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.

To modify, or not to modify: Experts discuss human germline modification at WSCS15

The question of whether human germline modification, or the genetic modification of human reproductive cells, should be allowed or banned was discussed by a panel of experts in the Ethics, Law and Society session during Day 1 of the World Stem Cell Summit.

On the panel were Aubrey de Grey, Chief Science Officer of the SENS Foundation, Paul Knoepfler, Associate Professor at the UC Davis school of medicine (and a CIRM grantee), and Aaron Levine, Associate Professor of Public Policy at Georgia Tech.

Aubrey de Grey, Paul Knoepfler, Aaron Levine

Aubrey de Grey, Paul Knoepfler, Aaron Levine

What Paul Knoepfler said…

On the basic research side, Paul discussed how CRISPR has revolutionized the way germline modification is being done from the older, costly, time-consuming method using homologous recombination to the faster, more efficient, and cheaper gene editing technology that is CRISPR.

In the big picture, he said that, “people will pursue germline modification with a variety of different goals.” He further explained that because this will likely happen in the future, scientists need to consider the risks (off target effects to name one) and the societal and ethical impacts of this technology. Another question he said we should consider is, whether as a society, we support the modification of the germline for health or enhancement reasons.

He concluded with a recap of last week’s International Summit on Human Gene Editing saying that while the organizers didn’t put forth a definitive statement on whether there should be a moratorium on editing the human germline, he himself believes that there should be a temporary moratorium on the clinical use of this technology since the idea is still very controversial and there is no overall consensus within the scientific community.

What Aubrey de Grey said…

Aubrey began by saying that as a gerontologist, he is interested in all potential therapies that could postpone the effects of old age, many of which could involve genetic modification. He went on to say that it might not seem intuitive that editing the human germline would be applicable to fighting aging, but that:

“Even though the medical imperative to engaging genetic germline modification may seem to be less clear in the case of aging than it is for inherited diseases, which people are unequivocally agreed on that is a bad thing, never-the-less, the potential application to aging may actually play a significant role in the debate, because we’ve all got aging.”

He gave an example of the ApoE4 gene. If you have two copies of this form of the gene instead of the normal ApoE3 gene, then you have a very high risk of getting Alzheimer’s disease and atherosclerosis. He posed the question to the audience, asking them whether if they knew that they had this disease causing gene, would they consider genetically altering their fertilized eggs back into the safe ApoE3 version to prevent their offspring from inheriting disease even if the therapy wasn’t approved by the FDA. It’s a hard question to answer and Aubrey further commented that if we begin using genetic modification to prevent one disease, where would we draw the line and where would modification end?

He ended with saying that the real question we need to consider is “whether people will want to do germline modification against aging, even though the modifications may really be more in the way of enhancements than genuine therapies.”

What Aaron Levine said…

Aaron Levine began with saying that the question of human germline modification is an old question with new twists. By new twists he meant the recent advances in gene editing technologies like CRISPR and Zinc Finger Nucleases. He further commented that the baseline question of this debate is whether we should modify the DNA of the germline, and that how we do it isn’t as significant.

He played devil’s advocate by saying that germline editing would greatly benefit single gene disorders, but that we should think of the full spectrum. Many traits that we might want, we don’t know enough about and attempting to add or remove these traits using gene editing would be like shooting in the dark.

On policy side, Aaron commented that international policy harmonization would be nice, but that we should treat it skeptically. He said that not everyone is going to agree or follow the same rules and we need to consider this going forward. As for the FDA, he said that its role and regulations regarding germline editing aren’t clear and that these need to be defined.

One really interesting point he made was the issue of unproven stem cell clinics. They exist and pose a huge risk to human health. The real question, he said, is could this turn into unproven CRISPR clinics around the world? He ended with saying that someone will claim to offer this technology soon and asked what we should do about it.

From the peanut gallery…

One of the questions asked by the audience was whether it’s just a matter of time that one of the world’s governments might go forward with human germline modification because of the huge medical implications.

Paul responded first saying that there was a consensus at the gene editing summit that it’s more of a question of when, rather than if this would happen. Aaron agreed and said that he believed it would happen but wasn’t sure when, and followed with saying that the more important question is how it will be done, overseen, and what reasons the editing will be done for.

Bernie Siegel, who is the co-Chair of the World Stem Cell Summit, spoke at the end and said that the panel delivered exactly what he hoped it would. He emphasized a theme that I didn’t mention in this blog but that was brought up by each of the panelists: the voice of patients.

