Stem cell stories that caught our eye: heart repair, a culprit in schizophrenia, 3-parent embryos and funding for young scientists

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.

Chemicals give stem cells heart.  Coaxing stem cells into improving the function of failing hearts has proven quite difficult. Many trials have used a type of stem cell found in fat and bone marrow, called mesenchymal stem cells, to release factors believed to reduce scarring after a heart attack and improve the growth of new blood vessels to nourish the damaged area. But they have produced spotty and only modest positive results. CIRM funds a team at Capricor that uses related cells, but retrieved from heart tissue and believed to release factors that are more efficient in fostering repair—the results are still pending.

Get-Over-Heartbreak-Step-08 This week a Belgian company, using technology developed by the Mayo Clinic in Minnesota, announced positive results for a third option. They start with the stem cells from bone marrow, but in the lab treat them with a cocktail of chemicals that take them part way down the path to becoming heart muscle—into cells called cardiac progenitors. Having shown safety and initial signs of benefit in Phase 1 and 2 trials in Europe, the company Celyad launched the first part of a Phase 3 trial in 2012 and released the results this week.

The company’s research team found that, as with many breakthrough therapies, the most important aspect of early trials is defining which patients are most likely to benefit. The results did not show a benefit for the entire patient group lumped together, but did show significant gain for the 60 percent who fit a certain profile of symptoms at the start of the study. Twin Cities Business wrote about the research that originated in its home state, quoting the lead researcher with OLV Hospital in Belgium, Jozef Bartunek:

 “The results seen for a large clinically relevant number of the patients are groundbreaking,” adding that the results would direct the selection of patients for the second part of the trial to be conducted in the U.S.

The fundamental work done by researchers at Mayo discovered the mechanisms that drive an embryonic stem cell to become heart cells and used that information to develop the cocktail of chemicals that can turn ordinary adult stem cells into cardiac progenitors.

 

Stem cell model fingers culprit in brain. We were all taught the dogma about the path from genes to our tissues: DNA to RNA to protein. And we learned that two types of RNA did the heavy lifting in this transition from genetic recipe to functioning tissue. But RNAs have turned out to be a much more complex family of genetic players, with several types regulating genes rather than coding for any specific function. Some of the most active of these are the micoRNAs with more than 2,000 identified.

A CIRM-funded team at the Salk Institute in La Jolla has fingered one microRNA, miR-19, as playing a role in the faulty wiring seen among nerves in patients with schizophrenia. We always have a few nerve progenitor cells maturing into nerves. But the team found that when they altered the levels of miR-19 the new nerves did not migrate to where they were needed. So, the researchers made iPS type stem cells from patients with schizophrenia, matured them into nerves and looked at miR-19 levels and found them elevated. They also showed the nerve cells did not migrate properly.

 “This is one of the first links between an individual microRNA and a specific process in the brain or a brain disorder,” said senior author Rusty Gage, in an institute press release posted by trueviralnews.

mir19-schizophrenia-neurosciencenews

Over expressing the microRNA miR-19 resulted in new nerves migrating and branching abnormally (right) compared to untreated cells (left)

 

Profile of 3-parent pioneer.  No matter where you stand on the ethics of the “three-parent” fertilization technique that has been much in the news this year, you will enjoy reading Karen Weintraub’s well researched and well written piece about the leading pioneer in the field, Shoukhrat Mitalipov in STAT this morning.

 

Mitalipov-2

Pioneer Mitalipov

The technique focuses on the 37 genes that reside in our cells’ mitochondria rather than in the cells’ nucleus. We only inherit those genes from our moms because we only get the mitochondria in mom’s egg. So, when a woman has a disease-causing mutation in one of those genes, she could have a healthy child that mostly matched her genetic makeup if she could just swap out her mitochondria for someone else’s. That is exactly what the new technique accomplishes.

So far, it has only been tried in monkeys, the oldest of those offspring are now 7 but they are males. The first female is just 4 and since monkeys don’t reproduce until age 6 or 7, and the FDA wants to see how her babies fare, it will be some time before the procedure gets the green light to move forward in humans. None of the 3-parent monkeys show any health issues so far.

Karen’s piece paints a detailed account of the research’s protractors and detractors, as well putting a human face on the man leading the charge. As someone who reads regular posts from a cousin with a child struggling from “Mito” disease, I am rooting for this protagonist.

