Stem cell-derived mini-intestines reveal bacteria’s key role in building up a newborn’s gut

The following factoid may induce an identity crisis for some people but it is true that our bodies carry more microbes than human cells. Some studies in 1970’s estimated the ratio at 10:1 though more recent calculations suggest we’re merely half microbe, half human.

Because microbes are much smaller than human cells they make up only about 1 or 2 percent of our total body mass. But that still amounts to trillions of micro-organisms, mostly bacteria, that live on and inside our bodies. The gut is one part of our body that is teeming with bacteria. Though that may sound gross, you’re very life depends on them. For example, these bacteria allow us to digest foods and take up nutrients that we wouldn’t be able to otherwise.

Intestines

E. coli bacteria, visible in this enhanced microscope image as tiny green rods, were injected into the center of a germ-free hollow ball of cells called a human intestinal organoid (inset image, top right). Within 48 hours, the cells formed much tighter connections with one another, visible as red in this image. Image courtesy of University of Michigan.

When we’re first born our intestines are germ-free but overtime helpful bacteria gain access to our gut and help it function, protecting it from infection by the continual exposure to harmful bacteria and viruses. New research out of the University of Michigan Medical School reported in eLife now shows that the initial bacterial infiltration is even more important than scientists previously thought. It appears to play a key role in stimulating human gut cells to shore up the intestine in preparation for the full wave of both micro-organisms and pathogens that are present throughout a person’s lifetime. The finding could help researchers discover methods to protect the gut from diseases like necrotizing enterocolitis, a rare but dangerous infection that strikes newborns.

To reach these conclusions, the research team grew human embryonic stem cells into miniature intestines in the lab. These so-called human intestinal organoids, or HIOs, are structures made up of a few thousand cells that form hollow tubes with many of the hallmarks of a bona fide intestine. The HIOs were first kept in a germ-free environment to mimic a newborn’s intestine. Then a form of helpful E. Coli bacteria, the same that’s often found in an infant’s diaper, was injected into the HIO and allowed to colonize the inside of the intestine.

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A single human intestinal organoid, or HIO — a hollow ball of cells grown from human embryonic stem cells and coaxed to become gut-lining cells. Scientists can use it to study basic gut development, and the effect of microbes on the cells, in a way that mimics the guts of newborn babies. Image courtesy of University of Michigan

The team observed several changes in gene activity shortly after the bacteria was introduced. Within a day or two, genes involved in producing proteins that fight off harmful microbes increased as well as genes that encode mucus production, a key part of protecting the cells that face the inside of the intestine. Other key features of a maturing intestine, such as tighter cell-to-cell connections and lowered oxygen levels were also stimulated by the presence of the bacteria. As co-senior author Vincent Young, M.D., Ph.D. explained in a press release, these results put the team in a position to uncover new insights about intestinal biology and disease:

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Vincent Young

“We have developed a system that faithfully reproduces the physiology of the immature human intestine, and will now make it possible to study a range of host-microbe interactions in the intestine to understand their functional role in health and disease.”

 

The particular mix of microbes found in one person versus another can differ a lot. And the impact of these differences on an individual’s health has been a trending topic in the media. Lead author David Hill, Ph.D., a postdoctoral fellow in the lab of Jason Spence, Ph.D., thinks that’s one specific research path that they aim to investigate with their HIO system:

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David Hill

“We hope to examine whether different bacteria produce different types of responses in the gut. This type of work might help to explain why different types of gut bacteria seem to be associated with positive or negative health outcomes.”

 

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Stories that caught our eye last week: dying cells trigger stem cells, CRISPR videogames and an obesity-stem cell link

A dying cell’s last breath triggers stem cell division. Most cells in your body are in a constant state of turnover. The cells of your lungs, for instance, replace themselves every 2 to 3 weeks and, believe it or not, you get a new intestine every 2 to 3 days. We can thank adult stem cells residing in these organs for producing the new replacement cells. But with this continual flux, how do the stem cells manage to generate just the right number of cells to maintain the same organ size? Just a slight imbalance would lead to either too few cells or too many which can lead to organ dysfunction and disease.

The intestine turnovers every five days. Stem cells (green) in the fruit fly intestine maintain organ size and structure. Image: Lucy Erin O’Brien/Stanford U.

