Stem cell stories that caught our eye: developing the nervous system, aging stem cells and identical twins not so identical

Here are the stem cell stories that caught our eye this week. Enjoy!

New theory for how the nervous system develops.

There’s a new theory on the block for how the nervous system is formed thanks to a study published yesterday by UCLA stem cell scientists in the journal Neuron.

The theory centers around axons, thin extensions projecting from nerve cells that transmit electrical signals to other cells in the body. In the developing nervous system, nerve cells extend axons into the brain and spinal cord and into our muscles (a process called innervation). Axons are guided to their final destinations by different chemicals that tell axons when to grow, when to not grow, and where to go.

Previously, scientists believed that one of these important chemical signals, a protein called netrin 1, exerted its influence over long distances in a gradient-like fashion from a structure in the developing nervous system called the floor plate. You can think of it like a like a cell phone tower where the signal is strongest the closer you are to the tower but you can still get some signal even when you’re miles away.

The UCLA team, led by senior author and UCLA professor Dr. Samantha Butler, questioned this theory because they knew that neural progenitor cells, which are the precursors to nerve cells, produce netrin1 in the developing spinal cord. They believed that the netrin1 secreted from these progenitor cells also played a role in guiding axon growth in a localized manner.

To test their hypothesis, they studied neural progenitor cells in the developing spines of mouse embryos. When they eliminated netrin1 from the neural progenitor cells, the axons went haywire and there was no rhyme or reason to their growth patterns.

Left: axons (green, pink, blue) form organized patterns in the normal developing mouse spinal cord. Right: removing netrin1 results in highly disorganized axon growth. (UCLA Broad Stem Cell Research Center/Neuron)

A UCLA press release explained what the scientists discovered next,

“They found that neural progenitors organize axon growth by producing a pathway of netrin1 that directs axons only in their local environment and not over long distances. This pathway of netrin1 acts as a sticky surface that encourages axon growth in the directions that form a normal, functioning nervous system.”

Like how ants leave chemical trails for other ants in their colony to follow, neural progenitor cells leave trails of netrin1 in the spinal cord to direct where axons go. The UCLA team believes they can leverage this newfound knowledge about netrin1 to make more effective treatments for patients with nerve damage or severed nerves.

In future studies, the team will tease apart the finer details of how netrin1 impacts axon growth and how it can be potentially translated into the clinic as a new therapeutic for patients. And from the sounds of it, they already have an idea in mind:

“One promising approach is to implant artificial nerve channels into a person with a nerve injury to give regenerating axons a conduit to grow through. Coating such nerve channels with netrin1 could further encourage axon regrowth.”

Age could be written in our stem cells.

The Harvard Gazette is running an interesting series on how Harvard scientists are tackling issues of aging with research. This week, their story focused on stem cells and how they’re partly to blame for aging in humans.

Stem cells are well known for their regenerative properties. Adult stem cells can rejuvenate tissues and organs as we age and in response to damage or injury. However, like most house hold appliances, adult stem cells lose their regenerative abilities or effectiveness over time.

Dr. David Scadden, co-director of the Harvard Stem Cell Institute, explained,

“We do think that stem cells are a key player in at least some of the manifestations of age. The hypothesis is that stem cell function deteriorates with age, driving events we know occur with aging, like our limited ability to fully repair or regenerate healthy tissue following injury.”

Harvard scientists have evidence suggesting that certain tissues, such as nerve cells in the brain, age sooner than others, and they trigger other tissues to start the aging process in a domino-like effect. Instead of treating each tissue individually, the scientists believe that targeting these early-onset tissues and the stem cells within them is a better anti-aging strategy.

David Sadden, co-director of the Harvard Stem Cell Institute.
(Jon Chase/Harvard Staff Photographer)

Dr. Scadden is particularly interested in studying adult stem cell populations in aging tissues and has found that “instead of armies of similarly plastic stem cells, it appears there is diversity within populations, with different stem cells having different capabilities.”

If you lose the stem cell that’s the best at regenerating, that tissue might age more rapidly.  Dr. Scadden compares it to a game of chess, “If we’re graced and happen to have a queen and couple of bishops, we’re doing OK. But if we are left with pawns, we may lose resilience as we age.”

The Harvard Gazette piece also touches on a changing mindset around the potential of stem cells. When stem cell research took off two decades ago, scientists believed stem cells would grow replacement organs. But those days are still far off. In the immediate future, the potential of stem cells seems to be in disease modeling and drug screening.

“Much of stem cell medicine is ultimately going to be ‘medicine,’” Scadden said. “Even here, we thought stem cells would provide mostly replacement parts.  I think that’s clearly changed very dramatically. Now we think of them as contributing to our ability to make disease models for drug discovery.”

