CIRM at Business of Personalized Medicine Summit

Exciting new technologies such as regenerative medicine, tissue engineering and gene therapy are already at the forefront of a new era of medicine. And today, CIRM’s own Business Development Officer, Neil Littman, moderated a panel titled The Impact of Next Generation Personalized Medicine Technologies: How Disruptive Tech Continues to Advance the Industry, at the annual Business of Personalized Medicine Summit.

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The panel discussed the innovative technologies we have at our disposal today, and provided a glimpse into the future—highlighting promising therapies already in the clinic as well as technologies that may be available in 5 to 10 years. For example, Curt Herberts, Senior Director of Corporate Development & Strategy from Sangamo BioSciences, discussed Sangamo’s grant under CIRM’s Strategic Partnership II Award, which uses genome-editing technology for a one-time treatment for the blood disorder Beta-thalassemia.

Importantly, the panel delved into potential paradigm shifts in medical care that may arise as a result of these new technologies, and discussed how to translate these cutting-edge technologies into human clinical trials. Carlos Olguin, Head of Bio/nano/Programmable Matter Group, Autodesk and Dr. Kumar Sharma, who directs the Center for Renal Translational Medicine University of California, San Diego La Jolla, rounded out the panel.

Finally, Neil asked panel members to discuss the issues surrounding market adoption and the potential resistance to paradigm-shifting technologies, the final hurdle in the delivery of much-needed therapies to patients.

Throwback Thursday: Scientists Create Synthetic Version of Earth’s Earliest Primordial Cells

Cells as we know them today—no matter the species—are feats of evolution; molecular machines with thousands of interlocking parts. But they didn’t start out that way.

Scientists have built a simplified cell membrane that mimics natural cellular processes and movements.

Scientists have built a simplified cell membrane that mimics natural cellular processes and movements.

Using the latest tools from the new field of synthetic biology, a team of biophysicists from Tecnische Universitaet Muenchen (TUM) in Munich, Germany, has constructed a synthetic version of an early cell, complete with some biomechanical function.

To build a primordial cell, the recipe is simple: all you need is a membrane shell, a couple of biomolecules that perform the most basic of functions, and some fuel to keep it going.

Here, TUM researchers used lipids (fat molecules) to create a double-layer cellular membrane that mimics a cell’s natural membrane. They then filled the membrane with microtubules, which acted as cellular ‘scaffolding’ to hold everything in place, and another molecule called ‘kinesin.’ These kinesin molecules serve as molecular ‘motors,’ transporting components throughout the cell by traveling along the microtubule scaffolding. Finally, they added the fuel: a compound called adenosine triphosphate, or ATP. The scientists likened this set-up to a liquid crystal layer within the membrane that is in a permanent state of motion. As lead author Felix Keber explained in a news release:

“One can picture the liquid crystal layer as tree logs drifting on the surface of a lake. When it becomes too congested, they line up in parallel but can still drift alongside each other.”

Once constructed, the research team then wanted to understand how these synthetic cells behaved, and if it would mimic natural cellular movements. And much to the team’s surprise—they did.

During a process called osmosis—where water droplets selectively pass through the membrane—the researchers noticed a change in the cells’ shape as water left the interior of the cell. The resulting membrane slack was causing the microtubules to stick out like spikes. These ‘spiked extensions’ were eerily similar to what the extensions that scientists have seen cells normally use to get around.

This observation cleared up a long-standing mystery: the way cells change shape and move around wasn’t random. The cells were simply following the basic laws of physics. This discovery then led the team to uncover the underlying mechanisms of other cellular behaviors—and even make predictions on other systems.

As the study’s lead author, Professor Andreas Bausch, stated in the same release:

“With our synthetic biomolecular model we have created a novel option for developing minimal cell models. It is ideally suited to increasing the complexity in a modular fashion in order to reconstruct cellular processes like cell migration or cell division in a controlled manner.”

In the future, the team hopes to build this knowledge to a point where they can understand the physical basis for deformed cells—with potential applications to disease modeling. Bausch added:

“That the artificially created system can be comprehensively described from a physical perspective gives us hope that in the next steps we will also be able to uncover the basic principles behind the manifold cell deformations.”

