Stem cell stories that caught our eye: shutting down cancer stem cells, safer BMT, better gene therapy and a 3rd ear

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.

A new route to shut down cancer stem cells. A team at Texas A&M University has discovered a specific protein’s role in keeping cancer stem cells active and shown the pathway it uses to do its dirty deed. That pathway immediately became a target for future cancer therapy.

Although not universally accepted by all cancer researchers, the theory that cancer stem cells circumvent traditional therapy and keep cancers coming back is gaining credence through studies like the current one. The Texas team looked at the protein FGF that has been implicated in cancer but has not been a target of drug research because it is involved in so much of normal cell processes. It has seemed impossible to halt its bad behavior without inhibiting its good behavior. They tracked down its impact on cells believed to be cancer stem cells and found the pathway it uses for that effect. So, future teams can target this pathway rather than FGF itself and its many roles.

“If we understand how to keep these cells dormant it means that although we may have to live with the presence of cancer stem cells, we can prevent them from causing the cancer to come back,” said one of the study lead authors, Fen Wang. “That’s what we are trying to understand. That is the future of cancer therapy.”

The NewsMedical web portal picked up the university’s release about the research published in The Journal of Biological Chemistry.  CIRM funds several teams trying to thwart cancer stem cells both in blood cancers and in solid tumors.

 

Safer bone marrow transplant. The most common stem cell therapy, commonly called bone marrow transplant, has a more than three-decade record of success treating cancer patients. As doctors have grown more comfortable with the procedure, they expanded its use beyond using a person’s own stem cells and stem cells from immunologically well-matched donors to using cells from only partially matched donors. As this has increased the number of lives saved it has also increased the number of patients put at risk for the horrible complication known as graft versus host disease (GVHD). Besides being painful and debilitating, GVHD frequently ends in death.

A team at Seattle’s Fred Hutchinson Cancer Center completed a genetic analysis of transplant patients that did and did not develop GVHD. They found a specific gene marker that increases the risk of the complication by more than 50 percent and the risk of death by 25 percent. The results should push physicians with patients who have the at-risk gene to search harder for a matching donor before they resort to a mismatched transplant.

“Our data provide new information on the role of HLA-DPB1 expression in transplantation associated risks that can be used to guide the selection of donors for future transplant recipients in order to minimize the risk of acute GVHD,” said Effie Petersdorf, one the study authors in an article in MEDPAGETODAY.

The study appears in this week’s New England Journal of Medicine, but anyone who does not want to climb the journal’s pay wall, can get considerable more detail in the MEDPAGE article written by a former colleague from my days editing a national medical magazine, Charles Bankhead. You can trust Charlie to get the story right.

 

Using evolution science to improve gene therapy. The field of gene therapy—providing a correct copy of a gene to someone born with a mutation or using a gene to deliver a desired protein—is finally starting to take off. But one of the oldest tools for getting desired genes into cells, a family of viruses called adeno-associated viruses (AAVs) has serious limitations when trying to directly deliver the gene into people. Most of us have been infected with various AAVs and developed immunity to them. So, our immune system may wipe out the virus carrying the desired payload before it can deliver its goods.

Many teams have developed various forms of AAV that help a bit; making the viruses a little less likely to be recognized. Now, a team at the Harvard Stem Cell Institute has taken a major step down that path using evolutionary science. They used existing records of how the virus has changed over time to construct surface proteins that would not be recognized by the immune systems of most people alive today. Bionity.com wrote about the research that appeared in the journal Cell Reports.

 

ear on arm jpegListen up for the week’s oddest story. An Australian performance artist who goes by the name Stelarc has worked with a team of surgeons to grow an ear on his forearm, which he intends to implant with a microphone connected to the internet so followers of his art can hear what he hears 24/7. Not surprisingly, his family is a little skeptical.

Surgeons built the main part of the ear by implanting a scaffold made from standard materials used in plastic surgery and the artist’s own cells populated it with blood vessels and other tissues. But to grow the exterior ear lobe he intends to work with a team using stem cells, which is why this story appeared in my news feed dozens of times this week.

CNN Style did one of the most thorough write-ups including a good discussion of the ethics of wasting valuable time of medical professionals, something Stelarc himself discussed. He concluded that the value grew from getting the science world and art world to intermingle and better understand each other, something that has been on our soapbox for years.

“But I’ve found there’s a lot of goodwill from people who ordinarily would not have contact with an artist, and ordinarily would not see the reason for wasting time and money and their expertise on doing something like this, and that’s heartening,” Stelarc said.

