Huge honor, hugely deserved for CIRM-funded stem cell researcher

Dr. Andy McMahon: Photo courtesy USC

Andy McMahon is one of the most understated, humble and low-key people you are ever likely to meet. He’s also one of the smartest. And he has a collection of titles to prove it. He is the W.M. Keck Provost and University Professor in USC’s departments of Stem Cell Biology and Regenerative Medicine at the Keck School of Medicine, and Biological Sciences at the Dornsife College of Letters, Arts and Sciences, a fellow of the American Association for the Advancement of Science, the American Academy of Arts and Sciences, the European Molecular Biology Organization, and the Royal Society.

Now you can add to that list that Andy is a member of the National Academy of Sciences (NAS). Election to the NAS is no ordinary honor. It’s one of the highest in the scientific world.

In a USC news release Dean Laura Mosqueda from the Keck School praised Andy saying: “We’re delighted that Dr. McMahon is being recognized as a newly elected member of the National Academy of Sciences. Because new members are elected by current members, this represents recognition of Dr. McMahon’s achievements by his most esteemed peers in all scientific fields.”

Not surprisingly CIRM has funded some of Andy’s work – well, we do pride ourselves on working with the best and brightest scientists – and that research is taking on added importance with the spread of COVID-19. Andy’s area of specialty is kidneys, trying to develop new ways to repair damaged or injured kidneys. Recent studies show that between 3 and 9 percent of patients with COVID-19 develop an acute kidney injury; in effect their kidneys suddenly stop working and many of these patients have to undergo dialysis to stay alive.

Even those who recover are at increased risk for developing more chronic, even end-stage kidney disease. That’s where Andy’s work could prove most useful. His team are using human stem cells to create mini artificial kidneys that have many of the same properties as the real thing. These so-called “organoids” enable us to study chronic kidney disease, come up with ideas to repair damage or slow down the progression of the disease, even help improve the chances of a successful transplant if that becomes necessary.

You can hear Andy talk about his work here:

CIRM is now funding a number of projects targeting COVID-19, including a clinical trial using convalescent plasma gel, and intends investing in more in the coming weeks and months. You can read about that here.

We are also funding several clinical trials targeting kidney failure. You can read about those on our Clinical Trials Dashboard page – diseases are listed alphabetically.

Tiny organs grown from snake stem cells produce real venom

Researchers grew tiny venom glands from nine different snake species, including the cape coral cobra pictured above.
Photo Credit: Michael D. Kern/Science Source

Snake venom can be deadly without proper treatment. Interestingly enough, it may also hold the key for treatments against pain, high blood pressure, and cancer according to one analysis. Despite this, scientists still do not understand much about the biology behind the wide range of different snake venoms, which can make it challenging to develop effective treatments in the event of snake bites.

Fortunately, a new study by Dr. Hans Clevers and his team at the Hubrecht Institute in the Netherlands could significantly aid the understanding of snake venom. Dr. Clevers and his team were able to grow miniature snake venom glands using snake stem cells. What’s more remarkable is that these “mini-organs” produced real venom!

Miniature, lab-grown snake venom glands
 Photo Credit: Ravian van Ineveld/Princess Maxima Center

In an article posted in Science Magazine, Dr. Clevers talks about how his study was navigating uncharted waters.

“Nobody knew anything about stem cells in snakes. We didn’t know if it was possible at all.”

To produce these “mini-organs”, the researchers removed the stem cells from the venom glands of nine different types of snake and placed them in a mixture of growth factors that contained different hormones and proteins. It turns out that the snake stem cells responded to the same factors used on human and mouse stem cells.

Eventually, the stem cells grew into little clumps of tissue and when the researchers removed the growth factors, they started to change into the same kind of cells that produce venom in the glands of snakes. Additionally, they were able to find that these “mini-organs” expressed similar genes as those observed in real venom glands.