 

Funding challenge for young stem cell scientists.  A new study in the journal Cell Stem Cell quantifies a lament you hear anytime you are around young researchers, they have a hard time competing with older researchers in the field. The author of the report, Misty Heggeness from the National Institutes of Health, was quoted in news outlets including the San Diego Union Tribune and the blog Science 2.0 on a related issue that should set off alarm bells. If young people are not attracted to the field or fail to stay in the field, at the same time established scientists are nearing retirement age, we could end up with a gap in the research workforce in a few years.

 “From a policy and leadership perspective, one needs to understand what the near future year implications of an aging workforce are. If a system discourages younger cohorts from staying and is heavily composed of older cohorts who will exit the workforce in the near term, who will replace them?”

Part of the problem young researchers have seems to be baked into the current system. Young researchers compete fairly well with older ones on individual applications, but older researchers have the resources to file a lot more applications.  They have more personnel in their labs, freeing them up to write applications, and that personnel also produces the preliminary data that are often needed to even meet application requirements.

The Union Trib piece pointed out that older and younger stem cell scientists are both doing better with funding in California because of CIRM.

Stem cell stories that caught our eye: Trifecta of nerve news on aging, Parkinson’s and myelin diseases, also expanding cord blood

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.

rapamycin-effect-on-MILS-neurons

Untreated (top) and treated nerves

To save nerves, make them slow down. Nerves, like all cells, constantly make protein, but that task uses up a lot of energy and older nerves have a limited energy supply. A CIRM-funded team at the Salk Institute has shown that an approved drug can slow down protein production in nerves, conserve energy and help them survive.

The Salk team led by Tony Hunter saw the tamping down effect in a disease-in-a-dish model of Leigh syndrome, an inherited neurodegenerative condition caused by a mutation in mitochondria, the cell’s power plant. They created iPS type stem cells by reprogramming skin cells from a Leigh syndrome patient, grew them into nerves and saw evidence of energy depletion that was reversed when they treated the cells with the drug rapamycin.

 “Reducing protein production in ageing neurons allows more energy for the cell to put toward folding proteins correctly and handling stress,” said team member Xinde Zheng, in a Salk release posted by Scicasts. “The impact of our finding is that modulation of protein synthesis could be a general approach to treating neurodegeneration.”

Next step for the team will be seeing if their finding holds true in an animal model of the syndrome. They published their findings in eLife.

 

For dopamine nerves turn them on and off.  Many researchers strive to turn stem cells into dopamine producing nerves to replace the chemical signal that is in short supply in Parkinson’s disease patients. But what if they succeed, put the new nerves in patients and they produce too much dopamine? A team, at the University of Wisconsin has a solution, make the new nerves responsive to a drug that can act as an on-and-off switch.

The team grew nerves from stem cells made from iPS type stem cells and genetically engineered them so that they would only produce dopamine in the presence of a certain drug. Brad Fikes at the San Diego Union Tribune wrote a brief story about the research that the team published in Cell Stem Cell.

 He put the news into perspective by noting that early trials implanting dopamine nerves from fetal tissue resulted in some patients having side effects from over production of the nerve signal transmitter.

 

And restoring nerves protective myelin.  Neurons form the basis of all brain function, but they take a family of support cells and tissues to do a good job of directing our muscles, recording memory, etc.  First nerves need the protective insulation called myelin to properly transmit signals. Cells called oligodendrocytes produce the myelin, but they need signals from cells called astrocytes to do their job well. Researchers have known for some time that immature astrocytes do a great job of fostering oligodendrocytes, but mature astrocytes do not, but they have not known why.

Now, CIRM-funded researchers at the University of California, Davis, have isolated a protein secreted by immature astrocytes called TIMP-1 that promotes proliferation of the needed oligodendrocytes, and down the line, the myelin needed to protect neurons.

In the study published in Cell Reports, the researchers created iPS type stem cells and directed them to become astrocytes, stopping the growth at an immature state and implanted them in mice. But before the transplants, they shut down the production of TIMP-1 in some of the astrocytes, and in those mice they saw no increase in the production of myelin.

 

Deng-headshot

Wenbin Deng of UC Davis

The research project leader, Wenbin Deng, speculated in a Davis press release on how the research could eventually help patients with any number of diseases involving myelin loss:

 “We are hopeful that his could lead to a promising therapy for premature brain injury, cerebral palsy, multiple sclerosis, spinal cord injury, white matter stroke and many neurodegenerative diseases.”