Specialized Embryonic Stem Cells Yield Insights into X Chromosome Inactivation

Please don’t be intimidated by the title of this post! By the end of this blog, you’ll be well versed in X chromosome inactivation, and you’ll understand why you should care about this topic.

Males and females are different in countless ways, but the underlying cause of these differences originates with chromosomes. Women have two X chromosomes while men have an X and a Y. The X chromosome is much larger than the Y chromosome, and consequently it harbors a larger number of genes (there are about 1000) with very important functions. Female cells have evolved to inactivate or silence one of their X chromosomes so that both male and female cells receive the same the same “dosage” of X chromosome genes.

Calico Cat.

Calico cats are a result of X-inactivation.

A great example of X-inactivation in nature is a cat with a calico coat. Did you notice that most calico cats are female? This is because there are two different versions of the fur color gene (orange and black) located on different X chromosomes. In calico cats, some patches of fur turn off the X-chromosome with the black gene while others turn off the one with the orange gene. The result is the beautiful and crazy patchwork of orange and black.

The process of X chromosome inactivation is extremely important for many reasons other than feline coat color. Think about that time you ate an extra-large pizza by yourself. That was pushing your limits right? Well imagine if you actually ate two of those pizzas. Your stomach would likely explode, and you would meet an untimely end. Apply this somewhat disturbing analogy to female cells with two active X chromosomes. You can now imagine that having double the dosage of X chromosome genes could be toxic and result in dead or very unhappy cells.

How X-inactivation works
The jury is still out on the full answer to how X-inactivation works; however, some pieces of the puzzle are known.

The major player in X-inactivation is a molecule called Xist. Xist is produced in cells with two X chromosomes, and its job is to inactivate one of these X’s. During X-inactivation, hundreds of Xist molecules swarm and attach to one of the two X chromosomes. Xist then recruits other molecule buddies to join the silencing party. These other molecules are thought to modify the X chromosome in a way that inactivates it.

This theory is where the field is at right now. However, a study published recently in Cell Reports by Dr. Anton Wutz’s group at ETH Zurich found another piece to this puzzle: a new molecule that’s critical to X-inactivation.

New Study Sheds Light on X-inactivation

Specialized haploid embryonic stem cells engineered to produce the X-inactivator Xist upon drug treatment. (Cell Reports)

Specialized haploid embryonic stem cells engineered to produce the X-inactivator Xist upon drug treatment were used to identify genes important to X-inactivation. (Cell Reports, Montfort et al. 2015)

The Wutz lab used a novel and powerful mouse embryonic stem cell (ESC) model that was engineered to have only one of each chromosome, and therefore only one X instead of two. These “haploid” ESCs were also manipulated to produce copious amounts of the X chromosome silencer Xist when treated with a specific drug. Thus, when these haploid ESCs received the drug, Xist was turned on and inactivated the only X chromosome in these cells, causing them to die.

In an example of brilliant science, Wutz and colleagues used this haploid ESC model to conduct a large-scale screen for genes that work with Xist to cause X-inactivation. Wutz and his colleagues identified genes whose loss of function (caused by mutations made in the lab) saved the lives of haploid ESCs treated with the Xist-inducing drug.

In total, the group identified seven genes that they think are important to Xist function. Their most promising candidate was a gene called Spen. When they mutated the Spen gene in their specialized ESC model, the ESCs survived treatment with the Xist-inducing drug. Further studies revealed that Spen directly interacts with Xist and recruits the other molecules that cause X-inactivation.

Big Picture
But why does this research matter? From a scientific standpoint, it highlights the power of embryonic stem cells as a model for understanding fundamental human processes. In terms of human health, it’s important because X-inactivation is actually a defense mechanism against diseases caused by mutations in genes on the X chromosome (X-linked genes).

In women with that have a disease-causing mutation in only one copy of an X-linked gene, X-inactivation of the chromosome with the mutation will prevent that woman from getting the disease. However, sometimes X-inactivation can be incomplete or biased (favoring the inactivation of one X chromosome over the other), both of which could cause activation of X chromosomes with X-linked disease mutations.

These events are hypothesized to be the cause of some cancers (although this hypothesis is still under speculation), mental impairment, and X-linked diseases such as Rett’s syndrome and autoimmune disorders. Therefore, a better understanding of X-inactivation may one day lead to treatments that prevent these diseases.

