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T cells used in immunotherapy treatments can get exhausted by the task of fighting cancer cells or get shutdown as they enter tumors. Using a CRISPR-based edit on these cells’ genomes, researchers at UC San Francisco and Gladstone Institutes have rendered the therapeutic cells more resilient. The discovery may help overcome a major factor limiting the success of these promising therapies in curbing both solid and liquid tumors.
“We’ve succeeded in engineering better, stronger, longer-lived T cells that we think will improve treatment of both blood and solid cancers,” said Alex Marson, MD, PhD, who, along with cancer biologist Alan Ashworth, PhD, FRS led the study, published in Nature on Aug. 24, 2022. “It’s an example of how we’re using the power of CRISPR to accelerate the design of improved T-cell therapies.”
Marson also heads up the Gladstone-UCSF Institute of Genomic Immunology, a joint effort of the two institutions to bring a combination of advanced genomic technologies to bear on the creation of new cell-based immunotherapies.
“These genomic innovations are creating avenues to tackle the challenges of developing highly effective and precisely targeted immunotherapies,” said Ashworth, president of the Helen Diller Family Comprehensive Cancer Center. “The capacity to direct cell behavior by manipulating the genome will likely lead to transformational changes in the treatment of many diseases.”
One of the major challenges of developing highly effective cancer immunotherapies is the fact that tumors exist in an environment that suppresses T cells and other immune cells, allowing the tumor to form and grow. Therapeutic T cells, engineered from a patient’s own T cells to recognize and kill tumor cells, often get exhausted or dysfunction as they battle this environment, becoming unable to take down the cancer cells.
“By knocking out one individual gene, we’ve created cells that are not just potent tumor cell killers but also more persistent killers over a long period of time,” said physician-scientist Julia Carnevale, MD, a corresponding author on the study, who has recently started her own lab in UCSF’s Department of Medicine, pursuing new strategies to engineer superior cell therapies for cancer treatment.

Plant-based milk alternatives are an attractive option for people with allergies or intolerances, or who prefer a dairy-free diet. However, because some essential minerals are required to be included on the Nutrition Facts label only under certain circumstances, consumers might not know if they are meeting their dietary needs. Now, researchers have analyzed plant-based beverages and found variability in mineral content by type and brand. They report that pea-based drinks had the most phosphorus, selenium and zinc, while soy milks had the most magnesium overall.
The researchers will present their results today at the fall meeting of the American Chemical Society (ACS).
“Plant-based milk alternatives have been growing in popularity, but there’s not a lot known about the mineral content of these products, especially in the U.S.,” says Ben Redan, Ph.D., research chemist at the U.S. Food and Drug Administration (FDA), who is the principal investigator on the project. “Although they can be voluntarily declared, from a regulatory perspective, these minerals are not always required to be on the Nutrition Facts label.”
Made from base ingredients such as soy, almonds or oats, these products provide an alternative to dairy milk for people with allergies or intolerances, or who choose dairy-free diets. Although non-dairy options are increasing in variety and availability, the nutritional content of certain minerals in each type largely remains unknown — with dietary health implications for those who use them as a dairy substitute.
Redan and his colleague Lauren Jackson, Ph.D., performed the study, and they are both at the Institute for Food Safety and Health, a research consortium that includes the Illinois Institute of Technology, FDA and the food industry.
Redan and Jackson chose to measure the amount of magnesium, phosphorus, zinc and selenium in plant-based milk alternatives because these essential minerals are not required on the Nutrition Facts label and are components of dairy milk. In fact, dairy milk is a key contributor of these micronutrients in American diets, and people’s bodies can’t make them. Because people must instead consume foods and beverages with these minerals in them, it’s important to know how much is provided by various milk alternatives.