I encourage you to read the full feature as I only mentioned a few of the highlights. It’s a nice overview of the current state of aging research and how stem cells play an important role in understanding the biology of aging and in developing treatments for diseases of aging.

Identical twins not so identical (Todd Dubnicoff)

Ever since Takahashi and Yamanaka showed that adult cells could be reprogrammed into an embryonic stem cell-like state, researchers have been wrestling with a key question: exactly how alike are these induced pluripotent stem cells (iPSCs) to embryonic stem cells (ESCs)?

It’s an important question to settle because iPSCs have several advantages over ESCs. Unlike ESCs, iPSCs don’t require the destruction of an embryo so they’re mostly free from ethical concerns. And because they can be derived from a patient’s cells, if iPSC-derived cell therapies were given back to the same patient, they should be less likely to cause immune rejection. Despite these advantages, the fact that iPSCs are artificially generated by the forced activation of specific genes create lingering concerns that for treatments in humans, delivering iPSC-derived therapies may not be as safe as their ESC counterparts.

Careful comparisons of DNA between iPSCs and ESCs have shown that they are indeed differences in chemical tags found on specific spots on the cell’s DNA. These tags, called epigenetic (“epi”, meaning “in addition”) modifications can affect the activity of genes independent of the underlying genetic sequence. These variations in epigenetic tags also show up when you compare two different preparations, or cell lines, of iPSCs. So, it’s been difficult for researchers to tease out the source of these differences. Are these differences due to the small variations in DNA sequence that are naturally seen from one cell line to the other? Or is there some non-genetic reason for the differences in the iPSCs’ epigenetic modifications?

Marian and Vivian Brown, were San Francisco’s most famous identical twins. Photo: Christopher Michel

A recent CIRM-funded study by a Salk Institute team took a clever approach to tackle this question. They compared epigenetic modifications between iPSCs derived from three sets of identical twins. They still found several epigenetic variations between each set of twins. And since the twins have identical DNA sequences, the researchers could conclude that not all differences seen between iPSC cell lines are due to genetics. Athanasia Panopoulos, a co-first author on the Cell Stem Cell article, summed up the results in a press release:

“In the past, researchers had found lots of sites with variations in methylation status [specific term for the epigenetic tag], but it was hard to figure out which of those sites had variation due to genetics. Here, we could focus more specifically on the sites we know have nothing to do with genetics. The twins enabled us to ask questions we couldn’t ask before. You’re able to see what happens when you reprogram cells with identical genomes but divergent epigenomes, and figure out what is happening because of genetics, and what is happening due to other mechanisms.”

With these new insights in hand, the researchers will have a better handle on interpreting differences between individual iPSC cell lines as well as their differences with ESC cell lines. This knowledge will be important for understanding how these variations may affect the development of future iPSC-based cell therapies.

Telomere length matters: scientists find shorter telomeres may cause aging-related disease

Aging is inevitable no matter how much you exercise, sleep or eat healthy. There is no magic pill or supplement that can thwart growing older. However, preventing certain age-related diseases is a different story. Genetic mutations can raise the risk of acquiring age-related diseases like heart disease, diabetes, cancer and dementia. And scientists are on the hunt for treatments that target these mutations in hopes of preventing these diseases from happening.

Telomeres shown in white act as protective caps at the ends of chromosomes.

Another genetic component that can accelerate diseases of aging are telomeres. These are caps made up of repeat sequences of DNA that sit at the ends of chromosomes and prevent the loss of important genetic material housed within chromosomes. Healthy cells have long telomeres, and ascells divide these telomeres begin to shorten. If telomere shortening is left unchecked, cells become unhealthy and either stop growing or self-destruct.

Cells have machinery to regrow their telomeres, but in most cases, the machinery isn’t activated and over time, the resulting shortened telomeres can lead to problems like an impaired immune system and organ degeneration. Shortened telomeres are associated with age-related diseases, but the reasons why have remained elusive until recently.

Scientists from the Gladstone Institutes have found a clue to this telomere puzzle that they shared in a study published yesterday in the Journal of Clinical Investigation. This research was funded in part by a CIRM Discovery stage award.

In their study, the team found that mice with a mutation that causes a heart condition known as calcific aortic valve disease (CAVD) were more likely to get the disease if they had short telomeres. CAVD causes the heart valves and vessels to turn hard as rock due to a buildup of calcium. It’s the third leading cause of heart disease and the only effective treatment requires surgery to replace the calcified parts of the heart.

Old age and mutations in one of the copies of the NOTCH1 gene can cause CAVD in humans. However, attempts to model CAVD in mice using the same NOTCH1 mutation have failed to produce symptoms of the disease. The team at Gladstone knew that mice inherently have longer telomeres than humans and hypothesized that these longer telomeres could protect mice with the NOTCH1 mutation from getting CAVD.

