genes of human eggs. Nick Stockton wrote about the diversity of opinion in the scientific community, but most importantly, about the fact this is not imminent. A lot of lab work lies between now and the ability to create designer babies. Here is one particular well-written caveat:

“Figuring out the efficacy and safety of embryonic gene editing means years and years of research. Boring research. Lab-coated shoulders hunched over petri dishes full of zebrafish DNA. Graduate students staring at chromatographs until their eyes ache.”

He discusses the fears of genetic errors and the opportunity to layer today’s existing inequality with a topping of genetic elitism. But he also discusses the potential to cure horrible genetic diseases and the possibility that all those strained graduate student eyes might bring down the cost to where the genetic fixes might be available to everyone, not just the well heeled.

The piece is worth the read. As he says in his closing paragraph, “be afraid, be hopeful, and above all be educated.”

Stem cell stories that caught our eye: spina bifida, review of heart clinical trials, tracking cells and cell switches

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Stem cells boost fetal surgery for spina bifida. Fetal surgery to correct the spinal defect that causes spina bifida has revolutionized treatment for the debilitating birth defect in the past few years. But for one of the researchers who pioneered the surgery it was only a half fulfilled hope. While the surgery let most of the treated kids grow up without cognitive deficits it did not improve their ability to walk.

spina_bifida-webNow that researcher, Diana Farmer at the University of California, Davis, has found a way to complete the job. Though it has only been used in an animal model so far, she found that when you engineer a stem cell patch that you insert into the gap before you push the protruding spinal cord back in its place during surgery, the animals are able to walk within a few hours of birth.

Specifically, she used a type of stem cell found in the placenta that has been shown to protect nerves. She incased those cells in a gel and placed them on a scaffold to hold them in place after transplant. All six lambs that had surgery plus the cell transplant walked. None of the ones who just had surgery did.

“Fetal surgery provided hope that most children with spina bifida would be able to live without (brain) shunts,” Farmer said. “Now, we need to complete that process and find out if they can also live without wheelchairs.”

CIRM awarded Farmer’s team funds in March to carry this work forward and prepare it for a possible clinical trial. The animal study appeared in Stem Cells Translational Medicine this week and the university’s press release was picked up by HealthCanal.

Thorough, digestible review of heart trials. Kerry Grens, writing in The Scientist, has produced the most complete and understandable review of the clinical trials using stem cells to treat heart disease that I have read. More important she provides significant detail about the three large Phase 3 trials that are ongoing that could provide make-or-break outcomes for using bone marrow stem cells for patients developing heart failure.

The bulk of the piece focuses on research using various types of mesenchymal stem cells found in bone marrow. All three of the late stage clinical trials use those cells, two use cells from the patient’s own marrow and one uses cells from donors. Grens uses a broad spectrum of the research community describe what we currently know about how those cells may work and more importantly, what we don’t know. The experts provide a good point-counter-point on why there are so many clinical trials when we don’t really know those stem cells’ “method of action,” why they might make someone’s heart stronger.

However she leads and ends with work CIRM funds at Cedars-Sinai and Capricor Therapeutics in Los Angeles. That work uses cells derived from the heart called cardiosphere-derived cells. Early trials suggested these cells might be better at reducing scar tissue and triggering regrowth of heart muscle. Those cells are currently being tested in a Phase 2 study to try to get a better handle on exactly what their benefit might be.

Monitoring stem cells after transplants. Early attempts to use stem cells as therapies have been hampered by an inability to see where the cells go after transplant and if they stay the desired location and function. A team at Stanford has used some ingenious new technologies to get over this hurdle, at least in laboratory animals.

Using a homegrown technology that recently won a major innovation prize for a Stanford colleague, optogenetics, the team was able to selectively activate the transplanted cells. Then they used the older technology, functional Magnetic Resonance Imaging (fMRI), to see if the cells were working. Because cell transplants in the brain have led to some of the most difficult to interpret results in humans, they chose to work with nerve stem cells transplanted into the brains of rats. The work was partially funded by CIRM.

Starting with iPS type stem cells made from Parkinson’s patients’ skin, they inserted a gene for a protein that is sensitive to certain wavelengths of light. They then matured those cells into nerve stem cells and implanted them along with a tube that could transmit the right wavelength of light. Over the course of many months they measured the activity of the cells via fMRI with and without the light stimulation. Because the fMRI measures blood flow it by default detects active nerve cells that require more nutrients from blood than inactive cells. Senior researcher, Jin Hyung Lee described the value of this imaging in the university’s press release picked up by HealthCanal:

“If we can watch the new cells’ behaviors for weeks and months after we’ve transplanted them, we can learn — much more quickly and in a guided way rather than a trial-and-error fashion — what kind of cells to put in, exactly where to put them, and how.”

