Eggciting News: Scientists developed fertilized eggs from mouse stem cells

A really eggciting science story came out early this week that’s received a lot of attention. Scientists in Japan reported in the journal Nature that they’ve generated egg cells from mouse stem cells, and these eggs could be fertilized and developed into living, breathing mice.

This is the first time that scientists have reported the successful development of egg cells in the lab outside of an animal. Many implications emerge from this research like gaining a better understanding of human development, generating egg cells from other types of mammals and even helping infertile women become pregnant.

Making eggs from pluripotent stem cells

The egg cells, also known as oocytes, were generated from mouse embryonic stem cells and induced pluripotent stem cells derived from mouse skin cells in a culture dish. Both stem cell types are pluripotent, meaning that they can generate almost any cell type in the human body.

After generating the egg cells, the scientists fertilized the eggs through in vitro fertilization (IVF) using sperm from a healthy male mouse. They allowed the fertilized eggs to grow into two cell embryos which they then transplanted into female mice. 11 out of 316 embryos (or 3.5%) produced offspring, which were then able to reproduce after they matured into adults.


These mice were born from artificial eggs that were made from stem cells in a dish. (K. Hayashi, Kyushu University)

Not perfect science

While impressive, this study did identify major issues with its egg-making technique. First, less than 5% of the embryos made from the stem-cell derived eggs developed into viable mice. Second, the scientists discovered that some of their lab-grown eggs (~18%) had abnormal numbers of chromosomes – an event that can prevent an embryo from developing or can cause genetic disorders in offspring.

Lastly, to generate mature egg cells, the scientists had to add cells taken from mouse embryos in pregnant mice to the culture dish. These outside cells acted as a support environment that helped the egg cells mature and were essential for their development. The scientists are working around this issue by developing artificial reagents that could hopefully replace the need for these cells.

Egg cells made from embryonic stem cells in a dish. (K. Hayashi, Kyushu University)

Egg cells made from embryonic stem cells in a dish. (K. Hayashi, Kyushu University)

Will human eggs be next?

A big discovery such as this one immediately raises ethical questions and concerns about whether scientists will attempt to generate artificial human egg cells in a dish. Such technology would be extremely valuable to women who do not have eggs or have problems getting pregnant. However, in the wrong hands, a lot could go wrong with this technology including the creation of genetically abnormal embryos.

In a Nature news release, Azim Surani who is well known in this area of research, said that these ethical issues should be discussed now and include the general public. “This is the right time to involve the wider public in these discussions, long before and in case the procedure becomes feasible in humans.”

In an interview with , James Adjaye, another expert from Heinrich Heine University in Germany, raised the point that even if we did generate artificial human eggs, “the final and ultimate test for fully functional human ‘eggs in a dish’ would be the fertilization using IVF, which is also ethically not allowed.”

Looking forward, senior author on the Nature study, Katsuhiko Hayashi, predicted that in a decade, lab-grown “oocyte-like” human eggs will be available but probably not at a scale for fertility treatments. Because of the technical issues his study revealed, he commented, “It is too preliminary to use artificial oocytes in the clinic.”

From Pig Parts to Stem Cells: Scientist Douglas Melton Wins Ogawa-Yamanaka Prize for Work on Diabetes

Since the 1920s, insulin injections have remained the best solution for managing type 1 diabetes. Patients with this disease do not make enough insulin – a hormone that regulates the sugar levels in your blood – because the insulin-producing cells, or beta cells, in their pancreas are destroyed.

Back then, it took two tons of pig parts to make eight ounces of insulin, which was enough to treat 10,000 diabetic patients for six months. Biotech and pharmaceutical companies have since developed different types of human insulin treatments that include fast and long acting versions of the hormone. It’s estimated that $22 billion will be spent on developing insulin products for patients this year and that costs will rise to $32 billion in the year 2019.

These costs are necessary to keep insulin-dependent diabetes patients alive and healthy, but what if there was a different, potentially simpler solution to manage diabetes? One that looks to insulin-producing beta cells as the solution rather than daily hormone shots?

Douglas Melton Receives Stem Cell Prize for Work on Diabetes

Harvard scientist Douglas Melton envisions a world where one day, insulin-dependent diabetic patients are given stem cell transplants rather than shots to manage their diabetes. In the 90s, Melton’s son was diagnosed with type 1 diabetes. Motivated by his son’s diagnosis, Melton dedicated the focus of his research on understanding how beta cells develop from stem cells in the body and also in a cell culture dish.

Almost 30 years later, Melton has made huge strides towards understanding the biology of beta cell development and has generated methods to “reprogram” or coax pluripotent stem cells into human beta cells.

Melton was honored for his important contributions to stem cell and diabetes research at the second annual Ogawa-Yamanaka Stem Cell Prize ceremony last week at the Gladstone Institutes. This award recognizes outstanding scientists that are translating stem cell research from the lab to clinical trials in patients.


Deepak Srivastava, director of the Gladstone Institute of Cardiovascular Disease, explained why Melton was selected as this year’s prize winner:

Deepak Srivastava, Gladstone Institutes

Deepak Srivastava, Gladstone Institutes

“Doug’s research on genetic markers expressed during pancreas development have led to a reliable way to reprogram stem cells into human beta cells. His work provides the foundation for the ultimate goal of transplantable, patient-specific beta cells.”