They decided to study NOTCH1 mutant mice that had short telomeres and found that these mice had symptoms of CAVD including hardened arteries. Furthermore, mice that had the shortest telomeres had the most severe heart-related symptoms.

First author on the study Christina Theodoris, explained in a Gladstone news release how telomere length matters in animal models of age-related diseases:

“Our findings reveal a critical role for telomere length in a mouse model of age-dependent human disease. This model provides a unique opportunity to dissect the mechanisms by which telomeres affect age-dependent disease and also a system to test novel therapeutics for aortic valve disease.”

Deepak Srivastava and Christina Theodoris created mouse models of CAVD that may be used to test drug therapies for the disease. (Photo: Chris Goodfellow, Gladstone Institutes)

The team believes that there is a direct relationship between short telomeres and CAVD, likely through alterations in the activity of gene networks related to CAVD. They also propose that telomere length could influence how severe the symptoms of this disease manifest in humans.

This study is important to the field because it offers a new strategy to study age-related diseases in animal models. Senior author on the study, Dr. Deepak Srivastava, elaborated on this concept:

Deepak Srivastava, Gladstone Institutes

“Historically, we have had trouble modeling human diseases caused by mutation of just one copy of a gene in mice, which impedes research on complex conditions and limits our discovery of therapeutics. Progressive shortening of longer telomeres that are protective in mice not only reproduced the clinical disease caused by NOTCH1 mutation, it also recapitulated the spectrum of disease severity we see in humans.”

Going forward, the Gladstone team will use their new mouse model of CAVD to test drug candidates that have the potential to treat CAVD in humans. If you want to learn more about this study, watch this Gladstone video featuring an interview of Dr. Srivastava about this publication.

Stem Cell Stories that caught our eye: a womb with a view, reversing aging and stabilizing stem cells

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Today we bring you a trifecta of stem cell stories that were partially funded by grants from CIRM.

A womb with a view: using 3D imaging to observe embryo implantation. Scientists have a good understanding of how the beginning stages of pregnancy happen. An egg cell from a woman is fertilized by a sperm cell from a man and the result is a single cell called a zygote. Over the next week, the zygote divides into multiple cells that form the developing embryo. At the end of that period, the embryo hatches out of its protective membrane and begins implanting itself into the lining of the mother’s uterus.

It’s possible to visualize the early stages of embryo development in culture dishes, which has helped scientists understand the biological steps required for an embryo to survive and develop into a healthy fetus. However, something that is not easy to observe is the implantation stage of the embryo in the uterus. This process is complex and involves a restructuring of the uterine wall to accommodate the developing embryo. As you can imagine, replicating these events would be extremely complicated and difficult to do in a culture dish, and current imaging techniques aren’t adequate either.

That’s where new CIRM-funded research from a team at UCSF comes to the rescue. They developed a 3D imaging technology and combined it with a previously developed “tissue clearing” method, which uses chemicals to turn tissues translucent, to provide clear images of the uterine wall during embryo implantation in mice. Their work was published this week in the journal Development.

According to a UCSF news release,

“Using their new approach, the team observed that the uterine lining becomes extensively folded as it approaches its window of receptivity for an embryo to implant. The geometry of the folds in which the incoming embryos dwell is important, the team found, as genetic mutants with defects in implantation have improper patterns of folding.”

Ultimately, the team aims to use their new imaging technology to get an inside scoop on how to prevent or treat pregnancy disorders and also how to improve the outcome of pregnancies by in vitro fertilization.

Senior author on the study, UCSF professor Diana Laird concluded:

“This new view of early pregnancy lets us ask fundamentally new questions about how the embryo finds its home within the uterus and what factors are needed for it to implant successfully. Once we can understand how these processes happen normally, we can also ask why certain genetic mutations cause pregnancies to fail, to study the potential dangers of environmental toxins such as the chemicals in common household products, and even why metabolic disease and obesity appears to compromise implantation.”

If you want to see this womb with a view, check out the video below.

Watch these two videos for more information:

Salk scientists reverse signs of aging in mice. For our next scintillating stem cell story, we’re turning back the clock – the aging clock that is. Scientists from the Salk Institute in La Jolla, reported an interesting method in the journal Cell  that reverses some signs of aging in mice. They found that periodic expression of embryonic stem cell genes in skin cells and mice could reverse some signs of aging.

The Salk team made use of cellular reprogramming tools developed by the Nobel Prize winning scientist Shinya Yamanaka. He found that four genes normally expressed in embryonic stem cells could revert adult cells back to a pluripotent stem cell state – a process called cellular reprogramming. Instead of turning adult cells back into stem cells, the Salk scientists asked whether the Yamanaka factors could instead turn back the clock on older, aging cells – making them healthier without turning them back into stem cells or cancer-forming cells.