Stem Cell Stories that Caught our Eye: A Zebrafish’s Stripes, Stem Cell Sound Waves and the Dangers of Stem Cell Tourism

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.

The zebrafish (Danio rerio) owes its name to a repeating pattern of blue stripes alternating with golden stripes. [Credit: MPI f. Developmental Biology/ P. Malhawar]

The zebrafish (Danio rerio) owes its name to a repeating pattern of blue stripes alternating with golden stripes. [Credit: MPI f. Developmental Biology/ P. Malhawar]

How the Zebrafish Got its Stripes. Scientists in Germany have identified the different pigment cells that emerge during embryonic development and that determine the signature-striped pattern on the skins of zebrafish—one of science’s most commonly studied model organisms. These results, published this week in the journal Science, will help researchers understand how patterns, from stripes to spots to everything in between, develop.

In the study, scientists at the Max Planck Institute for Developmental Biology mapped how three distinct pigment cells, called black cells, reflective silvery cells, and yellow cells emerge during development and arrange themselves into the characteristic stripes. While researchers knew these three cell types were involved in stripe formation, what they discovered here was that these cells form when the zebrafish is a mere embryo.

“We were surprised to observe such cell behaviors, as these were totally unexpected from what we knew about color pattern formation”, says Prateek Mahalwar, first author of the study, in a news release.

What most surprised the research team, according to the news release, was that the three cell types each travel across the embryo to form the skin from a different direction. According to Dr. Christiane Nüsslein-Volhard, the study’s senior author:

“These findings inform our way of thinking about color pattern formation in other fish, but also in animals which are not accessible to direct observation during development such as peacocks, tigers and zebras.”

Sound Waves Dispense Individual Stem Cells. It happens all the time in the lab: scientists need to isolate and study a single stem cell. The trick is, how best to do it. Many methods have been developed to achieve this goal, but now scientists at the Regenerative Medicine Institute (REMEDI) at NUI Galway and Irish start-up Poly-Pico Technologies Ltd. have pioneered the idea of using sound waves to isolate living stem cells, in this case from bone marrow, with what they call the Poly-Pico micro-drop dispensing device.

Poly-Pico Technologies Ltd., a start-up that was spun out from the University of Limerick in Ireland, has developed a device that uses sound energy to accurately dispense protein, antibodies and DNA at very low volumes. In this study, REMEDI scientists harnessed this same technology to dispense stem cells.

These results, while preliminary, could help improve our understanding of stem cell biology, as well as a number of additional applications. As Poly-Pico CEO Alan Crean commented in a news release:

“We are delighted to see this new technology opportunity emerge at the interface between biology and engineering. There are other exciting applications of Poly-Pico’s unique technology in, for example, drug screening and DNA amplification. Our objective here is to make our technology available to companies, and researchers, and add value to what they are doing. This is one example of such a success.”

The Dangers of Stem Cell Toursim. Finally, a story from ABC News Australia, in which they recount a woman’s terrifying encounter with an unproven stem cell technique.

In this story, Annie Levington, who has suffered from multiple scleoris (MS) since 2007, tells of her journey from Melbourne to Germany. She describes a frightening experience in which she paid $15,000 to have a stem cell transplant. But when she returned home to Australia, she saw no improvement in her MS—a neuroinflammatory disease that causes nerve cells to whither.

“They said I would feel the effects within the next three weeks to a year. And nothing – I had noticed nothing whatsoever. [My neurologist] sent me to a hematologist who checked my bloods and concluded there was no evidence whatsoever that I received a stem cell transplant.”

Sadly, Levington’s story is not unusual, though it is not as dreadful as other instances, in which patients have traveled thousands of miles to have treatments that not only don’t cure they condition—they actually cause deadly harm.

The reason that these unproven techniques are even being administered is based on a medical loophole that allows doctors to treat patients, both in Australia and overseas, with their own stem cells—even if that treatment is unsafe or unproven.