The researchers analyzed a selection of locally available plant-based beverages that were sold under a variety of brand names. Each product was made from a single base ingredient, such as almond, cashew, coconut, hemp, oat, pea, rice or soy. A technique called inductively coupled-mass spectrometry quantified the minerals present in a total of 85 samples. Using statistical analyses, the team found that the mineral content varied significantly across different product types — for example, soy-based versus almond-based drinks — and even between brands of the same type of product. When considering the amount of each specific mineral, they found that pea-based drinks had the most phosphorus, zinc and selenium, while soy drinks had the highest amounts of magnesium, on average.
Of all the samples analyzed, only pea- and soy-based drinks had higher levels of the four essential minerals than cow’s milk, with pea-based drinks containing about 50% higher levels of phosphorus, zinc and selenium. “These plant-based milk alternatives could be important sources of these micronutrients if you’re trying to reach the recommended dietary allowances for them,” Redan says. “That’s why these data points are important to get out to the public.”
In the end, the researchers hope that their data about essential minerals will help consumers make informed dietary decisions about non-dairy plant-based drink products.
The researchers acknowledge support and funding from FDA.
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Materials provided by American Chemical Society. Note: Content may be edited for style and length.

From life-like faces to elaborate nature scenes, tattoos are a true art form. Although people have decorated their bodies for millennia for ceremonial and religious reasons, many people today adorn themselves with these images as a form of self-expression. But the inks used for tattoos are unregulated in the U.S., resulting in products whose components are largely a mystery. Now, researchers have analyzed almost 100 inks and report that even when these products include an ingredient label, the lists often aren’t accurate. The team also detected small particles that could be harmful to cells.
The researchers will present their results today at the fall meeting of the American Chemical Society (ACS). 
“The idea for this project initially came about because I was interested in what happens when laser light is used to remove tattoos,” says John Swierk, Ph.D., the project’s principal investigator. “But then I realized that very little is actually known about the composition of tattoo inks, so we started analyzing popular brands.”
Swierk and undergraduates in his laboratory interviewed tattoo artists to see what they knew about the inks they use on their customers. The artists could quickly identify a brand they preferred, but they didn’t know much about its contents. “Surprisingly, no dye shop makes pigment specific for tattoo ink,” Swierk explains. “Big companies manufacture pigments for everything, such as paint and textiles. These same pigments are used in tattoo inks.” He also notes that tattoo artists must be licensed in the locales where they operate for safety reasons, yet no federal or local agency regulates the contents of the inks themselves.
Tattoo inks contain two parts: a pigment and a carrier solution. The pigment could be a molecular compound such as a blue pigment; a solid compound such as titanium dioxide, which is white; or a combination of the two compound types such as light blue ink, which contains both the molecular blue pigment and titanium dioxide. The carrier solution transports the pigment to the middle layer of skin and typically helps make the pigment more soluble. It can also control the viscosity of the ink solution and sometimes includes an anti-inflammatory ingredient.
Swierk’s team at Binghamton University (State University of New York) has been investigating the particle size and molecular composition of tattoo pigments using a variety of techniques, such as Raman spectroscopy, nuclear magnetic resonance spectroscopy and electron microscopy. From these analyses, they have confirmed the presence of ingredients that aren’t listed on some labels. For example, in one case ethanol was not listed, but the chemical analysis showed it was present in the ink. The team has also been able to identify what specific pigments are present in some inks.
“Every time we looked at one of the inks, we found something that gave me pause,” Swierk says. “For example, 23 of 56 different inks analyzed to date suggest an azo-containing dye is present.” Although many azo pigments do not cause health concerns when they are chemically intact, bacteria or ultraviolet light can degrade them into another nitrogen-based compound that is a potential carcinogen, according to the Joint Research Centre, which provides independent scientific advice to the European Union.
In addition, the team has analyzed 16 inks using electron microscopy, and about half contained particles smaller than 100 nm. “That’s a concerning size range,” says Swierk. “Particles of this size can get through the cell membrane and potentially cause harm.”