The team found that they could rejuvenate skin cells from mice without turning them back into stem cells if they turned on the Yamanaka genes on for a short period of time. These skin cells were taken from mice that had progeria – a disease that causes them to age rapidly. Not only did their skin cells look and act younger after the treatment, but when the scientists used a similar technique to turn on the Yamanaka genes in progeria mice, they saw rejuvenating effects in the mice including a more rapid healing and regeneration of muscle and pancreas tissue.

(Left) impaired muscle repair in aged mice; (right) improved muscle regeneration in aged mice subjected to reprogramming. (Salk Institute)

(Left) impaired muscle repair in aged mice; (right) improved muscle regeneration in aged mice subjected to reprogramming. (Salk Institute)

The senior author on the study, Salk Professor Juan Carlos Izpisua Belmonte, acknowledged in a Salk news release that this is early stage work that focuses on animal models, not humans:

“Obviously, mice are not humans and we know it will be much more complex to rejuvenate a person. But this study shows that aging is a very dynamic and plastic process, and therefore will be more amenable to therapeutic interventions than what we previously thought.”

This story was very popular, which is not surprising as aging research is particularly fascinating to people who want to live longer lives. It was covered by many news outlets including STATnews, Scientific American and Science Magazine. I also recommend reading Paul Knoepfler’s journal club-style blog on the study for an objective take on the findings and implications of the study. Lastly, you can learn more about the science of this work by watching the movie below by the Salk.

Movie:

Stabilizing unstable stem cells. Our final stem cell story is brought to you by scientists from the UCLA Broad Stem Cell Research Center. They found that embryonic stem cells can harbor genetic instabilities that can be passed on to their offspring and cause complications, or even disease, later in life. Their work was published in two separate studies in Cell Stem Cell and Cell Reports.

The science behind the genetic instabilities is too complicated to explain in this blog, so I’ll refer you to the UCLA news release for more details. In brief, the UCLA team found a way to reverse the genetic instability in the stem cells such that the mature cells that they developed into turned out healthy.

As for the future impact of this research, “The research team, led by Kathrin Plath, found a way to correct the instability by resetting the stem cells from a later stage of development to an earlier stage of development. This fundamental discovery could have great impact on the creation of healthy tissues to cure disease.”

Trash talking and creating a stem cell community

imilce2

Imilce Rodriguez-Fernandez likes to talk trash. No, really, she does. In her case it’s cellular trash, the kind that builds up in our cells and has to be removed to ensure the cells don’t become sick.

Imilce was one of several stem cell researchers who took part in a couple of public events over the weekend, on either side of San Francisco Bay, that served to span both a geographical and generational divide and create a common sense of community.

The first event was at the Buck Institute for Research on Aging in Marin County, near San Francisco. It was titled “Stem Cell Celebration” and that’s pretty much what it was. It featured some extraordinary young scientists from the Buck talking about the work they are doing in uncovering some of the connections between aging and chronic diseases, and coming up with solutions to stop or even reverse some of those changes.

One of those scientists was Imilce. She explained that just as it is important for people to get rid of their trash so they can have a clean, healthy home, so it is important for our cells to do the same. Cells that fail to get rid of their protein trash become sick, unhealthy and ultimately stop working.

Imilce is exploring the cellular janitorial services our bodies have developed to deal with trash, and trying to find ways to enhance them so they are more effective, particularly as we age and those janitorial services aren’t as efficient as they were in our youth.

Unlocking the secrets of premature aging

Chris Wiley, another postdoctoral researcher at the Buck, showed that some medications that are used to treat HIV may be life-saving on one level, preventing the onset of full-blown AIDS, but that those benefits come with a cost, namely premature aging. Chris said the impact of aging doesn’t just affect one cell or one part of the body, but ripples out affecting other cells and other parts of the body. By studying the impact those medications have on our bodies he’s hoping to find ways to maintain the benefits of those drugs, but get rid of the downside.

Creating a Community

ssscr

Across the Bay, the U.C. Berkeley Student Society for Stem Cell Research held it’s 4th annual conference and the theme was “Culturing a Stem Cell Community.”

The list of speakers was a Who’s Who of CIRM-funded scientists from U.C. Davis’ Jan Nolta and Paul Knoepfler, to U.C. Irvine’s Henry Klassen and U.C. Berkeley’s David Schaffer. The talks ranged from progress in fighting blindness, to how advances in stem cell gene editing are cause for celebration, and concern.