And while there have been some extreme cases of death or severe injury because of these treatments, experts warn that the most likely outcome of these untested treatments is similar to Levington’s—your health won’t improve, but your bank account will have dwindled.

Want to learn more about the dangers of stem cell tourism? Check out our Stem Cell Tourism Fact Sheet.

A Tumor’s Trojan Horse: CIRM Researchers Build Nanoparticles to Infiltrate Hard-to-Reach Tumors

Some tumors are hard to find, while others are hard to destroy. Fortunately, a new research study from the University of California, Davis, has developed a new type of nanoparticle that could one day do both.

UC Davis scientists have developed a new type of nanoparticle to target tumor cells.

UC Davis scientists have developed a new type of nanoparticle to target tumor cells.

Reporting in the latest issue of Nature Communications, researchers in the laboratory of UC Davis’ Dr. Kit Lam describe a type of ‘dynamic nanoparticle’ that they created, which not only lights up tumors during an MRI or PET scan, but which may also serve as a microscopic transport vehicle, carrying chemotherapy drugs through the blood stream—and releasing them upon reaching the tumor.

This is not the first time scientists have attempted to develop nanoparticles for medicinal purposes, but is perhaps one of the more successful. As Yuanpei Li, one of the study’s co-first authors stated in a news release:

“These are amazingly useful particles. As a contrast agent, they make tumors easier to see on MRI and other scans. We can also use them as vehicles to deliver chemotherapy directly to tumors.”

Nanoparticles can be constructed out of virtually any material—but the material used often determines for what purpose they can be used. Nanoparticles made of gold-based materials, for example, may be strong for diagnostic purposes, but have been shown to have issues with safety and toxicity. On the flip side, nanoparticles made from biological materials are safer, but inherently lack imaging ability. What would be great, the team reasoned, was a new type of nanoparticle that had the best qualities of both.

In this study, which was funded in part by CIRM, Lam and the UC Davis team devised a new type of nanoparticle that was ‘just right,’—simple to make, safe and able to perform the desired task, in this case: attack tumors.

Built of organic porphyrin and cholic acid polymers and coated with the amino acid cysteine, the 32 nanometer-wide particles developed in this study offer a number of advantages over other models. They are small enough to pass into tumors, can be filled with a chemo agent and with a specially designed cysteine coating, and don’t accidentally release their payload before reaching their destination.

And this is where the truly ingenious part kicks in. With a simple flash of light, the researchers could direct the particles to drop their payload—at just the right time, offering some intriguing possibilities for new ways to deliver chemotherapy drugs.

But wait, there’s more. The fact that these new particles, which the team are calling cysteine nanoparticles, or CNP’s, appear to congregate inside tumors means that they also end up being easy to spot on an MRI.

Continued Li in the same release:

“These particles can combine imaging and therapeutics. We could potentially use them to simultaneously deliver treatment and monitor treatment efficacy. This is the fist nanoparticle to perform so many different jobs. From delivering chemo, photodynamic and photothermal therapies to enhancing diagnostic imaging. It’s the complete package.”

And while the team cautions that these results are preliminary, they open the door to an entirely new and far more exact method of drug delivery to tumors—no matter how well-hidden in the body they may be.

FDA gives Asterias green light to start CIRM-funded clinical trial in spinal cord injury

This morning Asterias Biotherapeutics announced that they have been cleared by the Food and Drug Administration (FDA) to start a clinical trial using stem cells to treat spinal cord injury. It’s great news, doubly so as we are funding that trial.

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You can read more about the trial in a news release we just sent out.

This trial is a follow-on to the Geron trial that we funded back in 2010 that was halted after 5 patients, not because of any safety concerns but because of a change in Geron’s business strategy.

Katie Sharify was the fifth and final patient enrolled in that trial and treated with the stem cells. Like all of us she was disappointed when the trial was halted. And like all of us she is delighted that Asterias is now taking that work and building on it.