Making Beta Cells for Patients

During the awards ceremony, Melton discussed his latest work on generating beta cells from human stem cells and how this technology could transform the way insulin-dependent patients are treated.

Douglas Melton, Harvard University.

Douglas Melton, Harvard University.

“I don’t mean to say that this [insulin treatment] isn’t a good idea. That’s keeping these people alive and in good health,” said Melton during his lecture. “What I want to talk about is a different approach. Rather than making more and better insulins and providing them by different medical devices, why not go back to nature’s solution which is the beta cells that makes the insulin?”

Melton first described his initial research on making pancreatic beta cells from embryonic and induced pluripotent stem cells in a culture dish. He described the power of this system for not only modeling diabetes, but also screening for potential drugs, and testing new therapies in animal models.

He also mentioned how he and his colleagues are developing methods to manufacture large amounts of human beta cells derived from pluripotent stem cells for use in patients. They are able to culture stem cells in large spinning flasks that accelerate the growth and development of pluripotent stem cells into billions of human beta cells.

Challenges and Future of Stem-Cell Derived Diabetes Treatments

Melton expressed a positive outlook for the future of stem cell-derived treatments for insulin-dependent diabetes, but he also mentioned two major challenges. The first is the need for better control over the methods that make beta cells from stem cells. These methods could be more efficient and generate higher numbers of beta cells (beta cells make up 16% of stem cell-derived cells using their current culturing methods). The second is preventing an autoimmune attack after transplanting the stem-cell derived beta cells into patients.

Melton and other scientists are already working on improving techniques to make more beta cells from stem cells. As for preventing transplanted beta cells from being attacked by the patient’s immune system, Melton described two possibilities: using an encapsulation device or biological protection to mask the transplanted cells from an attack.


He mentioned a CIRM-funded clinical trial by ViaCyte, which is testing an encapsulation device that is placed under the skin. The device contains embryonic stem cell-derived pancreatic progenitor cells that develop into beta cells that secrete insulin into the blood stream. The device also prevents the immune system from attacking and killing the beta cells.

Melton also discussed a biological approach to protecting transplanted beta cells. In collaboration with Dan Anderson at MIT, they coated stem cell-derived beta cells in a biomaterial called alginate, which comes from seaweed. They injected alginate microcapsule-containing beta cells into diabetic mice and were able control their blood sugar levels.

At the end of his talk, Melton concluded that he believes that beta cell transplantation in an immunoprotective device containing stem cell-derived cells will have the most benefit for diabetes patients.

Gladstone Youtube video of Douglas Melton’s lecture at the Ogawa-Yamanaka Prize lecture.

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Stem Cell Experts Discuss the Ethical Implications of Translating iPSCs to the Clinic

Part of The Stem Cellar blog series on 10 years of iPSCs.

This year, scientists are celebrating the 10-year anniversary of Shinya Yamanaka’s Nobel Prize winning discovery of induced pluripotent stem cells (iPSCs). These are cells that are very similar biologically to embryonic stem cells and can develop into any cell in the body. iPSCs are very useful in scientific research for disease modeling, drug screening, and for potential cell therapy applications.

However, with any therapy that involves testing in human patients, there are ethical questions that scientists, companies, and policy makers must consider. Yesterday, a panel of stem cell and bioethics experts at the Cell Symposium 10 Years of iPSCs conference in Berkeley discussed the ethical issues surrounding the translation of iPSC research from the lab bench to clinical trials in patients.

The panel included Shinya Yamanaka (Gladstone Institutes), George Daley (Harvard University), Christine Mummery (Leiden University Medical Centre), Lorenz Studer (Memorial Sloan Kettering Cancer Center), Deepak Srivastava (Gladstone Institutes), and Bioethicist Hank Greely (Stanford University).

iPSC Ethics Panel

iPSC Ethics Panel at the 10 Years of iPSCs Conference

Below is a summary of what these experts had to say about questions ranging from the ethics of patient and donor consent, genetic modification of iPSCs, designer organs, and whether patients should pay to participate in clinical trials.

How should we address patient or donor consent regarding iPSC banking?

Multiple institutes including CIRM are developing iPSC banks that store thousands of patient-derived iPSC lines, which scientists can use to study disease and develop new therapies. These important cell lines wouldn’t exist without patients who consent to donate their cells or tissue. The first question posed to the panel was how to regulate the consent process.

Christine Mummery began by emphasizing that it’s essential that companies are able to license patient-derived iPSC lines so they don’t have to go back to the patient and inconvenience them by asking for additional samples to make new cell lines.

George Daley and Hank Greely discussed different options for improving the informed consent process. Daley mentioned that the International Society for Stem Cell Research (ISSCR) recently updated their informed consent guidelines and now provide adaptable informed consent templates that can be used for obtaining many type of materials for human stem cell research.  Daley also mentioned the move towards standardizing the informed consent process through a single video shared by multiple institutions.

Greely agreed that video could be a powerful way to connect with patients by using talented “explainers” to educate patients. But both Daley and Greely cautioned that it’s essential to make sure that patients understand what they are getting involved in when they donate their tissue.

Greely rounded up the conversation by reminding the audience that patients are giving the research field invaluable information so we should consider giving back in return. While we can’t and shouldn’t promise a cure, we can give back in other ways like recognizing the contributions of specific patients or disease communities.

