Stem cell stories that caught our eye: organ replacement, ovarian cancer and repairing damaged hearts.

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.

Numbers on organ shortage and review of lab replacements.
Vox, the four-month-old web site, is rapidly becoming a credible news source with more than five million page views so far. With a reputation for explaining the facts behind the news, it was nice to see they tackled the organ shortage and how researchers are using stem cells to try to solve it.

organ shortage.0After providing data on the incredible need, the author addressed several key advances, as well as remaining hurdles, to using stem cells to build replacement organs in the lab. She notes that an important step to growing an organ is being able to grow all the various types of cells that make up a complex organ.

“Each specialized type of cell in your body needs certain chemical clues from its environment in order to thrive and multiply. And even a simple-seeming body part, like a urethra, requires more than one cell type, arranged in certain ways relative to one another.”

In addition to a chart with data on organ donation and need, the article provides a link to a fun video on growing a rat lung in the lab. The author closes with the fact that the greatest need is for kidneys and a discussion of how tough they are to make because of the complex mix of tissues needed.

An advance in building kidneys also made the journals this week, with a press release from Cellular Dynamics describing how their lab grown cells succeeded in coating the inside of blood vessels in a scaffold for a rodent kidney.

Stem cell factors heal damaged hearts. The American Heart Association met in Chicago this week and as always the week of their fall enclave generates several news stories. Genetic Engineering & Biotechnology News wrote up a study from the Icahn School of Medicine at Mount Sinai in New York that suggested how your own stem cells might be recruited to repair damage after a heart attack.

The New York team used a form of gene therapy that introduced the genes for “stem cell factors” that they believe could summon a type of stem cell that some have suggested can repair heart muscle. Although, whether those cells, called c-Kit positive heart stem cells, are actually the cause of the repair remains a subject of debate. They did show that their treatment improved heart function and decreased heart muscle death in the rodent model they were using.

Stem cells improve survival of skin grafts.
With so many soldiers returning from deployments needing reconstructive surgery, several teams at our armed services medical institutes are trying to solve the problem of the soldiers’ immune systems rejecting large skin grafts from donors. One team reported a potentially major advance in the Journal Stem Cells Translational Medicine and the web site benzinga picked up the journal’s press release.

Working in mice the team got the best skin graft survival in animals that received two types of stem cells to induce immune tolerance to the graft. The mice received fat-derived stem cells from humans and an infusion of a small number of their own bone marrow stem cells. The grafts showed no sign of rejection after 200 days, a very long time in a mouse’s life. In the press release, the editor of the journal, Anthony Atala, suggested the results could have broad implications for the field.

“The implications of this research are broad. If these findings are duplicated in additional models and in human trials, there is potential to apply this strategy to many areas of transplantation.”

Leukemia drug may also work in ovarian cancer. The antibody named for CIRM in recognition of our funding of its discovery, cirmtuzumab, which is already in clinical trials in humans for leukemia, may also be effective in one of the most stubborn tumors, ovarian cancer.

Ovarian cancer cells

Ovarian cancer cells

The University of California, San Diego, team led by Thomas Kipps published a study in the Proceedings of the National Academy of Sciences this week showing that in mice the antibody kept transplanted human ovarian cancer cells in check. The tumor that is characterized by rapid spread did not metastasize at all. HealthCanal picked up the university’s press release explaining how the new drug works. You can read about the CIRM-funded clinical trial in leukemia in our fact sheet.

Versatile fingernail stem cells.
The stem cells that regrow our nails are prodigious little critters forcing us to constantly cut or file. But it turns out they are also versatile. They can stimulate nail growth but also growth of skin around the nail.

But if our nails get injured they become single minded and only make nail cells. A team at the University of Southern California has discovered that at the time of injury a particular protein signal gets turned on directing the stem cells to focus on the nails. So, the team is now looking for other signaling proteins that might direct these versatile cells to make other tissues making them potential tools for healing amputations. ScienceDaily picked up the university’s press release.

