Alzheimer’s

Stem Cell All-Stars, All For You

/ Kevin McCormack / Leave a comment

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Dr. Larry Goldstein, UC San Diego

It’s not often you get a chance to hear some of the brightest minds around talk about their stem cell research and what it could mean for you, me and everyone else. That’s why we’re delighted to be bringing some of the sharpest tools in the stem cell shed together in one – virtual – place for our CIRM 2020 Grantee Meeting.

The event is Monday September 14th and Tuesday September 15th. It’s open to anyone who wants to attend and, of course, it’s all being held online so you can watch from the comfort of your own living room, or garden, or wherever you like. And, of course, it’s free.

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Dr. Daniela Bota, UC Irvine

The list of speakers is a Who’s Who of researchers that CIRM has funded and who also happen to be among the leaders in the field. Not surprising as California is a global center for regenerative medicine. And you will of course be able to post questions for them to answer.

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Dr. Deepak Srivastava, Gladstone Institutes

The key speakers include:

Larry Goldstein: the founder and director of the UCSD Stem Cell Program talking about Alzheimer’s research

Irv Weissman: Stanford University talking about anti-cancer therapies

Daniela Bota: UC Irvine talking about COVID-19 research

Deepak Srivastava: Gladsone Institutes, talking about heart stem cells

Other topics include the latest stem cell approaches to COVID-19, spinal cord injury, blindness, Parkinson’s disease, immune disorders, spina bifida and other pediatric disorders.

You can choose one topic or come both days for all the sessions. To see the agenda for each day click here. Just one side note, this is still a work in progress so some of the sessions have not been finalized yet.

And when you are ready to register go to our Eventbrite page. It’s simple, it’s fast and it will guarantee you’ll be able to be part of this event.

We look forward to seeing you there.

Promising Advances in Alzheimer’s Research Could Create More Advanced Therapy Options

/ Adonica Shaw / Leave a comment
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Photo Courtesy of NIH

New developments in Alzheimer’s research are bringing us closer to more precise therapies for this debilitating disease.

Alzheimer’s disease, is characterized by the formation of amyloid plaques in the brain, which interfere with the normal communication flow between brain cells, leading to debilitating symptoms like memory loss and impaired decision-making. These plaques are made out of beta-amyloid proteins that stick together.

Over the past few years, researchers from several institutions have been working to develop antibodies that bind to and neutralize the toxic effects of the beta-amyloid. The search for effective antibodies, although promising, has been riddled with setbacks. Knowing this, a team of researchers from Brigham and Women’s Hospital in Boston, MA, decided to approach this issue from a different angle – by conducting experiments to identify a better way of targeting beta-amyloid. Their goal was to develop a more efficient antibody to be used in Alzheimer’s therapy.

Principal investigator Dominic Walsh and team came up with a novel technique to collect beta-amyloid and to prepare it in the laboratory.

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Dominic Walsh, PH.D.

“Many different efforts are currently underway to find treatments for Alzheimer’s disease, and anti-[beta-amyloid] antibodies are currently the furthest advanced,” says Walsh. “But the question remains: what are the most important forms of [beta-amyloid] to target? Our study points to some interesting answers,” the lead researcher adds, and these answers are now reported in an open access paper published in the journal Nature Communications.”

Beta-amyloid can be found in many forms. At one end of the spectrum, it exists as a single protein, or monomer, which isn’t necessarily toxic.

At the other end, there is the beta-amyloid plaque, in which many beta-amyloid proteins become tangled together. Beta-amyloid plaques are large enough to be observed using a traditional microscope, and they are involved in the development of Alzheimer’s.

In the current study, as well as in a previous one, Walsh and team looked at beta-amyloid structures to identify the ones that are most harmful in the brain.

Typically specialists use synthetic beta-amyloid samples to create a laboratory model of Alzheimer’s disease in the brain. Very few scientists actually collect beta-amyloid from the brains of individuals diagnosed with the disease.