Greely mentioned the resolution with Henrietta Lack’s family as a good example. For more than 60 years, scientists have used a cancer cell line called HeLa cells that were derived from the cervical cancer cells of a woman named Henrietta Lacks. Henrietta never gave consent for her cells to be used and her family had no clue that pieces of Henrietta were being studied around the world until years later.

In 2013, the NIH finally rectified this issue by requiring that researchers ask for permission to access Henrietta’s genomic data and to include the Lacks family in their publication acknowledgements.

Hank Greely, Stanford University

Hank Greely, Stanford University

“The Lacks family are quite proud and pleased that their mother, grandmother and great grandmother is being remembered, that they are consulted on various things,” said Hank Greely. “They aren’t making any direct money out of it but they are taking a great deal of pride in the recognition that their family is getting. I think that returning something to patients is a nice thing, and a human thing.”

What are the ethical issues surrounding genome editing of iPSCs?

The conversation quickly focused on the ongoing CRISPR patent battle between the Broad Institute, MIT and UC Berkeley. For those unfamiliar with the technique, CRISPR is a gene editing technology that allows you to cut and paste DNA at precise locations in the genome. CRISPR has many uses in research, but in the context of iPSCs, scientists are using CRISPR to remove disease-causing mutations in patient iPSCs.

George Daley expressed his worry about a potential fallout if the CRISPR battle goes a certain way. He commented, “It’s deeply concerning when such a fundamentally enabling platform technology could be restricted for future gene editing applications.”

The CRISPR patent battle began in 2012 and millions of dollars in legal fees have been spent since then. Hank Greely said that he can’t understand why the Institutes haven’t settled this case already as the costs will only continue to rise, but that it might not matter how the case turns out in the end:

“My guess is that this isn’t ultimately going to be important because people will quickly figure out ways to invent around the CRISPR/Cas9 technology. People have already done it around the Cas9 part and there will probably be ways to do the same thing for the CRISPR part.”

 Christine Mummery finished off with a final point about the potential risk of trying to correct disease causing mutations in patient iPSCs using CRISPR technology. She noted that it’s possible the correction may not lead to an improvement because of other disease-causing genetic mutations in the cells that the patient and their family are unaware of.

 Should patients or donors be paid for their cells and tissue?

Lorenz Studer said he would support patients being paid for donating samples as long as the payment is reasonable, the consent form is clear, and patients aren’t trying to make money off of the process.

Hank Greely said the big issue is with inducement and whether you are paying enough money to convince people to do something they shouldn’t or wouldn’t want to do. He said this issue comes up mainly around reproductive egg donation but not with obtaining simpler tissue samples like skin biopsies. Egg donors are given money because it’s an invasive procedure, but also because a political decision was made to compensate egg donors. Greely predicts the same thing is unlikely to happen with other cell and tissue types.

Christine Mummery’s opinion was that if a patient’s iPSCs are used by a drug company to produce new successful drugs, the patient should receive some form of compensation. But she said it’s hard to know how much to pay patients, and this question was left unanswered by the panel.

Should patients pay to participate in clinical trials?

George Daley said it’s hard to justify charging patients to participate in a Phase 1 clinical trial where the focus is on testing the safety of a therapy without any guarantee that there will be beneficial outcome to the patient. In this case, charging a patient money could raise their expectations and mislead them into thinking they will benefit from the treatment. It would also be unfair because only patients who can afford to pay would have access to trials. Ultimately, he concluded that making patients pay for an early stage trial would corrupt the informed consent process. However, he did say that there are certain, rare contexts that would be highly regulated where patients could pay to participate in trials in an ethical way.

Lorenz Studer said the issue is very challenging. He knows of patients who want to pay to be in trials for treatments they hope will work, but he also doesn’t think that patients should have to pay to be in early stage trials where their participation helps the progress of the therapy. He said the focus should be on enrolling the right patient groups in clinical trials and making sure patients are properly educated about the trial they are participating.

Thoughts on the ethics behind making designer organs from iPSCs?

Deepak Srivastava said that he thinks about this question all the time in reference to the heart:

Deepak Srivastava, Gladstone Institutes

Deepak Srivastava, Gladstone Institutes

“The heart is basically a pump. When we traditionally thought about whether we could make a human heart, we asked if we could make the same thing with the same shape and design. But in fact, that’s not necessarily the best design – it’s what evolution gave us. What we really need is a pump that’s electrically active. I think going forward, we should remove the constraint of the current design and just think about what would be the best functional structure to do it. But it is definitely messing with nature and what evolution has given us.”

Deepak also said that because every organ is different, different strategies should be used. In the case of the heart, it might be beneficial to convert existing heart tissue into beating heart cells using drugs rather than transplant iPSC-derived heart cells or tissue. For other organs like the pancreas, it is beneficial to transplant stem cell-derived cells. For diabetes, scientists have shown that injecting insulin secreting cells in multiple areas of the body is beneficial to Diabetes patients.

Hank Greely concluded that the big ethical issue of creating stem cell-derived organs is safety. “Biology isn’t the same as design,” Greely said. “It’s really, really complicated. When you put something into a biological organism, the chances that something odd will happen are extremely high. We have to be very careful to avoid making matters worse.”

For more on the 10 years of iPSCs conference, check out the #CSStemCell16 hashtag on twitter.

