SAVING RHINOS FROM EXTINCTION

Northern white rhinos are on the verge of extinction; only two females, Najin and Fatu, remain, at the Kenya’s Ol Pejeta Conservancy. However, the San Diego Zoo has stored skin cells from this species at -196° C. Researchers from the zoo and Scripps Research created induced pluripotent stem cells from the skin and showed they could make precursors of rhino egg and sperm cells. The researchers are now working to turn these cells into functional eggs and sperm, perform in vitro fertilization, and implant the resulting embryos in surrogate mothers — closely related southern white rhinos. 

REJUVENATING AGED CELLS

Adapting a Nobel-winning technique for reprogramming cells to an embryonic state, Stanford scientists partially turned back the clock of aged human cells, making them function more like youthful ones. In lab dishes, they treated aged cells with a low dose of a reprogramming cocktail consisting of mRNA. Treated cartilage cells from osteoarthritis patients no longer released inflammatory molecules that spark that disease, and treated muscle stem cells from older people were as potent as young stem cells in sparking tissue growth. The researchers have formed a company to develop drugs for age-related diseases.

CLOTTING IN COVID-19 PATIENTS

The Michigan researchers found that about half of hospitalized Covid-19 patients had autoimmune antibodies targeting phospholipids, and higher levels of these antibodies were associated with hyperactive neutrophils and activation of clotting pathways. When these antibodies from some patients were injected into mice, they promoted clotting. The findings suggest such antibodies might play a role in causing blood clots in many Covid-19 patients and targeting the autoantibodies with therapies used for autoimmune diseases might be a treatment strategy.

COVID-19 TURNS THE BODY ON ITSELF

An Emory-led team reported in October that some people with severe Covid-19 not only have an abnormal response to the virus, but their immune system starts to attack their own cells, resembling responses seen in autoimmune diseases such as lupus. This autoimmune response might explain why some patients who produce abundant antibodies against SARS-CoV-2 have poor outcomes, and might also be partially responsible for some of the symptoms of Covid-19 "long-haulers." A follow-up study found autoantibodies in patients with severe disease. The findings suggest immunomodulation treatments might be a good option for some patients.

GLIOBLASTOMA’S ACHILLES' HEEL

Glioblastoma is the most common and aggressive brain tumor and current therapeutic options such as surgery and chemotherapy are ineffective; only 10% of patients survive past three years. UVA researchers determined that a gene called advillin is often highly expressed in patient tumors and that its overexpression is crucial for glioblastoma proliferation and migration. Conversely, reducing the amount of advillin in glioblastoma cells in a dish and in a mouse slowed cell proliferation and reduced tumor formation. The researchers conclude that advillin is a "bona fide oncogene" and promising target for glioblastoma therapeutics.

MELANOMA GENETIC RISK FACTOR

The APOE4 gene is a major risk factor for Alzheimer's, while the APOE2 variant is protective. But in melanoma, the reverse is true, Rockefeller researchers found. Progression and metastasis of the skin cancer were reduced in mice with APOE4 compared with those with APOE2, and the former mice exhibited enhanced anti-tumor immune activity. In patients with melanoma, those with APOE4 had improved survival, and they also had better outcomes in two studies of immunotherapies, though not in a third. If confirmed in further studies, APOE might be a biomarker for relapse and treatment response.

ALS TREATMENT

A randomized, placebo-controlled clinical trial showed that a combination drug treatment for ALS modestly slowed the rate of decline in a measure of ability to perform daily activities over a 24-week period. When patients were followed for up to 35 months, a significant survival benefit emerged: There was a 44% lower chance of dying in the group originally assigned to the drug compared to the original placebo group. The results suggest that this drug combination might be the first to positively affect both physical function and survival in ALS.

REPLACING LOST NEURONS

UCSD scientists transformed brain cells called astrocytes into the dopamine-releasing neurons that are lost in Parkinson's disease, by depleting a single protein that regulates gene expression. In a mouse model of the disease, they converted astrocytes into functioning neurons that integrated into existing brain neural circuits and released dopamne, reversing Parkinson's-related symptoms. The researchers are working to validate and better understand how this cell reprogramming works so they can move it to the clinic as a possible treatment for various neurodegenerative diseases.

NEW TECHNIQUE FINDS KEY AUTISM GENES

Researchers from MIT's McGovern Institute, Harvard, and the Broad Institute developed a technique to simultaneously identify the function of numerous disease-risk genes in living animals, and to confirm whether they have a causal role in particular diseases. The team used CRISPR genome editing to mutate 35 suspected autism genes and introduced all of them into the brains of developing mice. Nine of the mutations had significant effects in a variety of brain cell types. This "Perturb-Seq" technique can be used in many other diseases and tissues.