In the current study, Walsh and team focused on finding better a more specific antibody to target the toxic forms of beta-amyloid but not the less harmful forms. To do so, they developed a novel screening test that requires extracting beta-amyloid from brain samples from people with Alzheimer’s. They added these extracts to induced pluripotent stem cell-derived human neurons and observed the ability of the different antibodies to block the toxic effects of the beta-amyloid.

This screening test allowed the team to discover a particular antibody — called “1C22” — that is able to block toxic forms of beta-amyloid more effectively than other antibodies currently being tested in clinical trials.

Walsh explained the implications of their novel screening method:

“We anticipate that this primary screening technique will be useful in the search to identify more potent anti-[beta-amyloid] therapeutics in the future.”

Using laughter to help find a treatment for Alzheimer’s

/ Kevin McCormack / Leave a comment

Alzheimer's

In 1983, when President Ronald Reagan designated an annual National Alzheimer’s Disease Awareness Month fewer than two million Americans had Alzheimer’s. Today, that number is close to 5.5 million and estimates suggest it will rise to 16 million by 2050. There are no treatments. No cure. But around the globe people are working hard to change that.

At CIRM we have invested more than $60 million in 21 projects aimed at developing a deeper understanding of the disease and, we hope, one day developing effective treatments.

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Lauren Miller Rogen

One of those helping lead that fight is our Board member Lauren Miller Rogen. Lauren has a family history of the disease and uses that to fuel her activism not just on our Board but through Hilarity for Charity, the organization she co-founded with her husband, Seth Rogen.

Lauren was recently profiled by the stem cell advocacy group Americans for Cures, talking about the impact the disease has had on her family, her advocacy on behalf of families struggling to cope with the disease and why she feels humor is such a powerful tool to raise awareness and hope in the fight against Alzheimer’s.

It’s a great interview and you can read it here.

Scientist grow diseased brain cells in bulk to study Alzheimer’s and Parkinson’s disease

/ Karen Ring / Leave a comment

Daily trips to the local grocery store have become a thing of the past for many with the rise of wholesale stores like Costco and online giants like Amazon. Buying in bulk is attractive for people who lead busy lives, have large families, or just love having endless pairs of clean socks.

Scientists who study neurodegenerative diseases like Alzheimer’s and Parkinson’s use disease-in-a-dish models that are much like the daily visits to the nearby Safeway. They can make diseased brain cells, or neurons, from human pluripotent stem cells and study them in the lab. But often, they can’t generate large enough quantities of cells to do important experiments like test new drugs or develop diagnostic platforms to identify disease at an earlier age.

What scientists need is a Costco for brain cells, a source that can make diseased brain cells in bulk. Such a method would open a new avenue of research into what causes neurodegeneration and how the aging process affects its progression.

This week, this need was answered. A team of researchers from Lund University in Sweden developed a method that can efficiently generate neurons from patients with a range of neurodegenerative diseases including Parkinson’s, Huntington’s and Alzheimer’s disease. The study was published in EMBO Molecular Medicine and was led by senior author Dr. Malin Parmar.

Diseased neurons made by the Lund University team. (Photo, Kennet Ruona)

Parmar and her team took an alternative approach to making their neurons. Their technology involves converting human skin cells into neurons without reprogramming the skin cells back to a pluripotent stem cell state first. This process is called “direct conversion” and is considered an effective shortcut for generating mature cells like neurons in a dish. Direct conversion of skin cells into neurons was first published by Dr. Marius Wernig, a CIRM-grantee and professor at Stanford University.

There is also scientific evidence suggesting that reprogramming patient cells back to a pluripotent state wipes out the effects of aging in those cells and has a Benjamin Button-like effect on the resulting neurons. By directly converting patient skin cells into neurons, many of these aging “signatures” are retained and the resulting neurons are more representative of the aging brain.

So how did they make brain cells in bulk? Parmar explained their method in a Lund University news release,

Malin Parmar

“Primarily, we inhibited a protein, REST, involved in establishing identity in cells that are not nerve cells. After limiting this protein’s impact in the cells during the conversion process, we’ve seen completely different results.”