CIRM’s Randy Mills: New FDA rules for stem cells won’t fix the problem

For the last two days the Food and Drug Administration (FDA) has been holding a hearing in Bethesda, Maryland on new regulations that would tighten control over stem cell treatments. The FDA invited public testimony during the hearing on the regulations that would impact many of the clinics that currently offer unproven therapies

The testimony has been impassioned to say the least. Supporters of the clinics say they offer a valuable service and that patients should be allowed to decide for themselves how they want their own cells to be used. Opponents say the clinics are little more than snake oil sales people, offering bogus, unproven treatments.

One of those presenting was Randy Mills, CIRM’s President and CEO. Randy has been very vocal in the past about the need for the FDA to change the way it regulates stem cell therapies.

In California Healthline Randy explained why he thinks the rules the FDA is proposing will not fix the problem, and may even make it worse:

FDA Must Find A Middle Ground For Sake Of Patients


Randy Mills

We aren’t happy, as a lot of people aren’t happy, with the proliferation of these stem cell clinics — some of which are probably doing good work. But some are clearly making rather outlandish claims for which there’s no real data. 

There are a couple of conditions coming together to create this storm.

One is that the need is very real. These patients are really struggling. They don’t have alternatives. They’re desperate and they need help. It’s not in the realm of possibility to talk to somebody who is suffering as badly as these patients are and to say, ‘You have to wait a few more decades for the science to catch up.’

On the other hand, we have a regulatory paradigm that only provides two pathways to put a cell therapy onto the market. One pathway is the most intense regulatory requirement anywhere in the world for any product — the biologics license application through the FDA, which takes 10 to 20 years and costs over $1 billion.

The other is through the exemptions the FDA has made, which require absolutely no pre-market approval whatsoever. You can be on the market in days, with no data.

The regulatory burden associated with one is massive and the other is almost nonexistent.

So it’s not at all surprising that we’re seeing a proliferation of these stem cell clinics popping up that are operating under the assumption that they fall under the exemption.

What the FDA is doing now is saying, ‘We’re not happy with this. We’re going to define some terms more narrowly than in the past … and make it more difficult to legally be on the market under the less burdensome regulatory pathway.’

That’s what this meeting is about.

The problem with their strategy is twofold. It doesn’t address the patients, or the need side of the equation. And I don’t think it has a chance of actually working because the FDA will acknowledge that they do not have the resources to enforce these types of regulations at the clinic level.

They would have to be essentially regulating the practice of physicians, which is well beyond their capabilities. Even if they were able to enforce it, it would just drive these patients somewhere else.

We’re advocating for the creation of some middle pathway that would bring essentially unregulated therapies into the regulatory fold, but in a manner which could be complied with.

I would rather know these clinics are being regulated and collecting data than have them operating under the radar screen of the FDA. I would like there to be a formal pre-market review of these therapies before they’re put on the market. I would like there to be safety and efficacy data.

I’m going to try hard to get the FDA to see that just plugging this hole won’t make the problem go away.

Thinking that they’re going to strengthen the regulation and that patients are going to be satisfied that there’s absolutely no chance for help is naive.

There isn’t a lot of evidence to suggest these types of procedures are overly risky. It’s not that they don’t have risk, but everything in medicine does. If you’re a patient who has absolutely no alternative, you’re probably willing to take the chance.

Young man with spinal cord injury regains use of hands and arms after stem cell therapy


Kris Boesen – Photo courtesy USC

Hope is such a fragile thing. We cling to it in bad times. It offers us a sense that we can bear whatever hardships we are facing today, and that tomorrow will be better.

Kris Boesen knows all about holding on to hope during bad times. On March 6th of this year he was left paralyzed from the neck down after a car accident. Kris and his parents were warned the damage might be permanent.

Kris says at that point, life was pretty bleak:

“I couldn’t drink, couldn’t feed myself, couldn’t text or pretty much do anything, I was basically just existing. I wasn’t living my life, I was existing.”

For Kris and his family hope came in the form of a stem cell clinical trial, run by Asterias Biotherapeutics and funded by CIRM. The Asterias team had already enrolled three patients in the trial, each of whom had 2 million cells transplanted into their necks, primarily to test for safety. In early April Kris became the first patient in the trial to get a transplant of 10 million stem cells.

Within two weeks he began to show signs of improvement, regaining movement and strength in his arms and hands:

“Now I have grip strength and do things like open a bottle of soda and feed myself. Whereas before I was relying on my parents, now after the stem cell therapy I am able to live my life.”

The therapy involves human embryonic stem cells that have been differentiated, or converted, into cells called oligodendrocyte progenitors. These are capable of becoming the kind of cells which help protect nerve cells in the central nervous system, the area damaged in spinal cord injury.

The surgery was performed by Keck Medicine of USC’s Dr. Charles Liu. In a news release about the procedure, he says improvements of the kind Kris has experienced can make a huge difference in someone’s life:


Dr. Charles Liu, Keck School of Medicine: Photo courtesy USC

“As of 90 days post-treatment, Kris has gained significant improvement in his motor function, up to two spinal cord levels. In Kris’ case, two spinal cord levels means the difference between using your hands to brush your teeth, operate a computer or do other things you wouldn’t otherwise be able to do, so having this level of functional independence cannot be overstated.”

We blogged about this work as recently as last week, when Asterias announced that the trial had passed two important safety hurdles.  But Kris’ story is the first to suggest this treatment might actually be working.

