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.

Harder, Better, Faster, Stronger: Scientists Work to Create Improved Immune System One Cell at a Time

The human immune system is the body’s best defense against invaders. But even our hardy immune systems can sometimes be outpaced by particularly dangerous bacteria, viruses or other pathogens, or even by cancer.

Salk Institute scientists have developed a new cellular reprogramming technique that could one day boost a weakened immune system.

Salk Institute scientists have developed a new cellular reprogramming technique that could one day boost a weakened immune system.

But what if we could give our immune system a boost when it needs it most? Last week scientists at the Salk Institute for Biological Sciences devised a new method of doing just that.

Reporting in the latest issue of the journal Stem Cells, Dr. Juan Carlos Izpisua Belmonte and his team announce a new method of creating—and then transplanting—white blood cells into laboratory mice. This new and improved method could have significant ramifications for how doctors attack the most relentless disease.

The authors achieved this transformation through the reprogramming of skin cells into white blood cells. This process builds on induced pluripotent stem cell, or iPS cell, technology, in which the introduction of a set of genes can effectively turn one cell type into another.

This Nobel prize-winning approach, while revolutionary, is still a many months’ long process. In this study, the Salk team found a way to shorten the cellular ‘reprogramming’ process from several months to just a few weeks.

“The process is quick and safe in mice,” said Izpisua Belmonte in a news release. “It circumvents long-standing obstacles that have plagued the reprogramming of human cells for therapeutic and regenerative purposes.”

Traditional reprogramming methods change one cell type, such as a skin cell, into a different cell type by first taking them back into a stem cell-like, or ‘pluripotent’ state. But here, the research team didn’t take the cells all the way back to pluripotency. Instead, they simply wiped the cell’s memory—and gave it a new one. As first author Dr. Ignacio Sancho-Martinez explained:

“We tell skin cells to forget what they are and become what we tell them to be—in this case, white blood cells. Only two biological molecules are needed to induce such cellular memory loss and to direct a new cell fate.”

This technique, which they dubbed ‘indirect lineage conversion,’ uses the molecule SOX2 to wipe the skin cell’s memory. They then use another molecule called miRNA 125b to reprogram the cell into a white blood cell.

These newly generated cells appear to engraft far better than cells derived from traditional iPS cell technology, opening the door to therapies that more effectively introduce these immune cells into the human body. As Sanchi-Martinez so eloquently stated:

“It is fair to say that the promise of stem cell transplantation is now closer to realization.”

Stem cell stories that caught our eye: first iPS clinical trial, cancer metabolism and magnates helping heal 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.

First clinical trial with reprogrammed stem cells.
Today, a Japanese woman became the first patient to be treated with cells derived from reprogrammed iPS-type stem cells. The patient received cells matured into a type of cell damaged in the most common form of blindness, age-related macular degeneration.

Those cells, a normal part of the eye’s retina, were made from stem cells created from a skin sample donated by the patient several months ago. In the intervening time the resulting retinal cells have been tested in mice and monkeys to make sure they will not cause tumors. Because the cells have the same genes as the patient, researchers believe they may not be rejected by the patient’s immune system in the absence of immune suppressive drugs—the beauty of iPS technology.

Right now, that technology is much too cumbersome and time consuming to result in a broadly applicable therapy. But if this first clinical trial proves the immune system get-out-of-jail-free theory, it should intensify efforts to make iPS technology more efficient.

When Japanese authorities gave permission to treat the first patient earlier this week Popular Science provided an easy read version of the story and Nature News provided a bit more detail.

Cancer cells don’t handle their sugar well. Sugar has a bad rep these days. Now, it looks like manipulating sugar metabolism might lead to ways to better treat leukemia and perhaps, make therapies less toxic to normal cells. It turns out cancer cells are much more sensitive to changes in sugar level than normal blood stem cells or the intermediate cells that give rise the various branches of the blood system.

David Scadden at the Harvard Stem Cell Institute has long studied the role of the stem cell's environment in its function.

David Scadden at the Harvard Stem Cell Institute has long studied the role of the stem cell’s environment in its function.

A team led by old friend and colleague at the Harvard Stem Cell Institute, David Scadden, first looked at sugar metabolism in normal blood forming stem cells and their intermediate cells. They found that the parent stem cell and their direct offspring, those intermediate cells, behave differently when faced with various manipulations in sugar level, which makes sense since the intermediate cells are usually much more actively dividing.

But when they manipulated the genes of both types of cells to make them turn cancerous, the cancer cells from both were much more sensitive to changes in sugar metabolism. In a university press release picked up by ScienceCodex David said he hoped to interest drug companies in developing ways to exploit these differences to create better therapies.

Magnets and nanoparticles steer stem cells.
Getting stem cells to where they are needed to make a repair, and keeping them there is a major challenge. A team at Los Angeles’ Cedars-Sinai hospital that we fund (but not for this study) has taken an approach to this problem that is the equivalent of holding your pants up with a double set of button, a belt and suspenders.

Treating damaged hearts in rats they first loaded iron-containing nanoparticles with two types of antibodies, one that recognizes and homes to injured heart tissue and one that attracts healing stem cells. After infusing them into the animal’s blood stream, they placed a magnet over its heart to hold the iron nanoparticles near by. The iron provided the added benefit of letting the team track the cells via magnetic resonance imaging (MRI) to verify they did get to and stay where they were needed.

In a press release from the hospital picked up by ScienceDaily the lead researcher Eduardo Marban said:

“The result is a kind of molecular matchmaking,”

The study was published in Nature Communications and you can read about other work we fund in Marban’s lab trying to figure out once you get the stem cells to the heart exactly how do they create the repair.

Reprogrammed stem cells turned into white blood cells. We have written often about the difficulties of getting stem cells to create fully mature blood cells. Last week we talked about a Wisconsin team breaking the barrier for red blood cells. Now, a team at the Salk Institute is reporting success for white blood cells.

Starting with iPS-type stem cells they got the mature white cells via a two-step process. First they manipulated one gene called Sox2 to get the stem cells to become the right intermediate cells. Then they used a gene-regulating molecule called a micro-RNA to get the middleman cells to mature into white blood cells.

In a press release from the Salk, lead researcher Juan Carlos Izpisua Belmonte noted the clinical importance of the work:

“In terms of potential clinical applications, the hematopoietic system represents one of the most suitable tissues for stem cell-based therapies. . .”

The team published the research in the journal Stem Cells and the web portal BioSpace picked up the release.

Book on early spinal cord injury clinical trial. The title of a book on the first ever clinical trial using cells from embryonic stem cells kind of says it all: Inevitable Collision: The Inspiring Story that Brought Stem Cell Research to Conservative America.

Katy Sharify's experience in the first embryonic stem cell trial is featured in a new book and she discussed it in a video from a CIRM workshop.

Katy Sharify’s experience in the first embryonic stem cell trial is featured in a new book and she discussed it in a video from a CIRM workshop.


The book details the personal stories of the first and fifth patients in the spinal cord injury trial conducted by Geron. That company made the financial decision to end its stem cell product development in favor of its cancer products. But the spinal cord injury trial is now set to restart, modified to treat neck injuries instead of back injuries and at higher doses, through CIRM funding to the company that bought the Geron stem cell business, Asterias.

In a press release from the publisher, the book’s author explained her goal:

“Through this book I hope to bridge the gap between science and religion and raise awareness of the importance and power of stem cell research.”

The fifth patient in the Geron study, Katie Sharify, is featured in our “Stories of Hope” that have filled The Stem Cellar this week.

Don Gibbons

Stories of Hope: Leukemia

This week on The Stem Cellar we feature some of our most inspiring patients and patient advocates as they share, in their own words, their Stories of Hope.

Stem cells create life. But if things go wrong, they can also threaten it. Theresa Blanda found that out the hard way. Fortunately for her, CIRM-funded research helped her fight this threat, and get her life back.

Theresa's battle with leukemia took a happier turn after entering into a stem cell-based clinical trial.

Theresa’s battle with leukemia took a happier turn after entering into a stem cell-based clinical trial.

In the first few days of human development embryonic stem cells are a blank slate; they don’t yet have a special, defined role, but have potential. The potential to turn into the cells that make up our kidneys, heart, brain, every other organ and every tissue in our body. Because of this flexibility, stem cells have shown great promise as a way to regenerate dead, diseased or injured tissue to treat many life-threatening or chronic conditions.

But some studies have suggested a secret, darker side to stem cells—so-called cancer stem cells. Like their embryonic cousins, these cells have the ability to both self-renew— to divide and make more copies of themselves – and specialize into other cell types. Many researchers believe they can serve as a reservoir for cancer, constantly reinvigorating tumors, helping them spread throughout the body. To complicate matters, these slow-growing cells are often impervious to cancer therapies, enabling them to survive chemotherapy.

For Theresa Blanda, cancer stem cells were dragging her down a slippery slope towards disease and possibly death. In 2003, she was diagnosed with polycythemia vera (CV), which causes the body to produce too many red blood cells. As sometimes happens with CV patients, her body began producing too many white blood cells as well. Eventually, she developed an even more serious condition, myelofibrosis, a form of bone marrow scarring that results in an enlarged spleen, bone pain, knee swelling and other debilitating symptoms.

“You couldn’t even breathe my way or I’d bruise,” says Theresa. “I didn’t think I was going to make it.”

Her doctors wanted to do a bone marrow transplant, but were having difficulty finding the right donor. “Finally, I just asked if there was some kind of clinical trial that could help me,” says Theresa.

Fortunately, there was.

The Root Cause
At UC San Diego’s Moores Cancer Center, Catriona Jamieson, M.D., Ph.D., had made a discovery that would have a big impact on Theresa’s health. In research funded in part by CIRM, Jamieson found a key mutation in blood-forming stem cells. Specifically, a mutation in a gene called JAK2 was being passed on to Theresa’s entire blood system, causing CV and myelofibrosis. Without effective treatment, her condition could have progressed into acute myeloid leukemia, a blood cancer with a very poor survival rate.

“These malignant stem cells create an inhospitable environment for regular stem cells, suppressing normal blood formation,” says Jamieson. “We needed to get rid of these mutated stem cells so the normal ones could breathe a sigh of relief.”

The answer was a JAK2 inhibitor being developed by San Diego-based TargeGen. Though the trial had already started, they made room for Theresa and the results were amazing. Within weeks, her discomfort had faded, her spleen had returned to normal and she was back at work.

“In a month or two I was feeling pretty good,” says Theresa. “I could climb stairs and the swelling in my knee had gone down.”

She continued on the drug for five years but safety issues forced the trial to be suspended. But the work continues. With continued support from CIRM, Jamieson and others are investigating new JAK2 inhibitors, and other alternatives, to help myelofibrosis patients.

“Because of CIRM funding, we’ve managed to develop a number of agents that have gone into clinical trials,” says Jamieson. “That means patients have lived to hold their grandchildren, attend their mom’s hundredth birthday party and live fruitful lives.”

For more information about CIRM-funded leukemia research, visit our Leukemia Fact Sheet. You can read more about Theresa’s Story of Hope on our website.

CIRM-Funded Scientists Test Recipe for Building New Muscles

When muscles get damaged due to disease or injury, the body activates its reserves—muscle stem cells that head to the injury site and mature into fully functioning muscle cells. But when the reserves are all used up, things get tricky.

Scientists at Sanford-Burnham may have uncovered the key to muscle repair.

Scientists at Sanford-Burnham may have uncovered the key to muscle repair.

This is especially the case for people living with muscle diseases, such as muscular dystrophy, in which the muscle degrades at a far faster rate than average and the body’s reserve stem cell supply becomes exhausted. With no more supply from which to draw new muscle cells, the muscles degrade further, resulting in the disease’s debilitating symptoms, such as progressive difficulty walking, running or speaking.

So, scientists have long tried to find a way to replenish the dwindling supply of muscle stem cells (called ‘satellite cells’), thus slowing—or even halting—muscle decay.

And now, researchers at the Sanford-Burnham Medical Research Institute have found a way to tweak the normal cycle, and boost the production of muscle cells even when supplies appear to be diminished. These findings, reported in the latest issue of Nature Medicine, offer an alternative treatment for the millions of people suffering not only from muscular dystrophy, but also other diseases that result in muscle decay—such as some forms of cancer and age-related diseases.

In this study, Sanford-Burnham researchers found that introducing a particular protein, called a STAT3 inhibitor, into the cycle of muscle-cell regeneration could boost the production of muscle cells—even after multiple rounds of repair that would otherwise render regeneration virtually impossible.

The STAT3 inhibitor, as its name suggests, works by ‘inhibiting,’ or effectively neutralizing, another protein called STAT3. Normally, STAT3 gets switched on in response to muscle injury, setting in motion a series of steps that replenishes muscle cells.

In experiments first in animal models of muscular dystrophy—and next in human cells in a petri dish—the team decided to modify how STAT3 functions. Instead of keeping STAT3 active, as would normally occur, the team introduced the STAT3 inhibitor at specific times during the muscle regeneration process. And in so doing, noticed a significant boost in muscle cell production. As Dr. Alessandra Sacco, the study’s senior author, stated in a news release:

“We’ve discovered that by timing the inhibition of STAT3—like an ‘on/off’ light switch—we can transiently expand the satellite cell population followed by their differentiation into mature cells.”

This approach to spurring muscle regeneration, which was funded in part by a CIRM training grant, is not only innovative, but offers new hope to a disease for which treatments have offered little. As Dr. Vittorio Sartorelli, deputy scientific director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), stated:

“Currently, there is no cure to stop or reverse any form of muscle-wasting disorders—only medication and therapy that can slow the process. A treatment approach consisting of cyclic bursts of STAT3 inhibitors could potentially restore muscle mass and function in patients, and this would be a very significant breakthrough.”

Sacco and her colleagues are encouraged by these results, and plan to explore their findings in greater detail—hopefully moving towards clinical trials:

“Our next step is to see how long we can extend the cycling pattern, and test some of the STAT3 inhibitors currently in clinical trials for other indications such as cancer, as this could accelerate testing in humans.”

Stem Cell Stories that Caught our Eye: What’s the Best Way to Treat Deadly Cancer, Destroying Red Blood Cells’ Barricade, Profile of CIRM Scientist Denis Evseenko

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.

Stem Cells vs. Drugs for Treating Deadly Cancer. When dealing with a potentially deadly form of cancer, choosing the right treatment is critical. But what if that treatment also poses risks, especially for older patients? Could advances in drug development render risky treatments, such as transplants, obsolete?

That was the focus of a pair of studies published this week in the New England Journal of Medicine, where a joint Israeli-Italian research team investigated the comparative benefits of two different treatments for a form of cancer called multiple myeloma.

Multiple myeloma attacks the body’s white blood cells. While rare, it is one of the most deadly forms of cancer—more than half of those diagnosed with the disease do not survive five years after being diagnosed. The standard form of treatment is usually a stem cell transplant, but with newer and better drugs coming on the market, could they render transplants unnecessary?

In the twin studies, the research team divided multiple myeloma patients into two groups. One received a combination of stem cell transplant and chemotherapy, while the other received a combination of drugs including melphalan, prednisone and lenalidmomide. After tracking these patients over a period of four years, the research team saw a clear advantage for those patients that had received the transplant-chemotherapy treatment combination.

To read more about these twin studies check out recent coverage in NewsMaxHealth.

Breaking Blood Cells’ Barricade. The process whereby stem cells mature into red blood cells is, unfortunately, not as fast as scientists would like. In fact, there is a naturally occurring barrier that keeps the production relatively slow. In a healthy person this is not necessarily a problem, but for someone in desperate need of red blood cells—it can prove to be very dangerous.

Luckily, scientists at the University of Wisconsin-Madison have found a way to break through this barrier by switching off two key proteins. Once firmly in the ‘off’ position, the team could boost the production of red blood cells.

These findings, published in the journal Blood, are critical in the context of disease anemia, where the patient’s red blood cell count is low. They also may lead to easier methods of stocking blood banks.

Read more about this exciting discovery at HealthCanal.

CIRM Scientist on the Front Lines of Cancer. Finally, HealthCanal has an enlightening profile of Dr. Denis Evseenko, a stem cell scientist and CIRM grantee from the University of California, Los Angeles (UCLA).

Born in Russia, the profile highlights Evseenko’s passion for studying embryonic stem cells—and their potential for curing currently incurable diseases. As he explains in the article:

“I had a noble vision to develop progressive therapies for the patient. It was a very practical vision too, because I realized how limited therapeutic opportunities could be for the basic scientist, and I had seen many great potential discoveries die out before they ever reached the clinic. Could I help to create the bridge between stem cells, research and actual therapeutics?”

Upon arriving at UCLA, Evseenko knew he wanted to focus this passion into the study of degenerative diseases and diseases related to aging, such as cancer. His bold vision of bridging the gap between basic and translational research has earned him support not only from CIRM, but also the National Institutes of Health and the US Department of Defense, among others. Says Evseenko:

“It’s my hope that we can translate the research we do and discoveries we make here to the clinic to directly impact patient care.”

UCSD Team Launches CIRM-Funded Trial to Test Safety of New Leukemia Drug

Ridding weeds from your lawn can be a frustrating experience without a good weeding tool in hand. If you don’t rip out the whole weed, root and all, it’s likely to grow back in no time.

Cancer patients and their physicians experience a similar frustration but with deadly consequences. Many current cancer treatment “tools” effectively destroy most but not all of the cancer. Often, the cancer ultimately returns with a vengeance, spreading throughout the body leading to organ failure and death.

What if you could figure out a way to seek out and destroy those few cancer cells that slip through the grasp of conventional anti-cancer drugs and therapy?

Blood smear showing chronic lymphocytic leukemia (CLL). The purple-stained cells are the CLL cells.

Blood smear showing chronic lymphocytic leukemia (CLL). The purple-stained cells are the CLL cells.

Today, a team from the UCSD Moore Cancer Center in partnership with Celgene Corporation announced that they’ve launched a CIRM-funded clinical trial that will embark on answering this question for people living with chronic lymphocytic leukemia (CLL). CLL is the most common form of blood cancer in adults. In the US alone, over 15,000 people are newly diagnosed annually.

In recent years, scientists have observed that a fraction of cancer cells within the leukemia or solid tumors have stem cell-like properties that allow them to continually grow in number and metastasize—in other words, spread throughout the body. During the development of an embryo, this immortal-like property is critical for the growth of the adult organism. But in taking advantage of this trait, these so-called cancer stem cells have made it very difficult for doctors to find and pull out the entire cancer “weed”.

But the UCSD team, led by Dr. Thomas Kipps, has potentially found the leukemia stem cells’ Achilles heel: a protein called ROR1 that sits on the surface of the cells and is responsible for boosting cell growth. ROR1 is normally not found on adult cells and only exists in embryonic cells. So the team produced a protein, called an antibody, that recognizes and clings tightly to ROR1, blocking its ability to function and to promote the cancer cells’ growth. No uncontrolled cell growth, no cancer.

Kipps summarized this point in a UCSD press release:

“Because cancer stem cells may require ROR1 for their growth, survival and movement through the body, targeting ROR1 could be a way to eradicate the seeds of the cancer that are responsible for metastasis or relapse after other forms of treatment.”

This initial clinical trial is focused on making sure the ROR1 antibody is safe and well-tolerated in 33 to 78 CLL patients in whom the cancer has either returned after conventional treatment or the treatments were ineffective from the start.

If the therapy, which goes by the name cirmtuzumab, is eventually found to be effective, Dr. Kipps envisions that it could be used in concert with conventional cancer drugs to hit the cancers from several angles:

“I see cirmtuzumab as perhaps also synergizing with other forms of treatment to provide for more effective anti-cancer therapies. It’s the cocktail approach, similar to what’s been shown to be effective in treating patients with HIV. Multiple drugs attack multiple targets of the cancer, each eliminating subsets of malignant cells. When combined with anti-ROR1 therapy, we might also block the recurrence of cancer after treatment.”

This announcement follows on the heels of last week’s announcements of the start of two other CIRM-funded trials for type 1 diabetes and spinal cord injury. There’s still a long road to approved therapies but the entire CIRM community is excited by these developments which we hope will bring treatments for people living with incurable diseases.

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.

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.