 

Besides blocking REST, the team also turned on the production of two proteins, Ascl1 and Brn2, that are important for the development of neurons. This combination of activating pro-neural genes and silencing anti-neural genes was successful at converting skin cells into neurons on a large scale. Parmar further explained,

“We’ve been playing around with changing the dosage of the other components in the previous method, which also proved effective. Overall, the efficiency is remarkable. We can now generate almost unlimited amounts of neurons from one skin biopsy.”

As mentioned previously, this technology is valuable because it provides better brain disease models for scientists to study and to screen for new drugs that could treat or delay disease onset. Additionally, scientists can study the effects of the aging in the brain at different stages of neurodegeneration. Aging is a well-known risk factor for many neurodegenerative diseases, especially Alzheimer’s, so the ability to make large quantities of brain cells from elderly Alzheimer’s patients will unlock new clues into how age influences disease.

Co-author Dr. Johan Jakobsson concluded,

Johan Jakobsson

“This takes us one step closer to reality, as we can now look inside the human neurons and see what goes on inside the cell in these diseases. If all goes well, this could fundamentally change the field of research, as it helps us better understand the real mechanisms of the disease. We believe that many laboratories around the world would like to start testing on these cells to get closer to the diseases.”

For more on this study, check out this short video provided by Lund University.

What’s the big idea? Or in this case, what’s the 19 big ideas?

/ Kevin McCormack / 1 Comment

supermarket magazineHave you ever stood in line in a supermarket checkout line and browsed through the magazines stacked conveniently at eye level? (of course you have, we all have). They are always filled with attention-grabbing headlines like “5 Ways to a Slimmer You by Christmas” or “Ten Tips for Rock Hard Abs” (that one doesn’t work by the way).

So with those headlines in mind I was tempted to headline our latest Board meeting as: “19 Big Stem Cell Ideas That Could Change Your Life!”. And in truth, some of them might.

The Board voted to invest more than $4 million in funding for 19 big ideas as part of CIRM’s Discovery Inception program. The goal of Inception is to provide seed funding for great, early-stage ideas that may impact the field of human stem cell research but need a little support to test if they work. If they do work out, the money will also enable the researchers to gather the data they’ll need to apply for larger funding opportunities, from CIRM and other institutions, in the future

The applicants were told they didn’t have to have any data to support their belief that the idea would work, but they did have to have a strong scientific rational for why it might

As our President and CEO Randy Mills said in a news release, this is a program that encourages innovative ideas.

Randy Mills, Stem Cell Agency President & CEO

Randy Mills, CIRM President & CEO

“This is a program supporting early stage ideas that have the potential to be ground breaking. We asked scientists to pitch us their best new ideas, things they want to test but that are hard to get funding for. We know not all of these will pan out, but those that do succeed have the potential to advance our understanding of stem cells and hopefully lead to treatments in the future.”

So what are some of these “big” ideas? (Here’s where you can find the full list of those approved for funding and descriptions of what they involve). But here are some highlights.

Alysson Muotri at UC San Diego has identified some anti-retroviral drugs – already approved by the Food and Drug Administration (FDA) – that could help stop inflammation in the brain. This kind of inflammation is an important component in several diseases such as Alzheimer’s, autism, Parkinson’s, Lupus and Multiple Sclerosis. Alysson wants to find out why and how these drugs helps reduce inflammation and how it works. If he is successful it is possible that patients suffering from brain inflammation could immediately benefit from some already available anti-retroviral drugs.

Stanley Carmichael at UC Los Angeles wants to use induced pluripotent stem (iPS) cells – these are adult cells that have been genetically re-programmed so they are capable of becoming any cell in the body – to see if they can help repair the damage caused by a stroke. With stroke the leading cause of adult disability in the US, there is clearly a big need for this kind of big idea.

Holger Willenbring at UC San Francisco wants to use stem cells to create a kind of mini liver, one that can help patients whose own liver is being destroyed by disease. The mini livers could, theoretically, help stabilize a person’s own liver function until a transplant donor becomes available or even help them avoid the need for liver transplantation in the first place. Considering that every year, one in five patients on the US transplant waiting list will die or become too sick for transplantation, this kind of research could have enormous life-saving implications.