Randy Mills, CIRM’s President & CEO, says:

 “With each patient treated in this clinical trial we learn.  We gain more experience, all of which helps us put into better context the significance of this type of event for all people afflicted with debilitating spinal cord injuries. But let us not lose sight of the individual here.  While each participant in a clinical trial is part of the group, for them success is binary.  They either improve or they do not.  Kris bravely and selflessly volunteered for this clinical trial so that others may benefit from what we learn.  So it is fitting that today we celebrate Kris’ improvements and stop to thank all those participating in clinical trials for their selfless efforts.”

For patient advocates like Roman Reed, this was a moment to celebrate. Roman has been championing stem cell research for years and through his Roman Reed Foundation helped lay the groundwork for the research that led to this clinical trial:

This is clear affirmative affirmation that we are making Medical History!  We were able to give a paralyzed quadriplegic patient back the use of his hands! With only half a clinical dosage. Now this person may hold and grasp his loved ones hands in his own hands because of the actions of our last two decades for medical research for paralysis CURE! CARPE DIEM!”

It’s not unheard of for people with the kind of injury Kris had to make a partial recovery, to regain some use of their arms and hands, so it’s impossible to know right now if the stem cell transplant was the deciding factor.


Kris at home: photo courtesy USC

Kris’ dad, Rodney, says he doesn’t care how it happened, he’s just delighted it did:

“He’s going to have a life, even if (the progress) stops just this second, and this is what he has, he’s going to have a better life than he would have definitely had before, because there are so many things that this opens up the world for him, he’s going to be able to use his hands.”

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Stem cell stories that caught our eye: functioning liver tissue, making new bone, stem cells and mental health

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.

Functioning liver tissue. Scientists are looking to stem cells as a potential alternative treatment to liver transplantation for patients with end-stage liver disease. Efforts are still in their early stages but a study published this week in Stem Cells Translational Medicine, shows how a CIRM-funded team at the Children’s Hospital Los Angeles (CHLA) successfully generated partially functional liver tissue from mouse and human stem cells.

Biodegradable scaffold (left) and human tissue-engineered liver (right) (Photo courtesy of The Saban Research Institute at Children’s Hospital Los Angeles)

Biodegradable scaffold (left) and human tissue-engineered liver (right) (Photo courtesy of The Saban Research Institute at Children’s Hospital Los Angeles)

The lab had previously developed a protocol to make intestinal organoids from mouse and human stem cells. They were able to tweak the protocol to generate what they called liver organoid units and transplanted the tissue-engineered livers into mice. The transplants developed cells and structures found in normal healthy livers, but their organization was different – something that the authors said they would address in future experiments.

Impressively, when the tissue-engineered liver was transplanted into mice with liver failure, the transplants had some liver function and the liver cells in these transplants were able to grow and regenerate like in normal livers.

In a USC press release, Dr. Kasper Wang from CHLA and the Keck school of medicine at USC commented:

“A cellular therapy for liver disease would be a game-changer for many patients, particularly children with metabolic disorders. By demonstrating the ability to generate hepatocytes comparable to those in native liver, and to show that these cells are functional and proliferative, we’ve moved one step closer to that goal.”


Making new bone. Next up is a story about making new bone from stem cells. A group at UC San Diego published a study this week in the journal Science Advances detailing a new way to make bone forming cells called osteoblasts from human pluripotent stem cells.

Stem cell-derived osteoblasts (bone cells). Image credit Varghese lab/UCSD.

Stem cell-derived osteoblasts (bone cells). Image credit Varghese lab/UCSD.

One way that scientists can turn pluripotent stem cells into mature cells like bone is to culture the stem cells in a growth medium supplemented with small molecules that can influence the fate of the stem cells. The group discovered that by adding a single molecule called adenosine to the growth medium, the stem cells turned into osteoblasts that developed vascularized bone tissue.

When they transplanted the stem cell-derived osteoblasts into mice with bone defects, the transplanted cells developed new bone tissue and importantly didn’t develop tumors.

 In a UC newsroom release, senior author on the study and UC San Diego Bioengineering Professor Shyni Varghese concluded:

“It’s amazing that a single molecule can direct stem cell fate. We don’t need to use a cocktail of small molecules, growth factors or other supplements to create a population of bone cells from human pluripotent stem cells like induced pluripotent stem cells.”


Stem cells and mental health. Brad Fikes from the San Diego Union Tribune wrote a great article on a new academic-industry partnership whose goal is to use human stem cells to find new drugs for mental disorders. The project is funded by a $15.4 million grant from the National Institute of Mental Health.

Academic scientists, including Rusty Gage from the Salk Institute and Hongjun Song from Johns Hopkins University, are collaborating with pharmaceutical company Janssen and Cellular Dynamics International to develop induced pluripotent stem cells (iPSCs) from patients with mental disorders like bipolar disorder and schizophrenia. The scientists will generate brain cells from the iPSCs and then work with the companies to test for potential drugs that could be used to treat these disorders.

In the article, Fred Gage explained that the goal of this project will be used to help patients rather than generate data points:

Rusty Gage, Salk Institute.

Rusty Gage, Salk Institute.

“Gage said the stem cell project is focused on getting results that make a difference to patients, not simply piling up research information. Being able to replicate results is critical; Gage said. Recent studies have found that many research findings of potential therapies don’t hold up in clinical testing. This is not only frustrating to patients, but failed clinical trials are expensive, and must be paid for with successful drugs.”

