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

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.

New stem cell technique gives brain support cells a starring role

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The Salk team. From left: Krishna Vadodaria, Lynne Moore, Carol Marchetto, Arianna Mei, Fred H. Gage, Callie Fredlender, Ruth Keithley, Ana Diniz Mendes. Photo courtesy Salk Institute

Astrocytes are some of the most common cells in the brain and central nervous system but they often get overlooked because they play a supporting role to the more glamorous neurons (even though they outnumber them around 50 to 1). But a new way of growing those astrocytes outside the brain could help pave the way for improved treatments for stroke, Alzheimer’s and other neurological problems.

Astrocytes – which get their name because of their star shape (Astron – Greek for “star” and “kyttaron” meaning cell) – have a number of key functions in the brain. They provide physical and metabolic support for neurons; they help supply energy and fuel to neurons; and they help with detoxification and injury repair, particularly in terms of reducing inflammation.

Studying these astrocytes in the lab has not been easy, however, because existing methods of producing them have been slow, cumbersome and not altogether effective at replicating their many functions.

Finding a better way

Now a team at the Salk Institute, led by CIRM-funded Professor Fred “Rusty” Gage, has developed a way of using stem cells to create astrocytes that is faster and more effective.

Their work is published in the journal Stem Cell Reports. In a news release, Gage says this is an important discovery:

“This work represents a big leap forward in our ability to model neurological disorders in a dish. Because inflammation is the common denominator in many brain disorders, better understanding astrocytes and their interactions with other cell types in the brain could provide important clues into what goes wrong in disease.”

Stylized microscopy image of an astrocyte (red) and neuron (green). (Salk Institute)

In a step by step process the Salk team used a series of chemicals, called growth factors, to help coax stem cells into becoming, first, generic brain cells, and ultimately astrocytes. These astrocytes not only behaved like the ones in our brain do, but they also have a particularly sensitive response to inflammation. This gives the team a powerful tool in helping develop new treatment to disorders of the brain.

But wait, there’s more!

As if that wasn’t enough, the researchers then used the same technique to create astrocytes from induced pluripotent stem cells (iPSCs) – adult cells, such as skin, that have been re-engineered to have the ability to turn into any other kind of cell in the body. Those man-made astrocytes also showed the same characteristics as natural ones do.

Krishna Vadodaria, one of the lead authors on the paper, says having these iPSC-created astrocytes gives them a completely new tool to help explore brain development and disease, and hopefully develop new treatments for those diseases.

“The exciting thing about using iPSCs is that if we get tissue samples from people with diseases like multiple sclerosis, Alzheimer’s or depression, we will be able to study how their astrocytes behave, and how they interact with neurons.”

Stories that caught our eye: frail bones in diabetics, ethics of future IVF, Alzheimer’s

The connection between diabetes and frail bones uncovered
Fundamentally, diabetes is defined by abnormally high blood sugar levels. But that one defect over time carries an increased risk for a wide range of severe health problems. For instance, compared to healthy individuals, type 2 diabetics are more prone to poorly healing bone fractures – a condition that can dramatically lower one’s quality of life.

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Bones of the healthy animals (top) form larger calluses during healing which lead to stronger repaired bones. Bones of the diabetic mice (bottom) have smaller calluses and the healed bones are more brittle. Image: Stanford University

To help these people, researchers are trying to tease out how diabetes impacts bone health. But it’s been a complicated challenge since there are many factors at play. Is it from potential side effects of diabetes drugs? Or is the increased body weight associated with type 2 diabetes leading to decreased bone density? This week a CIRM-funded team at Stanford pinpointed skeletal stem cells, a type of adult stem cell that goes on to make all the building blocks of the bone, as important pieces to this scientific puzzle.