 

Key protein for developing blood stem cells.  The stem cells found in umbilical cord have saved thousands of cancer patients by rebuilding their immune system after chemotherapy. But cord blood samples often have too few stem cells to be effective and while a couple teams have reported some progress in expanding the number of stem cells in any one cord sample, more progress is needed.

Researchers at McMaster University reported in the journal Nature this week that they had isolated a protein that controls the development of blood stem cells. That protein, Musashi-2, does not regulate genetic activity at the DNA level, but rather at the next step in the gene-to-protein pathway, regulating the activity of RNA.

In an article posted on the Bioscience Technology website, the team leader Kristin Hope speculated on the value to patients when they learn how to turn this knowledge into making cells for therapy:

“Providing enhanced numbers of stem cells for transplantation could alleviate some of the current post-transplantation complications and allow for faster recoveries, in turn reducing overall health care costs and wait times for newly diagnosed patients seeking treatment.”

 

Timing is everything: could CRISPR gene editing push CIRM to change its rules on funding stem cell research?

CRISPR

Talk about timely. When we decided, several months ago, to hold a Standards Working Group (SWG) meeting to talk about the impact of CRISPR, a tool that is transforming the field of human gene editing, we had no idea that our meeting would fall smack in the midst of a flurry of news stories about the potential, but also the controversy, surrounding this approach.

Within a few days of our meeting lawmakers in the UK had approved the use of CRISPR for gene editing in human embryos for fertility research —a controversial first step toward what some see as a future of designer babies. And a U.S. Food and Drug Advisory report said conducting mitochondrial therapy research on human embryos is “ethically permissible”, under very limited conditions.

So it was clear from the outset that the SWG meeting was going to be touching on some fascinating and fast moving science that was loaded with ethical, social and moral questions.

Reviewing the rules

The goal of the meeting was to see if, in the light of advances with tools like CRISPR, we at CIRM needed to make any changes to our rules and regulations regarding the funding of this kind of work. We already have some strong guidelines in place to help us determine if we should fund work that involves editing human embryos, but are they strong enough?

There were some terrific speakers – including Nobel Prize winner Dr. David Baltimore; Alta Charo, a professor of Law and Bioethics at the University of Wisconsin-Madison  ; and Charis Thompson, chair of the Center for the Science, Technology, and Medicine in Society at the University of California, Berkeley – who gave some thought-provoking presentations. And there was also a truly engaged audience who offered some equally thought provoking questions.

CIRM Board member Jeff Sheehy highlighted how complex and broad ranging the issues are when he posed this question:

“Do we need to think about the rights of the embryo donor? If they have a severe inheritable disease and the embryo they donated for research has been edited, with CRISPR or other tools, to remove that potential do they have a right to know about that or even access to that technology for their own use?”

Alta Charo said this is not just a question for scientists, but something that could potentially affect everyone and so there is a real need to engage as many groups as possible in discussing it:

“How and to what extent do you involve patient advocates, members of the disability rights community and social justice community – racial or economic or geographic.  This is why we need these broader conversations, so we include all perspectives as we attempt to draw up guidelines and rules and regulations.”

It quickly became clear that the discussion was going to be even more robust than we imagined, and the issues raised were too many and too complex for us to hope to reach any conclusions or produce any recommendations in one day.

As Bernie Lo, President of the Greenwall Foundation in New York, who chaired the meeting said:

“We are not going to resolve these issues today, in fact what we have done is uncover a lot more issues and complexity.”

Time to ask tough questions

In the end it was decided that the most productive use of the day was not to limit the discussion at the workshop but to get those present to highlight the issues and questions that were most important and leave it to the SWG to then work through those and develop a series of recommendations that would eventually be presented to the CIRM Board.

The questions to be answered included but were not limited to:

1) Do we need to reconsider the language used in getting informed consent from donors in light of the ability of CRISPR and other technologies to do things that we previously couldn’t easily do?

2) Can we use CRISPR on previously donated materials/samples where general consent was given without knowing that these technologies could be available or can we only use it on biomaterials to be collected going forward?

3) Clarify whether the language we use about genetic modification should also include mitochondrial DNA as well as nuclear DNA.