The scientists were even able to test the nature of the “mini-organ” venom as well. A chemical and genetic analysis of the venom revealed that it matched the one made by real snakes. After testing this venom on mouse muscle cells and rat neurons, they also found that it damaged these cells similar to real venom.

The type of toxins and concentration levels can vary drastically in snake venom, even within the same species. This can make developing treatments challenging since they can only be used to combat one type of venom.

Dr. Clevers and his team now plan to study the complexities of venom and venom glands by compiling a “biobank” of frozen organoids from venomous reptiles around the world that could help researchers find broader treatments. With the aid of their newly developed “mini-organs”, all of this can be done without the handling of live, dangerous snakes, some of which are rare and difficult to keep in captivity.

The full results of this study were published in Cell.

“Brains” in a dish that can create electrical impulses

Brain organoids in a petri dish: photo courtesy UCSD

For several years, researchers have been able to take stem cells and use them to make three dimensional structures called organoids. These are a kind of mini organ that scientists can then use to study what happens in the real thing. For example, creating kidney organoids to see how kidney disease develops in patients.

Scientists can do the same with brain cells, creating clumps of cells that become a kind of miniature version of parts of the brain. These organoids can’t do any of the complex things our brains do – such as thinking – but they do serve as useful physical models for us to use in trying to develop a deeper understanding of the brain.

Now Alysson Muotri and his team at UC San Diego – in a study supported by two grants from CIRM – have taken the science one step further, developing brain organoids that allow us to measure the level of electrical activity they generate, and then compare it to the electrical activity seen in the developing brain of a fetus. That last sentence might cause some people to say “What?”, but this is actually really cool science that could help us gain a deeper understanding of how brains develop and come up with new ways to treat problems in the brain caused by faulty circuitry, such as autism or schizophrenia.

The team developed new, more effective methods of growing clusters of the different kinds of cells found in the brain. They then placed them on a multi-electrode array, a kind of muffin tray that could measure electrical impulses. As they fed the cells and increased the number of cells in the trays they were able to measure changes in the electrical impulses they gave off. The cells went from producing 3,000 spikes a minute to 300,000 spikes a minute. This is the first time this level of activity has been achieved in a cell-based laboratory model. But that’s not all.

When they further analyzed the activity of the organoids, they found there were some similarities to the activity seen in the brains of premature babies. For instance, both produced short bursts of activity, followed by a period of inactivity.

Alysson Muotri

In a news release Muotri says they were surprised by the finding:

“We couldn’t believe it at first — we thought our electrodes were malfunctioning. Because the data were so striking, I think many people were kind of skeptical about it, and understandably so.”

Muotri knows that this research – published in the journal Cell Stem Cell – raises ethical issues and he is quick to say that these organoids are nothing like a baby’s brain, that they differ in several critical ways. The organoids are tiny, not just in size but also in the numbers of cells involved. They also don’t have blood vessels to keep them alive or help them grow and they don’t have any ability to think.

“They are far from being functionally equivalent to a full cortex, even in a baby. In fact, we don’t yet have a way to even measure consciousness or sentience.”

What these organoids do have is the ability to help us look at the structure and activity of the brain in ways we never could before. In the past researchers depended on mice or other animals to test new ideas or therapies for human diseases or disorders. Because our brains are so different than animal brains those approaches have had limited results. Just think about how many treatments for Alzheimer’s looked promising in animal models but failed completely in people.

These new organoids allow us to explore how new therapies might work in the human brain, and hopefully increase our ability to develop more effective treatments for conditions as varied as epilepsy and autism.

Organoids revolutionize approach to studying a variety of diseases

Organoids

There are limitations to studying cells under a microscope. To understand some of the more complex processes, it is critical to see how these cells behave in an environment that is similar to conditions in the body. The production of organoids has revolutionized this approach.

Organoids are three-dimensional structures derived from stem cells that have similar characteristics of an actual organ. There have been several studies recently published that have used this approach to understand a wide scope of different areas.