After the researchers run a few more tests and have the data peer reviewed, they will add the information to their website “What’s in My Ink?” “With these data, we want consumers and artists to make informed decisions and understand how accurate the provided information is,” says Swierk.
The researchers acknowledge support and funding from Binghamton University (State University of New York).
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Researchers from Trinity College Dublin have developed a new gene therapy approach that shows promise for treating the dry form of Age Related Macular Degeneration (AMD) — a progressive eye disease that affects up to 10% of adults over 65 years of age and is a leading cause of severe vision impairment and blindness in this age group.
Dry AMD cases represent around 85-90% of all AMD cases and there are no treatments available to treat or prevent disease progression, underlining the need for developing treatment options for this debilitating disease.
In adults, many diseases of aging have been found to have defects of mitochondrial function, including AMD.
The team, in Trinity’s School of Genetics and Microbiology, have developed a new gene therapy (ophNdi1) that is the first of its kind to directly target mitochondrial function in cells that are malfunctioning in AMD. Mitochondria are known as the “powerhouses” of the cell because they manage the production of energy but their performance dips greatly in dry AMD and this is linked to a deterioration in sight.
The new gene therapy cleverly uses a virus to access the cells that are suffering and deliver the code needed to give the failing mitochondria a lifeline, enabling them to generate extra energy and continue to function in supporting vision. The therapy has shown benefit in multiple models of dry AMD, offering hope that it could one day progress to a treatment that could help millions across the globe.
Professor Jane Farrar, senior author, said:
“Critically, this study provides the first evidence in models that directly modulating bioenergetics in eye cells can provide benefit and improve visual function in dry AMD. In doing so, the study highlights the energy powerhouses of the cell, mitochondria, as key targets for dry AMD.”
Dr Sophia Millington-Ward, first author and Research Fellow in Trinity’s School of Genetics and Microbiology, said:
“The novel gene therapy targeting cellular energy, or mitochondrial function, that we explored for dry AMD consistently provided benefit in the model systems tested. Many retinal cells, essential for vision, require particularly high levels of energy compared to most other cells, which makes them particularly vulnerable to mitochondrial dysfunction. The therapy we are developing directly targets mitochondrial function and increases energy production levels in the retina, which leads to better visual function in disease models of dry AMD.
Although there is further work to be done before this could be made available as a treatment for patients, the results give us hope that we are getting closer to a solution to this challenging, debilitating condition.”
The landmark work has just been published in the journal Clinical and Translational Medicine. 
The Research team in Trinity is funded by Enterprise Ireland and the European Regional Development Fund under Ireland’s European Structural and Investment Funds programme 1014-2020, Science Foundation Ireland, Fighting Blindness Ireland — Health Research Charities Ireland, EU Marie Curie Innovative Training Network, Health Research Board Ireland, Health Research Charities and the Irish Research Council (StarT).
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Materials provided by Trinity College Dublin. Note: Content may be edited for style and length.

A substance produced by gut microorganisms can lead to scarring and blood vessel damage in patients with scleroderma, a new study suggests.
The intestinal microbiome regulates immunity, and its alterations play a role in autoimmune conditions such as scleroderma. However, until now, researchers did not know how alterations in the intestinal microbiome contribute to fibrosis and vascular damage characteristic of scleroderma.
Researchers from Michigan Medicine investigated how a compound generated by the gut microbiome called trimethylamine N-oxide, or TMAO, could cause changes to cellular processes in scleroderma that trigger fibrosis, inflammation and vascular injury.
TMAO is formed in the liver after the gut metabolizes nutrients such as choline and carnitine, which are abundant in the Western diet that is rich in meat. Results published in iScience reveal that the TMAO can reprogram cells to become scar-forming myofibroblasts, which lead to fibrosis and vascular damage. Moreover, the enzyme responsible for the formation of TMAO, called FMO3, is elevated in patients with scleroderma.