Don Gibbons

10 Years/10 Therapies: 10 Years after its Founding CIRM will have 10 Therapies Approved for Clinical Trials

In 2004, when 59 percent of California voters approved the creation of CIRM, our state embarked on an unprecedented experiment: providing concentrated funding to a new, promising area of research. The goal: accelerate the process of getting therapies to patients, especially those with unmet medical needs.

Having 10 potential treatments expected to be approved for clinical trials by the end of this year is no small feat. Indeed, it is viewed by many in the industry as a clear acceleration of the normal pace of discovery. Here are our first 10 treatments to be approved for testing in patients.

HIV/AIDS. The company Calimmune is genetically modifying patients’ own blood-forming stem cells so that they can produce immune cells—the ones normally destroyed by the virus—that cannot be infected by the virus. It is hoped this will allow the patients to clear their systems of the virus, effectively curing the disease.

Spinal cord injury patient advocate Katie Sharify is optimistic about the latest clinical trial led by Asterias Biotherapeutics.

Spinal cord injury patient advocate Katie Sharify is optimistic about the clinical trial led by Asterias Biotherapeutics.

Spinal Cord Injury. The company Asterias Biotherapeutics uses cells derived from embryonic stem cells to heal the spinal cord at the site of injury. They mature the stem cells into cells called oligodendrocyte precursor cells that are injected at the site of injury where it is hoped they can repair the insulating layer, called myelin, that normally protects the nerves in the spinal cord.

Heart Disease. The company Capricor is using donor cells derived from heart stem cells to treat patients developing heart failure after a heart attack. In early studies the cells appear to reduce scar tissue, promote blood vessel growth and improve heart function.

Solid Tumors. A team at the University of California, Los Angeles, has developed a drug that seeks out and destroys cancer stem cells, which are considered by many to be the reason cancers resist treatment and recur. It is believed that eliminating the cancer stem cells may lead to long-term cures.

Leukemia. A team at the University of California, San Diego, is using a protein called an antibody to target cancer stem cells. The antibody senses and attaches to a protein on the surface of cancer stem cells. That disables the protein, which slows the growth of the leukemia and makes it more vulnerable to other anti-cancer drugs.

Sickle Cell Anemia. A team at the University of California, Los Angeles, is genetically modifying a patient’s own blood stem cells so they will produce a correct version of hemoglobin, the oxygen carrying protein that is mutated in these patients, which causes an abnormal sickle-like shape to the red blood cells. These misshapen cells lead to dangerous blood clots and debilitating pain The genetically modified stem cells will be given back to the patient to create a new sickle cell-free blood supply.

Solid Tumors. A team at Stanford University is using a molecule known as an antibody to target cancer stem cells. This antibody can recognize a protein the cancer stem cells carry on their cell surface. The cancer cells use that protein to evade the component of our immune system that routinely destroys tumors. By disabling this protein the team hopes to empower the body’s own immune system to attack and destroy the cancer stem cells.

Diabetes. The company Viacyte is growing cells in a permeable pouch that when implanted under the skin can sense blood sugar and produce the levels of insulin needed to eliminate the symptoms of diabetes. They start with embryonic stem cells, mature them part way to becoming pancreas tissues and insert them into the permeable pouch. When transplanted in the patient, the cells fully develop into the cells needed for proper metabolism of sugar and restore it to a healthy level.

HIV/AIDS. A team at The City of Hope is genetically modifying patients’ own blood-forming stem cells so that they can produce immune cells—the ones normally destroyed by the virus—that cannot be infected by the virus. It is hoped this will allow the patients to clear their systems of the virus, effectively curing the disease

Blindness. A team at the University of Southern California is using cells derived from embryonic stem cell and a scaffold to replace cells damaged in Age-related Macular Degeneration (AMD), the leading cause of blindness in the elderly. The therapy starts with embryonic stem cells that have been matured into a type of cell lost in AMD and places them on a single layer synthetic scaffold. This sheet of cells is inserted surgically into the back of the eye to replace the damaged cells that are needed to maintain healthy photoreceptors in the retina.

More Than Meets the Eye: Protein that Keeps Cancer in Check also Plays Direct Role in Stem Cell Biology, a Stanford Study Finds.