In one such instance, researchers at The University of Cambridge were able to grow a “mini-brain” from human stem cells. To demonstrate that this organoid had functional capabilities similar to that of an actual brain, the researchers hooked it up to a mouse spinal cord and surrounding muscle. What they found was remarkable– the “mini-brain” sent electrial signals to the spinal cord that made the surrounding muscles twitch. This model could pave the way for studying neurodegenerative diseases such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS).

Spinal muscular atrophy

Speaking of SMA, researchers in Singapore have used organoids to come up with some findings that might be able to help people battling the condition.

SMA is a neurodegenerative disease caused by a protein deficiency that results in nerve degeneration, paralysis and even premature death. The fact that it mainly affects children makes it even worse. Not much is known how SMA develops and even less how to treat or prevent it.

That’s where the research from the A*STAR’s Institute of Molecular and Cell Biology (IMCB) comes in. Using the iPSC method they turned tissue samples from healthy people and people with SMA into spinal organoids.

They then compared the way the cells developed in the organoids and found that the motor nerve cells from healthy people were fully formed by day 35. However, the cells from people with SMA started to degenerate before they got to that point.

They also found that the protein problem that causes SMA to develop did so by causing the motor nerve cells to divide, something they don’t normally do. So, by blocking the mechanism that caused the cells to divide they were able to prevent the cells from dying.

In an article in Science and Technology Research News lead researcher Shi-Yan Ng said this approach could help unlock clues to other diseases such as ALS.

“We are one of the first labs to report the formation of spinal organoids. Our study presents a new method for culturing human spinal-cord-like tissues that could be crucial for future research.”

Just yesterday the CIRM Board awarded almost $4 million to Ankasa Regenerative Therapeutics to try and develop a treatment for another debilitating back problem called degenerative spondylolisthesis.

And finally, organoid modeling was used to better understand and study an infectious disease. Scientists from the Max Planck Institute for Infection Biology in Berlin created fallopian tube organoids from normal human cells. Fallopian tubes are the pair of tubes found inside women along which the eggs travel from the ovaries to the uterus. The scientists observed the effects of chronic infections of Chlamydia, a sexually transmittable infection. It was discovered that chronic infections lead to permanent changes at the DNA level as the cells age. These changes to DNA are permanent even after the infection is cleared, and could be indicative of the increased risk of cervical cancer observed in women with Chlamydia or those that have contracted it in the past.

Stem Cell Roundup: The brain & obesity; iPSCs & sex chromosomes; modeling mental illness

Stem Cell Image of the Week:
Obesity-in-a-dish reveals mutations and abnormal function in nerve cells

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Image shows two types of hypothalamic neurons (in magenta and cyan) that were derived from human induced pluripotent stem cells.
Credit: Cedars-Sinai Board of Governors Regenerative Medicine Institute

Our stem cell image of the week looks like the work of a pre-historic cave dweller who got their hands on some DayGlo paint. But, in fact, it’s a fluorescence microscopy image of stem cell-derived brain cells from the lab of Dhruv Sareen, PhD, at Cedars-Sinai Medical Center. Sareen’s team is investigating the role of the brain in obesity. Since the brain is a not readily accessible organ, the team reprogrammed skin and blood cell samples from severely obese and normal weight individuals into induced pluripotent stem cells (iPSCs). These iPSCs were then matured into nerve cells found in the hypothalamus, an area of the brain that regulates hunger and other functions.

A comparative analysis showed that the nerve cells derived from the obese individuals had several genetic mutations and had an abnormal response to hormones that play a role in telling our brains that we are hungry or full. The Cedars-Sinai team is excited to use this obesity-in-a-dish system to further explore the underlying cellular changes that lead to excessive weight gain. Ultimately, these studies may reveal ways to combat the ever-growing obesity epidemic, as Dr. Sareen states in a press release:

“We are paving the way for personalized medicine, in which drugs could be customized for obese patients with different genetic backgrounds and disease statuses.”