We know not all of these ideas will work out. But all of them will help deepen our understanding of how stem cells work and what they can, and can’t, do. Even the best ideas start out small. Our funding gives them a chance to become something truly big.

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CRISPR cluster: How the media spotlight is focusing on gene editing tool

/ Kevin McCormack / Leave a comment
Illustration by Ashley Mackenzie: from New York Times Sunday Magazine

Illustration by Ashley Mackenzie: from New York Times Sunday Magazine

Getting in-depth stories about science in general, and regenerative medicine in particular, into the mainstream media is becoming increasingly hard these days. So when you get one major media outlet doing a really long, thoughtful piece about a potential game-changing gene-editing technology it’s good news. But when you get three major media outlets, all reporting on the same technology, all in the space of less than one week, and all devoting lots of words to the pieces, then it’s really a cause for celebration.

That’s what happened in the last few days with features on the gene editing technology CRISPR in the New York Times Sunday Magazine,  the New Yorker Magazine,  and STAT, a new online health and life-sciences publication produced by the Boston Globe.

Making the story personal

Feng Zhang: photo courtesy of the Broad Institute

Feng Zhang: photo courtesy of the Broad Institute

Each takes a similar approach, focusing on the individuals behind the new approach – Feng Zhang at Harvard/MIT and Jennifer Doudna at the University of California, Berkeley. The fact that the two are involved in a fight over patent rights for the process adds an extra element of friction to a story that already has more than its share of drama.

In the New Yorker, Michael Specter neatly summarizes why so many people are excited about this technology:

“With CRISPR, scientists can change, delete, and replace genes in any animal, including us. Working mostly with mice, researchers have already deployed the tool to correct the genetic errors responsible for sickle-cell anemia, muscular dystrophy, and the fundamental defect associated with cystic fibrosis. One group has replaced a mutation that causes cataracts; another has destroyed receptors that H.I.V. uses to infiltrate our immune system.”

Jennifer Doudna: Photo courtesy of iPSCell.com

Jennifer Doudna: Photo courtesy of iPSCell.com

Sharon Begley in STAT, writes that this discovery could bring cures to some of the deadliest health problems we face, from cancer to Alzheimer’s, but that it also comes with big ethical questions hanging over it:

“He (Zhang) has touched off a global furor over the possibility that a genetics tool he developed could usher in a dystopian age of designer babies.”

Jennifer Kahn in the New York Times Sunday Magazine follows up on that thought, writing about Doudna:

“But she also notes that the prospect of editing embryos so that they don’t carry disease-causing genes goes to the heart of CRISPR’s potential. She has received email from young women with the BRCA breast-cancer mutation, asking whether CRISPR could keep them from passing that mutation on to their children — not by selecting embryos in vitro, but by removing the mutation from the child’s genetic code altogether. ‘‘So at some point, you have to ask: What if we could rid a person’s germ line, and all their future generations, of that risk?’’ Doudna observed. ‘‘When does one risk outweigh another?’’

Each article makes for fascinating reading. Collectively they highlight why CRISPR is such a hot topic, on so many different levels, in science right now.

The topic is going to be the focus of a conference, featuring scientists from the US, Europe and China, being held at the National Academy of Sciences in Washington DC the first week of December.

CIRM is also getting involved in the debate and is holding a science-policy workshop on February 4th, 2016 in Los Angeles to consider the future use of genome editing technologies in studies sponsored by CIRM.

Could We Reverse Alzheimer’s Disease with Stem Cells?

/ Karen Ring / Leave a comment

What if you could give people whose memories have been stolen the ability to remember again? I’m talking about curing a population of more than 5 million Americans living with Alzheimer’s disease (AD) – not a small task. Unfortunately, this number is predicted to more than triple by 2050, and with it so will healthcare costs and other burdens to society. The situation is dire enough that president Barack Obama signed a law last year that increased the amount of money to fund AD research, education, outreach, and caregiver support.