“We have uncovered a novel mechanism linking the Western diet, the gut microbiome and some of the devastating effects of scleroderma,” said John Varga, M.D., senior author of the paper and chief of the Division of Rheumatology at University of Michigan Health. “We will next examine whether drugs, or food products like virgin olive oil, can be used to block formation of this compound in the gut to treat fibrosis.”
The research team also included investigators from the Cleveland Clinic and Northwestern University.
Additional authors include Seok-Jo Kim, Ph.D., Swarna Bale, Ph.D., Priyanka Verma,Ph.D., Qianqian Wan, M.D., Feiyang Ma, Ph.D., Johann E. Gudjonsson, M.D. Ph.D., , Paul W. Harms, Ph.D., Pei-Suen Tsou, Ph.D., Dinesh Khanna, MBBS, M.Sc., Lam C. Tsoi, Ph.D., all of Michigan Medicine, Stanley L. Hazen, M.D., Ph.D., Nilaksh Gupta, Ph.D., both of Cleveland Clinic, Karen J. Ho, M.D., Northwestern University Feinberg School of Medicine.
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Materials provided by Michigan Medicine – University of Michigan. Original written by Noah Fromson. Note: Content may be edited for style and length.

Our own immune system can become the enemy when mechanisms that are actually protective get out of control. In ANCA-associated vasculitis, excessive inflammatory reactions lead to pulmonary hemorrhages that can be fatal if left untreated. Researchers at the University of Bonn, together with colleagues from Germany, the Netherlands, Switzerland and England, have deciphered a mechanism in mice and patients that leads to the severe disease. The results are now published in the Journal of Experimental Medicine.
In ANCA-associated vasculitis, there is severe inflammation of the smaller and medium-sized blood vessels in the lungs. In addition, the skin and kidneys may also be affected. ANCA stands for “anti-neutrophil cytoplasmic antibodies,” which are antibodies produced by the body that target its own white blood cells. It is a rare, severe autoimmune disease that is often fatal if left untreated due to pulmonary hemorrhage.
Therapy involves the administration of drugs that suppress the immune system. Recently, attempts have also been made to block the inflammatory cascade with inhibitors. “The challenge in finding new therapies is that very little is known about the mechanisms that trigger the disease,” says Prof. Natalio Garbi of the Institute of Molecular Medicine and Experimental Immunology (IMMEI) at Bonn University Hospital.
Together with colleagues from Germany, the Netherlands, Switzerland and the United Kingdom, the scientists have now discovered a mechanism responsible for the development of the disease in the form of the cGAS/STING/IFN-I signaling pathway. “We were able to show in experiments with mice that the symptoms of this autoimmune disease — such as pulmonary hemorrhage — improve when this signaling pathway is blocked with drugs,” says first author and doctoral student Nina Kessler from Natalio Garbi’s team. The study involved 31 patients with ANCA vasculitis and, as controls, 57 healthy individuals as well as a novel mouse model.
Stray DNA
Normally, the genetic material DNA is located in the nucleus or mitochondria of cells. But if pathogens such as bacteria or viruses have taken up residence in the cell, they may leave behind a DNA trail in the cytosol that is detected by a special sensor called cGAS. This sentinel produces a molecule called cGAMP, which in turn activates the STING molecule. As a result, type 1 interferon (IFN-I) production occurs, leading to strong inflammation. This should prevent the pathogens from multiplying and even drive heavily infected cells into cellular suicide.
“It becomes problematic when these mechanisms are not triggered by pathogens but by our own cellular DNA,” Garbi explains. Then the cGAS/STING/IFN-I signaling pathway leads to cell death. “In our study, we show that for reasons still unknown, DNA is released from the cell nucleus and activates the signaling pathway. This leads to blood vessel destruction and frank hemorrhage,” says Garbi, a member of the ImmunoSensation2 cluster of excellence at the University of Bonn.