The study was published in Cell Stem Cell

Differences found in stem cells derived from male vs female.

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Microscope picture of a colony of iPS cells. Credit: Vincent Pasque

Scientists at UCLA and KU Leuven University in Belgium carried out a study to better understand the molecular mechanisms that control the process of reprogramming adult cells back into the embryonic stem cell-like state of induced pluripotent stem cells (iPSCs). Previous studies have shown that female vs male embryonic stem cells have different patterns of gene regulation. So, in the current study, male and female cells were analyzed side-by-side during the reprogramming process.  First author Victor Pasquale explained in a press release that the underlying differences stemmed from the sex chromosomes:

In a normal situation, one of the two X chromosomes in female cells is inactive. But when these cells are reprogrammed into iPS cells, the inactive X becomes active. So, the female iPS cells now have two active X chromosomes, while males have only one. Our results show that studying male and female cells separately is key to a better understanding of how iPS cells are made. And we really need to understand the process if we want to create better disease models and to help the millions of patients waiting for more effective treatments.”

The CIRM-funded study was published in Stem Cell Reports.

Using mini-brains and CRISPR to study genetic linkage of schizophrenia, depression and bipolar disorder.

If you haven’t already picked up on a common thread in this week’s stories, this last entry should make it apparent: iPSC cells are the go-to method to gain insight in the underlying mechanisms of a wide range of biology topics. In this case, researchers at Brigham and Women’s Hospital at Harvard Medical School were interested in understanding how mutations in a gene called DISC1 were linked to several mental illnesses including schizophrenia, bipolar disorder and severe depression. While much has been gleaned from animal models, there’s limited knowledge of how DISC1 affects the development of the human brain.

The team used human iPSCs to grow cerebral organoids, also called mini-brains, which are three-dimensional balls of cells that mimic particular parts of the brain’s anatomy. Using CRISPR-Cas9 gene-editing technology – another very popular research tool – the team introduced DISC1 mutations found in families suffering from these mental disorders.

Compared to cells with normal copies of the DISC1 gene, the mutant organoids showed abnormal structure and excessive cell signaling. When an inhibitor of that cell signaling was added to the growing mutant organoids, the irregular structures did not develop.

These studies using human cells provide an important system for gaining a better understanding of, and potentially treating, mental illnesses that victimize generations of families.

The study was published in Translation Psychiatry and picked up by Eureka Alert.

Building a better brain organoid

One of the reasons why it’s so hard to develop treatments for problems in the brain – things like Alzheimer’s, autism and schizophrenia – is that you can’t do an autopsy of a living brain to see what’s going wrong. People tend to object. To get around that, scientists have used stem cells to create models of what’s happening inside the brain. They’re good, but they have their limitations. Now a team at the Salk Institute for Biological Studies has found a way to create a better brain model, and hopefully a faster route to developing new treatments.

For a few years now, scientists have been able to take skin cells from patients with neurodegenerative disorders and turn them into neurons, the kind of brain cell affected by these different diseases. They grow these cells in the lab and turn them into clusters of cells, so-called brain “organoids”, to help us better understand what’s happening inside the brain and even allow us to test medications on them to see if those treatments can help ease some symptoms.

Human-organoid-tissue-green-grafted-into-mouse-tissue.-Neurons-are-labeled-with-red-dye.

Human organoid tissue (green) grafted into mouse tissue. Neurons are labeled with red. Credit: Salk Institute

But those models don’t really capture the complexity of our brains – how could they – and so only offer a glimpse into what’s happening inside our skulls.

Now the team at Salk have developed a way of transplanting these organoids into mouse brains, giving them access to oxygen and nutrients that can help them not only survive longer but also display more of the characteristics found in the human brain.

In a news release, CIRM Grantee and professor at Salk’s Laboratory of Genetics, Rusty Gage said this new approach gives researchers a powerful new tool:

“This work brings us one step closer to a more faithful, functional representation of the human brain and could help us design better therapies for neurological and psychiatric diseases.”