Da Mayor and the clinical trial that could help save his vision

Former San Francisco Mayor and California State Assembly Speaker Willie Brown is many things, but shy is not one of them. A profile of him in the San Francisco Chronicle once described him as “Brash, smart, confident”. But for years Da Mayor – as he is fondly known in The City – said very little about a condition that is slowly destroying his vision. Mayor Brown has retinitis pigmentosa (RP).

RP is a degenerative disease that slowly destroys a person’s sight vision by attacking and destroying photoreceptors in the retina, the light-sensitive area at the back of the eye that is critical for vision. At a recent conference held by the Everylife Foundation for Rare Diseases, Mayor Brown gave the keynote speech and talked about his life with RP.

Willie Brown

He described how people thought he was being rude because he would walk by them on the streets and not say hello. The truth is, he couldn’t see them.

He was famous for driving fancy cars like Bentleys, Maseratis and Ferraris. When he stopped doing that, he said, “people thought I was broke because I no longer had expensive cars.” The truth is his vision was too poor for him to drive.

Despite its impact on his life RP hasn’t slowed Da Mayor down, but now there’s a new clinical trial underway that might help him, and others like him, regain some of that lost vision.

The trial is the work of Dr. Henry Klassen at the University of California, Irvine (UCI). Dr. Klassen just announced the treatment of their first four patients, giving them stem cells that hopefully will slow down or even reverse the progression of RP.

“We are delighted to be moving into the clinic after many years of bench research,” Klassen said in a news release.

The patients were each given a single injection of retinal progenitor cells. It’s hoped these cells will help protect the photoreceptors in the retina that have not yet been damaged by RP, and even revive those that have become impaired but not yet destroyed by the disease.

The trial will enroll 16 patients in this Phase 1 trial. They will all get a single injection of retinal cells into the eye most affected by the disease. After that, they’ll be followed for 12 months to make sure that the therapy is safe and to see if it has any beneficial effects on vision in the treated eye, compared to the untreated one.

In a news release Jonathan Thomas, Ph.D., J.D., Chair of the CIRM Board said it’s always exciting when a therapy moves out of the lab and into people:

“This is an important step for Dr. Klassen and his team, and hopefully an even more important one for people battling this devastating disease. Our mission at CIRM is to accelerate the development of stem cell therapies for patients with unmet medical needs, and this certainly fits that bill. That’s why we have invested almost $19 million in helping this therapy reach this point.”

RP hasn’t defeated Da Mayor. Willie Brown is still known as a sharp dresser and an even sharper political mind. His message to the people at the Everylife Foundation conference was, “never give up, keep striving, keep pushing, keep hoping.”

To learn more about the study or to enroll contact the UCI Alpha Stem Cell Clinic at 949-824-3990 or by email at stemcell@uci.edu.

And visit our website to watch a presentation about the trial (link) by Dr. Klassen and to hear brief remarks from one of his patients.

A Stem Cell Summer with Taylor Swift, Jay-Z, and Carly Rae Jepsen (New Videos)

Was that a stem cell conference or a film festival?

It’s a question that may have been on some attendees’ minds last Friday at CIRM’s Creativity Day in San Mateo. The event showcased the accomplishments of about 70 high school students who did cutting-edge stem cell research as part of a CIRM-funded summer internship program at nine world-class institutions in California. The remarkable, young students gave graduate-level research presentations and showed off posters of their scientific findings to their lab mentors, the CIRM team, and proud family members.

While the main focus of the internship was lab research, we also included a social media assignment that asked students to capture their internship experiences by writing blogs, taking Instagram photos, or making movies. And just as the student poured their excitement, smarts, and hard work into their research, they also went all-in with the social media challenge.

I don’t know how they found the time, but eight videos were submitted in all – the most yet since the program started. And they’re fabulous! The CIRM team members who voted on the best videos were blown away by the inventiveness and artistry of the videos. Many students parodied popular songs by the likes of Taylor Swift, Jay-Z and Carly Rae Jepsen. They went above and beyond choreographing their own dance routines in the lab and injecting stem cell science into the lyrics. There was even a parody of the Jerry Seinfeld show called “Cirmfeld”.

The best social media submissions in each category were recognized at the Creativity Day (we blogged about the best blog yesterday). It was a very tough choice deciding on the best video, but in the end we choose one winner and two honorable mentions. In that moment just before the winner was announced, the students were holding their collective breaths and nervously sitting at the edge their seats. It really had the atmosphere of a film festival.