This weekend, a story was picked up in the news that brings hope for AD research. South China Morning Post covered a scientific study that claims it can reverse memory loss in mice with Alzheimer’s using a cell-based therapy. The study was published in Stem Cell Reports in mid October by a group of Chinese scientists.

Although the study is still in its early stages and the results are preliminary, what I like about it is its simplicity and logic. The authors decided to generate a type of nerve cell that is typically lost (or dysfunctional) in the brains of AD patients and some mouse models of AD. It’s called a basal forebrain cholinergic neuron, and it lives in an area near the bottom of our brains that’s responsible for processing certain functions such as learning and attention. The scientists proposed that they would replace these lost nerve cells in AD mice with healthy nerve cells derived from stem cells in hopes of restoring memory function.

How they did it

The authors first devised methods to make these specific nerve cells from both mouse and human embryonic stem cells in a dish. They were successful in making nerve cells that expressed the correct markers for cholinergic neurons and functioned properly, meaning they could send the correct electrical signals to other nerve cells.

The next step was to test the functionality of the nerve cells in mouse models of AD. Instead of transplanting adult nerve cells into the brain (which don’t survive very well), the authors transplanted progenitor cells, which developmentally, are more specialized than stem cells and eventually become adult nerve cells.

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Brain section from an Alzheimer’s mouse that received a transplant of progenitor cells (green) into the basal forebrain. (Yue et al., 2015)

When the mouse progenitor cells were transplanted into the basal forebrain of AD mice, most of them survived and matured into adult cholinergic nerve cells that were able to function in tandem with the original mouse nerve cells. When they transplanted human progenitor cells into the same area, a majority of the transplanted human cells did not survive (likely due to the mouse immune system rejecting them), however, the ones that did were able to turn into functioning cholinergic neurons.

Then came the final question, could the mouse and human progenitors improve the memory of these forgetful mice? The scientists compared the memories of AD mice that had received mouse or human cholinergic progenitor cells to AD mice that received no treatment and to healthy normal mice. The groups were put through a memory test where they were trained to find a hidden platform in a circular pool of water. Untreated AD mice had trouble finding the platform and couldn’t remember where it was in subsequent trials. However, the AD mice that received either mouse or human progenitor cell transplants six to eight weeks before were able to find the platform more quickly and remember where it was in multiple trials. This suggested that the transplanted nerve cells improved their ability to learn tasks and recall memories.

The water maze tests a mouse's ability to learn and recall where the hidden platform is. (Image adapted from Credit2M BioTech)

The water maze tests a mouse’s ability to learn and recall where the hidden platform is. (Image adapted from Credit2M BioTech)

Hold on: Primates before humans

So it seems from this study that replacing cholinergic nerve cells in the basal forebrain area of the brain is a potential approach to reversing memory loss in Alzheimer’s disease. However, the study’s senior author, Naihe Jing, cautioned everyone to not get ahead of themselves.

Dr. Naihe Jing, Shanghai Institutes of Biological Science

Dr. Naihe Jing

Mice are still very different from humans, so the results on mice do not guarantee the same success on human patients. Our next step is to test the method on primates. It will probably be a long time before clinical trials can be carried out on human volunteers.

 

But he also explained that his group is thoroughly testing the safety of their embryonic stem cell based therapy.

We used human embryonic stem cells because this method will eventually be used on humans. If the human neurons can get a footing and grow in the brain of a mouse, the chance is high the effect will be even better on a human host. The biggest concern of this development is safety. We were afraid that the transplanted cells would mutate to other types of neurons or even cause brain tumours. We have been improving the technology and making close observation of the mice for more than seven years. So far no mutation or cancerous development has been detected.

So while we might not have a cell therapy to treat Alzheimer’s in the near future, we can be comforted by the fact that groups like this one are taking all the precautions to develop safe and effective treatments.