Reporting in Science Translational Medicine, the team, led by Michael Longaker – co-director of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine – found that, compared to healthy animals, type 2 diabetic mice have a reduced number of skeletal stem cells after bone fracture. A study of the local cellular “neighborhood” of these stem cells showed that the diabetic mice also had a reduction in the levels of a protein called hedgehog. Blocking hedgehog activity in healthy mice led to the slow bone healing seen in the diabetic mice. More importantly, boosting hedgehog levels near the site of the fracture in diabetic mice lead to bone healing that was just as good as in the healthy mice.

To see if this result might hold up in humans, the team analyzed hedgehog levels in bone samples retrieved from diabetics and non-diabetics undergoing joint replacement surgeries. Sure enough, hedgehog was depleted in the diabetic bone exactly reflecting the mouse results.

Though more studies will be needed to develop a hedgehog-based treatment in humans, Longaker talked about the exciting big picture implications of this result in a press release:

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Michael Longaker

“We’ve uncovered the reason why some patients with diabetes don’t heal well from fractures, and we’ve come up with a solution that can be locally applied during surgery to repair the break. Diabetes is rampant worldwide, and any improvement in the ability of affected people to heal from fractures could have an enormously positive effect on their quality of life.”

 

Getting the ethics ahead of the next generation of fertility treatments
The Business Insider ran an article this week with a provocative title, “Now is the time to talk about creating humans from stem cells.” I initially read too much into that title because I thought the article was advocating the need to start the push for the cloning of people. Instead, author Rafi Letzter was driving at the importance for concrete, ethical discussion right now about stem cell technologies for fertility treatments that may not be too far off.

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These mice were born from artificial eggs that were made from stem cells in a dish.
It’s great news for infertility specialist but carries many ethical dilemmas. 
(Image: K. Hayashi, Kyushu University)

In particular, he alludes to a paper from October (read our blog about it) that reported the creation of female mouse eggs from stem cells. These eggs were fertilized, implanted into the mother and successfully developed into living mice. What’s more, one set of stem cells were derived from mouse skin samples via the induced pluripotent stem cell method. This breakthrough could one day make it possible for an infertile woman to simply go through a small skin biopsy or mouth swab to generate an unlimited number of eggs for in vitro fertilization (IVF). Just imagine how much more efficient, less invasive and less costly this procedure could be compared to current IVF methods that require multiple hormone injections and retrieval of eggs from a woman’s ovaries.

But along with that hope for couples who have trouble conceiving a child comes a whole host of ethical issues. Here, Letzter refers to a perspective letter published on Wednesday in Science Translation Medicine by scientists and ethicists about this looming challenge for researchers and policymakers.

It’s an important read that lays out the current science, the clinical possibilities and regulatory and ethical questions that must be addressed sooner than later. In an interview with Letzter, co-author Eli Adashi, from the Alpert Medical School at Brown University, warned against waiting too long to heed this call to action:

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Eli Adashi

“Let’s start the [ethical] conversation now. Like all conversations it will be time consuming. And depending how well we do it, and we’ve got to do it well, it will be demanding. It will not be wise to have that conversation when you’re seeing a paper in Science or Nature reporting the complete process in a human. That would not be wise on our collective part. We should be as much as possible ready for that.”

 

 

Tackling Frontotemporal dementia and Alzheimer’s by hitting the same target.
To develop new disease therapies, you usually need to understand what is going wrong at a cellular level. In some cases, that approach leads to the identification of a specific protein that is either missing or in short supply. But this initial step is just half the battle because it may not be practical to make a drug out of the protein itself. So researchers instead search for other proteins or small molecules that lead to an increase in the level of the protein.

A CIRM-funded project at the Gladstone Institutes has done just that for the protein called progranulin. People lacking one copy of the progranulin gene carry an increased risk for  frontotemporal dementia (FTD), a degenerative disease of the brain that is the most common cause of dementia in people under 60 years of age. FTD symptoms are often mistaken for Alzheimer’s. In fact, mutations in progranulin are also associated with Alzheimer’s.