Here’s what Katie had to say when she heard the news:

“Of course, I’m very happy that the trial has been revived. Knowing that the FDA approved the continuation based on the safety data I was a part of is great news. As you know, the trial was halted 2 days before I received the stem cells. A big part of why I ended up participating was because I figured that once the study is revived a bigger sample size (even if just by 1 person) was more valuable than a smaller one. I never regretted my choice to participate but I have doubted whether my contribution actually meant anything. I think now I finally feel a sense of accomplishment because the trial is not only being continued but also progressing in the right direction as a higher dose is going to be used. A lot remains unknown about human embryonic stem cells and that’s exactly why this research is so important. The scientific community is going to have a much greater understanding of these stem cells from the data that will be collected throughout the study and I’m glad to have been a part of this advancement.”

Building a Blueprint for the Human Brain

How does a brain blossom from a small cluster of cells into nature’s most powerful supercomputer? The answer has long puzzled scientists, but with new advances in stem cell biology, researchers are quickly mapping the complex suite of connections that together make up the brain.

UCLA scientists have developed a new system that can map the development of brain cells.

UCLA scientists have developed a new system that can map the development of brain cells.

One of the latest breakthroughs comes from Dr. Daniel Geschwind and his team at the University of California, Los Angeles (UCLA), who have found a way to track precisely how early-stage brain cells are formed. These findings, published recently in the journal Neuron, shed important light on what had long been considered one of biology’s black boxes—how a brain becomes a brain.

Along with co-lead authors and UCLA postdoctoral fellows Drs. Luis de la Torre-Ubieta and Jason Stein, Geschwind developed a new system that measures key data points along the lifetime of a cell, as it matures from an embryonic stem cell into a functioning brain cell, or neuron. These new data points, such as when certain genes are switched on and off, then allow the team to map how the developing human fetus constructs a functioning brain.

Geschwind is particularly excited about how this new information can help inform how complex neurological conditions—such as autism—can develop. As he stated in a news release:

“These new techniques offer extraordinary promise in the study of autism, because we now have an unbiased and genome-wide view of how genes are used in the development of the disease, like a fingerprint. Our goal is to develop new treatments for autism, and this discovery can provide the basis for improved high-efficiency screening methods and open up an enormous new realm of therapeutic possibilities that didn’t exist before.”

This research, which was funded in part by a training grant from CIRM, stands to improve the way that scientists model disease in a dish—one of the most useful applications of stem cell biology. To that end, the research team has developed a program called CoNTEXT that can identify the maturity levels of cells in a dish. They’ve made this program freely available to researchers, in the hopes that others can benefit. Said de la Torre-Ubieta:

“Our hope is that the scientific community will be able to use this particular program to create the best protocols and refine their methods.”

Want to learn more about how stem cell scientists study disease in a dish? Check out our pilot episode of “Stem Cells in your Face.”

Mapping Metastasis: Scientists Discover how Cancer Cells Colonize Distant Organs

How does cancer spread? How does it traverse from one organ to the next—often undetected—until it has colonized the far reaches of the human body? And more importantly, how can researchers stop this from happening?

These questions plague even the most renowned experts, but new research from scientists at Brown University has uncovered clues to cancers’ unique ability to invade our bodies—offering important insight into how we might develop tools to stop this disease’s most dangerous ability.

Cancer cells advance across a microchip designed to be an obstacle course for cells. The device sheds new light on how cancer cells invade and could be used to test drugs aimed at preventing cancer spread. [Credit: Ian Y. Wong / Brown University]

Cancer cells advance across a microchip designed to be an obstacle course for cells. The device sheds new light on how cancer cells invade and could be used to test drugs aimed at preventing cancer spread. [Credit: Ian Y. Wong / Brown University]

Reporting in this week’s issue of Nature Materials, biomedical engineer Dr. Ian Wong and his team devised a special microchip technology that tracks individual cancer cells as they navigate from one end of the chip to the other. Importantly, this tool uncovered how cancer cells hijack an otherwise normal cellular process to infect the body.

This process, called the epithelial-mesenchymal transition (or ‘EMT’) normally occurs in the developing embryo, when one type of cells, called epithelial cells, transforms into mesenchymal cells. Epithelial cells tend to clump together into larger groups, whereas mesenchymal cells can more easily and more quickly break away from the pack and travel individually. This transition is crucial to embryonic development, as it allows for cells to get to where they need to be at the appropriate time.