“The future of this will require more patients, replication between labs, and standardization of the procedures used.”

Clearing the first hurdle: spinal cord injury trial passes safety review

Jake 2

Jake Javier, participant in Asterias clinica trial

Starting a clinical trial is like taking a step into the unknown. It’s moving a potential therapy out of the lab and testing it in people. To reach this point the researchers have done a lot of work trying to ensure the therapy is safe. But that work was done in the lab, and on mice or other animals. Now it’s time to see what happens when you try it in the real world.

It can be quite nerve wracking for everyone involved: both the researchers, because years of hard work are at stake, and the patients, because they’re getting something that has never been tested in humans before; something that could, potentially, change their lives.

Today we got some good news about one clinical trial we are funding, the Asterias Biotherapeutics spinal cord injury trial. Asterias announced that its Data Monitoring Committee (DMC) has reviewed the safety data from the first two groups of patients treated and found no problems or bad side effects.

That’s an important first step in any clinical trial because it shows that, at the very least, the therapy is not going to make the patient’s condition any worse.

The big question now, is will it make their condition better? That’s something we’ll come back to at a later date when we have a better idea how the people treated in the trial are doing. But for now let’s take a deeper dive into the safety data.

Asterias – by the numbers

This current trial is a Phase 1/2a trial. The people enrolled have all experienced injuries in the C5-C7 vertebrae – that’s high up in the neck – and have essentially lost all feeling and movement below the injury site. All are treated between two weeks and one month after the injury was sustained.

The therapy involves transplants of Asterias’ AST-OPC1 cells which were made from human embryonic stem cells. The AST-OPC1 cells have been turned into oligodendrocyte progenitors, which are capable of becoming the kind of cells which help protect nerve cells in the central nervous system, the area damaged in spinal cord injury.

The first group of three patients in the Asterias trial was given 2 million cells. The second group of five patients received 10 million cells. The DMC said the safety data from those patients looked fine, that there were no signs of problems.

As Dr. Edward Wirth, the Chief Medical Officer at Asterias, said in a news release, this means the company can plan for its next phase:

“The positive safety data in the previous phase 1 study and in the ongoing phase 1/2a study gives us the confidence to now proceed to administration of 20 million cells, which based on our significant pre-clinical research is likely well within the dosing range where we would expect to see clinically meaningful improvement in these patients.”

Asterias is now looking to enroll 5-8 patients for this 20 million cell phase.

jake and family

For people like Jake Javier this news is not about numbers or data, it’s personal. Earlier this summer Jake broke his neck at a pool party, celebrating graduating from high school. It left him paralyzed from the chest down with extremely limited use of his arms and hands. On July 7th Jake was enrolled in the Asterias trial, and had ten million cells transplanted into his neck.

It could be months, even as much as one year, before we know if those cells are having any beneficial effect on Jake. But at least for now we know they don’t seem to be having any negative effects.

“First do no harm” is the cardinal rule that all budding physicians are taught. This trial seems to be meeting that benchmark. Our hope now is that it will do a lot more, and truly make a difference in the lives of people like Jake.

As Randy Mills, CIRM’s President and CEO, said in a news release:

“I recently met with Jake and heard first-hand what he and his family are going through in the aftermath of his injury. But I also saw a young man with remarkable courage and determination. It is because of Jake, and the others who volunteer to take part in clinical trials, that progress is possible. They are true heroes.”

* On a side note, Roman Reed, a great champion of stem cell research and a patient advocate extraordinaire, helped make much of this story happen. He helped Jake enroll in the Asterias trial ,and the research that led to this therapy was pioneered by Dr. Hans Keirstead who was funded by the Roman Reed Spinal Cord Injury Research Act.


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Here’s a new gene editing strategy to treat genetic blood disorders

If you’re taking a road trip across the country, you have a starting point and an ending point. How you go from point A to point B could be one of a million different routes, but the ultimate outcome is the same: reaching your final destination.

Yesterday scientists from St. Jude Children’s Research Hospital published exciting findings in the journal Nature Medicine on a new gene editing strategy that could offer a different route for treating genetic blood disorders such as sickle cell disease (SCD) and b-thalassemia.

The scientists used a gene editing tool called CRISPR. Unless you’ve been living under a rock, you’ve heard about CRISPR in the general media as the next, hot technology that could possibly help bring cures for serious diseases.

In simple terms, CRISPR acts as molecular scissors that facilitate cutting and pasting of DNA sequences at specific locations in the genome. For blood diseases like SCD and b-thalassemia, in which blood cells have abnormal hemoglobin, CRISPR gene editing offers ways to turn on and off genes that cause the clinical symptoms of these diseases.

Fetal vs. Adult hemoglobin

Before I get into the meat of this story, let’s take a moment to discuss hemoglobin. What is it? It’s a protein found in red blood cells that transports oxygen from the lungs to the rest of the body. Hemoglobin is made up of different subunits and the composition of these hemoglobin subunits change as newborns develop into adults.


Healthy red blood cell (left), sickle cell (right).

Fetal hemoglobin (HbF) is comprised of a and g subunits while adult hemoglobin (HbA) is typically comprised of a and b subunits. Patients with SCD and b-thalassemia typically have mutations in the b globin gene. In SCD, this causes blood cells to take on an unhealthy, sickle cell shape that can clog vessels and eventually cause premature death. In b-thalassemia, the b-globin gene isn’t synthesized into protein at the proper levels and patients suffer from anemia (low red blood cell count).