“One of the things missing from the [International Summit on Gene Editing] meeting was the voice of the patient community. Do they understand the concepts of CRISPR technology? Patients are a major stake holder group, and they have the most influence on creating change in policy. When we talk about a moratorium, the patients see it as a five-alarm fire. All they want is to see a few drips of water, and they can’t get it. From a societal and popular culture standpoint, these are a whole group of people that will be experiencing the sweeping changes of biotech today. When those voices that are receiving these technologies enter the conversation, it will be a full debate.”

Brain Stem Cells in a Dish to the Rescue

braindish

Image credit: CureCDKL5.org

The best way to impress your friends at the next party you attend might be to casually mention that scientists can grow miniature brain models in a dish using human stem cells. Sure, that might scare away some people, but when you explain how these tiny brain models can be used to study many different neurological diseases and could help identify new therapies to treat these diseases, your social status could sky rocket.

Recently, a group at UC San Diego used human stem cells to model a rare neurological disorder and identified a drug molecule that might be able to fix it. This work was funded in part by CIRM, and it was published today in the journal Molecular Psychiatry.

The disorder is called MECP2 duplication syndrome. It’s caused by a duplication of the MECP2 gene located in the X chromosome, and is genetically inherited as an X-linked disorder, meaning the disease is much more common in males. Having extra copies of this gene causes a number of unfortunate symptoms including reduced muscle tone (hypotonia), intellectual disabilities, impaired speech, seizures, and developmental delays, to name a few. So far, treatments for this disorder only help ease the symptoms and do not cure the disease.

The group from UCSD decided to model this disease using induced pluripotent stem cells (iPSCs) derived from patients with MECP2 duplication syndrome. iPSCs can form any cell type in the body, and the group used this to their advantage by coaxing the iPSCs into the specific type of nerve cell affected by the disorder. Their hard work was rewarded when they observed that the diseased nerve cells acted differently than normal nerve cells without the disease.

In fact, the diseased nerve cells generated more connections with other nearby nerve cells, and this altered their ability to talk to each other and perform their normal functions. The senior author Alysson Muotri described the difference as an “over-synchronization of the neuronal networks”, meaning that they were more active and tended to fire their signals in unison.

After establishing a relevant nerve cell model of MECP2 duplication disorder, the group tested out a library of drug molecules and identified a new drug candidate that was able to rescue the diseased nerve cells from their “over-synchronized” activity.

The senior author Alysson Muotri commented on the study in a press release:

Alysson Muotri (Photo by David Ahntholz)  

This work is encouraging for several reasons. First, this compound had never before been considered a therapeutic alternative for neurological disorders. Second, the speed in which we were able to do this. With mouse models, this work would likely have taken years and results would not necessarily be useful for humans.

 

The press release goes on to describe how Muotri and his team plan to push their preclinical studies using human stem-cell based models forward in hopes of entering clinical trials in the near future.


 

Related Links:

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.

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.

Stem Cell Scientists Reconstruct Disease in a Dish; Gain Insight into Deadly Form of Bone Cancer

The life of someone with Li-Fraumeni Syndrome (LFS) is not a pleasant one. A rare genetic disorder that usually runs in families, this syndrome is characterized by heightened risk of developing cancer—multiple types of cancer—at a very young age.

People with LFS, as the syndrome is often called, are especially susceptible to osteosarcoma, a form of bone cancer that most often affects children. Despite numerous research advances, survival rates for this type of cancer have not improved in over 40 years.

shutterstock_142552177 But according to new research from Mount Sinai Hospital and School of Medicine, the prognosis for these patients may not be so dire in a few years.

Reporting today in the journal Cell, researchers describe how they used a revolutionary type of stem cell technology to recreate LFS in a dish and, in so doing, have uncovered the series of molecular triggers that cause people with LFS to have such high incidence of osteosarcoma.

The scientists, led by senior author Ihor Lemischka, utilized induced pluripotent stem cells, or iPSCs, to model LFS—and osteosarcoma—at the cellular level.

Discovered in 2006 by Japanese scientist Shinya Yamanaka, iPSC technology allows scientists to reprogram adult skin cells into embryonic-like stem cells, which can then be turned into virtually any cell in the body. In the case of a genetic disorder, such as LFS, scientists can transform skin cells from someone with the disorder into bone cells and grow them in the lab. These cells will then have the same genetic makeup as that of the original patient, thus creating a ‘disease in a dish.’ We have written often about these models being used for various diseases, particularly neurological ones, but not cancer.