However, scientists have recently begun to hypothesize that cancer uses EMT as a tool to help it metastasize—traversing throughout the body and setting up shop in various tissues and organs. Metastasis is one of the biggest hurdles to eradicating cancer, and is responsible for 90% of all cancer-related deaths.

As Wong explained in yesterday’s news release:

“People are really interested in how EMT works and how it might be associated with tumor spread, but nobody has been able to see how it happens. We’ve been able to image these cells in a biomimetic system and carefully measure how they move.”

The research team used microchip technology to essentially build a microscopic ‘obstacle course,’ which cancer cells had to navigate. Made from a silicon wafer and tiny pillars just 10 micrometers in diameter and spaced so close together with just enough space for the cells to squeeze in between. Then, using fluorescent dye and time-lapse photography, they watched as the cells moved from one end of the chip to the other. According to Wong:

“We can track individual cells, and because the size and spacing of these pillars is highly controlled, we can start to do statistical analysis and categorize these cells as they move.”

This amazing video revealed that cells moved across the plate at two different speeds.

Most moved slowly, often clumping together, exhibiting classic epithelial cell behavior. But a minority of cells sped through the obstacle course individually—breaking away from the pack. These cells, Wong argues, have switched to mesenchymal cells after experiencing EMT.

“In the context of cell migration, EMT upgrades cancer cells from an economy model to a fast sports car. Our technology enabled us to track the motion of thousands of ‘cars’ simultaneously, revealing that…some sports cars break out of traffic and make their way aggressively to distant locations.”

These ‘breakaway’ cells are how cancer can reach, invade and, ultimately destroy, distant organs.

But this newfound knowledge also hints at a possible therapeutic strategy: developing a drug that reverses EMT in cancer cells, keeping them in clumps and slowing their progress.

“An interesting therapeutic strategy might be to develop drugs that downgrade mesenchymal ‘sports cars’ back to epithelial ‘economy models’ in order to keep them stuck in traffic, rather than aggressively invading surrounding tissues.’

Want to learn more about how cancer spreads? Check out our Solid Tumor Fact Sheet.

Blood Test Reveals Alzheimer’s Disease Risk, CIRM-Funded Study Finds

Could a simple blood test predict your risk for one day developing Alzheimer's disease?

Could a simple blood test predict your risk for developing one day developing Alzheimer’s disease?

By the time someone begins to experience the clinical symptoms of Alzheimer’s disease, the damage has already been done. An accumulation of toxic proteins is causing brain cells to whither and die, taking with them a lifetime of precious memories.

But what if we had a definitive test that could predict one’s risk of developing Alzheimer’s, even before the onset of symptoms? Could we use it to develop an early-detection method and—even more importantly—a way to slow or halt the disease before it is too late?

While this may seem closer to fiction than reality, scientists from the Western University of Health Sciences are reporting that they’ve done just that: a simple blood test that can accurately predict one’s Alzheimer’s risk—up to ten years before symptoms begin to develop.

Reporting in the latest issue of Translational Psychiatry, senior author Dr. Doug Ethell and his research team describe their ingenious method of tracking the earliest stages of Alzheimer’s via a simple blood test.

Their test, called the CD4see assay, tracks the body’s early immune response to toxic proteins—called amyloid beta proteins—that accumulate and form harmful plaques in the brains of Alzheimer’s patients.

Ethell has long been studying how a class of immune cells, called T cells, responds to the buildup of amyloid beta. Previously, he showed that these so-called amyloid beta-specific T cells could actually counter the cognitive decline seen in Alzheimer’s. So, lower amyloid T cell levels should correlate with symptoms. As he explained in an interview:

“If our mouse studies were correct, then there should be fewer of those cells in Alzheimer’s patients. Translating those studies from mouse to man was going to take a big effort—characterizing the small proportion of T cells that respond to amyloid-beta from the millions of other kinds of T cell would require technology that didn’t exist yet.”