Researchers recreate disease development in mice
The researchers recreated the most important steps of disease development in mice. To do this, they administered pathogenic autoantibodies to the animals and introduced bacterial products into their lungs to mimic an infection such as occurs during an ANCA vasculitis flare. The mice then developed lung disease and hemorrhage. At various points, the researchers interrupted the cGAS/STING/IFN-I signaling chain by “silencing” certain genes — for example, for IFN-I or for certain macrophages of the immune system.
From the results in the mice, the researchers conclude that it is indeed an overactivation of cGAS/STING by DNA misplaced in the cell that leads to the severe disease. Elevated blood levels of IFN-I and cGAMP in the patients studied suggest that the out-of-control DNA guardian in the cells is responsible for disease progression. “Immune cells are both friends and foes of the disease,” says Susanne Viehmann, PhD from the IMMEI lab of Prof. Christian Kurts. Macrophages originated from the blood produce the inflammatory molecule IFN-I, which drives the disease. At the same time, a different type of macrophages in the alveoli eat up red blood cells that leak out of the vessels, thereby reducing pro-inflammatory factors.
“By better understanding the molecular processes of severe ANCA vasculitis, we have been able to identify potential drug targets in the preclinical model that are already approved for other diseases,” Garbi says. However, more intensive research is still needed, he adds.
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Researchers at Karolinska Institutet in Sweden are developing a coronavirus vaccine designed to be less sensitive to mutations and equipped for future strains. The vaccine showed promising results in mice in a newly published study in EMBO Molecular Medicine, and the researchers now hope to be able to take it to safety studies on humans.
“This is a new generation of corona vaccine,” says Matti Sällberg, professor at the Department of Laboratory Medicine, Karolinska Institutet, and the study’s joint last author with Ali Mirazimi, adjunct professor at the same department. “The idea is that it will give broader protection that more resembles that gained after an actual infection and will be a bit more future-proof than the vaccines currently in use.”
Different types of vaccine have been highly instrumental in impeding the pandemic caused by the coronavirus SARS-CoV-2. One challenge is the virus’s mutability, which is to say its ability to change to avoid the human defence response.
Most current vaccines are based on using parts of the coronavirus’s so-called spike protein to trigger the body’s immune response to the virus. It is a good vaccine protein to use, but unfortunately it is the spike protein where frequent mutations occur, which can impact the vaccines’ effectiveness.
Contains more parts of the virus
The researchers at Karolinska Institutet are therefore developing a vaccine containing more parts of the virus, including ones that do not mutate at the same rate as the spike protein.

Researchers at Intermountain Healthcare have conducted a landmark, first-of-its-kind survey to identify and stratify antimicrobial stewardship programs into four different groups — a first step toward studying the effectiveness of these models to best enhance patient care and reduce the rise of antibiotic resistant superbugs.
Antimicrobial stewardship programs are a vital way for hospitals and healthcare systems to ensure that antibiotics are being appropriately used. If they keep being given to patients who don’t need them, they can harm those patients while also contributing to antibiotic resistance, thus making bacterial infections harder to treat.
These programs can be as varied as healthcare systems themselves, leaving researchers in the dark as to best practices in their antibiotic approach. That’s why this new work by the Intermountain Healthcare team is so vital.
“We brought together antimicrobial stewardship leaders from around the country to better understand both the structures and functions of their programs,” said researcher Whitney Buckel, PharmD, an antimicrobial stewardship pharmacist manager at Intermountain Healthcare. “We wanted to categorize different approaches to this work, with the hope of then identifying which methods are most effective, and what can be used as models for other healthcare systems.”
“You could find 50 different marathon training programs that would all get you to the finish line, but they may not all be efficient, or applicable to you. It’s the same with antimicrobial stewardship programs,” added researcher Eddie Stenehjem, MD, medical director of antibiotic stewardship at Intermountain Healthcare. “We wanted to get a better idea of what is happening out in mostly in-patient healthcare settings, so that we can start determining which programs are best suited to which kind of healthcare systems.”