What struck me most about both meetings was the age divide. At the Buck those presenting were young scientists, millennials; the audience was considerably older, baby boomers. At UC Berkeley it was the reverse; the presenters were experienced scientists of the baby boom generation, and the audience were keen young students representing the next generation of scientists.

Bridging the divide

But regardless of the age differences there was a shared sense of involvement, a feeling that regardless of which side of the audience we are on we all have something in common, we are all part of the stem cell community.

All communities have a story, something that helps bind them together and gives them a sense of common purpose. For the stem cell community there is not one single story, there are many. But while those stories all start from a different place, they end up with a common theme; inspiration, determination and hope.

 

Scientists tackle aging by stabilizing defective blood stem cells in mice

Aging is an inevitable process that effects every cell, tissue, and organ in your body. You can live longer by maintaining a healthy, active lifestyle, but there is no magic pill that can prevent your body’s natural processes from slowly breaking down and becoming less efficient. As author Chinua Achebe would say, “Things Fall Apart”.

Adult stem cells are an unfortunate victim of the aging process. They have the important job of replenishing the cells in your body throughout your lifetime. However, as you grow older, adult stem cells lose their regenerative ability and fail to maintain the integrity and function of their tissues and organs. This can happen for a number of reasons, but no matter the cause, dysfunctional stem cells can accelerate aging and contribute to a shortened lifespan.

So to put it simply, aging adult stem cells = decline in stem cell function = shortened lifespan.

Dysfunctional blood stem cells make an unhappy immune system

Human blood (red) and immune cells (green) are made from hematopoietic/blood stem cells. Photo credit: ZEISS Microscopy.

Human blood (red) and immune cells (green) are made from hematopoietic/blood stem cells. Photo credit: ZEISS Microscopy.

A good example of this process is hematopoietic stem cells (HSCs), which are adult stem cells found in bone marrow that make all the cells in our blood and immune system. When HSCs get old, they lose their edge and fail to generate some of the important blood cell types that are crucial for a healthy immune system. This can be life-threatening for elderly people who are at higher risk for infections and disease.

So how can we improve the function of aging HSCs to boost the immune system in older people and potentially extend their healthy years of life? A team of researchers from Germany might have an answer. They’ve identified a genetic switch that revitalizes aged, defective HSCs in mice and prolongs their lifespan. They published their findings this week in Nature Cell Biology.

Identifying the Per-petrator for aging HSCs

The perpetrator in this story is a gene called Per2. The team identified Per2 through a genetic screen of hundreds of potential tumor suppressor genes that could potentially impair the regenerative abilities of HSCs in response to DNA damage caused by aging.

It turns out that the Per2 gene is turned on in a subset of HSCs, called lymphoid-HSCs, that preferentially generate blood cells in the lymphatic system. These include B and T cells, both important parts of our immune system. When Per2 is turned on in lymphoid-HSCs, it activates the DNA damage response pathway. While responding to DNA damage may sound like a good thing, it also slows down the cell division process and prevents lymphoid-HSCs from producing their normal amount of lymphoid cells. Adding insult to injury, Per2 also activates the p53-dependent apoptosis pathway, which causes programmed cell death and further reduces the number of HSCs in reserve.

To address these problems, the team decided to delete the Per2 gene in mice and study the function of their HSCs as they aged. They found that removing Per2 stabilized lymphoid-HSCs and rescued their ability to generate the appropriate number of lymphoid cells. Per2 deletion also boosted their immune system, making the mice less susceptible to infection, and extended their lifespan by as much as 15 percent.

A key finding was that deleting Per2 did not increase the incidence of tumors in the aging mice – a logical concern as Per2 mutations in humans are link to increased cancer risk.

Per2 might not be a Per-fect solution for healthy aging

In summary, getting rid of Per2 in the HSCs of older mice improves their function and the function of their immune system while also extending their lifespan.

Senior author on the study, Karl Lenhard Rudolph, commented about their findings in a news release:

Karl Lenhard Rudolph. Photo: Anne Günther/FSU

Karl Lenhard Rudolph.

“All in all, these results are very promising, but equally surprising. We did not expect such a strong connection between switching off a single gene and improving the immune system so clearly.”

 

 

So Per2 may be a good healthy aging target in mice, but the real question is whether these results will translate to humans. Per2 is a circadian rhythm gene and is important for regulating the sleep-wake cycle. Deleting this gene in humans could cause sleep disorders and other unwanted side effects.

Rudolph acknowledges that his team needs to move their focus from mouse to humans.

“It is not yet clear whether this mutation in humans would have a benefit such as improved immune functions in aging — it is of great interest for us to further investigate this question.”

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.”