The winning video was a parody of Taylor Swift’s “Blank Space” by Vanessa Arreola & Camilia Kacimi who did their internships at the Gladstone Institutes in San Francisco. The duo shot, edited and scripted the video themselves. Their work is a great example of an effective way to communicate science to the public: start with a subject people know about, add creativity and humor, and teach some science along the way. Watch the video here:

The two honorable mentions also did fantastic jobs communicating science in an accessible way. The high school interns at City of Hope parodied Carly Rae Jepsen’s “I Really Like You” with their beautifully shot and edited video, “We’re Really Close (To a Breakthrough)”:

The students at Stanford also parodied Taylor Swift but in addition they threw down some fierce lyrics in their parody of a Jay-Z and Kayne West track. I do believe it’s the world’s first rap to include a reference to renown Stanford stem cell researcher, Irv Weissman:

You can watch all the videos on CIRMTV, the agency’s YouTube channel.

Congratulations and best of luck to all of the Creativity students. The future is bright for stem cell science!

Creativity sparks a bright future for science

When some people want to see the future they use a crystal ball. Others use tarot cards or runes. But when anyone at CIRM wants to see the future all we have to do is look into the faces of the students in our Creativity program.

Creativity students 2015 with program director Dr. Mani Vessal (front & center with tie)

Creativity students 2015 with program director Dr. Mani Vessal (front & center with tie)

Over the past three years the Creativity program has given some 220 California high school students a chance to spend the summer working in a world-class stem cell research facility. And when I say work, I mean work. They are required to attend lectures, grow their own stem cells, and do experiments. In short, they are expected to do what all the other scientists in the lab do. In return they get a great experience, and a modest stipend for their effort. At the end they produce papers on their work with titles like:

  • Notch Signaling as a Possible Regulator of Mesenchymal Stromal Cell Differentiation in the Hematopoietic Stem Cell Niche
  • RNA Splicing Factor ZRSR2 in Human Erythroleukemia and Stem Cells

We also ask the students to either write a blog or create a video about their experiences over the summer. Many do both. We’ll come back to the video portion later this week. The blogs make for a great read because they chart the students as they progress from knowing little if anything about stem cells, to being quite proficient at working with them. And all in just 8 weeks. One of the hardest parts of our job is choosing the best blog. For example Alice Lin, part of the City of Hope program, got an honorable mention for her blog that was a “diary” written by an embryonic stem cell. Here’s a small sample of her approach:

‘Also, this is NOT YOUR TYPICAL LAB JOURNAL ENTRY. It’s an autobiography chronicling my life. That way, when the stem cell controversy cools down, the general public can get a FIRST HAND ACCOUNT of what we do. This blog is going to rack up some serious views someday. Until then, I’m attached to my colony and the plate.’

Ryan Hale, part of the Scripps team, wrote about how the experience taught him to think like a scientist:

‘One day, after performing an experiment, our mentor asked us the reason behind our experiment. He wasn’t asking us about the experimental procedure or quizzing us on the pre-reading packet, he wanted us to understand the thought process a researcher would go through to actually think up such an experiment… Our mentor stressed how important it is to be creative, inquisitive, and critical if one wants to become a successful researcher.’

Selena Zhang

Selena Zhang

The winner was Selena Zhang, also part of the City of Hope team. She writes about her experiences in the lab, learning the ropes, getting to understand the technology and language of science. But it’s her closing paragraph that sealed the deal for us. In a few short sentences she manages to capture the romance, the mystery and the magic of science. And we’re also happy to say that this program is coming back next year, and the year after that, for five more years. Our Board has just approved renewed funding. The name of the program is changing, it will be called SPARK, but the essence will remain the same. Giving young students a glimpse at a future in science. You don’t need a crystal ball to know that with these students the future is bright. Here’s Selena’s winning blog:

My very own lab coat. It was a lot to live up to, my freshly laundered lab coat with the City of Hope logo. Looking around the lab, I was nervous and excited to start my very first day. There were papers to read and meetings with my mentor to hear about my project. I was starstruck, as I learned that I would be working with induced pluripotent stem cells, Alzheimer’s disease, and CRISPR. Terms that seemed to only exist in textbooks and science magazines that I lovingly read at the library were suddenly alive to me. Although, embarrassingly enough, the only thing that came to mind when my mentor mentioned CRISPR was a salad crisper. Fairly certain that she was a) speaking about something else and b) that I needed to eat more for breakfast, I asked her what that was. It turned out that CRISPR was a new genome editing tool we could use to create isogenic lines to study the independent effects of each allele of the APOE gene that is the most significant risk factor for Alzheimer’s. We would do this by converting a patient and wild-type fibroblast into induced pluripotent stem cells. From this, we would edit a normal allele into the patient’s cell for rescue and the mutated allele in the wild-type cell for insertion, respectively. We would eventually differentiate these cells into neurons and astrocytes to study how the change of this allele can impact neural interaction. This was real science in progress, not enshrined in a textbook, but free, fluid, and vibrant. I slowly grew into my own independence around the lab. I found myself more confident and emotionally invested with each experiment, every immunostaining and PCR. Science, for all of its realism, had always seemed like the unimaginable fantasy to me. Through this opportunity, science has become more tangible, grounded in unglamorous details: hard work and deadlines, mistakes and mishaps, long lab meetings and missed lunches. Yet, that has only made me more confident that I want to pursue science. Now, I’m embracing a reality, one that gives me something worth striving for. In fact, I am very fortunate that my project has encountered numerous obstacles. My initial response to these problems was and still is a lot less Zen and a lot more panic-driven. But I’ve slowly come to realize the beauty of the troubleshooting process for progress. My project has been an emotional rollercoaster, as our rescue cell line met success, but couldn’t advance to the next stage. Our insertion cell line appeared to have incorporated the mutation, but it turned out it only incorporated one allele. It’s been a process of finding the balance between defending our ideas and accepting new ones, the border between defending and defensiveness. My curiosity and drive to improve, to understand, to conquer the unknown is learning to coexist with the need for patience and flexibility No matter how solid our theory should have been, reality is fickle and all the more interesting for it. I thought science was all about doubt and skepticism, questioning everything. Through this internship, I’ve learned that there’s also a surprising amount of faith, the faith to accept any setbacks as part of the discovery process. I thought I loved science before because I loved how enough facts could help me make sense of things. But through this internship in the lab, I’m learning to love a larger part of science, which is not only loving knowledge, but also loving not knowing, loving discovery for all of its uncertainty and perfect imperfections. I’m learning to grow into my lab coat, and hopefully, to find my place in the field of science.

Stem cell stories that caught our eye: potentially safer cell reprogramming, hair follicle cells become nerve and liver stem cells

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.

A potentially safer way to reprogram cells. Ever since then soon-to-be Nobel Prize winner Shinya Yamanaka showed how to reprogram adult cells to an embryonic stem cell-like state labs around the world have jumped on that band wagon. But many of their experiments have not just been using those cells but rather looking for ways to make them more efficiently and possibly safer for clinical use.

The four “Yamanaka factors” traditionally used to make what are now called induced pluripotent stem cells (iPSCs) include genes that can induce cancer. So, folks have been justifiably nervous about using cells derived from iPSCs in patients.

Today in the journal Science two different Chinese teams report slightly different methods of using only chemicals to reprogram skin cells directly into nerves. One team worked at the Shanghai Institutes for Biological Sciences and the other worked at Peking University.

“In comparison with using transgenic reprogramming factors, the small molecules that are used in this chemical approach are cell permeable; cost-effective; and easy to synthesize, preserve, and standardize; and their effects can be reversible,” Hongkui Deng of the Peking team said in a press release used to write a piece in the International Business Times.

 

Stem cells in hair follicles may repair nerve. The base of our hair follicles contains skin stem cells as you would expect, but it also contains cells with markers suggesting they come from the area of the embryo known as the neural crest. A team at the University of Newcastle in the U.K. tested those cells to see if they have stem cell properties and they do.

They were able to use those cells to create Schwann cells, support cells that our bodies use to repair nerves and help with certain systems like sensation. The team’s Schwann cells interacted with nerve cells in lab dishes the way natural cells do in the body.

“We observed that the bulge, a region within hair follicles, contains skin stem cells that are intermixed with cells derived from the neural crest – a tissue known to give rise to Schwann cells,” said Maya Sieber-Blum, in a university press release picked up by Yahoo. “This observation raised the question whether these neural crest-derived cells are also stem cells and whether they could be used to generate Schwann cells.”

They showed that the cells can indeed become Schwann cells. The researchers now want to see if their cells can repair nerve damage in an animal model.

Prior work at Stanford had turned embryonic stem cells into liver cells.

Prior work at Stanford had turned embryonic stem cells into liver cells.

Drink up. Liver stem cells found. The liver creates new liver cells quite readily, whether damaged by alcohol or other factors. But no one has known exactly where the new cells come from, with most researchers assuming the remaining health cells divide to create new tissue. But a team at Stanford suggested that the liver works too hard for that to be the case. In order to remove all the toxins that come its way adult liver cells have amplified certain chromosomes, and team leader Roel Nusse said that would make them unable to divide and create new cells.