The study, led by Intermountain researchers in collaboration with scientists from Pew Charitable Trusts and the University of Utah, surveyed 20 different healthcare systems, including Kaiser Permanente, the Mayo Clinic and Veterans Health Administration.

Many tumor cells mist themselves with a protective perfume that disables the immune system. But a drug already approved for other purposes can apparently render this weapon harmless. This is shown in a study by the University of Bonn and the University Medical Center Hamburg-Eppendorf, which has now appeared in the Journal for ImmunoTherapy of Cancer. The researchers now want to further optimize the compound. In the medium term, this could pave the way for new anti-cancer drugs.
Many cancer cells surround themselves with a dense cloud of adenosine. On the one hand, the molecule suppresses the immune system. At the same time, it stimulates the formation of new blood vessels that supply the tumor with oxygen and nutrients. It also ensures that the malignant cells migrate to other organs and form metastases there.
Adenosine is produced from adenosine triphosphate, or ATP for short. Tumor cells secrete large amounts of it. They carry various enzymes on their surface that then convert the ATP to adenosine in several steps. One of these is known as CD39. “It catalyzes the first of the conversion steps,” explains Prof. Dr. Christa Müller from the Institute of Pharmacy at the University of Bonn. “If CD39 is inhibited, hardly any adenosine is produced.”
Around the globe, pharmaceutical researchers are therefore searching for an active ingredient that slows down CD39. Because without adenosine, tumors would no longer be protected from the immune system. “Instead, ATP would accumulate around the cancer cells, which would actually stimulate the immune response,” says Müller. “So the body’s own defenses would not be suppressed; on the contrary, they would be turned on extra sharp.”
50 approved active substances scrutinized
So far, the search has been largely unsuccessful. The Bonn research group therefore pursued a new search strategy in the study: “There are other enzymes in the body than CD39 that also process ATP,” explains Laura Schäkel. The collaborator of Prof. Müller carried out many of the central experiments in the study. “These include, for example, the so-called protein kinases. The nice thing is that there are already approved drugs that inhibit protein kinases. We now looked at whether they also work against CD39.”
At the start of the study, there were a total of 50 different agents approved for certain diseases that inhibit protein kinases. The research group examined all of them. With success: “One of the substances, ceritinib, also blocks the conversion of ATP by CD39,” Schäkel is pleased to report. “We were able to show this not only in the test tube, but also in cultures with so-called triple-negative breast cancer cells. These are extremely difficult to treat — they usually hardly respond to therapies.”

Gene therapy has partly restored the function of the retina’s cone receptors in two children who were born completely colourblind, reports a new study led by UCL researchers.
The findings, published in Brain, provide hope that the treatment is effectively activating previously dormant communication pathways between the retina and the brain, drawing on the plastic nature of the developing adolescent brain.
The academically-led study has been running alongside a phase 1/2 clinical trial in children with achromatopsia, using a new way to test whether the treatment is changing the neural pathways specific to the cones.
Achromatopsia is caused by disease-causing variants to one of a few genes. It affects cone cells, which (along with rods) are one of two types of photoreceptors in the eyes. As cones are responsible for colour vision, people with achromatopsia are completely colourblind, while they also have very poor vision overall and find bright light uncomfortable (photophobia). Their cone cells do not send signals to the brain, but many remain present, so researchers have been seeking to activate the dormant cells.
Lead author Dr Tessa Dekker (UCL Institute of Ophthalmology) said: “Our study is the first to directly confirm widespread speculation that gene therapy offered to children and adolescents can successfully activate the dormant cone photoreceptor pathways and evoke visual signals never previously experienced by these patients.
“We are demonstrating the potential of leveraging the plasticity of our brains, which may be particularly able to adapt to treatment effects when people are young.”
The study involved four young people with achromatopsia aged 10 to 15 years old, who were taking part in two trials led by Professor James Bainbridge at UCL and Moorfields Eye Hospital, sponsored by MeiraGTx-Janssen Pharmaceuticals.