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CIRM Scholar Helen Fong on Stem Cells and Brain Disease

/ Karen Ring / 1 Comment
Helen Fong, CIRM Scholar and Research Scientist at the Gladstone Institutes

Helen Fong, CIRM Scholar and Research Scientist at the Gladstone Institutes

Meet another one of our talented CIRM Scholars, Helen Fong. She is currently a Research Scientist at the Gladstone Institutes and did her graduate work at the University of California, Irvine. Her passions include stem cells, disease modeling, and playing with differentiation protocols – the processes that tell stem cells to mature into specific tissues. As a CIRM Scholar, part of our educational training programs, Helen published four articles where she was listed as the first author. Her most recent one was a stellar study published in Stem Cell Reports using induced pluripotent stem cells (iPSCs) to model and understand a nerve cell-destroying brain disease called frontotemporal dementia.

We interviewed Helen to learn more about her work in stem cell research.

Q: What was your graduate school research on?

HF: I did my graduate work in the lab of Dr. Peter Donovan, who is a prominent germ cell and stem cell scientist, and was newly recruited to UCI when I began my studies. I was his first graduate student from UCI. Dr. Donovan’s research was focused on understanding the regulation of early human development using embryonic stem cells (ESCs) and how to improve human pluripotent stem cell culture. He was also interested in understanding the biological mechanisms that keep stem cells pluripotent (the ability to become all the other cell types in the body) and the genetic factors that are important for maintaining pluripotency. My graduate research was on understanding the basic biology of human ESCs. Specifically, I studied the role of the gene Sox2 in maintaining stem cell pluripotency and self renewal in human ESCs.

Q: What about your postdoctoral research?

HF: After my PhD, I decided to continue to work with stem cells because I knew that the field would continue to grow. There was still so much to be learned about these unique cells. I also genuinely enjoyed working with stem cells and couldn’t imagine not seeing them every day. I realized that I had a solid understanding of the basic biology of ESCs, but I wanted to use stem cells to study human disease. This ability is one of the huge selling points of working with human induced pluripotent stem cells (iPSCs) [which are created by reprogramming adult cells back to a pluripotent state]. The Gladstone Institutes was an excellent place to continue my training and to begin using iPSCs to understand neurological disease. I joined Dr. Yadong Huang’s lab in 2011 and am currently using human iPSCs to study brain degenerative diseases including frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and Alzheimer’s disease (AD).

My recent publication in Stem Cell Reports used human iPSCs from a patient with FTD as a model to understand the mechanisms behind this condition. This patient carried a rare genetic mutation in the MAPT gene called TAU-A152T. Several studies have reported a number of patients with this specific mutation that could put them at risk for developing FTD, PSP, and AD. However, it wasn’t clear what this mutation was doing to cause these disorders.

One of the ways you can study neurodegenerative diseases is using stem cells derived from patients harboring the disease causing mutations. We obtained human iPSCs made from the skin cells of a patient with FTD and this TAU mutation. I then used zinc finger nuclease (ZFN) genome editing technology to genetically correct the mutation back to the wild type (normal) sequence to see if removing this mutation in the patient iPSCs would generate healthier neurons (nerve cells) that don’t have symptoms of FTD. I was able to study the disease-causing effects of the TAU mutation by comparing healthy neurons I made from the corrected (normal) iPSC line to diseased neurons made from the TAU mutant iPSC line.

Neurons generated from FTD patient iPSCs. (Image courtesy of Helen Fong)

Neurons generated from FTD patient iPSCs. (Image courtesy of Helen Fong)

The neurons that I differentiated from the iPSCs carrying the TAU mutation showed an increase in TAU protein fragmentation [meaning the protein gets degraded and isn’t present in its normal form], an abnormal characteristic that can be associated with FTD and AD. We didn’t see this phenomenon in the neurons from the corrected (normal) human iPSCs, indicating that removal of this TAU mutation could improve the symptoms of these diseases. These results were exciting because we now had a culprit for what could be causing disease in these patients with this mutation. There is still much to be learned about the mechanisms of this mutation and the iPSCs have been an invaluable resource.

Q: What was your experience like as a CIRM scholar?