New type of diabetes caused by old age may be treatable

I’m going to tell you a secret: I love sugar. I love it so much that as a little kid my mom used to tell me scary stories about how my teeth would fall out and that I might get diabetes one day if I ate too many sweets. Thankfully, none of these things happened. I have a full set of teeth (and they’re real), my blood sugar level is normal, and I’ve become one with the term “everything in moderation”.

I am not out of the woods, however: a newly discovered type of diabetes could strike in a few decades. A research team has found the cause of a type of diabetes that occurs because of old age, and a potential cure, at least in mice.

Diabetes comes in different flavors

People who suffer from diabetes (which is almost 30 million Americans) lack the ability to regulate the amount of sugar in their blood. The pancreas is the organ that regulates blood sugar by producing a hormone called insulin. If blood has a high sugar level, the pancreas releases insulin, which helps muscle, liver, and fat cells to absorb the excess sugar until the levels in the blood are back to normal.

There are two main forms of diabetes, type 1 and 2, both of which cause hyperglycemia or high blood sugar. Type 1 is an autoimmune disorder where the immune system attacks and kills the insulin-producing cells in the pancreas. As a result, these type 1 diabetics aren’t able to produce insulin and endure a lifetime of daily insulin shots to manage their condition. Type 2 diabetes is the more common form of the disease and occurs when the body’s cells become unresponsive, or resistant, to insulin and stop absorbing sugar from the bloodstream.

The cause of type 1 diabetes is not known although genetic factors are sure to be involved. Type 2 diabetes can be caused by a combination of factors including poor diet, obesity, genetics, stress, and old age. Both forms of the disease can be fatal if not managed properly and raise the risk of other medical complications such as heart disease, blindness, ulcers, and kidney failure.

While type 1 or 2 diabetes make up the vast majority of the cases, there are actually other forms of this disease that we are only just beginning to understand. One of them is type 3, which is linked to Alzheimer’s disease. (To learn more about the link between AD and diabetes, read this blog.)

Old age can cause diabetes

Another form of diabetes, which is in the running for the title of type 4, is caused by old age. Unlike type 2 diabetes which also occurs in adults, type 4 individuals don’t have the typical associated risk factors like weight gain. The exact mechanism behind age-related type 4 diabetes in humans isn’t known, but a CIRM-funded study published today in Nature identified the cause of diabetes in older, non-obese mice.

Scientists from the Salk Institute compared the immune systems of healthy mice to lean mice with age-associated insulin resistance or mice with obesity-associated insulin resistance (the equivalent to type 2 diabetes in humans). When they studied the fat tissue in the three animal models, they noticed a striking difference in the number of immune cells called T regulatory cells (Tregs). These cells are the “keepers of the immune system”, and they keep inflammation and excessive activity of other immune cells to a minimum.

Lean mice with age-related diabetes, had a substantially larger number of Tregs in their fat tissue compared to obesity-related diabetic and normal mice. Instead of being their usual helpful selves, the overabundance of Tregs in the age-related diabetic mice caused insulin resistance.

Salk researchers show that diabetes in elderly, lean animals is caused by an overabundance of immune cells in fat. In this graphic, fat tissue is shown with representations of the immune cells called Tregs (orange). In aged mice with diabetes (represented on the right), Tregs are overexpressed in fat tissue and trigger insulin resistance. When Tregs are blocked, the fat cells in mice become insulin sensitive again. (Image courtesy of Salk Institute)

Diabetes in elderly, lean animals is caused by an overabundance of immune cells called Tregs (orange)  in fat tissue (brown cells). In aged mice with diabetes (right), Tregs are overexpressed in fat tissue and trigger insulin resistance. When Tregs are blocked, the fat cells in mice become insulin sensitive again. (Image courtesy of Salk Institute)

In a Salk Institute press release, lead author Sagar Bapat explained:

Normally, Tregs help calm inflammation. Because fat tissue is constantly broken down and built back up as it stores and releases energy, it requires low levels of inflammation to constantly remodel itself. But as someone ages, the new research suggests, Tregs gradually accumulate within fat. And if the cells reach a tipping point where they completely block inflammation in fat tissue, they can cause fat deposits to build up inside unseen areas of the body, including the liver, leading to insulin resistance.

A cure for type 4 diabetes, but in mice…

After they identified the cause, the authors next searched for a solution. They blocked the build up of Tregs in the fat tissue of age-related diabetic mice using an antibody drug that inhibits the production of Tregs. The drug successfully cured the age-related diabetic mice of their insulin resistance, but didn’t do the same for the obesity-related diabetic mice. The authors concluded that the two forms of diabetes have different causes and type 4 can be cured by removing excessive Tregs from fat tissue.