Here’s a startling fact: the retinoblastoma protein —Rb, for short — is defective or missing in nearly all cancers.

Rb is called a tumor suppressor because it prevents excessive cell growth by acting as a crucial traffic stop for the cell cycle, a process that controls the timing for a cell to divide and multiply. Without a working Rb protein, that traffic barrier on cell division is effectively removed, allowing unrestricted cell growth and a path towards cancer.

Retinoblastoma - a known road block to cancer growth also inhibits a stem cell's capacity to change into any cell type

Retinoblastoma – a known road block to cancer growth also inhibits a stem cell’s capacity to change into any cell type

The Rb gene was cloned over two decades ago and its link to cancer has been known for years. But today in Cell Stem Cell, CIRM-funded scientists at Stanford University report an unexpected finding: Rb protein also inhibits a stem cell’s pluripotency, or it’s capacity to become any type of cell in the body. Julien Sage, a senior author of the report, described this new facet to Rb in a press release:

“We were very surprised to see that retinoblastoma directly connects control of the cell cycle with pluripotency. This is a completely new idea as to how retinoblastoma functions.”

The research team uncovered Rb’s versatility in experiments using the induced pluripotent stem cell (iPS) technique in which adult cells, such as a skin, are reprogrammed to an embryonic stem cell-like state that, in turn, can be transformed into any cell type.

Creating iPS cells is notoriously slow and inefficient. However, the Stanford scientists found that cells without Rb were much easier and faster to convert to iPS than cells with normal Rb. And when Rb protein levels in the cells were boosted, it was much more difficult to make the iPS cells — suggesting that the presence of Rb was encouraging the skin cells to remain skin and to resist reprogramming into an iPS cell. As Marius Wernig, the other senior author, sums it up:

“The loss of Rb appears to directly change a cell’s identity. Without the protein, the cell is much more developmentally fluid and is easier to reprogram into an iPS cell.”

And Dr. Sage further points out that:

“The process of creating iPS cells from fully differentiated, or specialized, cells is in many ways very similar to what happens when a cell becomes cancerous.”

So now that the team has established the Rb protein’s direct link between stem cell and cancer biology, they stand at unique vantage point to gain new insights on the inner workings of both, such as better iPS methods and new cancer therapy targets.

To hear about more aspects of Marius Wernig’s research, watch his 30 second elevator pitch below:

Unlocking the Wonder Drug’s Secrets: Aspirin Fends Off Colon Cancer by Killing Faulty Intestinal Stem Cells

Over 700,000 people worldwide died from colorectal cancer in 2010, up from 500,000 in 1990, making it the fourth leading cause of cancer death behind lung, stomach and liver.

Remarkably, your household bottle of aspirin – in addition to relieving the common headache – protects against colorectal cancer based on several clinical trials over the past few decades. Though its effect is clear, how exactly aspirin prevents colon cancer has remained murky.

Who cares how it works as long as it saves lives, right?

Ball and stick model of aspirin, the wonder drug: relieves pain and prevents cancer

Ball and stick model of the wonder drug, aspirin. It not only relieves pain but also prevents heart attacks and even cancer.

Well, it turns out that long-term daily use of aspirin carries risks of internal bleeding of the stomach and brain, kidney failure, and certain types of strokes. So unraveling what exactly aspirin does to fend off tumors is an important step to finding new drugs with fewer side effects.

Earlier this week, scientists at University of Pittsburgh Cancer Institute (UPCI) reported that they’ve unlocked the secrets of aspirin’s tumor-killing powers. In their study, published in the Proceedings of the National Academy of Sciences (PNAS), the UPCI team shows that aspirin prevents colon cancer by orchestrating the death of stem cells in the intestine that carry a dangerous mutation.

Most colorectal cancers initially crop up with a mutation in a gene called APC. The APC protein is a so-called tumor suppressor, which acts to keep a lid on any uncontrolled cell division, an early step to tumor growth. So a bad APC gene leads to a faulty APC protein and, in turn, the potential for normal intestinal cells to become cancerous. The intestine has a rich source of stem cells, which are particularly vulnerable to this mutation since stem cells already possess the ability for unlimited cell growth.