“Our study is among the first to use induced pluripotent stem cells as the foundation of a model for cancer,” said lead author and Mount Sinai postdoctoral fellow Dung-Fang Lee in today’s press release.

The team’s research centered on the protein p53. P53 normally acts as a tumor suppressor, keeping cell divisions in check so as not to divide out of control and morph into early-stage tumors. Previous research had revealed that 70% of people with LFS have a specific mutation in the gene that encodes p53. Using this knowledge and with the help of the iPSC technology, the team shed much-needed light on a molecular link between LFS and bone cancer. According to Lee:

“This model, when combined with a rare genetic disease, revealed for the first time how a protein known to prevent tumor growth in most cases, p53, may instead drive bone cancer when genetic changes cause too much of it to be made in the wrong place.”

Specifically, the team discovered that the ultimate culprit of LFS bone cancer is an overactive p53 gene. Too much p53, it turns out, reduces the amount of another gene, called H19. This then leads to a decrease in the protein decorin. Decorin normally acts to help stem cells mature into healthy, bone-making cells, known as osteoblasts. Without it, the stem cells can’t mature. They instead divide over and over again, out of control, and ultimately cause the growth of dangerous tumors.

But those out of control cells can become a target for therapy, say researchers. In fact, the team found that artificially boosting H19 levels could have a positive effect.

“Our experiments showed that restoring H19 expression hindered by too much p53 restored “protective differentiation” of osteoblasts to counter events of tumor growth early on in bone cancer,” said Lemischka.

And, because mutations in p53 have been linked to other forms of bone cancer, the team is optimistic that these preliminary results will be able to guide treatment for bone cancer patients—whether they have LFS or not. Added Lemischka:

“The work has implications for the future treatment or prevention of LFS-associated osteosarcoma, and possibly for all forms of bone cancer driven by p53 mutations, with H19 and p53 established now as potential targets for future drugs.”

Learn more about how scientists are using stem cell technology to model disease in a dish in our special video series: Stem Cells In Your Face:

All Things Being (Un)Equal: Scientists Discover Gene that Breaks Traditional Laws of Inheritance

One of the most fundamental laws of biology is about to be turned on its head, according to new research from scientists at the University of North Carolina (UNC) School of Medicine.

shutterstock_165017096

As reported in the journal PLOS Genetics, UNC researchers identified a gene that does not obey traditional laws that determine how genes get passed down from parents to offspring. In experiments on laboratory mice, they found a gene called R2d2 causes female mice to pass on more genetic information than the males did—an observation that appears to contradict principles of genetic inheritance set forth more than a century ago.

As you may (or may not) remember from freshmen biology class, the laws of inheritance were laid down by the 19th century monk Gregor Mendel. Through meticulous observations of his garden’s pea plants, he found that each parent contributes their genetic information equally to their offspring.

But 150 years of scientific discovery later, scientists have discovered that this isn’t always the case.

Instead, in some cases one of the parents will contribute a greater percentage of genetic information than the other, a process called meiotic drive. Scientists had seen evidence of this process occurring in mammals for quite some time, but hadn’t narrowed down the driver of the process to a particular gene. According to UNC researchers, R2d2 is that gene. Senior author Fernando Pardo-Manuel de Villena explains:

“R2d2 is a good example of a poorly understood phenomenon known as female meiotic drive—when an egg is produced and a ‘selfish gene’ is segregated to the egg more than half the time.”

Pardo-Manuel de Villena notes that one example of this process occurs during trisomies—when three chromosomes (two from one parent and one from the other) are passed down to the embryo. The most common trisomy, trisomy 21, is more commonly known as Down Syndrome.

With these findings, Pardo-Manuel de Villena and the team are hoping to gain important insights into the underlying cause of trisomies, as well as the underlying causes for miscarriage—which are often not known.

“Understanding how meiotic drive works may shed light on the … abnormalities underlying these disorders,” said Pardo-Manuel de Villena.

This research was performed in large part by first author John Didion, who first discovered R2d2 when breeding two different types of mice for genetic analysis. Using whole-genome sequencing of thousands of laboratory mice, Didion and his colleagues saw that genes were passed down equally from each mouse’s parents. But a small section, smack dab in the middle of chromosome 2, was different.

Further analysis revealed that this section of chromosome 2 had a disproportionately larger number of genes from the mouse’s mother, compared to its father—showing a clear example of female meiotic drive. And at the heart of it all, Didion discovered, was the R2d2 gene.