This study is only the beginning for understanding age-related diabetes. The authors next want to find out why Tregs accumulate in the fat tissue of older mice, and if they also build up in other tissues and organs. They are also curious to know if the same phenomenon happens in elderly humans who become diabetic but don’t have type 2 diabetes.

Understanding the cause of age-related diabetes in humans is of upmost importance to Ronald Evans who is the director of the Gene Expression Lab at the Salk Institute, and senior author on the study.

Ron Evans

Ron Evans

A lot of diabetes in the elderly goes undiagnosed because they don’t have the classical risk factors for type 2 diabetes, such as obesity. We hope our discovery not only leads to therapeutics, but to an increased recognition of type 4 diabetes as a distinct disease.

For more on this exciting study, check out a video interview of Dr. Evans from the Salk Institute:


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How Brain Stem Cells Could Stay Forever Young

As we age, so do the cells that make up our bodies. To keep us spry as we get older, our bodies rely on adult stem cells to replace the cells in our tissues and organs. Adult stem cells can only generate cell types specific to the organ or tissue that they live in. For instance, heart stem cells can only help regenerate or repair the heart, same for brain stem cells and the brain, etc.

While adult stem cells have built-in mechanisms to help them avoid the aging process for as long as possible, they can only delay the inevitable for so long. So as the function of our bodies decline, so does adult stem cell function and with it our ability to regenerate damaged tissue.

But now a new study has found out what happens to cause the aging of adult stem cells and points at ways to avoid it and keep these stem cells “forever young.”

Brain stem cells stay youthful

A group from Zurich, Switzerland studied how brain stem cells stay young as the brain ages. In a study published in Science on Friday, they found that young brain stem cells divide in a way that routes damaged proteins and aging-related factors away from the daughter stem cells and into their non-stem cell progeny, thus keeping brain stem cells healthy and youthful.

stemcelldivision

Brain stem cells divide asymmetrically into a daughter stem cell and a non-stem daughter cell that can differentiate into other brain cells (Image adapted from Berika et al., 2014).

The Zurich group took a closer look at brain stem cells in adult mouse brains and found that they divide asymmetrically. This means that instead of equally dividing its cellular components between two daughter cells, the mother cell instead herds all of the damaged proteins and aging factors into the non-stem daughter cell, leaving the new stem cell unexposed to cell damage. In this way, the new stem cell is protected and is able to maintain its regenerative capacity.

A barrier against aging?

Brain stem cells are able to preferentially shuttle damaged proteins into their non-stem cell progeny by a diffusion barrier called the endoplasmic reticulum (ER). The ER is a membrane structure in cells that has a number of important functions including deciding what factors or proteins end up in which cells.

The authors observed that during the division of brain stem cells, the ER forms a barrier between the non-stem and stem cell progeny that keeps the damaged proteins and aging factors in the non-stem daughter cell. This ER barrier remains intact during the division of young brain stem cells, however, they weren’t sure this was the case with older brain stem cells.

The scientists watched older brain stem cells to see if this anti-aging barrier was able to hold up with advancing age. They observed that this barrier actually weakens with age and allows aging factors to go with the stem cell progeny. This happens because an important cell structure called the nuclear lamina, which regulates cell division, doesn’t function properly in the old stem cells. When they disrupted the lamina structure in young brain stem cells, as expected, the anti-aging barrier couldn’t properly block the transfer of aging-factors into the new daughter stem cells.

youngvsold

Young brain stem cells on the left divide asymmetrically and have a barrier that keeps age-related damage in the non-stem daughter cell (red). This barrier weakens in older brain stem cells and aging factors are transferred to the stem cell progeny. (Moore et al., 2015)

 

Thus it seems that brain stem cells maintain their youth by generating diffusible barriers that block the transfer of damaged proteins and aging factors into their stem cell progeny during cell division. The strength of this barrier weakens with age, and when this happens, aging factors are more evenly divided between the non-stem and stem cell progeny, potentially causing stem cell damage and reducing their regenerative function.

Anti-aging implications

The authors note at the end of their report that further studies should be done to determine whether this anti-aging mechanism is unique to brain stem cells or if it occurs in other adult stem cells or cancer cells which display stem cell like properties. If similar anti-aging barriers exist, then targeting the age-related breakdown of this barrier could be a potential strategy to keep adult stem cells forever young and humans feeling and acting younger for a little longer.


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Even the early worm gets old: study unlocks a key to aging

A new study poses the question, ‘When does aging really begin?’ One glance in the mirror every morning is enough for me to know that regardless of where it begins I know where it’s going. And it’s not pretty.

But enough about me. Getting back to the question about aging, two researchers at Northwestern University have uncovered some clues that may give us a deeper understanding of aging and longevity, and even lead to new ways of improving quality of life as we get older.