One way that scientists are attempting to combat the negative side effects of mutant HbF is to tip the scales towards maintaining expression of the fetal g-globin gene. The idea spawned from individuals with hereditary persistence of fetal hemoglobin (HPFH), a condition where the hemoglobin composition fails to transition from HbF to HbA, leaving high levels of HbF in adult blood. Individuals who have HPFH and are predisposed to SCD or b-thalassemia amazingly don’t have clinical symptoms, suggesting that HbF plays either a protective or therapeutic role.

The current study is taking advantage of this knowledge in their attempt to treat blood disorders. Mitchell Weiss, senior author on the study and chair of the St. Jude Department of Hematology, explained the thought process behind their study:

“It has been known for some time that individuals with genetic mutations that persistently elevate fetal hemoglobin are resistant to the symptoms of sickle cell disease and beta-thalassemia, genetic forms of severe anemia that are common in many regions of the world. We have found a way to use CRISPR gene editing to produce similar benefits.”

CRISPRing blood stem cells for therapeutic purposes

Weiss and colleagues engineered red blood cells to have elevated levels of HbF in hopes of preventing symptoms of SCD. They used CRISPR to create a small deletion in a sequence of DNA, called a promoter, that controls expression of the hemoglobin g subunit 1 (HBG1) gene. The deletion elevates the levels of HbF in blood cells and closely mimics genetic mutations found in HPFH patients.

Weiss further explained the genome editing process in a news release:

Mitchell Weiss

Mitchell Weiss

“Our work has identified a potential DNA target for genome editing-mediated therapy and offers proof-of-principle for a possible approach to treat sickle cell and beta-thalassemia. We have been able to snip that DNA target using CRISPR, remove a short segment in a “control section” of DNA that stimulates gamma-to-beta switching, and join the ends back up to produce sustained elevation of fetal hemoglobin levels in adult red blood cells.”

The scientists genetically modified hematopoietic stem cells and blood progenitor cells from healthy individuals to make sure that their CRISPR gene editing technique was successful. After modifying the stem cells, they matured them into red blood cells in the lab and observed that the levels of HbF increased from 5% to 20%.

Encouraged by these results, they tested the therapeutic potential of their CRISPR strategy on hematopoietic stem cells from three SCD patients. While 25% of unmodified SCD blood stem cells developed red blood cells with a sickle cell shape under low-oxygen conditions (to induce stress), CRISPR edited SCD stem cells generated way fewer sickle cells (~4%) and had a higher level of HbF expression.

Many routes, one destination

The authors concluded that their genome editing technique is successful at switching hemoglobin expression from the adult form back to the fetal form. With further studies and safety testing, this strategy could be one day be developed into a treatment for patients with SCD and b-thalassemia

But the authors were also humble in their findings and admitted that there are many different genome editing strategies or routes for developing therapies for inherited blood diseases.

“Our results represent an additional approach to these existing innovative strategies and compare favorably in terms of the levels of fetal hemoglobin that are produced by our experimental system.”

My personal opinion is the more strategies thrown into the pipeline the better. As things go in science, many of these strategies won’t be successful in reaching the final destination of curing one of these diseases, but with more shots on goal, our chances of developing a treatment that works there are a lot higher.

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Unlocking the secrets of how stem cells decide what kind of cell they’re going to be

Laszlo Nagy, Ph.D., M.D.

Laszlo Nagy, Ph.D., M.D.: Sanford Burnham Prebys Medical Discovery Institute

Before joining CIRM I thought OCT4 was a date on the calendar. But a new study says it may be a lot closer to a date with destiny, because this study says OCT4 helps determine what kinds of cell a stem cell will become.

Now, before we go any further I should explain for people who have as strong a science background as I do – namely none – that OCT4 is a transcription factor, this is a protein that helps regulate gene activity by turning certain genes on at certain points, and off at others.

The new study, by researches at Sanford Burnham Prebys Medical Discovery Institute (SBP), found that OCT4 plays a critical role in priming genes that cause stem cells to differentiate or change into other kinds of cells.

Why is this important? Well, as we search for new ways of treating a wide variety of different diseases we need to find the most efficient and effective way of turning stem cells into the kind of cells we need to regenerate or replace damaged tissue. By understanding the mechanisms that determine how a stem cell differentiates, we can better understand what we need to do in the lab to generate the specific kinds of cells needed to replace those damaged by, say, heart disease or cancer.

The study, published in the journal Molecular Cell, shows how OCT4 works with other transcription factors, sometimes directing a cell to go in one direction, sometimes in another. For example, it collaborates with a vitamin A (aka retinoic acid) receptor (RAR) to convert a stem cell into a neuronal precursor, a kind of early stage brain cell. However, if OCT4 interacts with another transcription factor called beta-catenin then the stem cell goes in another regulatory direction altogether.

In an interview with PhysOrg News, senior author Laszlo Nagy said this finding could help develop more effective methods for producing specific cell types to be used in therapies:

“Our findings suggest a general principle for how the same differentiation signal induces distinct transitions in various types of cells. Whereas in stem cells, OCT4 recruits the RAR to neuronal genes, in bone marrow cells, another transcription factor would recruit RAR to genes for the granulocyte program. Which factors determine the effects of differentiation signals in bone marrow cells – and other cell types – remains to be determined.”