So Ethell turned to stem cells. With support from CIRM, Ethell and his team took human embryonic stem cells (hESCs) and developed a type of immune system cell called dendritic cells. These cells stimulated the growth of amyloid-beta T cells—effectively bringing them out of hiding and allowing the researchers to locate and count them.

“Everyone showed a decrease in these T cells as they aged, but the decline occurred earliest in women with the apoE4 gene (the single greatest genetic risk factor for Alzheimer’s), often right around the same time as menopause,” explained Ethell. “When our raw data was pasted on foam boards all over my office it seemed to us that older women had lower responses than men, and when the data was finally plotted the dramatic decline around menopause was clear.”

Interestingly, this observation seems to correlate with the fact that Alzheimer’s is more prevalent in women than in men.

Ethell and his team propose that the CD4see assay could soon be used to measure amyloid-beta-specific T cells against one’s age, sex and whether they carry apoE4. This could then be used to calculate the individual’s risk for developing Alzheimer’s symptoms in the future.

This assay could also prove helpful when looking to test new therapeutic strategies that treat early-stage Alzheimer’s—something that has proven difficult without a reliable early detection method.

“Alzheimer’s disease is a puzzle and every bit of knowledge adds a new piece,” added Ethell. “We now view Alzheimer’s disease very differently than we did even just a few years ago.”

A Glimpse Inside the Cellular Universe: Scientists Track the Growth of an Organism, One Cell at a Time

Trying to keep tabs on how an organism grows from a single fertilized egg into an embryo, cell by cell, is hard work. So hard in fact, that no one’s quite figured out how to do it.

Digital fruit fly embryo, reconstructed from live imaging data recorded with a SiMView light-sheet microscope. Each colored circle in the image shows one of the embryo's cells, and the corresponding tail indicates that cell's movement over a short time interval at around 3 hours post-fertilization [Credit: Kristin Branson, Fernando Amat, Bill Lemon and Philipp Keller (HHMI/Janelia Research Campus)]

Digital fruit fly embryo, reconstructed from live imaging data recorded with a SiMView light-sheet microscope. Each colored circle in the image shows one of the embryo’s cells, and the corresponding tail indicates that cell’s movement over a short time interval at around 3 hours post-fertilization
[Credit: Kristin Branson, Fernando Amat, Bill Lemon and Philipp Keller (HHMI/Janelia Research Campus)]

The problem, as researchers have lamented, is that there’s just too much happening—all at the same time—for the human eye to parse through all the data, even with the aid of the most powerful microscopes.

But now, scientists at the Howard Hughes Medical Institute (HHMI) have devised a high-tech shortcut: a new computational program that measures in real-time the three-dimensional development of each individual cell in a developing fetus.

This program stands to revolutionize how scientists understand the microscopic cellular ‘universe.’ As lead author, HHMI Group Leader Dr. Philipp Keller, explained in a news release:

“We wanted to reconstruct the elemental building plan of animals, tracking each cell from very early development until the late stages, so that we know everything that has happened in terms of cell movement and cell division.”

This technique, which is described in the latest issue of the journal Nature Methods, was built upon Keller’s 2012 development of a something called SiMView, a one-of-a-kind microscope that can capture precise 3D images of cells over a period of hours or even days.

But this was only the first step. Since the development of SiMView, Keller has been working on improving the system so that it could be used more broadly and over the course an organism’s development as an embryo. Specifically, Keller had sought to use this technique to look at how specific parts of the body develop—cell by cell. As Keller elaborated:

“In particular, we wanted to understand how the nervous system forms. Ultimately, we could like to collect the developmental history of every cell in the nervous system and link that information to the cell’s final function.”

In collecting and analyzing these vast datasets, researchers would then be well-poised to understand underlying molecular mechanisms of nervous system diseases.

Keller and his team have been looking for ways to both capture and analyze the vast amount of data hidden within each cell as it grows, matures and divides, with limited success—even the SiMView system was only active at a much smaller scale than what the team desired. One of the main issues is that as the cells in the embryo grow and divide, they become densely packed. They also shift around constantly, making tracking incredibly difficult to view.