Stanford University researchers published results on Friday in Nature that make inroads into explaining this fascinating, fundamental question about stem cell and developmental biology. Studying the cell turnover process of the intestine in fruit flies, the scientists discovered that, as if speaking its final words, a dying intestinal cell, or enterocyte, directly communicates with an intestinal stem cell to trigger it to divide and provide young, healthy enterocytes.

To reach this conclusion, the team first analyzed young enterocytes and showed that a protein these cells produce, called E-cadherin, blocks the release of a growth factor called EGF, a known stimulator of cell division. When young enterocytes became old and begin a process called programmed cell death, or apoptosis, the E-cadherin levels drop which removes the inhibition of EGF. As a result, a nearby stem cell now receives the EGF’s cell division signal, triggering it to divide and replace the dying cell. In her summary of this research in Stanford’s Scope blog, science writer Krista Conger explains how the dying cell’s signal to a stem cell ensures that there no net gain or loss of intestinal cells:

“The signal emitted by the dying cell travels only a short distance to activate only nearby stem cells. This prevents an across-the-board response by multiple stem cells that could result in an unwanted increase in the number of newly generated replacement cells.”

Because E-cadherin and the EGF receptor (EGFR) are each associated with certain cancers, senior author Lucy Erin O’Brien ponders the idea that her lab’s new findings may explain an underlying mechanism of tumor growth:

Lucy Erin O’Brien Image: Stanford U.

“Intriguingly, E-cadherin and EGFR are each individually implicated in particular cancers. Could they actually be cooperating to promote tumor development through some dysfunctional version of the normal renewal mechanism that we’ve uncovered?”

 

How a videogame could make gene editing safer (Kevin McCormack). The gene editing tool CRISPR has been getting a lot of attention this past year, and for good reason, it has the potential to eliminate genetic mutations that are responsible for some deadly diseases. But there are still many questions about the safety of CRISPR, such as how to control where it edits the genome and ensure it doesn’t cause unexpected problems.

Now a team at Stanford University is hoping to use a videogame to find answers to some of those questions. Here’s a video about their project:

The team is using the online game Eterna – which describes itself as “Empowering citizen scientists to invent medicine”. In the game, “players” can build RNA molecules that can then be used to turn on or off specific genes associated with specific diseases.

The Stanford team want “players” to design an RNA molecule that can be used as an On/Off switch for CRISPR. This would enable scientists to turn CRISPR on when they want it, but off when it is not needed.

In an article on the Stanford News website, team leader Howard Chang said this is a way to engage the wider scientific community in coming up with a solution:

Howard Chang
Photo: Stanford U.

“Great ideas can come from anywhere, so this is also an experiment in the democratization of science. A lot of people have hidden talents that they don’t even know about. This could be their calling. Maybe there’s somebody out there who is a security guard and a fantastic RNA biochemist, and they don’t even know it. The Eterna game is a powerful way to engage lots and lots of people. They’re not just passive users of information but actually involved in the process.”

They hope up to 100,000 people will play the game and help find a solution.

Altered stem cell gene activity partly to blame for obesity. People who are obese are often ridiculed for their weight problems because their condition is chalked up to a lack of discipline or self-control. But there are underlying biological processes that play a key role in controlling body weight which are independent of someone’s personality. It’s known that so-called satiety hormones – which are responsible for giving us the sensation that we’re full from a meal – are reduced in obese individuals compared to those with a normal weight.

Stem cells may have helped Al Roker’s dramatic weight loss after bariatric surgery. Photo: alroker.com

Bariatric surgery, which reduces the size of the stomach, is a popular treatment option for obesity and can lead to remarkable weight loss. Al Roker, the weatherman for NBC’s Today Show is one example that comes to mind of a weight loss success story after having this procedure. It turns out that the weight loss is not just due to having a smaller stomach and in turn smaller meals, but researchers have shown that the surgery also restores the levels of satiety hormones. So post-surgery, those individuals get a more normal, “I’m full”, feedback from their brains after eating a meal.

A team of Swiss doctors wanted to understand why the satiety hormone levels return to normal after bariatric surgery and this week they reported their answer in Scientific Reports. They analyzed enteroendocrine cells – the cells that release satiety hormones into the bloodstream and to the brain in response to food that enters the stomach and intestines – in obese individuals before and after bariatric surgery as well as a group of people with normal weight. The results showed that obese individuals have fewer enteroendocrine cells compared with the normal weight group. Post-surgery, those cells return to normal levels.