Previous studies have shown that increasing levels of progranulin in animals with diseases that mimic FTP and Alzheimer’s symptoms can reverse symptoms. But little was known how progranulin protein levels were regulated in the cells. Amanda Mason, the lead author on the Journal of Biological Chemistry report, explained in a press release how they tackled this challenge:

“We wanted to know what might regulate the levels of progranulin. Many processes in biology are controlled by adding or removing a small chemical group called phosphate, so we started there.”

These phosphate groups hold a lot of energy in their chemical bonds and can be harnessed to activate or turn off the function of proteins and DNA. The team systematically observed the effects of enzymes that add and remove phosphate groups and zeroed in on one called Ripk1 that leads to increases in progranulin levels. Now the team has set their sights on Ripk1 as another potential target for developing a therapeutic that could be effective against both FTP and Alzheimer’s. Steve Finkbeiner, the team lead, gave a big picture perspective on these promising results:

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Steve Finkbeiner

“This is an exciting finding. Alzheimer’s disease was discovered over 100 years ago, and we have essentially no drugs to treat it. To find a possible new way to treat one disease is wonderful. To find a way that might treat two diseases is amazing.”

 

Using stem cells to fix bad behavior in the brain

 

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Gladstone Institutes Steven Finkbeiner and Gaia Skibinski: Photo courtesy Chris Goodfellow, Gladstone Institutes

Diseases of the brain have many different names, from Alzheimer’s and Parkinson’s to ALS and Huntington’s, but they often have similar causes. Researchers at the Gladstone Institutes in San Francisco are using that knowledge to try and find an approach that might be effective against all of these diseases. In a new CIRM-funded study, they have identified one protein that could help do just that.

Many neurodegenerative diseases are caused by faulty proteins, which start to pile up and cause damage to neurons, the brain cells that are responsible for processing and transmitting information. Ultimately, the misbehaving proteins cause those cells to die.

The researchers at the Gladstone found a way to counter this destructive process by using a protein called Nrf2. They used neurons from humans (made from induced pluripotent stem cells – iPSCs – hence the stem cell connection here) and rats. They then tested these cells in neurons that were engineered to have two different kinds of mutations found in  Parkinson’s disease (PD) plus the Nrf2 protein.

Using a unique microscope they designed especially for this study, they were able to track those transplanted neurons and monitor what happened to them over the course of a week.

The neurons that expressed Nrf2 were able to render one of those PD-causing proteins harmless, and remove the other two mutant proteins from the brain cells.

In a news release to accompany the study in The Proceedings of the National Academy of Sciences, first author Gaia Skibinski, said Nrf2 acts like a house-cleaner brought in to tidy up a mess:

“Nrf2 coordinates a whole program of gene expression, but we didn’t know how important it was for regulating protein levels until now. Over-expressing Nrf2 in cellular models of Parkinson’s disease resulted in a huge effect. In fact, it protects cells against the disease better than anything else we’ve found.”

Steven Finkbeiner, the senior author on the study and a Gladstone professor, said this model doesn’t just hold out hope for treating Parkinson’s disease but for treating a number of other neurodegenerative problems:

“I am very enthusiastic about this strategy for treating neurodegenerative diseases. We’ve tested Nrf2 in models of Huntington’s disease, Parkinson’s disease, and ALS, and it is the most protective thing we’ve ever found. Based on the magnitude and the breadth of the effect, we really want to understand Nrf2 and its role in protein regulation better.”

The next step is to use this deeper understanding to identify other proteins that interact with Nrf2, and potentially find ways to harness that knowledge for new therapies for neurodegenerative disorders.

Translating great stem cell ideas into effective therapies

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CIRM funds research trying to solve the Alzheimer’s puzzle

In science, there are a lot of terms that could easily mystify people without a research background; “translational” is not one of them. Translational research simply means to take findings from basic research and advance them into something that is ready to be tested in people in a clinical trial.