So, his team set out to track down previously elusive liver stem cells. They bred mice that had cells that would have a green florescent glow if they carried a protein usually found only on stem cells. They indeed did find stem cells and tracked them as the animals matured and saw them both divide to create more stem cells and mature into adult liver cells.

“We’ve solved a very old problem,” said Nusse, who is a Howard Hughes investigator. “We’ve shown that like other tissues that need to replace lost cells, the liver has stem cells that both proliferate and give rise to mature cells, even in the absence of injury or disease.”

The Hughes Institute issued a press release and the International Business Times wrote the story and illustrated it with a photo from CIRM’s Flickr site.

Earliest stem cells made in lab; provide “extraordinary” potential

Embryonic stem cells are classified as pluripotent cells because they are able (“potent”) to mature into almost every (“pluri”) cell type. Thanks to Nobel Prize winner Shinya Yamanaka, researchers have been able to reprogram fully matured cells, like skin or blood, into embryonic stem cell-like induced pluripotent stem cells (iPS). The technique has revolutionized stem cell science, providing human models of disease and the prospect of personalized cell therapies.

150805_totipotentst1cf4

Human embryo about to complete 1st cell division. Each of these cells are totipotent: they have the ability (“potent”) can give rise to all (“toti”) the cell types of the developing embryo including placenta and umbilical cord. (Image credit: The Endowment for Human Development)

And yet it has remained unknown if reprogramming cells resembling so-called totipotent cells is possible. Unlike iPS or embryonic stem cells, totipotent cells have complete shape-shifting abilities in that they can give rise to all (“toti”) the cell types of the developing embryo including the placenta and umbilical cord. They appear briefly during the earliest stages of development when the fertilized embryo is made up of just one or a few cells. Could lab-derived totipotent cells provide an equally or even more powerful research tool than iPS cells?

The stem cell field is now in position to ask that question. This week scientists from French Institute of Health and Medical Research (INSERM) and the Max Planck Institute in Germany report in Nature Structural Biology that they successfully induced mouse embryonic stem cells to take on totipotent characteristics.

150805_TotipotentBlog

That question mark over the blue arrow can be removed after this week’s report that pluripotent stem cells can be induced to take on characteristics of totipotent cells. (image credit: IGBMC)

To achieve this feat, the scientists started with the known observation that a small amount of totipotent cells spontaneously appear when growing pluripotent stem cells in petri dishes. They are called 2C-like cells because of their likeness to the cells of the two-cell embryo. The team isolated those 2C cells and carefully compared them to the pluripotent embryonic stem cells. They noticed the DNA in 2C cells had a looser structure, which indicates more flexibility to switch on many different genes in a cell. With this information, they found that a protein called CAF1 known to play a role in making a tighter DNA structure, and inhibiting genes, was reduced in the totipotent 2C cells.

By experimentally blocking the function of CAF1 in pluripotent cells, the tightened DNA structure was loosened, leading to more genes being switched on and inducing a totipotent state. With these cells in hand, the team can now examine their possible impact on accelerating progress in regenerative medicine. Maria-Elena Torres-Padilla, the lead scientist on the project, pointed out in a press release the significance of these cells for future studies:

“Totipotency is a much more flexible state than the pluripotent state and its potential applications are extraordinary.”

Going back to figure out how the embryo makes muscles led team to way to mass produce muscle fibers

Sometimes in science what seems like the simpler task turns out to be the hardest. We have written extensively about research teams building mini-organs in lab dishes turning stem cells into multiple layers of tissues organized and functioning, at least in part, like the kidney, liver or stomach they mimic. Given these successes and the relative simplicity of our muscles, you would have thought we would have petri dishes with bulging biceps by now. We don’t. But a team at Harvard and Brigham and Women’s hospital has made a major stride toward that goal.

Smooth muscle cells grown from embryonic stem cells (courtesy Sanford-Burnham Institute).

Smooth muscle cells grown from embryonic stem cells (courtesy Sanford-Burnham Institute).

While previous work has created small amounts of short muscle fibers from stem cells, the Brigham group created large quantities of millimeter-long muscle fibers. This level of muscle development could produce therapeutic quantities of new muscle that would be needed to treat patients with muscular dystrophy. This goal has sent many teams back to the lab looking for better ways to direct stem cells to become muscle.