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Cells which can release satiety hormones are marked in green. For obese patients (middle), the number of these cells is markedly lower than for lean people (top) and for overweight patients three months after surgery (bottom). Image: University of Basil.

A deeper examination of the cells from the obese study group revealed altered patterns of gene activity in stem cells that are responsible for generating the enteroendocrine cells. In the post-surgery group, the patterns of gene activity, as seen in the normal weight group, are re-established. As mentioned in a University of Basil press release, these results stress that obesity is more than just a problem of diet and life-style choices:

“There is no doubt that metabolic factors are playing an important part. The study shows that there are structural differences between lean and obese people, which can explain lack of satiation in the obese.”

 

Mini-guts made from stem cells uncover mechanisms of viral infection in infants

Newborns: so precious, so vulnerable. Image: Wikimedia commons

Newborns: so precious, so vulnerable. Image: Wikimedia commons

Besides their chubby cheeks and cute little toes, I think what makes newborns so precious is how vulnerable they are in those first few days and months of life. For instance, infants are particularly easy targets for infections of the gut caused by enteroviruses. While healthy adults infected with these viruses may exhibit mild cold or flu-like symptoms, infants can have serious complications including sudden onset paralysis, infection of the heart and brain, even death.

Not much is known about how these viruses enter the gut and gain entry to other parts of the body. Reporting this week in PNAS, a research team at the Washington University School of Medicine in St. Louis used human stem cell-derived “mini-guts” to uncover some clues.

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Mini-gut grown from human intestinal stem cells. Image: Cliff Luke/Misty Good, U. Washington – St. Louis

The intestine is a very complex organ with several different cell types that work in concert to keep bacteria and viruses out, and to allow food to be absorbed into the bloodstream. This complexity has made it difficult to carry out human studies in the lab that adequately mimic enterovirus infection. To overcome these challenges, the team isolated stem cells from the small intestine of a premature infant and successfully generated mini-intestines in petri dishes.

The researchers then tested the ability of various enteroviruses to infect the mini-guts and observed they were most vulnerable to infection by enterovirus E11, the most common enterovirus infection seen in premature infants. The team went on to show that the E11 virus infects some cell types of the mini-gut but not others.

In a press release, Co-senior author Carolyn Coyne, an associate professor at the University of Pittsburgh School of Medicine, described the importance of this work for the 10 to 15 million enterovirus infections and tens of thousands of hospitalizations each year in the U.S.:

“Despite their major global impact, especially on the health of children, little is known about the route that these viruses take to cross the intestine, their primary point of entry. Our approach has for the first time shed some light on this process. This model also could be used for developing anti-enterovirus therapeutics targeting the gastrointestinal tract, given that no therapeutic approaches exist to combat infections of these viruses.”

Stem cell stories that caught our eye: cancer fighting virus, lab-grown guts work in dogs, stem cell trial to cure HIV

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.

Cancer fighting virus approved for melanoma

(Disclaimer: While this isn’t a story about stem cells, it’s pretty cool so I had to include it.)

The term “virus” generally carries a negative connotation, but in some cases, viruses can be the good guys. This was the case on Tuesday when our drug approval agency, the US Food and Drug Administration (FDA), approved the use of a cancer fighting virus for the treatment of advanced stage melanoma (skin cancer).

The virus, called T-VEC, is a modified version of the herpesvirus, which causes a number of diseases and symptoms including painful blisters and sores in the mouth. Scientists engineered this virus to specifically infect cancer cells and not healthy cells. Once inside cancer cells, T-VEC does what a virus normally does and wreaks havoc by attacking and killing the tumor.

The beauty of this T-VEC is that in the process of killing cancer cells, it causes the release of a factor called GM-CSF from the cancer cells. This factor signals the human immune system that other cancer cells are nearby and they should be attacked and killed by the soldiers of the immune system known as T-cells. The reason why cancers are so deadly is because they can trick the immune system into not recognizing them as bad guys. T-VEC rips off their usual disguise and makes them vulnerable again to attack.

T-VEC recruits immune cells (orange) to attack cancer cells (pink) credit Dr. Andrejs Liepins/SPL

T-VEC recruits immune cells (orange) to attack cancer cells (pink). Photo credit Dr. Andrejs Liepins/SPL.