The solution, Keller said, was to simplify the data. First, they clustered groups of 3D pixels called ‘voxels’ together into larger units, called ‘supervoxels.’ Next, they programmed the software to recognize the nuclei of each cell within the supervoxels. Then, using high-speed microscopy, they could capture images in a very quick sequence—so quick that individual cells wouldn’t be able to move out of the frame.

In this way, they are able to gather about 95% of all available data, a far higher number than that achieved by traditional methods. For the remaining 5%, the team employed even more complex algorithms to sort through the data. The end result, Keller says, is a wealth of knowledge that reveals more than many ever thought possible. According to Keller:

“You know the path, you know where it is at a certain time point. You know it divided from a certain point, you know the daughter cells, you know what mother cell it came from.”

In the early tests, the team studied the cellular ‘lineages’ of 295 early-stage nerve cells, called neuroblasts. Interestingly, they were not only able to trace these lineages in their entirety, but they could also predict their behavior later in their lifespan based on how they behaved early on.

The software, which is free and readily available to interested researchers, can be applied to a wide variety of data types—including different organisms and different microscopes.

This development stands to potentially become highly valuable to the stem cell research community. Increasingly, stem cell scientists are finding that in order to drive stem cells towards a desired adult tissue efficiently and completely, they need to try to recreate the stem cells’ natural environment. This should make it easier to build the right cellular “Neighborhood,” and help foster the transition from basic research into effective therapies.

Confining Cells within Geometric Structures Key to Replicating Embryonic Development

It’s like trying to capture, and then recreate, a moment in time: the exact instant after fertilization when a small group of dividing cells begin to organize themselves into the various cellular layers that will one day make up the skin, the heart, the liver and the brain. But for all the advances in our understanding of how an embryonic stem cell grows, matures and differentiates—scientists still can’t replicate that very important process in the lab.

Forty-two hours after they began to differentiate, embryonic cells are clearly segregating into the various layers that will one day become specific tissues and organs. Researchers say the key to achieving this patterning in culture is confining the colonies geometrically. [Credit: The Rockefeller University]

Forty-two hours after they began to differentiate, embryonic cells are clearly segregating into the various layers that will one day become specific tissues and organs. Researchers say the key to achieving this patterning in culture is confining the colonies geometrically. [Credit: The Rockefeller University]

But now, scientists at The Rockefeller University have tried something new, and in so doing have finally found a way to stimulate this organization, thus mimicking in a petri dish what happens in the human embryo. The missing ingredient, the researchers found, wasn’t a molecule or chemical compound. Rather, the team just had to use a bit of geometry.

Reporting in the June 29 issue of the journal Nature Methods, the Rockefeller team—led by Dr. Ali Brivanlou—describes how they constructed microscopic circular patterns on glass plates that confined embryonic stem cells inside, similar to a hedge maze.

To their amazement, the cells confined within these patterns soon began to go through gastrulation, the process by which embryonic stem cells begin to form highly organized layers that eventually mature into the body’s various organs and tissues. A second group of cells not confined within these patterns, however, did not.

The next question they had to figure out, according to the researchers, was why.

To solve this mystery, Brivanlou and his team next monitored specific chemical signals between the cells as they matured. In so doing they uncovered a delicate arrangement of chemical cues—molecular ‘on-and-off-switches’—that guided each cell down one developmental path as opposed to another. What were crucial to these cues going off without a hitch, the researchers found, were the geometric patterns.

As Dr. Aryeh Warmflash, one of the paper’s lead authors, stated in this week’s news release:

“At the fundamental level, what we have developed is a new model to explore how human embryonic stem cells first differentiate into separate populations with a very reproducible spatial order just as in an embryo. We can now follow individual cells in real time in order to find out what makes them specialize, and we can begin to ask questions about the underlying genetics of the process.”

Added Brivanlou:

“Understanding what happens in this moment, when individual members of this mass of embryonic stem cells begin to specialize for the very first time and organize themselves into layers, will be key to harnessing the promise of regenerative medicine.”