Yesterday our Governing Board approved $15 million in funding for four projects as part of our Translational Awards program, giving them the funding and support that we hope will ultimately result in them being tested in people.

Those projects use a variety of different approaches in tackling some very different diseases. For example, researchers at the Gladstone Institutes in San Francisco received $5.9 million to develop a new way to help the more than five million Americans battling Alzheimer’s disease. They want to generate brain cells to replace those damaged by Alzheimer’s, using induced pluripotent stem cells (iPSCs) – an adult cell that has been changed or reprogrammed so that it can then be changed into virtually any other cell in the body.

CIRM’s mission is to accelerate stem cell treatments to patients with unmet medical needs and Alzheimer’s – which has no cure and no effective long-term treatments – clearly represents an unmet medical need.

Another project approved by the Board is run by a team at Children’s Hospital Oakland Research Institute (CHORI). They got almost $4.5 million for their research helping people with sickle cell anemia, an inherited blood disorder that causes intense pain, and can result in strokes and organ damage. Sickle cell affects around 100,000 people in the US, mostly African Americans.

The CHORI team wants to use a new gene-editing tool called CRISPR-Cas9 to develop a method of editing the defective gene that causes Sickle Cell, creating a healthy, sickle-free blood supply for patients.

Right now, the only effective long-term treatment for sickle cell disease is a bone marrow transplant, but that requires a patient to have a matched donor – something that is hard to find. Even with a perfect donor the procedure can be risky, carrying with it potentially life-threatening complications. Using the patient’s own blood stem cells to create a therapy would remove those complications and even make it possible to talk about curing the disease.

While damaged cartilage isn’t life-threatening it does have huge quality of life implications for millions of people. Untreated cartilage damage can, over time lead to the degeneration of the joint, arthritis and chronic pain. Researchers at the University of Southern California (USC) were awarded $2.5 million to develop an off-the-shelf stem cell product that could be used to repair the damage.

The fourth and final award ($2.09 million) went to Ankasa Regenerative Therapeutics, which hopes to create a stem cell therapy for osteonecrosis. This is a painful, progressive disease caused by insufficient blood flow to the bones. Eventually the bones start to rot and die.

As Jonathan Thomas, Chair of the CIRM Board, said in a news release, we are hoping this is just the next step for these programs on their way to helping patients:

“These Translational Awards highlight our goal of creating a pipeline of projects, moving through different stages of research with an ultimate goal of a successful treatment. We are hopeful these projects will be able to use our newly created Stem Cell Center to speed up their progress and pave the way for approval by the FDA for a clinical trial in the next few years.”

Stem cell agency funds clinical trials in three life-threatening conditions

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A year ago the CIRM Board unanimously approved a new Strategic Plan for the stem cell agency. In the plan are some rather ambitious goals, including funding ten new clinical trials in 2016. For much of the last year that has looked very ambitious indeed. But today the Board took a big step towards reaching that goal, approving three clinical trials focused on some deadly or life-threatening conditions.

The first is Forty Seven Inc.’s work targeting colorectal cancer, using a monoclonal antibody that can strip away the cancer cells ability to evade  the immune system. The immune system can then attack the cancer. But just in case that’s not enough they’re going to hit the tumor from another side with an anti-cancer drug called cetuximab. It’s hoped this one-two punch combination will get rid of the cancer.

Finding something to help the estimated 49,000 people who die of colorectal cancer in the U.S. every year would be no small achievement. The CIRM Board thought this looked so promising they awarded Forty Seven Inc. $10.2 million to carry out a clinical trial to test if this approach is safe. We funded a similar approach by researchers at Stanford targeting solid tumors in the lung and that is showing encouraging results.

Our Board also awarded $7.35 million to a team at Cedars-Sinai in Los Angeles that is using stem cells to treat pulmonary hypertension, a form of high blood pressure in the lungs. This can have a devastating, life-changing impact on a person leaving them constantly short of breath, dizzy and feeling exhausted. Ultimately it can lead to heart failure.