This is exciting news for cancer patients and was covered in many news outlets. Nature News wrote a great article, which included the history of how we came to use viruses as tools to attack cancer. The piece also discussed options for improving current T-VEC therapy. Currently, the virus is injected directly into the cancer tumor, but scientists hope that one day, it could be delivered intravenously, or through the bloodstream, so that it can kill hard to reach tumors or ones that have spread to other parts of the body. The article suggested combining T-VEC with other cancer immunotherapies (therapies that help the immune system recognize cancer cells) or delivering a personalized “menu” of cancer-killing viruses to treat patients with different types of cancers.

As a side note, CIRM is also interested in fighting advanced stage melanoma and recently awarded $17.7 million to Caladrius Biosciences to conduct a Phase 3 clinical trial with their melanoma killing vaccine. For more, check out our recent blog.

Lab-grown guts work in mice and dogs

If you ask what’s trending right now in stem cell research, one of the topics that surely would pop up is 3D organoids. Also known as “mini-organs”, organoids are tiny models of human organs generated from human stem cells in a dish. To make them, scientists have developed detailed protocols that sometimes involve the use of biological scaffolds (structures on which cells can attach and grow).

A study published in Regenerative Medicine and picked up by Science described the generation of “lab-grown gut” organoids using intestine-shaped scaffolds. Scientists from Johns Hopkins figured out how to grow intestinal lining that had the correct anatomy and functioned properly when transplanted into mice and dogs. Previous studies in this area used flat scaffolds or dishes to grow gut organoids, which weren’t able to form proper functional gut lining.

Lab-grown guts could help humans with gut disorders. (Shaffiey et al., 2015)

Lab-grown guts could help humans with gut disorders. (Shaffiey et al., 2015)

What was their secret recipe? The scientists took stem cells from the intestines of human infants or mice and poured a sticky solution of them onto a scaffold made of suture-like material. The stem cells then grew into healthy gut tissue over the next few weeks and formed tube structures that were similar to real intestines.

They tested whether their mini-guts worked by transplanting them into mice and dogs. To their excitement, the human and mouse lab-grown guts were well tolerated and worked properly in mice, and in dogs that had a portion of their intestine removed. Even more exciting was an observation made by senior author David Hackham:

“The scaffold was well tolerated and promoted healing by recruiting stem cells. [The dogs] had a perfectly normal lining after 8 weeks.”

The obvious question about this study is whether these lab-grown guts will one day help humans with debilitating intestinal diseases like Crohn’s and IBS (inflammatory bowel disorder). Hackam said that while they are still a long way from taking their technology to the clinic, “in the future, scaffolds could be custom-designed for individual human patients to replace a portion of an intestine or the entire organ.”

Clinical trial using umbilical cord stem cells to treat HIV

This week, the first clinical trial using human umbilical cord stem cells to treat HIV patients was announced in Spain. The motivation of this trial is the previous success of the Berlin Patient, Timothy Brown.

The Berlin patient can be described as the holy grail of HIV research. He is an American man who suffered from leukemia, a type of blood cancer, but was also HIV-positive. When his doctor in Berlin treated his leukemia with a stem cell transplant from a bone-marrow donor, he chose a special donor whose stem cells had an inherited mutation in their DNA that made them resistant to infection by the HIV virus. Surprisingly, after the procedure, Timothy was cured of both his cancer AND his HIV infection.

Berlin patient Timothy Brown. Photo credit: Griffin Boyce/Flickr.

Berlin patient Timothy Brown. Photo credit: Griffin Boyce/Flickr.

The National Organization of Transplants (ONT) in Spain references this discovery as its impetus to conduct a stem cell clinical trial to treat patients with HIV and hopefully cure them of this deadly virus. The trial will use umbilical cord blood stem cells instead of bone-marrow stem cells from 157 blood donors that have the special HIV-resistance genetic mutation.

In coverage from Tech Times, the president of the Spanish Society of Hematology and Hemotherapy, Jose Moraleda, was quoted saying:

“This project can put us at the cutting edge of this field within the world of science. It will allow us to gain more knowledge about HIV and parallel offer us a potential option for curing a poorly diagnosed malignant hematological disease.”

The announcement for the clinical trial was made at the Haematology conference in Valencia, and ONT hopes to treat its first patient in December or January.

Stem cell stories that caught our eye: better heart muscle, first patient with eye cell patch, brain cross talk and gut bugs

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.