4) What is the possibility that somatic or adult cell gene editing may lead to inadvertent germ line editing (altering the genomes of eggs and sperm will pass on these genetic modifications to the next generation).

5) How do we engage with patient advocates and other community groups such as the social justice and equity movements to get their input on these topics? Do we need to do more outreach and education among the public or specific groups and try to get more input from them (after all we are a taxpayer created and funded organization so we clearly have some responsibility to the wider California community and not just to researchers and patients)?

6) As CIRM already funds human embryo research should we now consider funding the use of CRISPR and other technologies that can modify the human embryo provided those embryos are not going to be implanted in a human uterus, as is the case with the recently approved research in the UK.

Stay tuned, more to come!

This was a really detailed dive into a subject that is clearly getting a lot of scientific attention around the world, and is no longer an abstract idea but is rapidly becoming a scientific reality. The next step is for a subgroup of the SWG to put together the key issues at stake here and place them in a framework for another discussion with the full SWG at some future date.

Once the SWG has reached consensus their recommendations will then go to the CIRM Board for its consideration.

We will be sure to update you on this as things progress.

Stem cell stories that caught our eye: fixing defects we got from mom, lung repair and staunching chronic nerve pain

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.

Two ways to clean up mitochondrial defects. Every student gets it drilled into them that we get half our genes from mom and half from dad, but that is not quite right. Mom’s egg contains a few genes outside the nucleus in the so-called powerhouse of the cell, the mitochondria that we inherit only from mom. The 13 little genes in that tiny organelle that are responsible for energy use can wreak havoc when they are mutated. Now, a multi-center team working in Oregon and California has developed two different ways to create stem cells that match the DNA of specific patients in everyway except those defective mitochondrial genes.

The various mitochondrial mutations tend to impact one body system more than others. The end goal for the current research is to turn those stem cells into healthy tissue that can be transplanted into the area most impacted by the disease in a specific patient. That remains some years away, but this is a huge step in providing therapies for this group of diseases.

Currently, we have two ways of making stem cells that match the DNA of a patient, which hopefully result in transplantable cells that can avoid immune rejection. One is to reprogram adult tissue into induced pluripotent (iPS type) stem cells and the other uses the techniques called Somatic Cell Nuclear Transfer (SCNT), often called therapeutic cloning. The current research did both.

The team converted the SCNT stem cells into various needed tissues such as these nerve precursor cells.

The team converted the SCNT stem cells into various needed tissues such as these nerve precursor cells.

The iPS work relied on the fact that our tissues are mosaics because of the way mitochondria get passed on when cells divide. So not all cells show mitochondrial mutations in people with “mito disease” —how impacted families tend to refer to it, as I found out through a distant cousin with a child valiantly struggling with one form of the disease. Because each iPS stem cell line arises from one cell, the researchers could do DNA analysis on each cell line and sort for ones with few or no mutations, resulting in healthy stem cells, which could become healthy transplant tissue.

But for some patients, there are just too many mutations. For those the researchers inserted the DNA from the patient into a healthy donor egg containing healthy mitochondria using SCNT. The result: again healthy stem cells.

“To families with a loved one born with a mitochondrial disease waiting for a cure, today we can say that a cure is on the horizon,” explained co-senior author Shoukhrat Mitalipov at the Oregon Stem Cell Center in a story in Genetic Engineering News. “This critical first step toward treating these diseases using gene therapy will put us on the path to curing them and unlike unmatched tissue or organ donations, combined gene and cell therapy will allow us to create the patients’ own healthy tissue that will not be rejected by their bodies.”

ScienceDaily ran the Oregon press release, HealthCanal ran the press release from the Salk Institute in La Jolla home of the other co-senior author Juan Carlos Izpisua Belmonte, whose lab CIRM funds for other projects. And Reuters predictably did a piece with a bit more focus on the controversy around cloning. Nature published the research paper on Wednesday.

Stem cells to heal damaged lungs. Lung doctors dealing with emphysema, cystic fibrosis and other lung damage may soon take a page from the playbook of cancer doctors who transplant bone marrow stem cells. A team at Israel’s Weizmann Institute has tested a similar procedure in mice with damaged lungs and saw improved lung function

Transplanted lung cells continued to grow at six weeks (left) and 16 weeks (right).

Transplanted lung cells continued to grow at six weeks (left) and 16 weeks (right).