Understanding cell’s switchboard may speed therapy. Cells function by switching genes on and off. Learning which switches to hit to maximize stem cells’ ability to multiply and mature into desired cell types has occupied a significant part of the stem cell research community for years. Now, a team at the Salk Institute has shown that two known genetic switches pack an additive punch when working together.

Both those signaling processes, one called Wnt and one called Activin, are needed for stem cells to mature into specific adult tissue. The Salk team led by Kathy Jones found that when working together the two signals activate some 200 genes. Wnt seems to load the cellular equipment needed for copying the cells and Activin increases the speed and efficiency of the process. In an institute press release picked up by Science Newsline, Jones discussed the practical implications of the finding:

“Now we understand stem cell differentiation at a much finer level by seeing how these cellular signals transmit their effects in the cells. Understanding these details is important for developing more robust stem cell protocols and optimizing the efficiency of stem cell therapies.”

Stem cell stories that caught our eye: multiple sclerosis, virus genes in embryos and preventing cancer’s spread to the brain

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Drugs activate brain stem cells in MS. We have frequently written that in some situations our own stem cells may do a better job at repairing the body than transplanted cells. A team at Case Western in Cleveland has done just that with lab and animal models of Multiple Sclerosis (MS). Even better, they did it with drugs that are already approved for other uses.

They used a steroid, clobetasol, and an antifungal, miconazole, to get a type of stem cell found in the brain to more effectively produce the myelin sheets that protect our nerves and that get destroyed in MS. But in a story in Science Blog the researchers cautioned that patients should not go ask a doctor to inject those drugs. They are currently used only as topical agents on the skin and no one knows what they would do internally in people.

“Off-label use of the current forms of these drugs is more likely to increase other health concerns than alleviate multiple sclerosis symptoms. We are working tirelessly to ready a safe and effective drug for clinical use,” said Paul Tesar who led the study.”

Specifically, the team worked with stem cells called oligodendrocyte progenitor cells. Growing them in the lab they tested hundreds of approved drugs to see if any would nudge those cells into producing myelin. They found these two and tested them in a mouse model of MS and saw improved function in the mice. They are now looking to test other drugs hoping to find one safe for internal use in humans.

Viral genes active in early embryos. Virus genes, mostly left over from infections of our ancestors thousands of years ago, make up some eight percent of the genetic material in our chromosomes. In general those genes just sit there and don’t do anything. But a CIRM funded team at Stanford has found that in the early days of embryo development some of them become quite active.

In fact, they seem to commandeer the growing embryo’s cellular machinery to produce whole virus particles that the researchers detected in the interior of the cells. What they could not determine is whether that activity is benign or somehow directs the development of the embryo—or might be the virus reasserting its parasitic ways.

“It’s both fascinating and a little creepy,” said Joanna Wysocka, the senior author on the study that appeared this week in Nature. “We’ve discovered that a specific class of viruses that invaded the human genome during recent evolution becomes reactivated in the early development of the human embryo, leading to the presence of viral-like particles and proteins in the human cells.”

In the press release, Stanford’s Krista Conger does a nice job of laying out some of the prior research about the origins and nature of all the viral genes hidden amongst our DNA. The release, picked up by HealthCanal makes it clear the finding raises more questions than it provides answers. Edward Grow, the graduate student who was first author on the paper put it this way:

“Does the virus selfishly benefit by switching itself on in these early embryonic cells? Or is the embryo instead commandeering the viral proteins to protect itself? Can they both benefit? That’s possible, but we don’t really know.”

Stem cells with multiple genetic tricks fight cancer. Breast cancer wreaks the most havoc when it spreads and about a third of the time it spreads to the brain. To fight that insidious spread a team a Massachusetts General Hospital and the Harvard Stem Cell Institute has rigged nerve stem cells with multiple genetic tricks to prevent breast cancer cells from growing after they get to the brain.

Certain types of nerve stem cells are naturally attracted to tumors. So the team led by Khalid Shah genetically manipulated those stem cells to express a gene called TRAIL. That gene produces a protein that activates a receptor on the surface of cancer cells that causes them to self-destruct. Then to make sure those stem cells did not stick around and multiply when they are no longer needed, the researchers added another gene that made them susceptible to a common antiviral drug. That drug could be given once the cells had done their work of delivering the suicide note to the cancer cells and the stem cells themselves would then be eliminated.

A press release on the work from MGH was picked up by ScienceNewsline and quoted Shah on the significance of the findings:

“Our results are the first to provide insight into ways of targeting brain metastases with stem-cell-directed molecules that specifically induce the death of tumor cells and then eliminating the therapeutic stem cells.”

In order to measure their results the team started with yet another genetic trick. They wanted to make sure the loaded stem cells were getting to the tumors. So, before they injected breast cancer cells into the carotid arteries in the necks of mice, they modified the cells so that they would express fluorescent markers. That glow could be tracked allowing the researchers to monitor the disappearance of the cancer cells.

This mouse work is obviously many steps away from use in humans, but it provides an ingenious path to follow.