Growing better heart muscle in the lab. While researchers have been able to grow beating heart cells from stem cells in a dish for many years, those beating blobs of cells have not looked or acted much like the long strong muscle fibers found in a normal heart. A team at Stanford, with collaborators at the Gladstone Institutes have spent much of the past five years looking for ways to make lab-grown heart muscle more like the real thing.

Heart muscle matured from stem cells functions better when grown in long, thin shapes.

Heart muscle matured from stem cells functions better when grown in long, thin shapes.

They published a couple of solutions in the Proceedings of the National Academy of Sciences this week. One of the keys was to make the stem cells feel more like they are in their natural environment, which is full of physical tension. When they grew the stem cells on substrates that provided that type of tension they got stronger heart muscle better able to beat in a synchronized rhythm. They also found that stem cells grown in long, narrow chambers produced heart muscle closer in appearance and function to the narrow muscle fibers found in normal hearts.

The press release, written by our former colleague Amy Adams who now works for the University, was picked up by Medical Express.

First patient in trial for blindness. Doctors at the Moorfields Eye Hospital in London have used specialized eye cells derived from embryonic stem cells and grown on a synthetic scaffold to try to reverse blindness caused by age-related macular degeneration(AMD). Prior clinical trials have injected similar cells but without the supporting structure of the patch to hold them in place.

Also, prior trials have aimed to halt the progressive loss of vision in the dry form of macular degeneration. This trial is trying to reverse damage already done by the wet form of AMD. Each of the groups use embryonic stem cells and first mature the cells into a type of cell found in the back of the eye’s retina, retinal pigmented epithelium (RPE) cells.

“The reason we are very excited is that we have been able to create these very specific cells and we have been able to transfer them to the patient,” lead researcher Lyndon Da Cruz told a writer for the Huffington Post. “It’s the combination of being able to create the cells that are missing and demonstrate that we can safely transplant them.”

CIRM funds a team at the University of Southern California and the University of California, Santa Barbara that has collaborated with the London team and plans to use a similar patch system on a trial set to begin in the next few weeks.

The London news got broad pick up in the media, including this BBC Video.

Cross-talk in the brain linked to success. The National Institutes of Health issued a press release this week describing two early results of its major Brain Initiative. One team from the University of California, San Francisco, provided an explanation about why primate brains are so much bigger than other mammals, and a team from Oxford and Washington University in St. Louis mapped cross talk between different parts of the brain to various personality traits.

The second group collected data on 280 measures such as IQ, language performance, rule-breaking behavior and anger that they mined from the initiative’s Connectome Project. Their analysis of 461 people found a strong correlation to sections of the brain talking to each other when in a resting state and positive personality and demographic traits. Those included high performance on memory tests, life satisfaction, years of education and income.

The UCSF team showed that brain stem cells during early development produce as much as 1,000-fold more neurons in primates than in lower mammals. More important, they isolated a reason for this strong performance. As the brain gets bigger the stem cells don’t have to continually migrate greater distance from their homes, called the stem cell niche. Instead they seem to pack their bags and take the niche with them.

“It is great to see data from large investments like the Human Connectome Project and the BRAIN Initiative result in such interesting science so quickly,” said Greg Farber of the National Institute of Mental Health in the release.

Have to agree.

The interplay of bugs and genes in our gut. The consumer press spends a considerable amount of time talking about the bacteria in our digestive tract, and now a team a Baylor College of Medicine in Houston has produced some data that suggests these microbial cohabitants of our bodies, called the microbiome, become important early in our development.

In research published in the journal Genome Biology and in a press release picked up by Medical Express, the researchers showed that the microbiome in mice during the period they are nursing helps determine which genes are turned on or turned off, and those settings, called epigenetics, follow the mice through their adult life. Specifically, they found that the gut microbiome impacted the function of gut stem cells that we rely on to replace the lining of our digestive system approximately every four days.

“This promises some exciting opportunities to understand how we might be able to tailor one’s microbiome exposure during infancy to maximize health and reduce gastrointestinal disease throughout life,” said one member of the team, Robert Waterland.

Stem cell stories that caught our eye: lab-grown kidneys that work, finding blood stem cells’ home and colitis

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.

Lab grown kidneys able to take a leak. While a few teams have been able to grow parts of kidneys in the lab using stem cells, they could never show full function because kidneys are not a closed system. They need connecting plumbing and a shutterstock_251360653bladder to collect fluid before urine can be expelled. Now, a team in Japan has built kidneys as well as those other parts in the lab. When they were implanted in rats and pigs and connected to the animals’ own plumbing the man-made organs successfully peed.