The current work, published this week in Nature Biotechnology, went back to the basics and tried to understand each step that a stem cell goes through on the way to becoming muscle in the embryo. Medical Daily wrote a piece on the work, and used a quote in the Brigham press release from the senior author Olivier Pourquie:

“We analyzed each stage of early development and generated cell lines that glowed green when they reached each stage. Going step by step, we managed to mimic each stage of development and coax cells toward muscle cell fate.”

Stem cell scientist often find that going back to learn and mimic the natural steps of development works better than guessing what factors are most important in a cell’s fate. Now that they hold a map to the path between stem cell and muscle fibers, they can use it to study many different muscle diseases and work toward therapies for those often-untreatable conditions.

“This has been the missing piece: the ability to produce muscle cells in the lab could give us the ability to test out new treatments and tackle a spectrum of muscle diseases,” Pourquie said.

CIRM funds a dozen projects working to understand and develop therapies for muscle disease.

The road to a cure for HIV/AIDS

Something wonderful sometimes happens when scientists and the public get together to talk about research. All the jargon, all the technical language falls away and it becomes instead a conversation between the two groups with most at stake, the people in need of a treatment or cure, and the people trying to develop it.

HIV Matters Town Hall, West Hollywood

HIV Matters Town Hall, West Hollywood

Last week CIRM joined with the AIDS Project Los Angeles to hold a Town Hall event in West Hollywood called HIV Matters: Countdown to a Cure: California Leads the Way. Around 120 people showed up to listen to stem cell scientists from City of Hope, University of Southern California (USC), Calimmune, and Sangamo Biosciences all of whom are using CIRM funding to develop new treatments, hopefully even cures, for HIV/AIDS.

Just a few years ago an event like this would have been unthinkable. The idea of talking about curing HIV/AIDS would have opened you up to ridicule and accusations of hyping the science. Today CIRM is funding three projects that have been approved for clinical trials (you can read about those here, here and here) and other research that is pushing the boundaries of our knowledge in search of even better approaches.

As David Hardy, the Chief Medical Officer for Calimmune, said:

“What is exciting today is that cure is now something that can be talked about as a potential reality.”

After brief presentations to discuss their work and the science behind it the panel opened the event up to questions from the audience.

Panel L to R: John Zaia, Dale Ando, David Hardy, Paula Cannon

Panel L to R: John Zaia, Dale Ando, David Hardy, Paula Cannon

One of the first questions silenced the room. “Is death a possible side effect of these clinical trials?”

Dr. John Zaia, the Chief of Virology at City of Hope near Los Angeles (and the lead investigator on one of the clinical trials) answered without any hesitation. “Yes”.

“We do everything we can to limit all side effects, especially the most extreme ones, but we have to be honest with patients and explain it is a remote possibility. That’s why it is covered in the informed consent process that every person goes through before signing up for the trial. We want to make sure everyone completely understands what they are signing up for.”

Dr. Dale Ando, Chief Medical Officer at Sangamo BioSciences, talked about the other approaches that are currently being explored to kill the AIDS virus, such as “shock and kill”, where a combination of drugs flushes the virus from hidden reservoirs in the body and then a boost to the immune system kills it.

Paula Cannon, PhD., a CIRM grantee and stem cell scientist at the Keck School of Medicine at USC, talked about her research aimed at developing the next generation of stem cell therapy targeting HIV/AIDS.

Current approaches take blood stem cells out of the body, genetically modify them so they are resistant to the virus, then return them to create a new blood and improved immune system. Cannon’s work is going to try and do that inside the body, without the need to remove the blood stem cells, in essence copying what the AIDS virus does when it infects cells and using that approach against it, creating a one-stop anti-viral approach to kill HIV.

It’s an audacious idea. But sometimes audacity is what you need to make big changes.

CIRM Board member and Patient Advocate for HIV/AIDS, Jeff Sheehy, moderated the discussion and ended the evening with a tribute to all the people who volunteered to be part of these, and every, clinical trial.

“They know, particularly in these early stage clinical trials where the focus is just showing that this approach is safe, that they are not likely to experience any benefit themselves. But they still volunteer, because they want to be part of something that could help many others. There’s a real sense of altruism. They want to advance the science.”

And the science is advancing. Maybe not always as fast as everyone would hope but we are making progress. And with each advance we get one step closer to our ultimate goal, of advancing stem cell therapies to patients with unmet medical needs.

Stem cell stories that caught our eye: Prostate cancer and BPA, mini organs and diabetes trial

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.