HF: CIRM has funded me for almost all of my stem cell training and research. I got my first CIRM training grant as a graduate student at UCI in 2006 and was funded for three years as a postdoc at the Gladstone. So I have CIRM to thank for all of my training.

When I first started out as a CIRM scholar, I believe I was part of one of their earlier pre-doctoral training grant programs. As the program expanded, I got to meet many of the other trainees at CIRM research conferences and interact with prominent stem cell scientists in the area. This was an incredible experience because I was exposed to stem cell research outside of my own institute, and I was able to meet all the big players in the field!

CIRM has also been very generous and provided me a travel allowance to attend any scientific conference of my choice. Over the years, I’ve gone to a lot of conferences nationally and internationally including ISSCR (International Society for Stem Cell Research), Keystone symposia, and the Society for Neuroscience (SfN). I have given scientific talks both at Keystone and SfN, and they proved to be excellent exposure for my work as well as a good place to get feedback. Another one of my favorite perks was the ability to purchase reagents for my own work at my own discretion, which gave me some freedom in dictating which direction I wanted my project to go. If I wanted to study a particular protein and needed a specific antibody to do that, I was able to get it with my CIRM funding.

Q: What’s next for your career?

HF: Currently, I am hoping to wrap up the project I am working on in the lab right now and generate a publication. I plan to continue to work on stem cells in the next step of my career and to work on challenging and cutting-edge projects. I feel fortunate for all the training and resources that I’ve received that got me to where I am today, and I hope to pass on many of my skills and knowledge to budding, young scientists.

Q: What is your favorite thing about being a scientist?

HF: I really enjoy the fact that I have so much control over the fate of my stem cells. They have the ability to turn into almost any cell type, and we’ve developed so many protocols to guide them into the exact cell type we want. They don’t always behave, but I think figuring out the personality of each and every cell line is part of the fun.

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Keeping elderly cells old to understand the aging process

/ Todd Dubnicoff / Leave a comment

Aging is a key risk factor for many diseases, particularly disorders of the brain like Alzheimer’s or Parkinson’s, which primarily occur in the elderly. So a better understanding of the aging process should provide a better understanding of these neurodegenerative diseases.

The induced pluripotent stem cell (iPSC) technique makes it possible to grow human brain cells, or neurons, in the lab from elderly patient skin samples. Unfortunately, this method has a major pitfall when it comes to aging research: reprogramming skin cells back into the embryonic stem cell-like state of iPSCs strips away many of their old age-related characteristics.

Based on data published last week in Cell Stem Cell, Salk Institute researchers used a different technique called direct reprogramming as a means to keep old cells old. This alternative method sidesteps the need to make iPSCs (which brings cells all the way back to the pluripotent state) and instead converts a skin cell directly into the desired cell type.

First author Jerome Mertens and senior author Rusty Gage (Courtesy of the Salk Institute for Biological Studies).

First author Jerome Mertens and senior author Rusty Gage (Courtesy of the Salk Institute for Biological Studies).

iPSC and direct reprogramming go head-to-head

The study, funded in part by CIRM, relied on skin samples from people ranging in age from newly born to 89 years. The team generated iPSC and iPSC-derived neurons from these samples. They also made so-called induced neurons (iNs) from the skin cells using the direct reprogramming method. Other CIRM grantees have pioneered direct reprogramming of skin into nerve cells (see link below).

Skin cell samples from elderly human donors are directly converted into induced neurons (iNs), shown. (image: Courtesy of the Salk Institute for Biological Studies)

Skin cells from elderly human donors are directly converted into induced neurons (iNs), shown. (Image courtesy of the Salk Institute for Biological Studies).

When comparing skin cells from donors younger than 40 years old versus cells from the over 40 group, the team found several genes had age-dependent activity patterns. Those differences virtually disappeared in the iPSCs and iPSC-derived neurons from the same individuals. However, unlike iPSCs, direct reprogramming of the skin cells to neurons (iNs) hung on to age-dependent differences in gene activity.