In a way it’s like programming all the different devices that are attached to your TV at home. If you hit a certain combination of buttons you get to one set of stations, hit another combination and you get to Netflix. Same basic set up, but completely different destinations.

“In a sense, we’ve found the code for stem cells that links the input—signals like vitamin A and Wnt—to the output—cell type. Now we plan to explore whether other transcription factors behave similarly to OCT4—that is, to find the code in more mature cell types.”



Cloning breakthrough: Dolly the sheep has sister clones and they’re healthy

On the topic of famous farm animals, a few come to mind: Babe the pig, Old Yeller, Mr. Ed, and the cast of Charlotte’s Web. Many of us grew up with these fictional characters and hold them near and dear to our heart, but what about real, living farm animals? The first that comes to my mind is Dolly the sheep.

Back in 1996, scientists made a major breakthrough when they cloned a sheep which they named after the famous singer and actress Dolly Parton. This famous sheep was born in a test tube – a product of a scientific process called somatic cell nuclear transfer (SCNT). It involves transferring the nucleus (which contains a cell’s genetic material) from an adult cell – a mammary gland cell in the case of Dolly – into an unfertilized egg cell that has had its own nucleus removed. Much like jumping a car, scientists use an electric shock to trigger the egg cell to divide and develop into an embryo that has the exact genetic makeup as the original organism it was derived from.

Are cloned animals healthy?

SCNT is a very inefficient process with a high failure rate during embryonic and fetal development. Dolly was a huge achievement for scientists as she was the first mammal to be successfully cloned using SCNT. Unfortunately, even though Dolly lived to the age of six and a half years, she wasn’t the healthiest of sheep. She suffered from a severe form of arthritis and tumors in her lungs and was eventually put down to relieve her from pain. Scientists hypothesized that the lung cancer was likely caused by a common virus that infects sheep, but they questioned whether some of Dolly’s other symptoms were caused by accelerated aging resulting from the cloning process.

Whether cloned animals are physically healthy and age normally are questions that have spurred much debate amongst scientists since Dolly’s inception. Further experiments have shown that cloned mammals that survive past their infancy are typically healthy, but some experiments in mice showed that cloned mice tended to be more obese, have diabetic symptoms, and live shorter lives. Concerns about the safety of cloning prompted many countries to ban reproductive cloning in mammals until more was known about the process.

Good news for Dolly’s sisters

Dolly’s 20th anniversary since her birth was earlier this year, and in celebration, many journals and news outlets wrote about the progress of SCNT and cloning over the past two decades. This week, a new study added an exciting new chapter to these recent stories about Dolly.

Published in Nature Communications, scientists from the University of Nottingham in Britain reported that cloned sheep are healthy and live normal lives. They studied 13 cloned sheep, four of which were Dolly’s sisters cloned from the same mammary gland cell line as Dolly. These sheep were between 7-9 years of age which is near the end of a healthy sheep’s average lifespan of 10 years.

Cloned sheep, sisters to the famous Dolly the Sheep. (University of Nottingham)

Cloned sheep, sisters to the famous Dolly the Sheep. (University of Nottingham)

The scientists wanted to know whether cloning had any negative impact on the health and lifespan of these sheep. Lead author on the study, Dr. Kevin Sinclair, explained to the Washington Post:

“When we did the study, these clones were already 2½ years older than Dolly was when she died. And they appeared to be perfectly healthy, but we wanted to see if they might be harboring subtle defects.”

They conducted studies that assessed symptoms typically caused by aging in both humans and sheep. These included tests for blood pressure, insulin sensitivity, arthritis, and heart disease. They also conducted MRI scans and X-rays to look at the integrity of their bones, joints, and muscles.

On the whole, the sheep were healthy and their tests yielded normal results. A few of the cloned sheep had early signs of arthritis, but their conditions were similar to normal non-cloned sheep of the same age. The scientists concluded that there were no obvious signs of premature aging in this group of cloned sheep and that the cloning process did not have negative effects on the health and lifespan of these animals.

“It was quite obvious that the concerns of Dolly just didn’t relate,” Sinclair said. “So you can’t extend beyond the Dolly experience and say this premature aging applies to all clones.”

Cloning breakthrough but questions remain about safety

This study, which many scientists are considering as a “breakthrough in cloning”, has received a lot of attention in the media from major news outlets like the New York Times, Washington Post, Statnews, and NPR.

The New York Times piece does a great job of discussing how the advancements in cloning could have positive impacts on reproductive technology, the farming industry (raising cloned farm animals as a food source), therapeutic development, and saving endangered species. But the article also balances this optimism with caution over the safety and ethics behind reproductive cloning. They posed the cloning safety question to Dr. Sinclair, the lead author on the study, whose response was positive but referenced the remaining issue of cloning being an inefficient process:

“If they [cloned sheep] could speak, they would say ‘yes; it’s perfectly safe. They’re perfectly healthy, and they’re old ladies now, and for them, their whole process worked perfectly. But there are others who struggled to adapt after birth.”

The STATNews piece also made a good point that further scientific studies on the cloned sheep need to be done to test for molecular signs of aging such as shortened telomeres, before the scientists can truly claim that these sheep are living normal healthy lives. The cloned sheep probably will live for another year at which point the scientists said they will conduct further experiments to look for other signs of aging at the cellular level.