The research team compared colorectal tumor samples from patients who had taken aspirin to those who had not. Using these samples in animal studies, the researchers showed that aspirin triggers cell suicide in intestinal stem cells that carry the APC mutation, effectively killing off the cells with the potential of feeding tumor growth. Healthy intestinal cells, on the other hand, are left unscathed by aspirin.

With this important discovery of cell suicide, or programmed cell death in scientific jargon, as the instigator of aspirin’s ability to prevent colon cancer, the research team finds themselves at an exciting new starting line to find drugs for cancer patients with less harmful side effects.

As the senior author Lin Zhang states in a university press release:

“We want to use our new understanding of this mechanism as a starting point to design better drugs and effective cancer prevention strategies for those at high risk of colon cancer.”

What everybody needs to know about CIRM: where has the money gone

It’s been almost ten years since the voters of California created the Stem Cell Agency when they overwhelmingly approved Proposition 71, providing us $3 billion to help fund stem cell research.

In the last ten years we have made great progress – we will have ten projects that we are funding in or approved to begin clinical trials by the end of this year, a really quite remarkable achievement – but clearly we still have a long way to go. However, it’s appropriate as we approach our tenth anniversary to take a look at how we have spent the money, and how much we have left.

Of the $3 billion Prop 71 generates around $2.75 billion was set aside to be awarded to research, build laboratories etc. The rest was earmarked for things such as staff and administration to help oversee the funding and awards.

Of the research pool here’s how the numbers break down so far:

  • $1.9B awarded
  • $1.4B spent
  • $873M not awarded

So what’s the difference between awarded and spent? Well, unlike some funding agencies when we make an award we don’t hand the researcher all the cash at once and say “let us know what you find.” Instead we set a series of targets or milestones that they have to reach and they only get the next installment of the award as they meet each milestone. The idea is to fund research that is on track to meet its goals. If it stops meetings its goals, we stop funding it.

Right now our Board has awarded $1.9B to different institutions, companies and researchers but only $1.4B of that has gone out. And of the remainder we estimate that we will get around $100M back either from cost savings as the projects progress or from programs that are cancelled because they failed to meet their goals.

So we have approximately $1B for our Board to award to new research, which means at our current rate of spending we’ll have enough money to be able to continue funding new projects until around 2020. Because these are multi-year projects we will continue funding them till around 2023 when those projects end and, theoretically at least, we run out of money.

But we are already working hard to try and ensure that the well doesn’t run dry, and that we are able to develop other sources of funding so we can continue to support this work. Without us many of these projects are at risk of dying. Having worked so hard to get these projects to the point where they are ready to move out of the laboratory and into clinical trials in people we don’t want to see them fall by the wayside for lack of support.

Of the $1.9B we have awarded, that has gone to 668 awards spread out over five different categories:

CIRM spending Oct 2014

Increasingly our focus is on moving projects out of the lab and into people, and in those categories – called ‘translational’ and ‘clinical’ – we have awarded almost $630M in funding for more than 80 active programs.

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Under our new CIRM 2.0 plan we hope to speed up the number of projects moving into clinical trials. You can read more about how we plan on doing there in this blog.

It took Jonas Salk almost 15 years to develop a vaccine for polio but those years of hard work ended up saving millions of lives. We are working hard to try and achieve similar results on dozens of different fronts, with dozens of different diseases. That’s why, in the words of our President & CEO Randy Mills, we come to work every day as if lives depend on us, because lives depend on us.

From Stem Cells to Stomachs: Scientists Generate 3D, Functioning Human Stomach Tissue

The human stomach can be a delicate organ. For example, even the healthiest stomach can be compromised by H. pylori bacteria—a tiny but ruthless pathogen which has shown to be linked to both peptic ulcer disease and stomach cancer.

The best way to study how an H. pylori infection leads to conditions like cancer would be to recreate that exact environment, right down to the stomach itself, in the lab. But that task has proven far more difficult than originally imagined.

Part of a miniature stomach grown in the lab, stained to reveal various cells found in normal human stomachs [Credit: Kyle McCracken]

Part of a miniature stomach grown in the lab, stained to reveal various cells found in normal human stomachs [Credit: Kyle McCracken]

But now, scientists at the Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine have successfully grown functional, human stomach tissue in a dish—the first time such a feat has been accomplished.

Further, they were then able to test how human stomach tissue reacts to an invasion by H. pylori—a huge leap forward toward one day developing treatments for potentially deadly stomach disease.

Reporting in today’s issue of the journal Nature, senior author Jim Wells describes his team’s method of turning human pluripotent stem cells into stomach cells, known as gastric cells. Wells explained the importance of their breakthrough in a news release:

“Until this study, no one had generated gastric cells from human pluripotent stem cells. In addition, we discovered how to promote formation of three-dimensional gastric tissue with complex architecture and cellular composition.”

The team called this stomach tissue gastric organoids, a kind of ‘mini-stomach’ that mimicked the major cellular processes of a normal, functioning human stomach. Developing a human model of stomach development—and stomach disease—has long been a goal among scientists and clinicians, as animal models of the stomach did not accurately reflect what would be happening in a human stomach.

In this study, the research team identified the precise series of steps that can turn stem cells into gastric cells. And then they set these steps in motion.

Over the course of a month, the team coaxed the formation of gastric organoids that measured less than 1/10th of one inch in diameter. But even with this small size, the team could view the cellular processes that drive stomach formation—and discover precisely what happens when that process goes awry.

But what most intrigued the researchers, which also included first author University of Cincinnati’s Kyle McCracken, was how quickly an H. pylori infection impacted the health of the stomach tissue.

“Within 24 hours, the bacteria had triggered biochemical changes in the organ,” said McCracken.

According to McCracken, as the H. pylori infection spread from cell to cell, the researchers also recorded the activation of c-Met, a gene known to be linked to stomach cancer—further elucidating the relationship between H. pylori and this form of stomach disease.

Somewhat surprisingly, little was known about how gastric cells play a role in obesity-related diseases, such as type 2 diabetes. But thanks to Wells, McCracken and the entire Cincinnati Children’s research team—we are that much closer to shedding light on this process.

Wells also credits his team’s reliance on years of preliminary data performed in research labs around the world with helping them reach this landmark:

“This milestone would not have been possible if it hadn’t been for previous studies from many other basic researchers on understanding embryonic organ development.”

Scientists Develop Stem Cell ‘Special Forces’ in order to Target, Destroy Brain Tumors

Curing someone of cancer is, in theory, a piece of cake: all you have to do is kill the cancer cells while leaving the healthy cells intact.

But in practice, this solution is far more difficult. In fact, it remains one of the great unsolved problems in modern oncology: how do you find, target and destroy each individual cancer cell in the body—while minimizing damage to the surrounding cells.

Encapsulated toxin-producing stem cells (in blue) help kill brain tumor cells in the tumor resection cavity (in green). [Credit: Khalid Shah, MS, PhD]

Encapsulated toxin-producing stem cells (in blue) help kill brain tumor cells in the tumor resection cavity (in green). [Credit: Khalid Shah, MS, PhD]

But luckily, Harvard Stem Cell Institute scientists at Massachusetts General Hospital may have finally struck gold: they have designed special, toxin-secreting stem cells that can target and destroy brain tumors. Their findings, which were performed in laboratory mice and which appear in the latest issue of the journal STEM CELLS, offer up an entirely unique method for eradicating deadly cancers.

Harvard Neuroscientist Khalid Shah, who led the study, explained in last Friday’s news release that the idea of engineering stem cells to kill cancer cells is not new—but there was a key difference in scientists’ ability to target individual cells vs. difficult-to-reach tumors, which is often the case with brain cancer:

“Cancer-killing toxins have been used with great success in a variety of blood cancers, but they don’t work as well in solid tumors because the cancers aren’t as accessible and the toxins have a short half-life.”

The solution, Shah and his team argued, was stem cells. Previously, Shah and his team discovered that stem cells could be used to circumvent these problems. The fact that stem cells continuously renew meant that they could also be used to continually deliver toxins to brain tumors.

“But first, we needed to genetically engineer stem cells that could resist being killed themselves by the toxins,” said Shah.

In this study, the research team introduced a small genetic change, or mutation, into the stem cells so that they become impervious to the toxin’s harmful effects. They then introduced a second mutation that allowed the stem cells to maintain and produce and secrete toxins throughout the cells’ lifetime—effectively giving it an unlimited supply of ammunition to use once it encountered the brain tumor.

They then employed a common technique whereby the toxins were tagged so that they only sought out and infected cancer cells—leaving healthy cells unscathed.

“We tested these stem cells in a clinically relevant mouse model of brain cancer,” Shah described. “After doing all of the molecular analysis and imaging to track the inhibition of protein synthesis within brain tumors, we do see the toxins kill the cancer cells and eventually prolonging the survival in animal models.”

While preliminary, these results are encouraging. As the team continues to refine their method of development and delivery, they are optimistic that they can bring their methods to clinical trial within the next five years.

CIRM-Funded Scientists Make New Progress Toward Engineering a Human Esophagus

Creating tissues and organs from stem cells—often referred to as ‘tissue engineering’—is hard. But new research has discovered that the process may in fact be a little easier than we once thought, at least in some situations.

Engineered human esophageal tissue [Credit: The Saban Research Institute].

Engineered human esophageal tissue [Credit: The Saban Research Institute].

Last week, scientists at The Saban Research Institute of Children’s Hospital Los Angeles announced that the esophagus—the tube that transports food, liquid and saliva between the mouth and the stomach—can be grown inside animal models after injecting the right mix of early-stage, or ‘progenitor,’ esophageal cells.

These findings, published in the journal Tissue Engineering Part A, are an important step towards generating tissues and organs that have been damaged due to disease or—in some cases—never existed in the first place.

According to stem cell researcher Tracy Grikscheit, who led the CIRM-funded study, the researchers first implanted a biodegradable ‘scaffold’ into laboratory mice. They then injected human progenitor cells into the mice and watched as they first traveled to the correct location—and then began to grow. The ability to both migrate to the right location and differentiate into the right cell type, without the need for any external coaxing, is crucial if scientists are to successfully engineer such a critical type of tissue.

“Different progenitor cells can find the right ‘partner’ in order to grow into specific esophageal cell types—and without the need for [outside] growth factors,” explained Grikscheit in a news release. “This means that successful tissue engineering of the esophagus is simpler than we previously thought.”

Grikscheit, who is also a pediatric surgeon as Children’s Hospital Los Angeles, was particularly hopeful with how their findings might one day be used to treat children born with portions of the esophagus missing—as well as adults suffering from esophageal cancer, the fastest-growing cancer in the U.S.

“We have demonstrated that a simple and versatile, biodegradable polymer is sufficient for the growth of a tissue-engineered esophagus from human cells. This not only serves as a potential source of tissue, but also a source of knowledge—as there are no other robust models available for studying esophageal stem cell dynamics.”

Want to learn more about tissue engineering? Check out these video highlights from a recent CIRM Workshop on the field.

Cells’ Knack for Hoarding Proteins Inadvertently Kickstarts the Aging Process

Even cells need to take out the trash—mostly damaged or abnormal proteins—in order to maintain a healthy clean environment. And scientists are now uncovering the harmful effects when cells instead begin to hoard their garbage.

Cells' penchant for hoarding proteins may spur the cellular aging process, according to new research.

Cells’ penchant for hoarding proteins may spur the cellular aging process, according to new research. [Labyrinth (1986)]

Aging, on the cellular level is—at its core—the increasing inability for cells to repair themselves over time. As cells begin to break down faster than they can be repaired, the risk of age-related diseases escalates. Cancer, heart disease and neurological conditions such as Alzheimer’s disease are some of aging’s most deadly effects.

As a result, scientists have long searched for ways to give our cells a little help and improve our quality of life as we age. For example, recent research has pointed to a connection between fasting (restricting calories) and a longer lifespan, though the molecular mechanisms behind this connection remain somewhat cryptic.

But now Dr. Daniel Gottschling, a scientist at the Fred Hutchinson Cancer Research Center and an aging expert, has made extraordinary progress toward solving some of the mysteries of aging.

In two studies published this month in the Proceedings of the National Academy of Sciences and eLife, Gottschling and colleagues discover that a particular long-lasting protein builds up over time in certain cell types, causing the buildup of a protein hoard that damages the cell beyond repair.

Clearing out the Cobwebs

Some cells, such as those that make up the skin or that reside in the gut, are continually replenished by a stockpile of adult stem cells. But other cells, such as those found in the eye and brain, last for years, decades and—in some cases—our entire lifetimes.

Within and surrounding these long-lived cells are similarly long-lived proteins which help the cell perform essential functions. For example, the lens of the human eye, which helps focus light, is made up of these proteins that arise during embryonic development and last for a lifetime.

Dr. Daniel Gottschling is looking to unlock the mysteries behind cellular aging.

Dr. Daniel Gottschling is looking to unlock the mysteries behind cellular aging. [Image courtesy of the Fred Hutchinson Cancer Research Center]

“Shortly after you’re born, that’s it, you get no more of that protein and it lives with you the rest of your life,” explained Gottschling.

As a result, if those proteins degrade and die, new ones don’t replace them—the result is the age-related disease called cataracts.

But scientists weren’t exactly sure of the relationship between these dying proteins and the onset of conditions such as cataracts, and other disease related to aging. Did these conditions occur because the proteins were dying? Or rather because the proteins were building up to toxic levels?

So Gottschling and his team set up a series of experiments to find out.

Stashing Trash

They developed a laboratory model by using yeast cells. Interestingly, yeast cells share several key properties with human stem cells, and are often the focus of early-stage research into basic, fundamental concepts of biology.

Like stem cells, yeast cells grow and divide asymmetrically. In other words, a ‘mother’ cell will produce many ‘daughter’ cells, but will itself remain intact. In general, yeast mother cells produce up to 35 daughter cells before dying—which usually takes just a few days.

 Yeast “mother” cells budding and giving birth to newborn “daughter” cells.  [Image courtesy of Dr. Kiersten Henderson / Gottschling Lab]

Yeast “mother” cells budding and giving birth to newborn “daughter” cells.
[Image courtesy of Dr. Kiersten Henderson / Gottschling Lab]

Here, the research team used a special labeling technique that marked individual proteins that exist within and surrounding these mother cells. These microscopic tracking devices then told researchers how these proteins behaved over the entire lifespan of the mother cell as it aged.

The team found a total of 135 long-lived proteins within the mother cell. But what really surprised them was what they found upon closer examination: all but 21 of these 135 proteins appeared to have no function. They appeared to be trash.

“No one’s ever seen proteins like this before [in aging],” said Nathanial Thayer, a graduate student in the Gottschling Lab and lead author of one of the studies.

Added Gottschling, “With the number of different fragments [in the mother cell], we think they’re going to cause trouble. As the daughter yeast cells grow and split off, somehow mom retains all these protein bits.”

This startling discovery opened up an entirely new set of questions, explained Gottschling.

“It’s not clear whether the mother’s trash keeper function is a selfless act designed to give her daughters the best start possible, or if she’s hanging on to them for another reason.”

Hungry, Hoarding Mother Cells

So Gottschling and his team took a closer look at one of these proteins, known as Pma1.

Recent work by the Gottschling Lab found that cells lose their acidity over time, which itself leads to the deterioration of the cells’ primary energy source. The team hypothesized that Pma1 was somehow intricately tied to corresponding levels of pH (high pH levels indicate an acidic environment, while lower pH levels signify a more basic environment).

In the second study published in eLife, led by Postdoctoral Fellow Dr. Kiersten Henderson, the team made several intriguing discoveries about the role of Pma1.

First, they uncovered a key difference between mother and daughter cells: daughter cells are born with no Pma1. As a result, they are far more acidic than their mothers. But when they ramped up Pma1 in the mother cells, the acidity levels in subsequent generations of daughter cells changed accordingly.

“When we boosted levels of the protein, daughter cells were born with Pma1 and became more basic (they had a lower pH), just like their mothers.”

Further examination uncovered the true relationship between Pma1 and these cells. At its most fundamental, Pma1 helps the mother cells eat.

“Pma1 plays a key role in cellular feeding,” said Gottschling. “The protein sits on the surface of cells and helps them take in nutrients from their environment.”

Pma1 gives the mother cell the ability to gorge herself. The more access to food she has, the easier it is for her to produce more daughter cells. By hoarding Pma1, the mother cell can churn out more offspring. Unfortunately, she is also signing her own death certificate—she’s creating a more basic environment that, in the end, proves toxic and contributes to her death.

The hoarding, it turns out, may not all be due to the mother cells’ failure to ‘take out the trash.’ Instead, she wants to keep eating and producing daughters—and hoarding Pma1 allows her to do just that.

“There’s this whole trade off of being able to divide quickly and the negative side is that the individual, the mother, does not get to live as long.”

Together, the results from these two studies provide a huge boost for researchers like Gottschling who are trying to unravel the molecular mysteries of aging. But the process is incredibly intricate, and there will likely be no one simple solution to improving quality of life as we get older.

“The whole issue of aging is so complex that we’re still laying the groundwork of possibilities of how things can go awry,” said Gottschling. “And so we’re still learning what is going on. We’re defining the aging process.”

New Cellular Tracking Device Tests Ability of Cell-Based Therapies to Reach Intended Destination

Therapies aimed at replacing damaged cells with a fresh, healthy batch hold immense promise—but there remains one major sticking point: once you have injected new, healthy cells into the patient, how do you track them and how do you ensure they do the job for which they were designed?

New tracking technique could improve researchers' ability to test potential cell therapies.

New tracking technique could improve researchers’ ability to test potential cell therapies.

Unfortunately, there’s no easy solution. The problem of tracking the movement of cells during cell therapy is that it’s hard to stay on their trail they enter the body. They can get mixed up with other, native cells, and in order to test whether the therapy is working, doctors often have to rely on taking tissue samples.

But now, scientists at the University of California, San Diego School of Medicine and the University of Pittsburgh have devised an ingenious way to keep tabs on where cells go post injection. Their findings, reported last week in the journal Magnetic Resonance in Medicine, stand to help researchers identify whether cells are arriving at the correct destination.

The research team, lead by UCSD Radiology Professor Dr. Eric Ahrens, developed something called a periflourocarbon (PFC) tracer in conjunction with MRI technology. Testing this new technology in patients receiving immune cell therapy for colorectal cancer, the team found that they were better able to track the movement of the cells than with traditional methods.

“This is the first human PFC cell tracking agent, which is a new way to do MRI cell tracking,” said Ahrens in a news release. “It’s the first example of a clinical MRI agent designed specifically for cell tracking.”

They tagged these cells with atoms of fluorine, a compound that normally occurs at extremely low levels. After tagging the immune cells, the researchers could then see where they went after being injected. Importantly, the team found that more than one-half of the implanted cells left the injection site and headed towards the colon. This finding marks the first time this process had been so readily visible.

Ahrens explained the technology’s potential implications:

“The imaging agent technology has been shown to be able to tag any cell type that is of interest. It is a platform imaging technology for a wide range of diseases and applications.”

A non-invasive cell tracking solution could serve as not only as an attractive alternative to the current method of tissue sampling, it could even help fast-track through regulatory hurdles new stem cell-based therapies. According to Ahrens:

“For example, new stem cell therapies can be slow to obtain regulatory approvals in part because it is difficult, if not impossible, with current approaches to verify survival and location of transplanted cells…. Tools that allow the investigator to gain a ‘richer’ data set from individual patients mean it may be possible to reduce patient numbers enrolled in a trial, thus reducing total trial cost.”

What are the ways scientists see stem cells in the body? Check out our Spotlight Video on Magnetic Particle Imaging.