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Cells in the human body contain power-generating mitochondria, each with their own mtDNA — a unique set of genetic instructions entirely separate from the cell’s nuclear DNA that mitochondria use to create life-giving energy. When mtDNA remains where it belongs (inside of mitochondria), it sustains both mitochondrial and cellular health — but when it goes where it doesn’t belong, it can initiate an immune response that promotes inflammation.
Now, Salk scientists and collaborators at UC San Diego have discovered a novel mechanism used to remove improperly functioning mtDNA from inside to outside the mitochondria. When this happens, the mtDNA gets flagged as foreign DNA and activates a cellular pathway normally used to promote inflammation to rid the cell of pathogens, like viruses.
The findings, published in Nature Cell Biology on February 8, 2024, offer many new targets for therapeutics to disrupt the inflammatory pathway and therefore mitigate inflammation during aging and diseases, like lupus or rheumatoid arthritis.
“We knew that mtDNA was escaping mitochondria, but how was still unclear,” says senior and co-corresponding author Professor Gerald Shadel, director of the San Diego-Nathan Shock Center of Excellence in the Basic Biology of Aging and holder of the Audrey Geisel Chair in Biomedical Science at Salk. “Using imaging and cell biology approaches, we’re able to trace the steps of the pathway for moving mtDNA out of the mitochondria, which we can now try to target with therapeutic interventions to hopefully prevent the resulting inflammation.”
One of the ways our cells respond to damage and infection is with what’s known as the innate immune system. While the innate immune response is the first line of defense against viruses, it can also respond to molecules the body makes that simply resemble pathogens — including misplaced mtDNA. This response can lead to chronic inflammation and contribute to human diseases and aging.
Scientists have been working to uncover how mtDNA leaves mitochondria and triggers the innate immune response, but the previously characterized pathways did not apply to the unique mtDNA stress conditions the Salk team was investigating. So, they turned to sophisticated imaging techniques to gather clues as to where and when things were going awry in those mitochondria.
“We had a huge breakthrough when we saw that mtDNA was inside of a mysterious membrane structure once it left mitochondria — after assembling all of the puzzle pieces, we realized that structure was an endosome,” says first author Laura Newman, former postdoctoral researcher in Shadel’s lab and current assistant professor at the University of Virginia. “That discovery eventually led us to the realization that the mtDNA was being disposed of and, in the process, some of it was leaking out.”
The team discovered a process beginning with a malfunction in mtDNA replication that caused mtDNA-containing protein masses called nucleoids to pile up inside of mitochondria. Noticing this malfunction, the cell then begins to remove the replication-halting nucleoids by transporting them to endosomes, a collection of organelles that sort and send cellular material for permanent removal. The endosome gets overloaded with these nucleoids, springs a leak, and mtDNA is suddenly loose in the cell. The cell flags that mtDNA as foreign DNA — the same way it flags a virus’s DNA — and initiates the DNA-sensing cGAS-STING pathway to cause inflammation.