Loss of RanBP17 protein a fountain of youth in reverse

A deeper analysis identified one gene called RanBP17 whose activity levels declined with increased age of the donor in both the original skin cells and those directly converted into iNs. But when those same donor skin cells were turned into iPSCs or even iPSC-derived neurons, RanBP17 levels in the older cells were no longer reduced and were on par with RanBP17 levels in the younger cells. In follow up experiments, a reduction in RanBP17 protein led to glitches in the transport of proteins into the cell’s nucleus, which other studies have linked to neurodegenerative diseases as well as the aging process.

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Gene expression patterns of age-related factors like RanBP17 are maintained in induced neurons but not iPSCs. (Mertens et al., 2015)

Altogether, these results encourage researchers to select iNs over iPSC-derived neurons when it comes to faithfully representing the aging process of brain cells. Based on a Salk Institute press release, you can tell that professor Martin Hezter, a contributing author, is excited about future studies with iNs:

By using this powerful approach, we can begin to answer many questions about the physiology and molecular machinery of human nerve cells–not just around healthy aging but pathological aging as well.

 

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The Stem Cell Bank is open for business

/ Kevin McCormack / 1 Comment
Creating a stem cell bank

Creating a stem cell bank

When you go to a bank and withdraw money you know that the notes you get are all going to look the same and do the same job, namely allow you to buy things. But when you get stem cells for research that’s not necessarily the case. Stem cells bought from different laboratories don’t always look exactly the same or perform the same in research studies.

That’s why CIRM has teamed up with the Coriell Institute and Cellular Dynamics International (CDI) to open what will be the world’s largest publically available stem cell bank. It officially opened today. In September the Bank will have 300 cell lines available for purchase but plans to increase that to 750 by February 2016.

300 lines but no waiting

Now, even if you are not in the market for stem cells this bank could have a big impact on your life because it creates an invaluable resource for researchers looking into the causes of, and potential therapies for, 11 different diseases including autism, epilepsy and other childhood neurological disorders, blinding eye diseases, heart, lung and liver diseases, and Alzheimer’s disease.

The goal of the Bank – which is located at the Buck Institute for Research on Aging in Novato, California – is to collect blood or tissue samples from up to 3,000 volunteer donors. Some of those donors have particular disorders – such as Alzheimer’s – and some are healthy. Those samples will then be turned into high quality iPSCs or induced pluripotent stem cells.

Now, iPSC lines are particularly useful for research because they can be turned into any type of cell in the body such as a brain cell or liver cell. And, because the cells are genetically identical to the people who donated the samples scientists can use the cells to determine how, for example, a brain cell from someone with autism differs from a normal brain cell. That can enable them to study how diseases develop and progress, and also to test new drugs or treatments against defects observed in those cells to see which, if any, might offer some benefits.

Power of iPSCs

In a news release Kaz Hirao, Chairman and CEO of CDI, says these could be game changers:

“iPSCs are proving to be powerful tools for disease modeling, drug discovery and the development of cell therapies, capturing human disease and individual genetic variability in ways that are not possible with other cellular models.”

Equally important is that researchers in different parts of the world will be able to compare their findings because they are using the same cell lines. Right now many researchers use cell lines from different sources so even though they are theoretically the same type of tissue, in practice they often produce very different results.

Improving consistency

CIRM Board Chair, Jonathan Thomas, said he hopes the Bank will lead to greater consistency in results.

“We believe the Bank will be an extraordinarily important resource in helping advance the use of stem cell tools for the study of diseases and finding new ways to treat them. While many stem cell efforts in the past have provided badly needed new tools for studying rare genetic diseases, this Bank represents both rare and common diseases that afflict many Californians. Stem cell technology offers a critical new approach toward developing new treatments and cures for those diseases as well.”

Most banks are focused on enriching your monetary account. This bank hopes to enrich people’s lives, by providing the research tools needed to unlock the secrets of different diseases, and pave the way for new treatments.

For more information on how to buy a cell line go to http://catalog.coriell.org/CIRM or email CIRM@Coriell.org