The BBC ran a story on the work that included a quote from noted stem cell expert Chris Mason of University College, London:

”This is an interesting step forward. The science looks strong and they have good data in animals. But that’s not to say this will work in humans. We are still years off that. It’s very much mechanistic. It moves us closer to understanding how the plumbing might work.”

The team published the research in the U.S. Proceedings of the National Academy of Sciences.

Seeing through bone to track stem cells. Yes we know blood-forming stem cells reside in bone marrow, but that is a pretty big base of operations. We really haven’t known where in the marrow they tend to hang out and in what sort of groupings. A team at Children’s Research Institute at the University of Texas Southwestern published research this week using new imaging techniques to map the home of all the blood stem cells in marrow and it showed some surprising results.

“The bone marrow and blood-forming stem cells are like a haystack with needles inside. Researchers in the past have been able to find a few stem cells, but they’ve only seen a small percentage of the stem cells that are there, so there has been some controversy about where exactly they’re located,” said UT’s Sean Morrison in a press release posted by Technology Networks.

“We developed a technique that allows us to digitally reconstruct the entire haystack and see all the needles – all the blood-forming stem cells that are present in the bone marrow – and to know exactly where they are and how far they are from every other cell type.”

They found the blood-forming stem cells clustered in the center of the bone marrow rather than near the edges of the bone as was presumed. This improved understanding of the stem cells’ natural environment should make it easier to replicate the cells behavior in the lab and, in turn, lead to improved stem cell therapies.

Help for colitis patients resistant to therapy. About two-thirds of patients with colitis and Crohn’s disease do not respond to one of the leading medications that blocks a protein considered key to the inflammatory process, Tumor Necrosis Factor (TNF). A CIRM-funded team at the Children’s Hospital Los Angeles published research this week suggesting why and offering possible new options for treatment.

“Understanding this mechanism allows us to target new therapeutic approaches for patients who don’t respond to current therapies,” said principal investigator Brent Polk in a university press release posted at Eurekalert.

The mechanism surprised his team. They found that TNF in these patients actually protected against inflammation by inhibiting one type of the immune system’s T cells. The interplay between TNF and those culprit T cells now becomes a target to therapeutic intervention.

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: EU approves a cell therapy, second ALS treatment shows promise and new gut cells work

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.

Europe approves first 2nd generation stem cell therapy.
While blood stem cells in bone marrow have been used to treat patients with certain blood cancers for more than 40 years, it has been a long wait for other uses of stem cells to gain official nods from regulatory bodies. The first came in 2012 when Canada approved Prochymal a stem cell therapy for kids who have a severe immune reaction after bone marrow transplant for cancer. That therapy helps the patients regulate their immune response and can be life saving.

Now the European Medicines Agency has approved a therapy for repairing eyes with damaged corneas—the first of a new generation of stem cell therapies that replace or repair specific tissues. The therapy uses a type of stem cell found in the eye called a limbal stem cell. An Italian team pioneered the procedure that has successfully restored vision to scores of patients whose eyes were damaged by chemicals or burns. An official with the EMA noted the significance of this approval in an agency press release.

“This recommendation represents a major step forward in delivering new and innovative medicines to patients.”

The BBC broke the news with a brief story, and MSN followed up with a bit more detail. (And no, this did not happen “this week” but it did happen after we went dark for the holidays.) CIRM also funds work with limbal stem cells.

Second type of stem cells shows benefit for ALS patients. Over the past couple years we have been writing about positive early trial results from Neuralstem for its therapy using a nerve stem cell for treating patients with ALS, also called Lou Gehrig’s disease. This week the company Brainstorm reported data showing improvement in most of the patients treated with a type of stem cell found in bone marrow and fat, mesenchymal stem cells.

The Neuralstem trials used donor stem cells and the Brainstorm trial uses a patient’s own cells, hence the drug name NeuOwn. But they have be revved up in the lab so that they secrete large quantities of what are called neurotrophic factors, chemicals that seem to protect nerves from damage by the disease and potentially foster healing of already damaged nerves.

Eleven of 12 patients experienced a decrease in the rate of progression of this normally very aggressive disease. The Israeli company completed its early trials in Israel but began a second stage trial at Massachusetts General Hospital in April. Reuters ran a story about the announcement.