The transplanted human brain organoids showed plenty of signs that they were becoming engrafted in the mouse brain:

  • They had blood vessels form in them and blood flowing through them
  • They formed neurons
  • They formed other brain support cells called astrocytes

They also used a series of imaging techniques to confirm that the neurons in the organoid were not just connecting but also sending signals, in essence, communicating with each other.

Abed AlFattah Mansour, a Salk research associate and the paper’s first author, says this is a big accomplishment.

“We saw infiltration of blood vessels into the organoid and supplying it with blood, which was exciting because it’s perhaps the ticket for organoids’ long-term survival. This indicates that the increased blood supply not only helped the organoid to stay healthy longer, but also enabled it to achieve a level of neurological complexity that will help us better understand brain disease.”

A better understanding of what’s going wrong is a key step in being able to develop new treatments to fix the problem.

The study is published in the journal Nature Biotechnology.

CIRM has a double reason to celebrate this work. Not only is the team leader, Rusty Gage, a CIRM grantee but one of the Salk team, Sarah Fernandes, is a former intern in the CIRM Bridges to Stem Cell Research program.

Gage-Natbiotech-press-release

From left: Sarah Fernandes, Daphne Quang, Stephen Johnston, Sarah Parylak, Rusty Gage, Abed AlFattah Mansour, Hao Li Credit: Salk Institute

Stem Cell Roundup: Backup cells to repair damaged lungs; your unique bowels; and California Cures, 71 ways CIRM is changing the face of medicine

It’s good to have a backup plan

3D illustration of Lungs, medical concept.

Our lungs are amazing things. They take in the air we breathe and move it into our blood so that oxygen can be carried to every part of our body. They’re also surprisingly large. If you were to spread out a lung – and I have no idea why you would want to do that – it would be almost as large as a tennis court.

But lungs are also quite vulnerable organs, relying on a thin layer of epithelial cells to protect them from harmful materials in the air. If those materials damage the lungs our body calls in local stem cells to repair the injury.

Now researchers at the University of Iowa have identified a new group of stem cells, called glandular myoepithelial cells (MECs), that also appear to play an important role in repairing injuries in the lungs.

These MECs seem to be a kind of “reserve” stem cell, waiting around until they are needed and then able to spring into action and develop into new replacement cells in the lungs.

In a news release study author Preston Anderson, said these cells could help develop new approaches to lung regeneration:

“We demonstrated that MECs can self-renew and differentiate into seven distinct cell types in the airway. No other cell type in the lung has been identified with this much stem cell plasticity.”

The study is published in Cell Stem Cell.

Your bowels are unique

About_Bowel_Cancer_What-is-Bowel-Cancer_370newfinal

Not to worry, that’s a plastic model of  a bowel

If you are eating as you read this, you should either put your food down or skip this item for now. A new study on bowel cancer says that every tumor is unique and every cell within that tumor is also genetically unique.

Researchers in the UK and Netherlands took samples of normal bowel tissue and cancerous bowel tissue from three people with colorectal cancer. They then grew these in the labs and turned them into mini 3D organoids, so they could study them in greater detail.

In the study, published in the journal Nature, the researchers say they found that tumor cells, not surprisingly, had many more mutations than normal cells, and that not only was each bowel cancer genetically different from each other, but that each cell they studied within that cancer was also different.

In a news release, Prof Sir Mike Stratton, joint corresponding author on the paper from the Wellcome Sanger Institute, said:

“This study gives us fundamental knowledge on the way cancers arise. By studying the patterns of mutations from individual healthy and tumour cells, we can learn what mutational processes have occurred, and then look to see what has caused them. Extending our knowledge on the origin of these processes could help us discover new risk factors to reduce the incidence of cancer and could also put us in a better position to create drugs to target cancer-specific mutational processes directly.”