MAKING MOVIES OF PROTEIN SYNTHESIS

UMass researchers used advanced electron microscopy to see how ribosomes, cellular machines that assemble proteins, “read” RNA in more detail than ever before. Previously, scientists had to pause this process to observe it, but this group was able to make “live movies” of how RNA is read and how ribosomes ensure the correct amino acid is added to a protein. This new method can be used to answer questions about what happens when protein synthesis goes awry in disease or how viral RNA is read in human cells.

ROOM-TEMPERATURE COVID-19 VACCINE

University of Washington bioengineers created a nanoparticle vaccine candidate against Covid-19, consisting of an array of multiple copies of the receptor-binding domain of the coronavirus spike protein — the prime target of neutralizing antibodies generated during infection with the virus. With a structure that mimics that of the coronavirus, the vaccine elicited a potent and protective antibody response in mice at low doses. It is stable at room temperature, making it convenient for use in regions without ready access to refrigeration. A clinical trial is planned.

ONE-DOSE COVID-19 VACCINE

The BIDMC team, working with Johnson & Johnson, developed and conducted preclinical testing of a single-dose Covid-19 vaccine, which is one of three authorized in the U.S. The others require two doses. The researchers tested seven versions of the vaccine, each a different variant of the virus spike protein, and identified one that generated the strongest immune response in monkeys. The candidate vaccine induced four times the level of neutralizing antibodies seen in patients recovered from Covid-19 and fully protected five of six animals from infection — paving the way for clinical trials that led to its approval.

TARGETING TAU IN ALZHEIMER'S

With the failure of Alzheimer's drug candidates targeting beta-amyloid, researchers are pivoting to target tau, another toxic protein that clumps together inside brain cells of Alzheimer's patients. A Boston Children's Hospital team found that tau is chemically modified as the disease progresses, and that specific changes correlate with disease severity. The changes they characterized could be useful for designing antibody and small-molecule drugs, as well as imaging reagents and diagnostics, that better target the protein at specific stages of Alzheimer's.

SURPRISE MEDICAL BILLS

By analyzing insurance claims data, University of Michigan researchers found that among patients undergoing seven common elective surgeries (including knee replacement, gallbladder removal, heart bypass, and hysterectomy) with in-network surgeons and facilities, more than 20% had an out-of-network bill. The average charge over the in-network fee averaged more than $2,000 per episode, with anesthesiologists and surgical assistants accounting for the largest share of such bills. The study, and a follow-up on ambulance charges, were the first to show the extent of surprise billing in these settings.

HIV GENE THERAPY

The isolation of anti-HIV antibodies from rare individuals able to generate them has inspired hope they can be used to treat or prevent HIV infections. Repeated large doses would be required, but a one-time gene therapy is another possible strategy. University of Miami scientists report that six years after a monkey was injected with a gene therapy encoding for an antibody against a monkey version of HIV, its muscle cells were still pumping out high levels of the antibody, the animal was infection-free, and it had produced no "anti-drug antibodies" against the delivered antibody, a frequent hurdle to such treatments.

HIV’S SHAPE-SHIFTING RNA

HIV has a tiny RNA genome, yet it's able to induce infected cells to make all the proteins it needs, by combining the "letters" of its RNA in different ways — like in a game of Boggle. A Whitehead group developed an algorithm that predicts the many shapes HIV’s RNA genome can fold into to make the most of its genome. They are using this algorithm to analyze the Covid-19 viral genome and hope use of this tool can help develop drugs that more effectively target viral replication.

COVID DOWN THE DRAIN

Tracking the spread of Covid-19 infection in communities has been hampered by gaps in testing, so researchers from the Brigham, MIT, and Biobot Analytics found a way to test entire towns — by checking for SARS-CoV-2 in sewer water. They developed a sampling device to measure viral load at wastewater treatment plants and in manholes around Massachusetts. Levels were higher than expected based on clinically confirmed cases and they found viral levels peaked in wastewater five days before the onset of cases requiring medical care. The group is now providing data to cities, businesses, and schools across the U.S.

RAPID COVID-19 TEST USING SMARTPHONE

A team from Gladstone, UC Berkeley, and UCSF devised a prototype of a rapid Covid-19 test using CRISPR genome editing technology and a smartphone camera equipped with a compact microscope to detect fluorescence emitted when viral RNA is cleaved. The new test skips processing steps required by other CRISPR-based tests, eliminating the need for specialized lab equipment, providing faster results — in under 30 minutes — and measuring viral load, not just whether a person is positive or negative, which could help monitor the course of a person's infection.

WHY MITOCHONDRIA LOSE POWER

Diminished function of the mitochondria, the cell's power plants, underlies many age-related and metabolic diseases. Utah researchers uncovered an important role for the amino acid cysteine in driving this decline during aging, showing that cellular pools of cysteine are mishandled in aged cells. While normally beneficial for cells, too much cysteine leads to mitochondrial impairment by altering the availability of intracellular iron, a critical cofactor for many mitochondrial processes. Cysteine-driven mitochondrial decline can be suppressed by iron supplementation, pointing to a new avenue for treating age-related disorders such as Parkinson's and Alzheimer's.