Stem cells are homebodies. They tend to hang out in their own special compartments we call the stem cell niche, and if infused elsewhere in the body will return home to the niche. Bone marrow transplants make use of that tendency in two ways. Doctors wipe out the stem cells in the niche so that there is room there when stem cells previously harvested from the patient or donor cells are infused after therapy.

The Weizmann team did this in the lungs by developing a method to clear out the lung stem cell niche and isolating a source of stem cells capable of generating new lung tissue that could be infused. They now need to perfect both parts of the procedure. ScienceDaily ran the institute’s press release.

Stem cells for chronic pain due to nerve damage. Neuropathy, damaged nerves caused by diabetes, chemotherapy or injury tends to cause pain that resists treatment. A team at Duke University in North Carolina has shown that while a routine pain pill might provide relief for a few hours, a single injection of stem cells provided relief for four to five weeks—in mice.

They used a type of stem cell found in bone marrow known to have anti-inflammatory properties called Bone Marrow Stromal Cells (BMSCs). They infused the cells directly into the spinal cavity in mice that had induced nerve damage. They found that one chemical released by the stem cells, TGF Beta1, was present in the spinal fluid of the treated animals at higher than normal levels. This finding becomes a target for further research to engineer the BMSCs so that they might be even better at relieving pain. ScienceNewsline picked up the Duke press release about the research published in the Journal of Clinical Investigation.

British Parliament votes to approve “three parent” baby law

After what is being described as “an historic debate”, the British Parliament today voted to approve the use of an IVF technique that critics say will lead to the creation of “three parent” babies.

UK Parliament

UK Parliament

Parliament voted 382 to 128 in favor of the technique known as mitochondrial donation, which will prevent certain genetic diseases being passed on from parents to children; diseases that can cause a wide range of conditions such as fatal heart problems, liver failure, brain disorders and blindness.

Mitochondrial donation involves replacing a small amount of faulty DNA from a mother’s egg with healthy DNA from a second woman. The technique involves taking two eggs, one from the mother and another from the donor. The nucleus of the donor egg is removed, leaving the rest of the egg contents, including the mitochondria. The nucleus from the mother’s egg is then placed in the donor egg. This means that the baby would have genes from the mother, the father and the female donor.

The vote makes the UK the first country in the world to endorse this process. It comes at the end of what supporters of the measure described in a letter to Parliament as “seven years of consultation and inquiry that have revealed broad scientific, ethical and public approval.”

Mitochondrial donation is a controversial process opposed by many religious and faith-based groups who say it creates “designer babies” because it involves implanting genetically modified embryos, and because it could result in genetic alterations that might be passed on to subsequent generations.

While many scientists support the technique some have raised concerns about it. Among those are Dr. Paul Knoepfler, a stem cell researcher at U.C. Davis, (CIRM is funding some of his work). In a recent blog on the process Paul wrote that while he is not opposed to the technique in theory, he thinks this move at this time is premature:

“There is no doubt that mitochondrial diseases are truly terrible and need to be addressed, but if the potential outcomes from the technology are still vague, there are safety concerns, and it raises profound ethical issues such as changing the human genome heritably as is the case here, then my view is that a careful approach is both practical and logical. We cannot at this time have a reasonable expectation that this technology would be safe and effective. That may change in coming years with new knowledge. I hope so.”

Supporters in the UK say the science is already good enough to proceed. Dame Sally Davies, Britain’s Chief Medical Officer, calls it the genetic equivalent of “changing a faulty battery in a car.”

Professor Lord Winston, a fertility expert at Imperial College, London, says:

“I think the case is self-evident and reasonable. This is about something that is unusual and will benefit a small number of patients. I know there are some people who think it is a slippery slope that the next thing will be choosing intelligence or blond hair, but I don’t think that. For 20 years, it’s been scientifically possible to have sex selection of embryos; we still don’t allow it in Britain apart from for heritable diseases.”

It’s important to point out that while the House of Commons passed the regulations they still have to be approved by the House of Lords before they become law. A vote is scheduled for the end of this month. Even then any future trial involving the technique will still require the approval of the Human Fertilisation and Embryology Authority (HFEA) before it can go ahead.

Even if the process is ultimately approved in the UK it will likely face an uphill battle to be approved here in the U.S. where the debate over the ethical, as well as the scientific and technical implications of the process, has already generated strong feelings on both sides of the divide.