California Cures: a great title for a great book about CIRM

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CIRM Board Chair Jonathan Thomas (L) and Don Reed

One of the first people I met when I started working at CIRM was Don Reed. He impressed me then with his indefatigable enthusiasm, energy and positive outlook on life. Six years later he is still impressing me.

Don has just completed his second book on stem cell research charting the work of CIRM. It’s called “California Cures: How the California Stem Cell Research Program is Fighting Your Incurable Disease”. It’s a terrific read combining stories about stem cell research with true tales about Al Jolson, Enrico Caruso and how a dolphin named Ernestine burst Don’s ear drum.

On his website, Stem Cell Battles, Don describes CIRM as a “scrappy little stage agency” – I love that – and says:

“No one can predict the pace of science, nor say when cures will come; but California is bringing the fight. Above all, “California Cures” is a call for action. Washington may argue about the expense of health care (and who will get it), but California works to bring down the mountain of medical debt: stem cell therapies to ease suffering and save lives. We have the momentum. We dare not stop short. Chronic disease threatens everyone — we are fighting for your family, and mine!”

 

UC Davis researchers make stem cell-derived mini-brains that contain blood vessels

Growing neurons on a flat petri dish is a great way to study the inner workings of nerve signals in the brain. But I think it’s safe to argue that a two-dimensional lawn of cells doesn’t capture all the complexity of our intricate, cauliflower-shaped brains. Then again, cracking open the skulls of living patients is also not a viable path for fully understanding the molecular basis of brain disorders.

two-spheroids-in-a-dish

Brain organoids (two white balls) growing in petri dish.
Image: Pasca Lab, Stanford University.

The recent emergence of stem cell-derived mini-brains, or brain organoids, as a research tool is bridging this impasse. With induced pluripotent stem cells (iPSCs) derived from a readily-accessible skin sample from patients, it’s possible to generate three-dimensional balls of cells that mimic particular parts of the brain’s anatomy. These mini-brains have the expected type of neurons, as well as other cells that support neuron function. We’ve written many blogs, most recently in January, on the applications of this cutting-edge tool.

With any new technology, there is always room for improvement. One thing that most mini-brains lack is their own system of blood vessels, or vasculature. That’s where Dr. Ben Waldau, a vascular neurosurgeon at UC Davis Medical Center, and his lab come into the picture. Last week, their published work in NeuroReport showed that incorporating blood vessels into a brain organoid is possible.

UCDavisorganoid

A stained cross-section of a brain organoid showing that blood vessels (in red) have penetrated both the outer, more organized layers and the inner core. Image: UC Davis Institute for Regenerative Cures

Using iPSCs from one patient, the Waldau team separately generated brain organoids and blood vessels cells, also called endothelial cells. After growing each for about a month, the organoids were embedded in a gelatin containing the endothelial cells. In an excellent Wired article, writer Megan Molteni explains what happened next:

“After incubating for three weeks, they took a single organoid and transplanted it into a tiny cavity carefully carved into a mouse’s brain. Two weeks later the organoid was alive, well—and, critically, had grown capillaries that penetrated all the way to its inner layers.”

Every tissue relies on nutrients and oxygen from the blood. As Molteni suggests, being able to incorporate blood vessels and brain organoids from the same patient’s cells may make it possible to grow and study even more complex brain structures without the need of a mouse using fluidic pumps.

As Waldau explains in the Wired article, this vascularized brain organoid system also adds promise to the ultimate goal of repairing damaged brain tissue:

waldau

Ben Waldau

“The whole idea with these organoids is to one day be able to develop a brain structure the patient has lost made with the patient’s own cells. We see the injuries still there on the CT scans, but there’s nothing we can do. So many of them are left behind with permanent neural deficits—paralysis, numbness, weakness—even after surgery and physical therapy.”

 

 

Modeling the Human Brain in 3D

(Image from Pasca Lab, Stanford University)

Can you guess what the tiny white balls are in this photo? I’ll give you a hint, they represent the organ that you’re using right now to answer my question.