New intestine engineered from stem cells. CIRM-grantee Tracy Grikscheit has previously reported growing tissues that look like intestinal cells and that have all the right cellular dog tags of our guts. Today the university announced she has shown she can grow tissues that actually function like our guts. They can absorb life-sustaining nutrients.

Because her work focuses on the devastating condition that results when a baby is born with insufficient intestine, it was not surprising this morning to find a good story about her work on the web site MotherBoard. The site quotes her on the latest advance:

“What’s important about this study is it’s not just taking pictures of the cells and saying ok, they’re in the proper location. We’re actually also looking at the function, so we’re showing that not only are the cells present that would for example absorb the sugar in your breakfast, but they actually are doing that job of absorbing sugar.”

Grikscheit works at Children’s Hospital Los Angeles and you can read about her CIRM-funded work to build new intestine here.


Luck’s role in stem cell mutations key to cancer.
Most of the popular talk about risk and cancer centers on inheriting bad genes and being exposed to nasty chemicals in our daily lives. But a new study says the biggest risk is more akin to a roulette wheel.

A study published in Science by a team at Johns Hopkins looked at 31 types of tissue in our bodies and found that random mutations that occur while our tissue-specific stem cells divide correlates better with cancer risk than what we inherit or environmental risks combined. The Scientist produced one of the more thoughtful pieces of the many on the research that appeared in the media this week.

A personal story about getting into stem cell research. I enjoy hearing about how people get into this fascinating field and the media team at the University of Southern California has provided a good example. They profile recent recruit, Michael Bonaguidi who explains how he made the switch from physical to biological science:

“Growing up on Legos and Lincoln Logs, I was very fascinated with building things. As I took more biology courses and was exposed to other facets of science — from chemistry to physics — I became more interested not in the outside but within. And that’s what got me into bioengineering versus structural engineering.”

Described as shaping brains instead of cities he is looking for the types of cells that can rebuild the brain after injury or stroke. HealthCanal picked up the university’s feature.

10 Years/10 Therapies: 10 Years after its Founding CIRM will have 10 Therapies Approved for Clinical Trials

In 2004, when 59 percent of California voters approved the creation of CIRM, our state embarked on an unprecedented experiment: providing concentrated funding to a new, promising area of research. The goal: accelerate the process of getting therapies to patients, especially those with unmet medical needs.

Having 10 potential treatments expected to be approved for clinical trials by the end of this year is no small feat. Indeed, it is viewed by many in the industry as a clear acceleration of the normal pace of discovery. Here are our first 10 treatments to be approved for testing in patients.

HIV/AIDS. The company Calimmune is genetically modifying patients’ own blood-forming stem cells so that they can produce immune cells—the ones normally destroyed by the virus—that cannot be infected by the virus. It is hoped this will allow the patients to clear their systems of the virus, effectively curing the disease.

Spinal cord injury patient advocate Katie Sharify is optimistic about the latest clinical trial led by Asterias Biotherapeutics.

Spinal cord injury patient advocate Katie Sharify is optimistic about the clinical trial led by Asterias Biotherapeutics.

Spinal Cord Injury. The company Asterias Biotherapeutics uses cells derived from embryonic stem cells to heal the spinal cord at the site of injury. They mature the stem cells into cells called oligodendrocyte precursor cells that are injected at the site of injury where it is hoped they can repair the insulating layer, called myelin, that normally protects the nerves in the spinal cord.

Heart Disease. The company Capricor is using donor cells derived from heart stem cells to treat patients developing heart failure after a heart attack. In early studies the cells appear to reduce scar tissue, promote blood vessel growth and improve heart function.

Solid Tumors. A team at the University of California, Los Angeles, has developed a drug that seeks out and destroys cancer stem cells, which are considered by many to be the reason cancers resist treatment and recur. It is believed that eliminating the cancer stem cells may lead to long-term cures.

Leukemia. A team at the University of California, San Diego, is using a protein called an antibody to target cancer stem cells. The antibody senses and attaches to a protein on the surface of cancer stem cells. That disables the protein, which slows the growth of the leukemia and makes it more vulnerable to other anti-cancer drugs.

Sickle Cell Anemia. A team at the University of California, Los Angeles, is genetically modifying a patient’s own blood stem cells so they will produce a correct version of hemoglobin, the oxygen carrying protein that is mutated in these patients, which causes an abnormal sickle-like shape to the red blood cells. These misshapen cells lead to dangerous blood clots and debilitating pain The genetically modified stem cells will be given back to the patient to create a new sickle cell-free blood supply.

