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.

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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.”

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CIRM spending Oct 2014

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

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

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

Slowing Down the Clock on Aging Hearts

It’s like something from a nightmare: a disease that ages you at a breakneck pace, so that by age 12, your body more closely resembles someone in their 80’s—inside and out.

Instead of enjoying your childhood and adolescence, you suffer from diseases usually reserved for octogenarians: including heart disease, kidney failure and stroke.

Chances are, you won’t make it past your 13th birthday.

However fantastical this may seem, this condition is real. Called progeria, this rare genetic disorder affects only about 100 people worldwide. But with the help of the latest stem cell technology, a few determined scientists are speeding towards a cure.

In the May 19 issue of the Proceedings of the National Academy of Sciences, University of Maryland researchers have uncovered what may be driving the accelerated aging process. Specifically, the team identified a toxic protein that wreaks havoc on the patient’s arteries from a young age—thereby priming the young patient for disease.

The study’s senior author, Dr. Kan Cao, says in a recent news release that these findings offer hope not just for progeria patients and their families, but also for anyone suffering from or at risk of developing age-related diseases:

“This gives us a very good model for testing drugs to treat progeria. And it may help us understand how cardiovascular disease develops in people aging normally.”

Scientists have long known that progeria was caused by a genetic change, or mutation, that results in the production of a faulty version of a protein called progerin. But until now, they have been unable to pin down precisely how this faulty protein leads to progeria’s deadly symptoms.

Seen through a microscope, these color-enhanced skin cells from progeria patients have been induced to become smooth muscle cells, some with abnormalities such as double nuclei. [Credit: Haoyue Zhang]

Seen through a microscope, these color-enhanced skin cells from progeria patients have been induced to become smooth muscle cells, some with abnormalities such as double nuclei. [Credit: Haoyue Zhang]


Confounding the efforts, progeria has been extremely difficult to study, in large part because of the frailty of the patients. The disease most seriously affects the patient’s internal organs, but obtaining tissue samples is not generally possible, as the procedure is far too invasive. So Dr. Cao and her team tried a different approach.

They took skin samples from progeria patients and, using induced pluripotent stem cell (iPS cell) technology, transformed them into smooth muscle cells. Smooth muscle cells are a type of cell that lines the walls of blood vessels and other tissues. In this case, these smooth muscle cells were genetically identical to the patients’ native muscle cells, effectively allowing the researchers to model the disease in a dish over time, cell by cell. And when they did so, they solved a big part of the riddle.

The faulty version of progerin, the team realized, was interfering with a process essential the health and well being of cells: DNA repair.

As cells grow, age and divide, the DNA housed within them can sometimes break. When this happens, a protein called PARP-1 senses this break and, like a molecular handyman, repairs the damage. But in the case of progeria, the faulty progerin protein builds up within the cells. As it does so, PARP-1 levels drop. Without the expertise of PARP-1, the cells are unable to correctly repair DNA breaks. Sometimes they get it right, but usually they get it wrong. And when the cells try to divide, they can’t. Some end up as one cell with two nuclei, while others end up killing themselves in an act called “mitotic catastrophe.”

Cao and her team reasoned that people with progeria, who are losing smooth muscle cells much faster than is normal, are more vulnerable to stresses, such as blood pressure, which then increases their likelihood of heart disease and stroke.

CIRM-funded researchers at the Salk Institute reported a similar finding in 2011, when they derived muscle cells from iPS cells made from a patient with a different form of progeria. In our 2011 blog post about that work, the Salk team found that lamin A, a protein that accumulates in the normal aging process, also builds up in patients suffering from this form of progeria.

The next step for Cao’s team, she says, will be to find out the nature of the relationship between progerin and PARP-1. She also hopes to use iPS cell technology to test potential treatments for the disease. Since beginning her work on progeria, Cao has become close with progeria patients, and their families. It is these relationships that have spurred Cao and her young research team to understand the disease—and to find a cure:

“[My] students began thinking, ‘My research is so important for the families.’ It’s a lot of motivation for them. And a lot of pressure for all of us to work quickly.”