“Using our cutting-edge imaging tools for probing mitochondria dynamics and mtDNA release, we have discovered an entirely novel release mechanism for mtDNA,” says co-corresponding author Uri Manor, former director of the Waitt Advanced Biophotonics Core at Salk and current assistant professor at UC San Diego. “There are so many follow-up questions we cannot wait to ask, like how other interactions between organelles control innate immune pathways, how different cell types release mtDNA, and how we can target this new pathway to reduce inflammation during disease and aging.”
The researchers hope to map out more of this complicated mtDNA-disposal and immune-activation pathway, including what biological circumstances — like mtDNA replication dysfunction and viral infection — are required to initiate the pathway and what downstream effects there may be on human health. They also see an opportunity for therapeutic innovation using this pathway, which represents a new cellular target to reduce inflammation.
Other authors include Sammy Weiser Novak, Gladys Rojas, Nimesha Tadepalle, Cara Schiavon, Christina Towers, Matthew Donnelly, Sagnika Ghosh, Sienna Rocha, and Ricardo Rodriguez-Enriquez of Salk; Danielle Grotjahn and Michaela Medina of The Scripps Research Institute; Marie-Ève Tremblay of the University of Victoria in Canada; Joshua Chevez of UC San Diego; and Ian Lemersal of the La Jolla Institute for Immunology.
The work was supported by the National Institutes of Health (R01 AR069876, P30AG068635, 1K99GM141482, 1F32GM137580, T32GM007198, 5R00CA245187, and 5R00CA245187-04S1), an Allen-AHA Initiative in Brain Health and Cognitive Impairment award (19PABH134610000H), a National Science Foundation NeuroNex Award (2014862), Chan-Zuckerberg Initiative Imaging Scientist Award, the LIFE Foundation, a George E. Hewitt Foundation for Medical Research Postdoctoral Fellowship, Paul F. Glenn Foundation for Medical Research Postdoctoral Fellowship, Salk Pioneer Fund Postdoctoral Scholar Award, the Waitt Foundation, Yale University School of Medicine Center for Cellular and Molecular Imaging, a Canada Research Chair (Tier 2) in Neurobiology of Aging and Cognition, and a Canada Foundation for Innovation John R. Evans Leaders Fund (grant 39965).

Katie ThompsonBBC NewsPublished48 minutes agoCases of measles are continuing to rise at “disproportionately high rates” in the West Midlands, the UK Health Security Agency (UKHSA) has warned.Figures published on Thursday show 329 of 465 (71%) cases across England from October to February were in the region.It said a sharp rise over the past six weeks was mainly driven by cases in Birmingham.A GP in the Sparkbrook area of the city said the majority of cases medics were seeing were in unvaccinated people.Dr Frances Dutton, of Sparkbrook Children’s Zone, said many of the children and families in the area were experiencing poverty and deprivation.”This contributes to the bigger picture of child health,” she said.”There’s lots of vulnerabilities. “If you haven’t had the vaccines for measles which is the MMR vaccine, which is completely safe and effective, then you are more likely to get measles.”Address concernsDr Dutton, who also works at Birmingham Children’s Hospital, said it was harder for families living in financial hardship or precarious housing, or where there was a language barrier, to access vaccination appointments.She said: “We have been organising sessions with schools and organisations to listen to their experiences about the MMR vaccine and their concerns to try to address them directly.”Why are cases rising and what is the MMR vaccine?Universities urge students to be aware of measlesMeasles cases in West Midlands highest since 1990sImmunisation teams have been out in the area putting up posters on Coventry Road in a bid to raise awareness about the MMR jab.Elsewhere there have been 62 cases in London, and 32 in Yorkshire and the Humber in the same period. The remaining cases were reported in other regions of England.Of the 465 cases in England, the majority – 66% (306) – were in children under the age of 10, while 25% (115) were in young people and adults over the age of 15.Dr Vanessa Saliba, consultant epidemiologist at UKHSA, said: “The measles outbreak in the West Midlands continues to be a concern. “MMR vaccine uptake has been falling over the last decade with one out of 10 children starting school in England not protected. Measles is highly infectious and there is a real risk it will spread to other areas.”Vaccination is the best way to protect yourself and your children. I strongly urge parents to take up the offer as soon as possible and protect their child now.”More about measlesParents of baby with measles in vaccination pleaPublished31 JanuaryWest Midlands has 75% of England’s measles casesPublished30 JanuaryWhy are measles cases rising and what is the MMR vaccine?Published23 JanuaryRelated Internet LinksUKHSA

Published32 minutes agoShareclose panelShare pageCopy linkAbout sharingImage source, Getty ImagesBy Nick TriggleHealth correspondentCancer waiting times for 2023 in England were the worst on record, a BBC News analysis reveals.Just 64.1% of patients started treatment within 62 days of cancer being suspected, meaning nearly 100,000 waited longer than they should for life-saving care.The waits have worsened every year for the past 11.The figures follow Monday’s announcement the King had started treatment after his cancer diagnosis.He has been treated in a private hospital, after the cancer was spotted following treatment for an enlarged prostate at the end of last month.The records go back to 2010, shortly after the cancer target was introduced.How common is King’s incidental cancer diagnosis?Macmillan Cancer Support chief executive Gemma Peters called the figures “shocking”.”These alarming figures mark a new low and highlight the desperate situation for people living with cancer,” she said.”Behind the figures are real lives being turned upside down, with thousands of people waiting far too long to find out if they have cancer and to begin their treatment, causing additional anxiety at what is already a very difficult time. “With over three million people in the UK living with cancer and an ageing population, this is only set to rise.”

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Other parts of the UK have also been struggling on cancer waiting times.It is more than a decade since Wales, Northern Ireland or Scotland have hit their 62-day cancer targets.Data analysis by Megan RiddellMore on this storyHospital waiting list tops 7.5 million in EnglandPublished10 August 2023Key cancer waiting target set to be missed in EnglandPublished7 March 2023NHS struggling to provide safe cancer care, say doctorsPublished8 June 2023

The top executives of three major companies are set to appear on Thursday before a Senate panel led by Mr. Sanders, who has made lowering drug costs a signature issue.The chief executives of three major pharmaceutical companies are set to appear in front of the Senate health committee on Thursday to defend how much they charge for drugs in the United States, drawing them further into a confrontation with lawmakers and the Biden administration over the cost of some of the most widely used prescription medications.The three executives scheduled to testify — Joaquin Duato of Johnson & Johnson, Robert M. Davis of Merck and Christopher Boerner of Bristol Myers Squibb — are expected to clash with the health committee’s chairman, Senator Bernie Sanders of Vermont, an independent who has made reining in drug prices a signature cause of his late-career years in Congress.Mr. Sanders plans to focus the hearing on why drug prices are higher in the United States than in other wealthy countries. His staff has singled out several widely used drugs, including Eliquis, a blood thinner made by Bristol Myers Squibb, and Januvia, a diabetes drug from Merck, that can be bought for much less in Canada and Europe than in the United States.The hearing comes as a new federal program authorizing Medicare to negotiate the prices of some costly medications is getting underway. Federal health officials last week made their initial offers to the makers of the first 10 drugs selected for negotiations, a list that includes Eliquis and Januvia.Five of the 10 drugs picked for price talks are made by the companies whose executives will be testifying on Thursday. Drug makers, including all three companies that will be represented at the hearing, have filed a flurry of lawsuits arguing that the negotiation program is unconstitutional.We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

His mouth always tasted like metal and he vomited several times a week. Nothing seemed to help. Then his sister got him the help he needed.“We were thinking about going bowling with the kids tomorrow,” the woman told her 43-year-old brother as they settled into their accustomed spots in the living room of their mother’s home in Chicago. It was late — nearly midnight — and he had arrived from Michigan to spend the days between Christmas and New Year’s with this part of his family. She and her husband and her brother grew up together and spent many late nights laughing and talking. She knew her brother was passionate about bowling. He had spent almost every day in his local alley two summers ago. So she was taken by surprise when he answered, “I can’t do that anymore.”Certainly, her brother had had a tough year. It seemed to start with his terrible heartburn. For most of his life, he had what he described as run-of-the-mill heartburn, usually triggered by eating late at night, and he would have to take a couple of antacid tablets. But that year his heartburn went ballistic. His mouth always tasted like metal. And the reflux of food back up the esophagus would get so bad that it would make him vomit. Nothing seemed to help. He quit drinking coffee. Quit drinking alcohol. Stopped eating spicy foods. He told his doctor, who started him on a medication known as a proton pump inhibitor (P.P.I.) to reduce the acid or excess protons his stomach made. That pill provided relief from the burning pain. But he still had the metallic taste in his mouth, still felt sick after eating. He still vomited several times a week. When he discovered that he wouldn’t throw up when he drank smoothies, he almost completely gave up solid foods. When he was still feeling awful after weeks on the P.P.I., his gastroenterologist used a tiny camera to take a look at his esophagus. His stomach looked fine, but the region where the esophagus entered the stomach was a mess. Normally the swallowing tube ends with a tight sphincter that stays closed to protect delicate tissue from the harsh acid of the stomach. It opens when swallowing, to let the food pass. But his swallowing tube was wide open and the tissue around the sphincter was red and swollen. He had, he was told, something called Barrett’s esophagus — a precancerous condition — caused by the injury done by the stomach acid. He was put on higher doses of the P.P.I. Even that wasn’t enough. So the day after Thanksgiving, he had surgery to prevent that reflux of acid up his throat. And it worked — mostly. The vomiting stopped. He could eat solid foods. But the metallic taste and the nausea were still there. The patient restarted the P.P.I., and that helped a little. But he had what he thought were side effects: He felt off-balance and uncoordinated. It was better on the lower dose, he told his sister. But he still felt too unstable to go bowling. His sister, a neurologist, knew some of this medical back story, but her brother was not much of a complainer. Besides, for the past year or so, many of their conversations had to do with his and his wife’s efforts to have a baby. They were trying in vitro fertilization, and that had been tough for both of them. Now, hearing that her brother’s balance was off, she was worried. She asked him something that, until that night, she could not have imagined asking: “May I examine you?” Photo illustration by Ina JangWe are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

For the longest time, researchers focused on diagnosing and treating girls, but that is changing.For decades, eating disorders were thought to afflict mostly, if not exclusively, women and girls. In fact, until 2013, the loss of menstruation had long been considered an official symptom of anorexia nervosa.Over the last decade, however, health experts have increasingly recognized that boys and men also suffer from eating disorders, and they have gained a better understanding of how differently the illness presents in that group. A small but growing body of scientists and physicians have dedicated themselves to identifying the problem, assessing its scope and developing treatments.Recently, two of these experts spoke to The New York Times about how the disease is affecting adolescent boys, what symptoms and behaviors parents should look for, and which treatments to consider. Dr. Jason Nagata is a pediatrician at the University of California, San Francisco, who specializes in eating disorders; he is senior editor of the Journal of Eating Disorders and editor of the book “Eating Disorders in Boys and Men.” Dr. Sarah Smith is a child and adolescent psychiatrist at the University of Toronto who specializes in eating disorders; she was the lead author on a study published in JAMA Open Network in December that showed sharp increases in the rates of hospitalizations for boys with eating disorders.The conversation was condensed and edited for clarity.The medical and scientific understanding of eating disorders is changing and expanding. What happened?Dr. Smith: Historically, eating disorders have been conceptualized mostly as anorexia, which has been portrayed as an illness of adolescent females who want to lose weight for aesthetic reasons.Dr. Nagata: There’s increasing recognition, particularly in the last decade or so, that some people with body image dissatisfaction are not trying to lose weight at all. Some men and boys are trying to become large and muscular. In fact, one-third of teenage boys across the United States report that they’re trying to bulk up and get more muscular. And a subset of those may develop eating disorders or muscle dysmorphia that can lead to significant psychological distress and physical health complications.We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

Image source, GettyEleanor LawsonBBC News, West MidlandsPublished2 hours agoThe first UK patient has been recruited to take part in a clinical trial for a new drug for adults with severe eczema, an NHS trust said.Researchers in Walsall recruited the patient to the global clinical trial which is currently in its second phase.Dr James Halpern, from Walsall Healthcare NHS Trust, said the medication was “potentially highly effective” for people with the “debilitating condition”.The trial will last for up to 36 weeks and participants will visit a clinic 17 times in total for the treatment, which is an injection just under the skin.Image source, Walsall Healthcare NHS TrustThe trial is looking at a new drug, LEO 138559, for the treatment of moderate to severe eczema.Eczema is a chronic disease that causes inflammation, redness, and irritation of the skin. The NHS trust said researchers did not know what caused eczema but they did know that genes, the immune system and the environment played a role in the disease. “We are really proud to have recruited the first patient in the UK to this exciting phase II commercial clinical trial,” Dr Halpern said.”Our success in previous clinical trials has led to major pharmaceutical companies actively seeking to work with us and delivering huge benefits to our local population.”Follow BBC West Midlands on Facebook,

Published40 minutes agoShareclose panelShare pageCopy linkAbout sharingImage source, Getty ImagesMen who take drugs for erectile dysfunction, such as Viagra, may reduce their risk of Alzheimer’s disease, a study suggests.In research on more than 260,000 men, those taking the drugs were 18% less likely to develop the dementia-causing condition.But more research is needed to prove that the drugs are causing the effect.Two new Alzheimer’s drugs have shown huge promise at slowing the pace of the disease in its earliest stages.By attacking gunge called beta amyloid which builds up in the brains of people with Alzheimer’s, they have the potential to change the way the disease is treated.But scientists are also continuing to look for existing drugs that could prevent or delay it developing in the first place.Prescription recordsDrugs like Viagra were originally designed to treat high blood pressure and angina. They work by acting on a cell-signalling messenger that may also be linked to memory. They are also known to affect brain cell activity, and research in animals suggests they have some protective effect on the brain.In the new study in Neurology, researchers from University College London looked at prescription records of thousands of men with erectile dysfunction, comparing those who had been given the drugs with those who hadn’t.Image source, Getty ImagesOver the following five years, they found 8.1 cases of Alzheimer’s per 10,000 person years in the group prescribed the drugs, and 9.7 cases in the group not taking them.Men who had been issued the most prescriptions for erectile dysfunction drugs were least likely to develop Alzheimer’s, suggesting regular use of the drug could have a greater impact on the disease.The researchers say their study doesn’t show that the drugs themselves were reducing people’s risk of Alzheimer’s, but could point to a new avenue of research.New drugs for Alzheimer’s hailed as turning pointNew Alzheimer’s drug slows disease by a thirdFiona Phillips: How common is early Alzheimer’s?Lead author Dr Ruth Brauer said: “More research is needed to confirm these findings, learn more about the potential benefits and mechanisms of these drugs and look into the optimal dosage.” The researchers also want to run a trial in women as well as men, to see if the drug has any impact.There are many factors which could be causing the disease. The study adjusted its findings for some of them, including age, underlying health conditions, other medicines taken and whether the participant was a smoker.”This study does not conclusively prove that erectile dysfunction drugs reduce Alzheimer’s risk but provide good evidence that this type of drug is worth further study in future,” said Prof Tara Spires-Jones, from the University of Edinburgh, and president of the British Neuroscience Association.Dr Francesco Tamagnini, neurophysiologist at the University of Reading, said it was “a great study”, but more hard evidence on how the drug affected the brain was needed.”It could be that it exerts a therapeutic effect directly affecting neurons (if the drug is able to cross the blood brain barrier) and/or by increasing blood flow, but both these hypotheses need to be tested,” he said.More on this storyNew drugs for Alzheimer’s hailed as turning pointPublished17 July 2023New Alzheimer’s drug slows disease by a thirdPublished3 May 2023Alzheimer’s drug hailed as momentous breakthroughPublished30 November 2022Fiona Phillips: How common is early Alzheimer’s?Published5 July 2023Lifestyle changes that could lower your dementia riskPublished14 July 2019

If you’re pregnant, you may want to think twice before making a hamburger run or reaching for a prepackaged pastry, according to research published last month in the journal Environmental International.
Oddly enough it’s not the food that the report targets — not the fries, burgers or even the shakes and cakes — but what touches the food before you eat it.
Research shows that phthalates, a class of chemicals associated with plastics, can shed from the wrapping, packaging and even from plastic gloves worn by food handlers into food. Once consumed during pregnancy, the chemicals can get into the bloodstream, through the placenta and then into the fetal bloodstream.
The chemical can cause oxidative stress and an inflammatory cascade within the fetus, researchers noted. Previous literature has indicated that exposure to phthalates during pregnancy can increase the risk of low birth weight, preterm birth and child mental health disorders such as autism and ADHD.
This is the first study in pregnant women to show that diets higher in ultraprocessed foods are linked to greater phthalate exposures, the authors wrote.
“When moms are exposed to this chemical, it can cross the placenta and go into fetal circulation,” said senior author Dr. Sheela Sathyanarayana, a UW Medicine pediatrician and researcher at the Seattle Children’s Research Institute.
This analysis involved data in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) research cohort, which comprised 1,031 pregnant individuals in Memphis, Tenn., who were enrolled between 2006 and 2011. Phthalate levels were measured in urine samples collected from during the second trimester of pregnancy.

The researchers found that ultraprocessed food composed 10% to 60% of participants’ diets, or 38.6%, on average. Each 10% higher dietary proportion of ultraprocessed food was associated with 13% higher concentration of di(2-ethylhexyl) phthalate, one of the most common and harmful phthalates. The phthalate amounts were derived through urine samples taken from the women in the study.
Ultraprocessed foods, according to the researchers, are made mostly from substances extracted from foods such as oils, sugar and starch, but have been so changed from processing and the addition of chemicals and preservatives to enhance their appearance or shelf life that they are hard to recognize from their original form, researchers noted. These include packaged cake mixes, for example, or packaged french fries, hamburger buns and soft drinks.
When it comes to fast food, gloves worn by the employees and the storage, preparation, serving equipment or tools may be the main sources of exposure. Both frozen and fresh ingredients would be subject to these sources, said lead author Brennan Baker, a postdoctoral researcher in Sathyanarayana’s lab.
This is the first study, researchers say, to identify ultraprocessed foods as a link between exposure to phthalates and the socio-economics issues facing the mothers. The mothers’ vulnerability might stem from experiencing financial hardships and from living in “food deserts” where healthier, fresh foods are harder to obtain and transportation to distant markets is unrealistic.
“We don’t blame the pregnant person here,” said Baker. “We need to call out manufacturers and legislators to offer replacements, and ones that may not be even more harmful.”
More legislation is needed, the authors said, to prevent phthalate contamination in foods by regulating the composition of food wrapping or even the gloves that food handlers may use.
What should pregnant women do now? Sathyanarayana said that pregnant women should try to avoid ultraprocessed food as much as they can, and seek out fruits, vegetables and lean meats. Reading labels can come into play here, she added.
“Look for the lower number of ingredients and make sure you can understand the ingredients,” she said. This applies even to “healthy foods” such as breakfast bars. See if it’s sweetened with dates or has a litany of fats and sugars in it, she said.
This study was funded in part by the National Institutes of Health (UG3UH3OD023271).

A tiny device built by scientists at MIT and the Singapore-MIT Alliance for Research and Technology could be used to improve the safety and effectiveness of cell therapy treatments for patients suffering from spinal cord injuries.
In cell therapy, clinicians create what are known as induced pluripotent stem cells by reprogramming some skin or blood cells taken from a patient. To treat a spinal cord injury, they would coax these pluripotent stem cells to become progenitor cells, which are destined to differentiate into spinal cord cells. These progenitors are then transplanted back into the patient.
These new cells can regenerate part of the injured spinal cord. However, pluripotent stem cells that don’t fully change into progenitors can form tumors.
This research team developed a microfluidic cell sorter that can remove about half of the undifferentiated cells — those that can potentially become tumors — in a batch, without causing any damage to the fully-formed progenitor cells.
The high-throughput device, which doesn’t require special chemicals, can sort more than 3 million cells per minute. In addition, the researchers have shown that chaining many devices together can sort more than 500 million cells per minute, making this a more viable method to someday improve the safety of cell therapy treatments.
Plus, the plastic chip that contains the microfluidic cell sorter can be mass-produced in a factory at very low cost, so the device would be easier to implement at scale.
“Even if you have a life-saving cell therapy that is doing wonders for patients, if you cannot manufacture it cost-effectively, reliably, and safely, then its impact might be limited. Our team is passionate about that problem — we want to make these therapies more reliable and easily accessible,” says Jongyoon Han, an MIT professor of electrical engineering and computer science and of biological engineering, a member of the Research Laboratory of Electronics (RLE), and co-lead principal investigator of the CAMP (Critical Analytics for Manufacturing Personalized Medicine) research group at the Singapore-MIT Alliance for Research and Technology (SMART).

Han is joined on the paper by co-senior author Sing Yian Chew, professor of chemistry, chemical engineering, and biotechnology at the Lee Kong Chian School of Medicine and Materials Science and Engineering at Nanyang Technological University in Singapore and a CAMP principal investigator; co-lead authors Tan Dai Nguyen, a CAMP researcher; Wai Hon Chooi, a senior research fellow at the Singapore Agency for Science, Technology, and Research (A*STAR); and Hyungkook Jeon, an MIT postdoc; as well as others at NTU and A*STAR. The research appears today in Stem Cells Translational Medicine.
Reducing risk
The cancer risk posed by undifferentiated induced pluripotent stem cells remains one of the most pressing challenges in this type of cell therapy.
“Even if you have a very small population of cells that are not fully differentiated, they could still turn into cancer-like cells,” Han adds.
Clinicians and researchers often seek to identify and remove these cells by looking for certain markers on their surfaces, but so far researchers have not been able to find a marker that is specific to these undifferentiated cells. Other methods use chemicals to selectively destroy these cells, yet the chemical treatment techniques may be harmful to the differentiated cells.
The high-throughput microfluidic sorter, which can sort cells based on size, had been previously developed by the CAMP team after more than a decade of work. It has been previously used for sorting immune cells and mesenchymal stromal cells (another type of stem cell), and now the team is expanding its use to other stem cell types, such as induced pluripotent stem cells, Han says.

“We are interested in regenerative strategies to enhance tissue repair after spinal cord injuries, as these conditions lead to devasting functional impairment. Unfortunately, there is currently no effective regenerative treatment approach for spinal cord injuries,” Chew says. “Spinal cord progenitor cells derived from pluripotent stem cells hold great promise, since they can generate all cell types found within the spinal cord to restore tissue structure and function. To be able to effectively utilize these cells, the first step would be to ensure their safety, which is the aim of our work.”
The team discovered that pluripotent stem cells tend to be larger than the progenitors derived from them. It is hypothesized that before a pluripotent stem cell differentiates, its nucleus contains a large number of genes that haven’t been turned off, or suppressed. As it differentiates for a specific function, the cell suppresses many genes it will no longer need, significantly shrinking the nucleus.
The microfluidic device leverages this size difference to sort the cells.
Spiral sorting
Microfluidic channels in the quarter-sized plastic chip form an inlet, a spiral, and four outlets that output cells of different sizes. As the cells are forced through the spiral at very high speeds, various forces, including centrifugal forces, act on the cells. These forces counteract to focus the cells in a certain location in the fluid stream. This focusing point will be dependent on the size of the cells, effectively sorting them through separate outlets.
The researchers found they could improve the sorter’s operation by running it twice, first at a lower speed so larger cells stick to the walls and smaller cells are sorted out, then at a higher speed to sort out larger cells.
In a sense, the device operates like a centrifuge, but the microfluidic sorter does not require human intervention to pick out sorted cells, Han adds.
The researchers showed that their device could remove about 50 percent of the larger cells with one pass. They conducted experiments to confirm that the larger cells they removed were, in fact, associated with higher tumor risk.
“While we can’t remove 100 percent of these cells, we still believe this is going to reduce the risk significantly. Hopefully, the original cell type is good enough that we don’t have too many undifferentiated cells. Then this process could make these cells even safer,” he says.
Importantly, the low-cost microfluidic sorter, which can be produced at scale with standard manufacturing techniques, does not use any type of filtration. Filters can become clogged or break down, so a filter-free device can be used for a much longer time.
Now that they have shown success at a small scale, the researchers are embarking on larger studies and animal models to see if the purified cells function better in vivo.
Nondifferentiated cells can become tumors, but they can have other random effects in the body, so removing more of these cells could boost the efficacy of cell therapies, as well as improve safety.
“If we can convincingly demonstrate these benefits in vivo, the future might hold even more exciting applications for this technique,” Han says.
This research is supported, in part, by the National Research Foundation of Singapore and the Singapore-MIT Alliance for Research and Technology.