The team at Cedars-Sinai will use cells called cardiospheres, derived from heart stem cells, to reduce inflammation in the arteries and reduce blood pressure. CIRM is funding another project by this team using a similar  approach to treat people who have suffered a heart attack. This work showed such promise in its Phase 1 trial it’s now in a larger Phase 2 clinical trial.

The largest award, worth $20 million, went to target one of the rarest diseases. A team from UCLA, led by Don Kohn, is focusing on Adenosine Deaminase Severe Combined Immune Deficiency (ADA-SCID), which is a rare form of a rare disease. Children born with this have no functioning immune system. It is often fatal in the first few years of life.

The UCLA team will take the patient’s own blood stem cells, genetically modify them to fix the mutation that is causing the problem, then return them to the patient to create a new healthy blood and immune system. The team have successfully used this approach in curing 23 SCID children in the last few years – we blogged about it here – and now they have FDA approval to move this modified approach into a Phase 2 clinical trial.

So why is CIRM putting money into projects that it has either already funded in earlier clinical trials or that have already shown to be effective? There are a number of reasons. First, our mission is to accelerate stem cell treatments to patients with unmet medical needs. Each of the diseases funded today represent an unmet medical need. Secondly, if something appears to be working for one problem why not try it on another similar one – provided the scientific rationale and evidence shows it is appropriate of course.

As Randy Mills, our President and CEO, said in a news release:

“Our Board’s support for these programs highlights how every member of the CIRM team shares that commitment to moving the most promising research out of the lab and into patients as quickly as we can. These are very different projects, but they all share the same goal, accelerating treatments to patients with unmet medical needs.”

We are trying to create a pipeline of projects that are all moving towards the same goal, clinical trials in people. Pipelines can be horizontal as well as vertical. So we don’t really care if the pipeline moves projects up or sideways as long as they succeed in moving treatments to patients. And I’m guessing that patients who get treatments that change their lives don’t particularly

Stem cell stories that caught our eye: relief for jaw pain, vitamins for iPSCs and Alzheimer’s insights

Jaw bone stem cells may offer relief for suffers of painful joint disorder
An estimated 10 million people in the US – mostly women –  suffer from problems with their temporomandibular joint (TMJ) which sits between the jaw bone and skull. TMJ disorders can lead to a number of symptoms such as intense pain in the jaw, face and head; difficulty swallowing and talking; and dizziness.

ds00355_im00012_mcdc7_tmj_jpgThe TMJ is made up of fibrocartilage which, when healthy, acts as a cushion to enable a person to move their jaw smoothly. But this cartilage doesn’t have the capacity to heal or regenerate so treatments including surgery and pain killers only mask the symptoms without fixing the underlying damage of the joint.

Reporting this week in Nature Communications, researchers at Columbia University’s College of Dental Medicine identified stem cells within the TMJ that can form cartilage and bone – in cell culture studies as well as in animals. The research team further showed that the signaling activity of a protein called Wnt leads to a reduction of these fibrocartilage stem cells (FSCSs) in animals and as a result causes deterioration of cartilage. But injecting a known inhibitor of Wnt into the animals’ damaged TMJ spurred growth and healing of the joint.

The team is now in search of other Wnt inhibitors that could be used in a clinical setting. In a university press release, Jeremy Mao, a co-author on the paper, talked about the implications of these results:

“They suggest that molecular signals that govern stem cells may have therapeutic applications for cartilage and bone regeneration. Cartilage and certain bone defects are notoriously difficult to heal.”

Take your vitamins: good advice for people and iPS cells
From a young age, we’re repeatedly told how getting enough vitamins each day is important for a healthy life. Our bodies don’t produce these naturally occurring chemicals but they carry out critical biochemical activities to keep our cells and organs functioning properly.