These are 3D brain organoids generated from human pluripotent stem cells growing in a culture dish. You can think of them as miniature models of the human brain, containing many of the brain’s various cell types, structures, and regions.

Scientists are using brain organoids to study the development of the human nervous system and also to model neurological diseases and psychiatric disorders. These structures allow scientists to dissect the inner workings of the brain – something they can’t do with living patients.

Brain-in-a-Dish

Dr. Sergiu Pasca is a professor at Stanford University who is using 3D cultures to understand human brain development. Pasca and his lab have previously published methods to make different types of brain organoids from induced pluripotent stem cells (iPSCs) that recapitulate human brain developmental events in a dish.

Sergiu Pasca, Stanford University (Image credit: Steve Fisch)

My colleague, Todd Dubnicoff, blogged about Pasca’s research last year:

“Using brain tissue grown from patient-derived iPSCs, Dr. Sergiu Pasca and his team recreated the types of nerve cell circuits that form during the late stages of pregnancy in the fetal cerebral cortex, the outer layer of the brain that is responsible for functions including memory, language and emotion. With this system, they observed irregularities in the assembly of brain circuitry that provide new insights into the cellular and molecular causes of neuropsychiatric disorders like autism.”

Pasca generated brain organoids from the iPSCs of patients with a genetic disease called Timothy Syndrome – a condition that causes heart problems and some symptoms of autism spectrum disorder in children. By comparing the nerve cell circuits in patient versus healthy brain organoids, he observed a disruption in the migration of nerve cells in the organoids derived from Timothy Syndrome iPSCs.

“We’ve never been able to recapitulate these human-brain developmental events in a dish before,” said Pasca in a press release, “the process happens in the second half of pregnancy, so viewing it live is challenging. Our method lets us see the entire movie, not just snapshots.”

The Rise of 3D Brain Cultures

Pasca’s lab is just one of many that are working with 3D brain culture technologies to study human development and disease. These technologies are rising in popularity amongst scientists because they make it possible to study human brain tissue in normal and abnormal conditions. Brain organoids have also appeared in the mainstream news as novel tools to study how epidemics like the Zika virus outbreak affect the developing fetal brain (more here and here).

While these advances are exciting and promising, the field is still in its early stages and the 3D organoid models are far from perfect at representing the complex biology of the human brain.

Pasca addresses the progress and the hurdles of 3D brain cultures in a review article titled “The rise of three-dimensional brain cultures” published this week in the journal Nature. The article, describes in detail how pluripotent stem cells can assemble into structures that represent different regions of the human brain allowing scientists to observe how cells interact within neural circuits and how these circuits are disrupted by disease.

The review goes on to compare different approaches for creating 3D brain cultures (see figure below) and their different applications. For instance, scientists are culturing organoids on microchips (brains-on-a-chip) to model the blood-brain barrier – the membrane structure that protects the brain from circulating pathogens in the blood but also makes drug delivery to brain very challenging. Brain organoids are also being used to screen for new drugs and to model complex diseases like Alzheimer’s.

Human pluripotent stem cells, adult stem cells or cancer cells  can be used to derive microfluidics-based organs-on-a-chip (top), undirected organoids (middle), and region-specific brain organoids or organ spheroids (bottom). These 3D cultures can be manipulated with CRISPR-Cas9 genome-editing technologies, transplanted into animals or used for drug screening. (Pasca, Nature)

Pasca ends the review by identifying the major hurdles facing 3D brain culture technologies. He argues that “3D cultures only approximate the appearance and architecture of neural tissue” and that the cells and structures within these organoids are not always predictable. These issues can be address over time by enforcing quality control in how these 3D cultures are made and by using new biomaterials that enable the expansion and maturation of these cultures.

Nonetheless, Pasca believes that 3D brain cultures combined with advancing technologies to study them have “the potential to give rise to novel features for studying human brain development and disease.”