The UNC team are already busy diving deeper into the relationship between R2d2 and meiotic drive with a focus on understanding, and one day perhaps correcting, genetic abnormalities in the developing embryo.

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.

Stem Cell Stories that Caught Your Eye: The Most Popular Stem Cellar Stories of 2014

2014 marked an extraordinary year for regenerative medicine and for CIRM. We welcomed a new president, several of our research programs have moved into clinical trials—and our goal of accelerating treatments for patients in need is within our grasp.

As we look back we’d like to revisit The Stem Cellar’s ten most popular stories of 2014. We hope you enjoyed reading them as much as we did reporting them. And from all of us here at the Stem Cell Agency we wish you a Happy Holidays and New Year.

10. UCSD Team Launches CIRM-Funded Trial to Test Safety of New Leukemia Drug

9. Creating a Genetic Model for Autism, with a Little Help from the Tooth Fairy

8. A Tumor’s Trojan Horse: CIRM Researchers Build Nanoparticles to Infiltrate Hard-to-Reach Tumors

7. CIRM funded therapy for type 1 diabetes gets FDA approval for clinical trial

6. New Videos: Living with Crohn’s Disease and Working Towards a Stem Cell Therapy

5. Creativity Program Students Reach New Heights with Stem Cell-Themed Rendition of “Let it Go”

4. Scientists Reach Yet Another Milestone towards Treating Type 1 Diabetes

3. Meet the Stem Cell Agency President C. Randal Mills

2. Truth or Consequences: how to spot a liar and what to do once you catch them

1. UCLA team cures infants of often-fatal “bubble baby” disease by inserting gene in their stem cells; sickle cell disease is next target

Speak Friend and Enter: How Cells Let the Right Travelers through their Doors

For decades, it’s been a molecular mystery that scientists were seemingly unable to solve: how do large molecules pass through the cell and into the nucleus, while others half their size remain stranded outside?

These are nuclear pores imaged by atomic force microscopy, appearing as a craterlike landscape in which each crater corresponds to a pore of ~100 nm diameter. [Credit: UCL]

Nuclear pores imaged by atomic force microscopy, appearing as a crater-like landscape in which each crater corresponds to a pore of ~100 nm diameter. [Credit: UCL]

But as reported in the latest issue of Nature Nanotechnology, researchers now believe they may have cracked the case. By shedding light on this strange anomaly, University College London (UCL) scientists have opened the door for one day delivering gene therapies directly into the nucleus. With numerous research teams working on ways to merge stem cell therapy and gene therapy, this could be extremely valuable to our field.

Scientists already knew that the membrane that surrounds the cell’s nucleus is ‘punctured’ with millions of tiny holes, known as nuclear pores. Co-lead author Bart Hoogenboom likened the pores to a strange kind of sieve:

“The pores have been to known to act like a sieve that could hold back sugar while letting grains of rice fall through at the same time, but it was not clear how they were able to do that.”

In this study—which used cells taken from frog eggs—Hoogenboom, along with co-lead author Ariberto Fassati, harnessed atomic force microscopy (AFM) to give them a new understanding of how these pores work. Like a blind person moving their fingers to read braille, AFM uses a tiny needle to pass over the nuclear pores in order to measure their shape and structure.

“AFM can reveal far smaller structures than optical microscopes,” said Hoogenboom, “but it’s feeling more than seeing. The trick is to press hard enough to feel the shape and the hardness of the sample, but not so hard that you break it. [In this study], we used it to successfully probe the membrane…to reveal the structure of the pores.”

And what they found, adds Fassati, offered an explanation for how these pores worked:

“We found that the proteins in the center of the pores tangle together just tightly enough to form a barrier—like a clump of spaghetti. Large molecules can only pass through [the pores] when accompanied by chaperone molecules. These chaperones, called nuclear transport receptors, have the property of lubricating the [spaghetti] strands and relaxing the barrier, letting the larger molecules through.”

Astoundingly, Fassati said that this process happens upwards of several thousand times per second.

These results are exciting not only for solving a long-standing mystery, but also for pointing to new ways of delivering gene therapies.

As evidenced by recent clinical advances in conditions such as sickle cell disease and SCID (‘bubble baby’ disease), gene therapy represents a promising way to treat—and even cure—patients. Hoogenboom and Fassati are optimistic that their team’s discovery could lead further refinements to gene therapy techniques.

Said Fassati, “It may be possible to improve the design of current mechanisms for delivering gene therapy to better cross the nuclear pores and deliver their therapeutic genes into the nucleus.”