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Carrots: a great source of vitamin A. Image source: Wikimedia Commons

Well, it turns out that vitamins are also an important ingredient in stem cell research labs. Results published the Proceedings of the National Academy of Sciences (PNAS) this week by scientists in the UK and New Zealand show that vitamin A and C work together synergistically to improve the efficiency of reprogramming adult cells, like skin or blood, into the embryonic stem cell-like state of induced pluripotent stem cells (iPSCs).

By the time a stem cell has specialized into, let’s say, a skin cell, only skin cell-specific genes are active while others genes, like those needed for liver function, are shut down. Those non-skin genes are silenced through the attachment of chemical tags on the DNA, a process called methylation. It essentially provides the DNA with the means of maintaining a skin cell “memory”. To convert a skin cell back into a stem cell-like state, researchers in the lab must erase this “memory” by adding factors which demethylate, or remove the methylation tags on the silenced, non-skin related genes.

In the current research picked up by Science Daily, the researchers found that both vitamin A and C increase demethylation but in different ways. The study showed that vitamin A acts to increase the production of proteins that are important for demethylation while vitamin C acts to enhance the enzymatic activity of demethylation.

These insights may help add to the growing knowledge on how to most efficiently reprogram adult cells into iPSCs. And they may prove useful for a better understanding of certain cancers which contain cells that are essentially reprogrammed into a stem cell-like state.

New angles for dealing with the tangles in the Alzheimer’s brain
The memory loss and overall degradation of brain function seen in people with Alzheimer’s Disease (AD) is thought to be caused by the accumulation of amyloid and tau proteins which form plaques and tangles in the brain. These abnormal structures are toxic to brain cells and ultimately lead to cell death.

But other studies of post-mortem AD brains suggest a malfunction in endocytosis – a process of taking up and transporting proteins to different parts of the cell – may also play a role. While follow up studies corroborated this initial observation, they didn’t look at endocytosis in nerve cells so it remained unclear how much of a role it played in AD.

In a CIRM-funded study published this week in Cell Reports, UC San Diego researchers made nerve cells from human iPSCs and used the popular CRISPR and TALEN gene editing techniques to generate mutations seen in inherited forms of AD. One of those inherited mutations is in the PS1 gene which has been shown to play a role in transporting amyloid proteins in nerve cells. The research confirmed that this mutation as well as a mutation in the amyloid precursor protein (APP) led to a breakdown in the proper trafficking of APP within the mutated nerve cells. In fact, they found an accumulation of APP in a wrong area of the nerve cell. However, blocking the action of a protein called secretase that normally processes the APP protein helped restore proper protein transport. In a university press release, team leader Larry Goldstein, explained the importance of these findings:

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Larry Goldstein.
Image: UCSD

“Our results further illuminate the complex processes involved in the degradation and decline of neurons, which is, of course, the essential characteristic and cause of AD. But beyond that, they point to a new target and therapy for a condition that currently has no proven treatment or cure.”

 

 

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

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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Stem cell stories that caught our eye: two-week old embryos in the lab, gene edited disease model, recipe for bone and cancer milestone

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

Two-week embryos grabbed headlines. I have rarely seen as many online news outlets pick up a basic science story as happened this week with the news that an international team had nearly doubled the time it is possible to keep an embryo alive in a lab dish. While the research has tremendous potential to improve the chances couples can bring a new life into their families, the bulk of the coverage focused on the ethical issues surrounding the research embryo itself.

 

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Molecular markers highlight various parts of a 12-day old embryo

After countless national and international confabs in the late 1970s and into the 1980s, research organizations around the world adopted the policy that no one would grow an embryo in the lab beyond 14 days. That is the point the “primitive streak” develops marking the first time cells within the embryo adopt individual identities. But the rule required no enforcement because no one knew how to coax an embryo into growing beyond nine days, and few could get them even to grow seven.

That changed this week, when the team led by Ali Brivanlou at Rockefeller University got embryos to grow to 13 days. They followed a procedure developed by a team colleague in Cambridge, UK, in mice reported earlier. They basically made the embryos feel more at home. They tested many different chemicals to add to the lab dish to optimize growth and gave the embryos a rigid structure more like a uterine wall.

They successfully mimicked implantation, the key step when the few-day-old embryo attaches to the uterus. Failure in this critical step is a key cause of infertility, but we have never been able to find out how it happens, and what little we do know suggests the mouse model for that step is not a good one for looking at human fertility.

 “This portion of human development was a complete black box,” said Brivanlou in a university press release picked up by many outlets including Bioscience Technology. She later added: “With this work, we can really appreciate the differences between human and mouse, and across all mammals. Because of the variations between species, what we learn in model systems is not necessarily relevant to our own development, and these results provide crucial information we couldn’t learn elsewhere.”

Because of that incredible potential value in this work, the journal Nature that published the research paper also ran a commentary about the current 14-day limit on growing embryos in the lab. It does not call for changing the policy at this time, but it does suggest the conversation–likely to be long–about whether the benefits of this work outweigh the ethical trip wires should begin soon.

The Washington Post wrote one of the most balanced pieces discussing both sides of the issue.

 

A mightier disease-in-a-dish model.  We frequently write about using iPS type stem cells to model diseases. Usually this involves getting a skin sample from a patient with a genetically-linked disease, converting it to stem cells and then growing the nerve or other tissue impacted by the disease. But you can also mimic the disease by genetically modifying normal stem cells to have specific mutations. This allows you to start to sorting out the role of individual genes in diseases linked to multiple genes.

 

Neurons from stem cells_TessierLavigne_neurons

Nerves grown from stem cells

One problem with the latter had been that gene editing techniques, particularly the wildly popular CRISPR-Cas9 method, usually edit both strands of DNA, but many disease mutations can do their damage with only a single incorrect gene, so-called heterozygous mutations. Now, another Rockefeller University team, this one led by the University’s president Marc Tessier-Lavigne, developed a way to make the CRISPR edit much more specific and only impact one strand of DNA.

HealthCanal picked up the university’s press release about the work published in Nature. The specific gene editing in this reports involved mutations linked to Alzheimer’s disease.

 

bone-scaffold Hopkins

Printed jaw

A better recipe for bone. Researchers trying to grow new tissue are finding the make-up of the scaffold you use can be more important than the stem cells you put on the structure. A Johns Hopkins team recently reported an improved recipe for making a scaffold for growing bone. Their formula: 30 percent pulverized natural bone and the remainder a special plastic with the mixture extruded using a 3D printer.

 “Bone powder contains structural proteins native to the body plus pro-bone growth factors that help immature stem cells mature into bone cells,” said Hopkins’ Warren Grayson. “It also adds roughness to the PCL (plastic), which helps the cells grip and reinforces the message of the growth factors.”

MDTmag posted the university press release about the research published in ACS Biomaterials Science & Engineering.

 

Licensing moved cancer therapy forward.  We at CIRM are always thrilled when one of our projects hurdles a milestone toward becoming a widely available therapy. One such critical move was announced last month and picked up this week by HealthCanal.

 Oncternal Therapeutics licensed the antibody drug named for our agency, Cirmtuzumab, for further testing of its ability to fight leukemia, and potentially other cancers. The antibody selectively targets a protein on cancer stem cells, ROR1, which has the unwieldy full name “receptor-tyrosine kinase-like orphan receptor 1.” The license also includes rights to other drugs that might be developed targeting ROR1.

University of California, San Diego, which developed Cirmtuzumab, has begun a clinical trial but has not got to a point where it can report results. We covered it in more detail in our series CIRM Fights Cancer.

Alzheimer’s and the Inflamed Brain: Their Links Run Deeper than Thought

Given that Alzheimer’s disease (AD) is a brain disorder and the leading cause of dementia, it seems logical to assume that some sort of breakdown in the connections of the brain’s nerve cells is mostly to blame.

But based on an increasing volume of research, it turns out that our immune system is also closely linked in a negative way to the disease. Yes, the very same immune system that fights off infections from the bacteria and viruses we come in contact with everyday.

The brain’s local cleaning crew overwhelmed by beta-amyloid and Alzheimer’s
Like a foot soldier keeping watch over the castle for enemy invaders or internal traitors, immune cells called microglia that reside in the brain constantly survey the brain, and literally gobble up any potentially harmful “enemies”. This is true for the potentially harmful protein clumps called beta-amyloid plaques that form in the Alzheimer’s brain. But studies suggest the microglia’s clearance of beta-amyloid plaques gets overwhelmed in Alzheimer’s, shifting the cells’ activity into primarily an inflammation mode and leading to progressive damage to the brain.

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Microglia (green) surround an amyloid plaque (blue) in the brain of an Alzheimer’s disease mouse model. Image: Samuel Marsh/UC Irvine

Microglia (green) surround an amyloid plaque (blue) in the brain of an Alzheimer’s disease mouse model. UCI researchers have shown that endogenous mouse antibodies (red) associate with microglia in the brains of such mice and boost microglia’s ability to degrade plaques.
Samuel Marsh

Microglia represent the localized, first-responder arm of the immune system also called the innate immune system. A second wave, composed namely of immune cells called B cells and T cells, which targets the “enemy” with much more specificity, is initiated outside the brain. To what extent this so-called adaptive immune system is also linked to Alzheimer’s is less understood.

Now, scientists with the Sue & Bill Gross Stem Cell Research Center at the UC Irvine report in  PNAS that they have some answers.

Knocking out B and T cells makes matters worse
Beginning with a strain of mice that mimics Alzheimer’s symptoms with severe beta-amyloid plaque deposits in their brains, the research team bred the animals to also lack B and T cells. Six months later, the results were dramatic. The level of beta-amyloid plaques in AD mice without B and T cells was twice that of AD mice with an intact immune system. As Mathew Blurton-Jones, the team’s lead and UCI assistant professor (he’s also a CIRM-grantee though we did not fund this research), mentioned in a press release on Tuesday, this finding was unexpected:

blurton-jones

Mathew Blurton-Jones, assistant professor of neurobiology & behavior at UCI. Image: Steve Zylius / UCI

“We were very surprised by the magnitude of this effect. We expected the influence of the deficient immune system on Alzheimer’s pathology to be much more subtle.”

So what’s going on here? Why does knocking out the adaptive immune system in AD mice lead to even more beta-amyloid plaques? One hint came from a careful analysis of microglial cells in the brains of the AD mice lacking B and T cells. These cells showed a weakened “eating” activity compared to microglia in AD mice with an intact immune system. This result suggests that without B and T cells, the beta-amyloid plaques are not cleared away by microglial as well.

Additional experiments pointed to the importance of B cells on microglial function. First author Samuel March explained the result in the press release:

“We found that in Alzheimer’s mice with intact immune systems, antibodies – which are made by B-cells – accumulated in the brain and associated with microglia. This, in turn, helped increase the clearance of beta-amyloid.”

Restoring beta-amyloid clean up with a blood stem cell transplant
So, in other words, eliminating B cells eliminates the recruitment of antibodies in the brain which in turn impairs the microglia’s ability to clear away beta-amyloid. To prove this point, the team transplanted healthy blood stem cells into the AD mice lacking B and T cells. The stem cells are capable of restoring all the cell types of the immune system. Sure enough, four months after the transplantation, antibodies were present in the brain near microglia and were associated with a nearly 50% reduction in beta-amyloid plaques.

All together, this data points to Alzheimer’s as a disease of an aging immune system, an idea that Blurton-Jones plans to tackle next:

“We know that the immune system changes with age and becomes less capable of making T- and B-cells. So whether aging of the immune system in humans might contribute to the development of Alzheimer’s is the next big question we want to ask.”