He concludes the review with a cautiously optimistic outlook:

“This is an exciting new field and as with many technologies, it may follow a ‘hype’ cycle in which we overestimate its effects in the short run and underestimate its effects in the long run. A better understanding of the complexity of this platform, and bringing interdisciplinary approaches will accelerate our progress up a ‘slope of enlightenment’ and into the ‘plateau of productivity’.”

3D brain culture from the Pasca Lab, Stanford University


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Stem cell-derived mini-intestines reveal bacteria’s key role in building up a newborn’s gut

The following factoid may induce an identity crisis for some people but it is true that our bodies carry more microbes than human cells. Some studies in 1970’s estimated the ratio at 10:1 though more recent calculations suggest we’re merely half microbe, half human.

Because microbes are much smaller than human cells they make up only about 1 or 2 percent of our total body mass. But that still amounts to trillions of micro-organisms, mostly bacteria, that live on and inside our bodies. The gut is one part of our body that is teeming with bacteria. Though that may sound gross, you’re very life depends on them. For example, these bacteria allow us to digest foods and take up nutrients that we wouldn’t be able to otherwise.

Intestines

E. coli bacteria, visible in this enhanced microscope image as tiny green rods, were injected into the center of a germ-free hollow ball of cells called a human intestinal organoid (inset image, top right). Within 48 hours, the cells formed much tighter connections with one another, visible as red in this image. Image courtesy of University of Michigan.

When we’re first born our intestines are germ-free but overtime helpful bacteria gain access to our gut and help it function, protecting it from infection by the continual exposure to harmful bacteria and viruses. New research out of the University of Michigan Medical School reported in eLife now shows that the initial bacterial infiltration is even more important than scientists previously thought. It appears to play a key role in stimulating human gut cells to shore up the intestine in preparation for the full wave of both micro-organisms and pathogens that are present throughout a person’s lifetime. The finding could help researchers discover methods to protect the gut from diseases like necrotizing enterocolitis, a rare but dangerous infection that strikes newborns.

To reach these conclusions, the research team grew human embryonic stem cells into miniature intestines in the lab. These so-called human intestinal organoids, or HIOs, are structures made up of a few thousand cells that form hollow tubes with many of the hallmarks of a bona fide intestine. The HIOs were first kept in a germ-free environment to mimic a newborn’s intestine. Then a form of helpful E. Coli bacteria, the same that’s often found in an infant’s diaper, was injected into the HIO and allowed to colonize the inside of the intestine.

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A single human intestinal organoid, or HIO — a hollow ball of cells grown from human embryonic stem cells and coaxed to become gut-lining cells. Scientists can use it to study basic gut development, and the effect of microbes on the cells, in a way that mimics the guts of newborn babies. Image courtesy of University of Michigan

The team observed several changes in gene activity shortly after the bacteria was introduced. Within a day or two, genes involved in producing proteins that fight off harmful microbes increased as well as genes that encode mucus production, a key part of protecting the cells that face the inside of the intestine. Other key features of a maturing intestine, such as tighter cell-to-cell connections and lowered oxygen levels were also stimulated by the presence of the bacteria. As co-senior author Vincent Young, M.D., Ph.D. explained in a press release, these results put the team in a position to uncover new insights about intestinal biology and disease:

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Vincent Young

“We have developed a system that faithfully reproduces the physiology of the immature human intestine, and will now make it possible to study a range of host-microbe interactions in the intestine to understand their functional role in health and disease.”

 

The particular mix of microbes found in one person versus another can differ a lot. And the impact of these differences on an individual’s health has been a trending topic in the media. Lead author David Hill, Ph.D., a postdoctoral fellow in the lab of Jason Spence, Ph.D., thinks that’s one specific research path that they aim to investigate with their HIO system:

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David Hill

“We hope to examine whether different bacteria produce different types of responses in the gut. This type of work might help to explain why different types of gut bacteria seem to be associated with positive or negative health outcomes.”