The researchers were focused on C. elegans, a transparent roundworm. They initially thought that aging was a gradual process: that it began slowly and then picked up pace as the animal got older. Instead they found that in C. elegans aging begins just as soon as the animal reaches reproductive maturity. It hits its peak of fertility, and it is all downhill from there.

The researchers say that once C. elegans has finished producing eggs and sperm – ensuring its line will continue – a genetic switch is thrown by germline stem cells. This flipped switch begins the aging process by turning off the ‘heat shock response’; that’s a mechanism the body uses to protect cells from conditions that would normally pose a threat or even be deadly.

In a news release Richard Morimoto, the senior author of the study, says that without that protective mechanism in place the aging process begins:

C. elegans has told us that aging is not a continuum of various events, which a lot of people thought it was. In a system where we can actually do the experiments, we discover a switch that is very precise for aging. All these stress pathways that insure robustness of tissue function are essential for life, so it was unexpected that a genetic switch is literally thrown eight hours into adulthood, leading to the simultaneous repression of the heat shock response and other cell stress responses.”

You read that right. In the case of poor old C. elegans the aging process begins just eight hours into adulthood. Of course the lifespan of the worm is only about 3 weeks so it’s not surprising the aging process kicks in quite so quickly.

To further test their findings the researchers carried out an experiment where they blocked the genetic switch from flipping, and the worm’s protective mechanisms remained strong.

Now, taking findings from something as small as a worm and trying to extrapolate them to larger animals is never easy. Nonetheless understanding what triggers aging in C. elegans could help us figure out if a similar process was taking place at the cellular level in people.

Morimoto says that knowledge might help us develop ways to improve our cellular quality of life and delay the onset of many of the diseases of aging:

“Wouldn’t it be better for society if people could be healthy and productive for a longer period during their lifetime? I am very interested in keeping the quality control systems optimal as long as we can, and now we have a target. Our findings suggest there should be a way to turn this genetic switch back on and protect our aging cells by increasing their ability to resist stress.”

The study is published in the journal Molecular Cell.

Extending the Lease: Stanford Scientists Turn Back Clock on Aging Cells

In the end, all living things—even the cells in our bodies—must die. But what if we could delay the inevitable, even just for a bit? What new scientific advances could come as a result?

Stanford scientists have found a way to temporarily extend the life of an aging cell.

Stanford scientists have found a way to temporarily extend the life of an aging cell.

In research published this week in the FASEB Journal, scientists at the Stanford University School of Medicine have devised a new method that gives aging DNA a molecular facelift.

The procedure, developed by Stanford Stem Cell Scientist Helen Blau and her team at the Baxter Laboratory for Stem Cell Biology, physically lengthens the telomeres—the caps on the ends of chromosomes that protect the cell from the effects of aging.

When born, all cells contain chromosomes capped with telomeres. But during each round of cell division, those telomeres shrink. Eventually, the telomeres shorten to such an extent that the chromosomes can no longer replicate at the rate they once could. For the cell, this is the beginning of the end.

The link between telomeres and cellular aging has been an intense focus in recent years, including the subject of the 2009 Nobel Prize in Physiology or Medicine. Extending the lifespan of cells by preventing—or reversing— the shortening of telomeres can not only boost cell division during laboratory studies, but can also lead to new therapeutic strategies to treat age-related diseases.

“Now we have found a way to lengthen human telomeres… turning back the internal clock in these cells by the equivalent of many years of human life,” explained Blau in a press release. “This greatly increases the number of cells available for studies such as drug testing or disease modeling.”

The method Blau and her team describe involves the use of a modified bit of RNA that boosts the production of the protein telomerase. Telomerase is normally present in high levels in stem cells, but drops off once the cells mature. Blau’s modified RNA gives the aging cells a shot of telomerase, after which they begin behaving like cells half their age. But only for about 48 hours, after which they begin to degrade again.

The temporary nature of this change, say the researchers, offers significant advantages. On the biological level, it means that the treated cells won’t begin dividing out of control indefinitely, minimizing the risk of tumor formation. The study’s first author John Ramunas offers up some additional pluses to their method:

“Existing methods of extending telomeres act slowly, whereas our method acts over just a few days to reverse telomere shortening that occurs over more than a decade of normal aging. This suggests that a treatment using our method could be brief and infrequent.”

Indeed, the genetic disease Duchenne muscular dystrophy is in part characterized by abnormally short telomeres. Blau reasons that their discovery could lead to better treatments for this disease. Their immediate future steps involve testing their method in a variety of cell types. Said Blau:

“We’re working to understand more about the differences among cell types, and how we can overcome those differences to allow this approach to be more universally successful.”

Hear more about stem cells and muscular dystrophy in our recent Spotlight on Disease featuring Helen Blau: