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The gene coding for the protein p53 is probably the most important factor in protecting human cells from cancer caused by DNA-damaging agents. The protein allows cells to repair damage to their DNA and thereby prevents the development of cancers, which is why it has been nicknamed “the guardian of the genome.” An inactivation of p53 can be found in about one in two tumours. Cells lacking p53 function become genomically instable, which implies that they are prone to acquire mutations in their DNA, helping the tumours to grow in uncontrolled ways, form metastases, and resist therapy. Hence, the cancer cell becomes more aggressive.
But even when there are no DNA-damaging agents around, it is an extremely difficult task for cells to maintain their genomic (DNA) stability. Researchers have suspected that p53’s protective function also covers healthy cells. The mechanism by which the protein would gain such capabilities, however, has remained unclear. A research team led by Ivano Amelio, Professor of Systems Toxicology at the University of Konstanz, and involving his Konstanz colleague Marcel Leist, Professor of In-Vitro Toxicology and Biomedicine, has now shed new light on this mystery.
Cell division is a vulnerable process
Cells — and their DNA integrity — are particularly at risk when they divide, as they duplicate their DNA in the process. “Like in any other replication process, such as photocopying a document or copying a digital file, it is disastrous if the template moves or is changed while the copy is being made. For this reason, genes cannot be transcribed — i.e. used as templates for proteins — while the DNA is being copied,” Amelio explains. If they are transcribed anyway, serious disruptions occur, which can lead to cancer-promoting mutations. The results from Amelio and his team, now appearing as the cover story in Cell Reports, show that p53 inactivation favours such copy-related damage. They found that p53 normally acts by changing cell metabolism in a way that prevents activation of genome regions that should remain inactive.
The scientists painstakingly dissected the underlying mechanism down to the last detail. They made use of the knowledge that some parts of the genome, called heterochromatin, are packed densely to prevent transcription of genes in these regions. For this reason, such regions are called “silent,” and they are controlled by what is known as epigenetic mechanisms, i.e. processes that do not affect the genes as such, but their overall packaging and accessibility in the genome. One of the most interesting findings of the recent study was that in the absence of p53 these usually inaccessible or “silent” regions of our DNA were transcribed, leading to catastrophic consequences.
Crosstalk between p53-driven metabolism and epigenetic integrity
“Normally, transcription of these areas of the genome should be kept under tight control, and p53 is the key to keeping their information locked-away by controlling metabolism in a way that renders the heterochromatin inaccessible,” Amelio says. When p53 is absent, as in p53-inactivated tumours, the cell loses its metabolic homeostasis, and the information hidden in the heterochromatin becomes aberrantly accessible and is transcribed. This causes so much damage that it will drive cells into a state of genomic instability that favours and worsens cancer progression. “By unravelling this mechanism, we could demonstrate that there is a link between metabolism, epigenetic integrity and genomic stability. In addition, we provided evidence that p53 represents the switch controlling the on/off status of this protection system in the response to environmental stress,” Amelio summarizes the finding.
The question of how p53-inactivated tumours develop genomic instability has plagued the scientific community for quite some time. “Now we have certainty that, in these tumours, there is a problem at the metabolic level that is reflected in the integrity of the epigenome. Hence, p53 should actually be called guardian of the (epi-)genome. This essential insight can direct research to identify potential new therapeutic strategies for the very frequent forms of cancers that carry p53 inactivation,” Amelio concludes.
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As the largest organ of the human body, the skin literally provides a major barrier exposed to environmental stimuli and pathogens. Painful inflammation can be mounted if this barrier is compromised — as anyone who has ever had a sunburn knows. But exactly how this is triggered was not understood in detail until now. “In our study, we took a closer look at the processes involved,” explains Prof. Dr. Florian Schmidt, who heads a research group at the Institute of Innate Immunity at the University Hospital Bonn.
UV stress triggers signal chain
UV light is very high in energy. When it hits the skin, it can therefore damage important cellular molecules, sparking inflammation as a common consequence. However, it was unclear how this exactly happens. “We have now been able to show that a known cellular stress signaling pathway can trigger these inflammatory responses,” explains Schmidt, who is also a member of the Transdisciplinary Research Area (TRA) “Life and Health” and the ImmunoSensation2 Cluster of Excellence at the University of Bonn.
The cell’s own “engineering offices,” the ribosomes, normally assemble proteins based on the instructions in the genetic material. When this is impaired due to UV damage, they sound the alarm: They trigger the so-called ribotoxic stress response. It has been known for years that this causes a signaling cascade resulting in the activation of an enzyme called p38. “Our research shows that p38 molecularly modifies NLRP1, a critical switch for inflammation in the skin, and thus activates it in a novel way. This initiates the assembly of inflammasomes from many molecular building blocks.”
Inflammasomes are powerful weapons of the innate immune system. Among other things, these complex molecular machines can convert inactive messenger substances for inflammation into their active form. At the same time, they ensure that numerous holes are formed in the cell membrane. This allows messenger substances to reach the outside and thus call the body’s own defense forces to its aid. Ultimately, the holes lead to the death of the cell: At some point, it practically explodes and empties its contents into the tissue. The molecules that are now abruptly released from within the cell are another warning sign for the immune system.
Viruses also activate p38
Interestingly, p38 is not only activated by excessive sunbathing. “We were able to show that mosquito-borne viruses can activate NLRP1 through p38 as well,” emphasizes Lea-Marie Jenster, a PhD student in the Schmidt lab and the lead author of this study. “These include, for instance, chikungunya virus, which is a major problem in parts of Africa and Asia and could also reach Germany in the wake of climate change.” Viruses probably even trigger the activation of p38 via several different pathways.
“P38 is a molecular information hub in the skin, in which various warning signals converge — similar to the fire department’s control center,” Schmidt explains. “However, not every incoming call for help immediately triggers the assembly of inflammasomes — this only happens when the number and intensity of alerts exceed a certain threshold.” This regulation is important, since inflammasomes are dangerous weapons which cause considerable collateral damage. For example, the strong inflammation that is triggered causes parts of the skin tissue to perish.
Sometimes, however, inflammasomes are controlled not strictly enough — as in the case of sunburn or even some autoimmune diseases. Perhaps p38 opens up a new possibility to specifically suppress such exuberant immune reactions in the skin.
In addition to the University Hospital of Bonn and the University of Bonn, the University of Melbourne (Australia) and Boston Children’s Hospital (USA) were involved in the study.
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A novel metric that estimates our “burden,” or cumulative exposure, to a family of thousands of synthetic chemicals that we encounter in everyday life with potentially adverse health impacts, has been created by a team of researchers at Mount Sinai.
In a paper published in Environmental Health Perspectives, the team reported that its sophisticated tool could have distinct advantages for epidemiologists and researchers who routinely measure exposure levels to this class of chemicals, known as PFAS (per- and polyfluoroalkyl substances), which have been associated with high cholesterol, liver damage, thyroid disease, and hormone disorders.
“There are few existing methods to quantify total exposure burden of individuals to mixtures of PFAS chemicals that are found in our everyday lives,” says lead author Shelley Liu, PhD, Assistant Professor in the Center for Biostatistics, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai. “For the first time we’ve developed a PFAS burden calculator that takes into account patterns of exposure to many chemicals within the PFAS family, and not just individual chemical concentrations which current methods are focused on. As a result, this robust tool could be extremely useful for biomonitoring by regulatory agencies, and for disease and health risk assessment.”
PFAS is a class of more than 5,000 chemicals whose fluorine-carbon bond gives them the ability to repel oil and water. That construct has made them an integral part of a growing number of industrial applications and consumer products in recent decades, such as stain and water repellents, Teflon nonstick pans, paints, cleaners, and food packaging. Moreover, PFAS chemicals do not disintegrate in the environment or in our bodies. Instead, they accumulate in our surroundings and in our blood, kidneys, and liver, as underscored by a Centers for Disease Control and Prevention study in 2007 that found PFAS could be detected in the blood of 98 percent of the U.S. population.
Mount Sinai researchers used national biomonitoring data from the National Health and Nutrition Examination Survey to develop their exposure burden score using item response theory. Item response theory was developed in the educational testing literature to score standardized tests, and Mount Sinai researchers are the first to use it in environmental epidemiology to develop an exposure burden score, highlighted by this transdisciplinary investigation. Specifically, they used serum concentrations from eight common PFAS chemicals taken from adults and children. By combining a participant’s core biomarker concentrations with their much broader “exposure pattern,” that is, their relative exposure to other PFAS biomarkers within the entire chemical class, researchers were able to estimate a cumulative or summary PFAS exposure burden. This statistical methodology can be accessed by other researchers and epidemiologists by simply plugging their data sets into the PFAS burden calculator, which is available online.
The benefits are significant. “We found our method enables comparisons of exposure burden to chemical mixtures across studies even if they do not measure the same set of chemicals, which supports harmonization across studies and consortia,” explains Dr. Liu, whose research is heavily focused on environmental health through latent variable modeling and longitudinal data analysis. Moreover, the calculator offers a straightforward way to include exposure biomarkers with low detection frequencies, and to reduce exposure measurement errors by considering both a participant’s concentrations and their exposure patterns to estimate exposure burden to chemical mixtures.
“By capturing individual biomarker variability, we’re essentially holding the exposure metric constant so it can be used for a variety of applications,” says Dr. Liu. “These could include, for example, looking across populations to determine if there are differences in exposure burden across racial/ethnic or socioeconomic strata, or if exposure burdens are the same between people in the United States or Canada. Or looking across physiological systems and health outcomes — such as cardiometabolic, hormonal, and immune — to see which are most perturbed by exposure to PFAS chemicals. This range of applications takes us well beyond anything currently available to the field of population health.”
Other co-authors in the study were from the Johns Hopkins Bloomberg School of Public Health, the Department of Psychology at Fordham University, and the Stroud Center at Columbia University. Dr. Liu’s research is supported by grants from the National Institute of Child Health and Human Development (K25HD104918) and National Institute of Environmental Health Sciences (R03ES033374).

A team of Canadian researchers from Université de Montréal has designed and validated a new class of drug transporters made of DNA that are 20,000 times smaller than a human hair and that could improve how cancers and other diseases are treated
Reported in a new study in Nature Communications, these molecular transporters can be chemically programmed to deliver optimal concentration of drugs, making them more efficient than current methods.
Optimal dosing at all times: a medical challenge
One of the key ways to successfully treat disease is to provide and maintain a therapeutic drug dosage throughout treatment. Sub-optimal therapeutic exposure reduces efficiency and typically leads to drug resistance, while overexposure increases side effects.
Maintaining an optimal concentration of drugs in the blood remains a major challenge in modern medicine. Since most drugs undergo rapid degradation, patients are forced to (and often forget) to take multiple doses at regular intervals. And because each patient has a distinct pharmacokinetic profile, the drugs concentration in their blood varies significantly.
Observing that only about 50 per cent of cancer patients get an optimal drug dosage during certain chemotherapy, UdeM Chemistry associate professor Alexis Vallée-Bélisle, an expert in bio-inspired nanotechnologies, started to explore how biological systems control and maintain the concentration of biomolecules.

Bipartisan legislation in the House targets not only the online activity of individual users but also the website operators hosting it.Lawmakers are seeking to make online assistance of suicide a federal crime, pushing to hold accountable both individual users and the tech companies and websites that allow such content on their platforms.A bipartisan bill introduced in the House of Representatives on Monday, the Stop Online Suicide Assistance Forums Act, comes amid rising concern over suicide rates among young people, and mounting evidence of online dangers.The bill’s primary sponsor cited a Times investigation published last December into a website where members share detailed instructions on how to die and encourage one another to follow through with suicide plans. The investigation identified 45 deaths connected to the site and found hundreds of posts suggesting that the true toll was much higher. “As a mom,” said Representative Lori Trahan, Democrat of Massachusetts, the findings were “terrifying, and it motivated us to act.” Co-sponsoring the bill with her were Katie Porter, Democrat of California, and the Republicans Mike Carey of Ohio and Chris Stewart of Utah.Even as the trail of suicides connected to the site grows longer — The Times has since identified dozens more deaths, including several young teenagers — no one involved has faced legal consequences.While most states have laws against assisting suicide, they are inconsistent and rarely enforced, and don’t explicitly address online activity. It is not clearly established to what extent speech about suicide is protected by the First Amendment.The new federal bill draws on a Minnesota State Supreme Court ruling, which affirmed that offering suicide instructions in an online exchange was a crime. Previous legislation aimed at this issue, the Suzanne Gonzales Suicide Prevention Act, first proposed in 2007 and named for a 19-year-old who had killed herself after receiving instruction on the internet, would also have made online assistance of suicide a federal crime. It was introduced several times but never received a vote.The new bill would allow prosecution under an existing exception to Section 230 of the Communications Decency Act, the law that governs online activity and typically shields website operators from liability for content posted by users. Exempt from protection are website operators who host content that violates federal criminal law.While Facebook, Twitter, Reddit and other platforms have in recent years prohibited users from sharing suicide methods and encouraging self-harm, they haven’t fully eliminated it. Under the new bill, they could be subject to penalties of up to five years in prison and hundreds of thousands of dollars in fines.The bill does not criminalize the act of suicide or the encouragement of it. It also does not interfere with state laws that explicitly allow physician-assisted death for the terminally ill.Suicide awareness and prevention organizations and the families of young people who died in connection with the suicide website have urged such legislation.“It’s at least one important step. We need to get this online help taken down,” said Sharon Luft, whose 17-year-old son Matthew killed himself last year less than a month after joining the site.When Matthew inquired about a specific method, another member was quick to reply with a link to detailed instructions on how to use it to die. He later sought and received more detailed advice to make sure his efforts would work. At one point, he wondered if the method was working and asked if he should keep going. Another member responded, “If you want the attempt to be a success, then yes.”“Websites that encourage suicide and offer instructions are harmful, particularly to youth and young adults,” said Robert Gebbia, the chief executive of the American Foundation for Suicide Prevention.Diego Joaquín Galante and Lamarcus Small, revealed by The Times as the two men who created the suicide website and operated it for years, framed it as a “pro-choice” forum supporting members’ decisions to live or die, and presented themselves as defenders of free speech. In online posts under the name Marquis, Mr. Small repeatedly said that the site complied with U.S. law.After the Times investigation, the two men announced that they had handed over the site to new administrators who espoused similar beliefs. In September, according to the analytics firm Similarweb, the site drew nearly 10 million views.If you are having thoughts of suicide, call or text the National Suicide Prevention Lifeline at 988 or go to SpeakingOfSuicide.com/resources for a list of additional resources.

Could the disease be back?The doctor’s voice over the phone was warm and reassuring. The patient, a 62-year-old man, had a chest CT earlier that day, and Dr. David Smith, his longtime P.C.P., was telling him that the radiologist saw a mass. It sounded bad, but it probably wasn’t cancer, Smith told him. “I didn’t want you to see the report and worry,” he added. The report said that the mass in his lungs looked like a neoplasm — the fancy word for tumor. But it went on to acknowledge that it could also just be left over from the really bad pneumonia the man had three months earlier.And it had been a bad pneumonia. First he started coughing. Then he had trouble taking a deep breath. He burned with fever and had a stabbing pain in the upper right part of his back with every breath. He tried to tough it out with cough syrup and ibuprofen, but when it wasn’t getting better, his fiancée insisted that he call his doctor. The nurse who called him back sent him straight to Yale New Haven Hospital. A chest X-ray showed a large cloud of white and gray taking up most of the upper part of his right lung — pneumonia.He was given antibiotics to treat a presumed bacterial infection, and by the next day he started to feel a little better. He was sent home to finish the five-day course. The fever went away, and then the back pain, but the cough lingered. Just taking a breath or talking could trigger a long bout of hacking so violent it left him breathless.Chest X-rays repeated after one month and then two months looked better. The cloud shrank to a blob the size of a peanut. But when it was still there after three months, Smith ordered a chest CT. That was the report that Smith was calling his patient about. The patient listened quietly but was still worried. He already had cancer once, decades earlier, and the possibility that he could have it again scared him.Samples to the C.D.C.Smith knew his patient well and had already reached out to one of the lung-cancer experts at Yale New Haven Hospital to consult her on whether a biopsy was needed. She agreed with the radiologist: It was probably just left over from his pneumonia. Give it a couple of more months, she advised, and if the mass was still there, that’s when you’d do a biopsy.A few weeks later, the cough finally went away, and the man felt quite well. Still, the possibility of lung cancer haunted him. He had never smoked, but he was a woodworker, a sculptor, and often eschewed the mask, even when exposed to airborne particles. As an artist, he sometimes felt that the mask was a barrier between him and his work.When his doctor called after the second CT and told him that the mass in his chest had grown, the man felt a pang of real fear. The biopsy was uncomfortable but not painful. He lay on his back and a long needle was introduced between two ribs. Because of the medications he was given, he felt only an intense pressure. The results were a relief. It wasn’t cancer, they said. Instead, it looked like some kind of infection. A few of the samples showed strange-looking cellular organisms that no one seemed to be able to identify. The pathologist sent pictures of the tissue and the unrecognized organisms to the Centers for Disease Control and Prevention in search of a diagnosis.Days later they sent back their answer. This was, they believed, a fungus called blastomyces. Had the patient been in the Ohio or Mississippi River Valleys recently? Or anywhere in the Midwest or South? Blasto, as it’s called familiarly, lives in the dirt there and few other places. If inhaled, it can cause a serious infection in the lungs called blastomycosis, which could be fatal if not treated. Smith immediately referred the patient to the infectious-disease team. The doctor on service that week was Dr. Marwan Mikheal Azar, who, as luck had it, was an expert in fungal diseases.Azar had only recently finished his specialty training. He had done additional training in microbiology and examined the images that had been sent to the C.D.C. eagerly. After the first look, though, he wasn’t sure the C.D.C. had got it right. The fungi seen in the slides were too big to be blastomyces. Those were tiny organisms — less than one-tenth the diameter of a human hair. The organism shown in these pictures was big in comparison — maybe about the width of that human hair. Moreover, one of the cells had a recognizable pattern. It couldn’t be seen completely but looked like a sack filled with tiny beads.That image suggested a very different fungus, one known as coccidioides. Like blastomyces, cocci (as it’s called) lives in dirt. But it is endemic to a region on the other side of the country — especially the Western desert of Arizona, California and Mexico. If inhaled, the organisms could end up in the lungs and cause a pneumonia called, variously, coccidioidomycosis or desert rheumatism or Valley fever. Each of the tiny beads Azar saw inside the organism was actually a baby fungus. When the beads grew large enough, the sack would rupture, releasing the offspring. Each bead would grow and develop tiny seeds of its own.Photo illustration by Ina JangA Visit to a Dude RanchThe patient was a slender, energetic man who looked younger than his 62 years, Azar noted when he met the man the following week. Informed by the results of the biopsy, the infectious-disease doctor asked the patient the same questions the C.D.C. raised about his recent travel. Had he been to the Midwest or the South in the past year or so? Maybe around the Mississippi or Ohio River Valleys?He had, the patient replied, but not for decades. But, he added, he spent several days at a dude ranch in Arizona a few weeks before he got sick. The pneumonia had been awful, but he felt fine now. Azar felt a moment of satisfaction: He was in Arizona just before getting sick? This probably was coccidioidomycosis. And yet the C.D.C. thought it was blasto. Azar needed to be sure of what he was treating. Blastomycosis was a much more serious disease than coccidioidomycosis, requiring significantly longer treatment. He sent a sample of the tissue taken from the man’s lungs to the C.D.C. for genetic identification of the yeast. In the meantime, Azar started the man on an antifungal medication, itraconazole, that worked against both types of yeast.It took weeks for the results to come back. But finally they had a definitive answer: It was cocci.Relieved to be free of a possible cancer diagnosis, the patient jumped onto the internet to read up on Valley fever. It was all over Arizona. His sister-in-law reminded him later that there used to be a card about the disease in the rooms of the dude ranch they visited every year for the past 30-something years. He quickly found the Valley Fever Center for Excellence at the University of Arizona College of Medicine-Tucson, only a few miles from the dude ranch. It was set up to teach doctors and patients about the infection. Two-thirds of all patients with cocci got it right there in Arizona. These were the real experts in cocci, the patient told Azar. He should call them. Azar wasn’t sure what he could learn from these folks. But he did have some questions. So when the patient brought it up again, he called.He had read the guidelines on the treatment of this disease — written, as it turned out, by the physician who led the Center for Excellence — and their recommendation was to stop treatment if the patient didn’t have symptoms. Could that be right? “I learned so much,” Azar acknowledged to the patient. Most important: The man didn’t need the medication. His body had already neutralized the bug.It’s amazing, Azar told me, that something can be so ordinary in one part of the country and so rare every place else. If that patient had presented to the E.R. in Tucson, it’s more likely that they would have recognized what he had as Valley fever. If he had symptoms, they would have treated him; if he didn’t, they wouldn’t. But they certainly would not have ordered a biopsy. And they would have never thought for a moment that he had cancer.Lisa Sanders, M.D., is a contributing writer for the magazine. Her latest book is “Diagnosis: Solving the Most Baffling Medical Mysteries.” If you have a solved case to share, write her at Lisa.Sandersmdnyt@gmail.com.

People with post-traumatic stress disorder (PTSD) experienced better sleep, a reduction in the severity of PTSD symptoms and more effective treatments after exposure to blue light therapy, according to a new study conducted by researchers in the University of Arizona College of Medicine — Tucson’s Department of Psychiatry and recently published in Frontiers in Behavioral Neuroscience.
Sleep is crucial for maintaining physical and mental health, and inadequate sleep over time can impact all aspects of life with serious implications for long-term health, relationships, cognitive abilities such as learning, and healing.
The influence of sleep disruption on PTSD symptom severity is well established. Those who seek treatment to allay their PTSD symptoms often face a vicious cycle where poor sleep interferes with the effectiveness of treatments, negating any lessening of symptoms, which in turn contributes to sleep disruptions. To reduce and eliminate the emotional impact of traumatic memories, the patient needs quality sleep to integrate healing mechanisms achieved through cognitive or exposure therapy treatments.
“This research is exciting and unique because it points to an easy-to-use method for helping those with PTSD to retain the benefits of therapy long after the treatment ends,” said psychiatry professor William “Scott” Killgore, PhD, director of the Social, Cognitive and Affective Neuroscience (SCAN) Lab and senior author on the paper, “Morning blue light treatment improves sleep complaints, symptom severity, and retention of fear extinction memory in post-traumatic stress disorder.”
Dr. Killgore and the SCAN Lab team conducted a comprehensive assessment of daily morning blue-wavelength light exposure on individuals with clinically significant levels of PTSD. The goal was to ascertain if blue light therapy would help improve sleep and PTSD symptoms and sustain learned fear extinction memories, an analog of therapeutic treatment for trauma.
Study participants committed to 30 minutes of morning light exposure daily for six weeks, with half of the participants using blue-wavelength light and half using amber light. Researchers examined the neurobiological, autonomic and behavioral outcome changes during the study.
The 43 participants who received blue light therapy not only demonstrated significant improvements in the severity of their PTSD symptoms, but also reported improvements in sleep and showed an increased retention of fear extinction memories. In comparison, the 39 study participants who received amber light did not show the same retention of the extinction memories, but rather showed a return of the original fear memories.
“While the limitations of the research include its modest sample size and difficulties monitoring compliance, the possibilities of utilizing a treatment that is relatively simple, drug-free and inexpensive can offer hope for the large population of people living with the intense challenges of post-traumatic stress disorder,” Dr. Killgore said.
“The data are thrilling,” said Jordan Karp, MD, professor and chair of the College of Medicine — Tucson’s Department of Psychiatry. “This nonpharmacological intervention is a promising life-changing and life-saving possibility for people suffering from PTSD.”
This study was supported by the US Army Medical Research and Development Command (W81XWH-14-0570).
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A multi-institution study led by Rohan Dharmakumar, PhD, of Indiana University School of Medicine, has identified that iron drives the formation of fatty tissue in the heart and leads to chronic heart failure in about fifty percent of heart attack survivors. The discovery, recently published in Nature Communications, paves the way for treatments that have the potential to prevent heart failure in nearly half a million people a year in the United States, and many millions more worldwide.
“For the first time, we have identified a root cause of chronic heart failure following a heart attack,” Dharmakumar said.
Dharmakumar is executive director of IU’s Krannert Cardiovascular Research Center and associate director for research at the Cardiovascular Institute, a joint enterprise between IU School of Medicine and IU Health.
“While advances across populations have made survival after a heart attack possible for most, too many survivors suffer long-term complications like heart failure,” said Subha Raman, MD, who is physician director of the Cardiovascular Institute. “Dr. Dharmakumar’s breakthrough science illuminates who is at risk and why and points to an effective way to prevent these complications.”
The multi-million-dollar study, which involved collaborators from institutions in the United States and Canada, followed large animal models over six months. It found that in heart attacks that result in bleeding within the heart muscle — which is about half of them — scar tissue is slowly replaced by fat. Fatty tissue can’t push blood from the heart effectively, and this is what leads to heart failure and eventually to death in many survivors of hemorrhagic heart attacks, Dharmakumar said.
“Using noninvasive imaging, histology and molecular biology techniques, and various other technologies, we have shown that iron from red blood cells is what drives this process,” he explained. “When we removed the iron, we reduced the amount of fat in the heart muscle. This finding establishes a pathway for clinical investigations to remedy or mitigate the effects associated with iron in hemorrhagic myocardial infarction patients.”
Dharmakumar’s team is currently testing iron chelation therapy to do just that in a just-launched clinical trial.
“Thanks to a clinical trial underway being led by his team at Indiana University, I’m excited to see this treatment improve the lives of millions of heart attack survivors worldwide,” said Raman.
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Using an approach based on CRISPR proteins, MIT researchers have developed a new way to precisely control the amount of a particular protein that is produced in mammalian cells.
This technique could be used to finely tune the production of useful proteins, such as the monoclonal antibodies used to treat cancer and other diseases, or other aspects of cellular behavior. In their new study, which appears in Nature Communications, the researchers showed that this system can work in a variety of mammalian cells, with very consistent results.
“It’s a highly predictable system that we can design up front and then get the expected outcome,” says William C.W. Chen, a former MIT research scientist. “It’s a very tunable system and suitable for many different biomedical applications in different cell types.”
Chen, who is now an assistant professor of biomedical sciences at the University of South Dakota, is one of the lead authors of the new study, along with former MIT Research Scientist Leonid Gaidukov and postdoc Yong Lai. Senior author Timothy Lu led the research as an MIT associate professor of biological engineering and of electrical engineering and computer science.
Gene control
Many therapeutic proteins, including monoclonal antibodies, are produced in large bioreactors containing mammalian cells that are engineered to generate the desired protein. Several years ago, researchers in MIT’s Synthetic Biology Center, including Lu’s lab, began working with Pfizer Inc. on a project to develop synthetic biology tools that could be used to boost the production of these useful proteins.

A decrease in protein synthesis in cells of the developing gut contributes to a rare genetic disorder, and an inexpensive nutritional supplement may help reverse that decrease, according to a new study publishing November 1 in the open access journal PLOS Biology by Yun-Fei Li of Zhejiang University School of Medicine in Hangzhou, China, and colleagues. The finding is an advance in understanding the pathogenesis of the disease, and may lead to new treatments.
Feingold syndrome type 1 leads to multiple problems in development, including of the skeleton and nervous system, but the symptom with the greatest impact on patients’ lives is intestinal atresia, or incomplete development of the gastrointestinal tract. The disorder is caused by loss-of-function mutations in the gene Mycn, which encodes a critical transcription factor that regulates the activity of many genes, but to date there has been no animal model to study the effects of that loss.
The authors created that model by using CRISPR genome editing to delete a portion of the Mycn gene in zebrafish, whose gut development shares important similarities with that of humans. They found that the resulting loss of gene activity led to a dramatic reduction in the size of the intestine, both in length and in the folding that gives the intestine its enormous surface area for absorption. Within a particularly affected subgroup of cells in the developing intestine, they found a significant down-regulation of numerous ribosomal genes, leading to reduced gene translation and protein synthesis.
Particularly affected were genes in the mTOR signaling pathway, a central regulator of protein synthesis; treatment of wild-type zebrafish with an mTOR inhibitor recapitulated the intestinal developmental defects seen in Mycn mutants. When the authors treated the mutant fish with leucine, an amino acid known to activate the mTOR pathway, the result was a partial normalization of the intestinal size in the mutants.
“Our work shows that during embryonic development, intestinal cells, which are in a highly proliferative state, require high Mycn expression levels,” the corresponding authors, Peng-Fei Xu and Xi Jin, say, “and that the proliferation arrest caused by reduced protein synthesis was the main reason for the developmental defects in the intestines of the Mycn mutant. This suggests a possible treatment strategy for the intestinal symptoms in patients with Feingold syndrome type 1, although confirmation in a human intestinal organoid system is essential.”
The first authors, Yun-Fei Li and Tao Cheng, add, “Feingold syndrome resulting from Mycn deficiency has been discovered for decades, however, the mechanism that leads to gastrointestinal atresia in Feingold syndrome type 1 is still unclear. We developed a Mycn mutant zebrafish model which recapitulates key phenotypes of Feingold syndrome type 1, and also provided a possible treatment strategy for Feingold syndrome type 1.”
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