Latest mini-organ, a prostate, fingers BPA. A team at the University of Illinois, at Chicago, has added the prostate gland to the growing list of “organoids” that have been grown from stem cells in the lab. The tiny gland that produces semen in men has an unusually high rate of cancer compared to other organs. Prior research has linked that cancerous nature to exposure to the hormone estrogen during fetal growth, including synthetic estrogen mimics like the chemical BPA (bisphenol A) found in many plastics.

Unlike the other organs associated with male gender, which form very early in fetal development, the prostate develops later when stem cells’ roles are more narrowly defined to creating specific tissues. The team, led by Gail Prins, had previously shown that prostate stem cells grown in the presence of BPA formed cells more likely to show signs of cancer. But that did not allow them to determine what really triggered the increase in cancer. So, they decided to grow mini prostates and look at all the cells as they developed in the organoid.

“What we were doing originally with the human prostate stem cells is we were mixing and growing them in vivo,” Prins told Medical Daily. “The idea to generate this organoid came from the first author, Esther Calderon-Gierszal; she was my graduate student. ‘They’ve done it for other organs,’ she thought. ‘Let’s try it for a prostate.’”

The researchers pushed embryonic stem cells to grow into the several different tissues found in a prostate gland using a cocktail of hormones. Although much smaller than a normal prostate the cells did self-organize into structures that resembled the gland. When they grew the organoid in the presence of BPA they found an unusually large number of prostate specific stem cells. So, it appears just the increased number of stem cells increases the likelihood a few will go bad and form cancer.

A round up of all the mini-organs. The journal Nature has written a very accessible wrap up in its news section on all the various organs that have been simulated in a lab dish since a Japanese team reported the phenomenon for the first time in 2008. After a fun lead-in explaining the science, Cassandra Willyard runs through what has been accomplished so far in the stomach, kidney, and liver.

Part of a miniature stomach grown in the lab, stained to reveal various cells found in normal human stomachs [Credit: Kyle McCracken]

Part of a miniature stomach grown in the lab, stained to reveal various cells found in normal human stomachs [Credit: Kyle McCracken]

The fun in the opening section comes from the fact that given the right environment, stem cells are pretty darn good at self-organizing into the multiple tissue types that become a specific organ. So much so, that the early teams that saw it in the lab were shocked and did not at first know what they had.

Willyard starts with quotes from Madeline Lancaster, a post-doctoral fellow in a lab at the Institute for Molecular Biotechnology in Vienna, Austria. She found milky looking spheres in the lab cultures and when she cut into them she found multiple types of nerves. So she grabbed her mentor and reported:

“I’ve got something amazing. You’ve got to see it.”

She also discusses the work that led Hans Clevers, a researcher at Hubrecht Institute in Utrecht, the Netherlands, to report the creation of mini-guts in 20009. They grew the cells in a gel that resembled the structure that naturally surrounds cells. In this “at-home” environment stem cells formed much more complex tissue than he had hoped.

“The structures, to our total astonishment, looked like real guts,” Clevers said. “They were beautiful.”

The author also lets Clevers talk about taking his work the next step, using the gut organoids to screen for drugs for related diseases. If you have been following this work, Willyard’s piece is a must read.

Second clinical trial site for diabetes. Opening multiple clinical trial sites accelerates the process of determining whether a new therapy is safe and effective. So we were thrilled to get the announcement from ViaCyte that they would begin enrolling patients at a second location for the diabetes trial we helped them launch by funding the first clinical trial site at the University of California, San Diego.

That trial uses pancreatic cells grown from embryonic stem cells that are protected from immune attack by a semi-permeable pouch. The second site, at the University of Alberta Hospitals in Edmonton, Canada, is being funded in part by Alberta Innovates as well as by the JDRF Canadian Clinical Trials Network. JDRF also helps support the San Diego trial through its US office.

The lead researcher for the Alberta trial, James Shapiro, developed the procedure for transplanting pancreatic tissue from cadavers that became known as “the Edmonton Protocol.” That protocol has changed many lives, but because it requires life-long immunosuppression, doctors only recommend it for the most severe diabetics. The small number of donor pancreases also limits its use. Shapiro commented about the value and need for something like the ViaCyte therapy in a company press release picked up by Yahoo Finance, and dozens of other sites:

“The fact remains that new treatments are sorely needed, not only for the high risk patients but for all patients suffering from this life-altering disease.  The remarkable promise of the (ViaCyte) product candidate is that a virtually limitless source of appropriate human cells can be transplanted without the need for lifetime immunosuppression.”