Solid Tumors. A team at Stanford University is using a molecule known as an antibody to target cancer stem cells. This antibody can recognize a protein the cancer stem cells carry on their cell surface. The cancer cells use that protein to evade the component of our immune system that routinely destroys tumors. By disabling this protein the team hopes to empower the body’s own immune system to attack and destroy the cancer stem cells.

Diabetes. The company Viacyte is growing cells in a permeable pouch that when implanted under the skin can sense blood sugar and produce the levels of insulin needed to eliminate the symptoms of diabetes. They start with embryonic stem cells, mature them part way to becoming pancreas tissues and insert them into the permeable pouch. When transplanted in the patient, the cells fully develop into the cells needed for proper metabolism of sugar and restore it to a healthy level.

HIV/AIDS. A team at The City of Hope is genetically modifying patients’ own blood-forming stem cells so that they can produce immune cells—the ones normally destroyed by the virus—that cannot be infected by the virus. It is hoped this will allow the patients to clear their systems of the virus, effectively curing the disease

Blindness. A team at the University of Southern California is using cells derived from embryonic stem cell and a scaffold to replace cells damaged in Age-related Macular Degeneration (AMD), the leading cause of blindness in the elderly. The therapy starts with embryonic stem cells that have been matured into a type of cell lost in AMD and places them on a single layer synthetic scaffold. This sheet of cells is inserted surgically into the back of the eye to replace the damaged cells that are needed to maintain healthy photoreceptors in the retina.

What everybody needs to know about CIRM: where has the money gone

It’s been almost ten years since the voters of California created the Stem Cell Agency when they overwhelmingly approved Proposition 71, providing us $3 billion to help fund stem cell research.

In the last ten years we have made great progress – we will have ten projects that we are funding in or approved to begin clinical trials by the end of this year, a really quite remarkable achievement – but clearly we still have a long way to go. However, it’s appropriate as we approach our tenth anniversary to take a look at how we have spent the money, and how much we have left.

Of the $3 billion Prop 71 generates around $2.75 billion was set aside to be awarded to research, build laboratories etc. The rest was earmarked for things such as staff and administration to help oversee the funding and awards.

Of the research pool here’s how the numbers break down so far:

  • $1.9B awarded
  • $1.4B spent
  • $873M not awarded

So what’s the difference between awarded and spent? Well, unlike some funding agencies when we make an award we don’t hand the researcher all the cash at once and say “let us know what you find.” Instead we set a series of targets or milestones that they have to reach and they only get the next installment of the award as they meet each milestone. The idea is to fund research that is on track to meet its goals. If it stops meetings its goals, we stop funding it.

Right now our Board has awarded $1.9B to different institutions, companies and researchers but only $1.4B of that has gone out. And of the remainder we estimate that we will get around $100M back either from cost savings as the projects progress or from programs that are cancelled because they failed to meet their goals.

So we have approximately $1B for our Board to award to new research, which means at our current rate of spending we’ll have enough money to be able to continue funding new projects until around 2020. Because these are multi-year projects we will continue funding them till around 2023 when those projects end and, theoretically at least, we run out of money.

But we are already working hard to try and ensure that the well doesn’t run dry, and that we are able to develop other sources of funding so we can continue to support this work. Without us many of these projects are at risk of dying. Having worked so hard to get these projects to the point where they are ready to move out of the laboratory and into clinical trials in people we don’t want to see them fall by the wayside for lack of support.

Of the $1.9B we have awarded, that has gone to 668 awards spread out over five different categories:

CIRM spending Oct 2014

Increasingly our focus is on moving projects out of the lab and into people, and in those categories – called ‘translational’ and ‘clinical’ – we have awarded almost $630M in funding for more than 80 active programs.

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Under our new CIRM 2.0 plan we hope to speed up the number of projects moving into clinical trials. You can read more about how we plan on doing there in this blog.

It took Jonas Salk almost 15 years to develop a vaccine for polio but those years of hard work ended up saving millions of lives. We are working hard to try and achieve similar results on dozens of different fronts, with dozens of different diseases. That’s why, in the words of our President & CEO Randy Mills, we come to work every day as if lives depend on us, because lives depend on us.