MITOCHONDRIA'S ROLE IN METASTASIS

With metastasis causing almost all deaths from breast cancer, UCI researchers used single-cell RNA sequencing to study changes in gene activity of cancer cells when they spread and seed new tumors. In mouse models of breast cancer, they found that cancer cells shift the way they generate energy during metastasis, relying more on oxidative phosphorylation in the mitchondria. Inhibiting this pathway in cancer cells reduced spread to the lungs, showing its critical role in metastasis. Drugs targeting mitochondrial metabolism are already on the market, though more study is needed.

IMMUNOLOGY OF PANCREATIC CANCER

Pancreatic cancer is resistant to promising immunotherapies, keeping its five-year survival rate at about 10%. Researchers don’t have a full picture of why these tumors are resistant or how they silence the body’s immune response, allowing it to exponentially grow relatively undetected. Researchers from Michigan's Rogel Cancer Center analyzed the immune response in patient tumors at the molecular level, revealing a complex network of immunosuppressive interactions and broad variation in immune responses from patient to patient. These findings could inform the design of clinical trials for immunotherapies.

NEW CANCER IMMUNOTHERAPY

At MD Anderson, chimeric antigen receptor (CAR)-modified natural killer (NK) cells are being developed as a new type of immunotherapy for blood cancers, using cells obtained from umbilical cord blood and genetically engineered to recognize certain cancer targets. In an ongoing Phase 1/2a clinical trial of this therapy, 7 of 11 patients went into remission and none had major side effects, such as the life-threatening cytokine release syndrome or neurotoxicity seen in some patients treated with CAR-T cell therapies. If further research confirms these early results, this new approach could provide an easier-to-manufacture, off-the-shelf treatment.

PRESCRIPTION VIDEO GAMES

Children with ADHD significantly improved their performance on a test of attention after playing a therapeutic video game designed by Akili Interactive Labs, showed a company-sponsored study led by Duke researchers. The study led to FDA approval of EndeavorRx, the first of a prescription video game as a treatment. Medication and behavioral therapy for ADHD have issues including inaccessibility, side effects, and poor adherence. In this study, 83% of children played at least 25 minutes a day for as much as five days a week. Additional research is exploring the durability of the benefits.

TRACING IMAGES ON THE BRAIN

Most efforts to restore vision rely on the unproven assumption that the brain can assemble pinpoints of light, created by stimulating the visual cortex with implanted electrodes, into an image, like pixels do on a computer screen. A Baylor team devised a new paradigm they compare to tracing letters on the palm of a hand. In a test of this technique, blind individuals could identify letters "drawn" on their cortex by stimulating electrodes in sequence. Much more work is needed before this technology is ready for clinical use, however.

ANTIFUNGAL FROM SEA SQUIRTS

New antifungal agents are urgently needed to combat spreading drug-resistant fungal pathogens. University of Wisconsin researchers, using advanced tools to screen the microbiomes of marine animals, identified a series of antifungal molecules. The most promising, turbinmicin — from a sea squirt — showed potent efficacy toward multiple-drug-resistant human fungal pathogens, including C. auris, in experiments in mice and lab dishes. The compound's safety profile and highly selective mechanism of action make it a promising drug candidate, the authors say.

PROGRAMMING EVOLUTION

Researchers at Cleveland Clinic and Case Western Reserve University for the first time applied a method commonly used in quantum physics to biological problems, showing how a mathematical algorithm could be used to design interventions to combat the evolution of drug resistance in pathogens or cancer. They demonstrated how varying external parameters, such as drug concentrations and types, temperature, and nutrients, can keep a system on a desired path to, for example, favor the evolution of drug-sensitive over drug-resistant cells.

MICROSCOPIC FROG-CELL ROBOTS

Scientists from Tufts and the University of Vermont made science fiction a reality by designing programmable, microscopic machines in a dish using cells from a frog embryo. Unlike “robots” made from steel or plastic, if these biological machines are damaged, they can fix themselves. The researchers developed a method that can design other such machines — coined xenobots — using computer simulations to find the best design and tissues. The researchers plan to use these bots to answer basic questions about life, but they might also be used one day for clinical applications such as drug delivery.

COATING THE GUT

Researchers at MIT and Brigham and Women's Hospital devised a non-invasive way to temporarily coat the small intestine with an adhesive polymer that, with further development, might improve medication delivery and treat diseases. Their key insight was that the polymer could be created within the gut, simply by drinking a solution that would react with an enzyme in the intestinal lining. In pigs, they showed that the coating might be useful to treat lactose intolerance, help people with diabetes reduce glucose uptake after meals, and slow absorption of medications, allowing for drugs to be dosed less frequently.

COVID-19 TUG-OF-WAR

A comprehensive "multi-omic" analysis of blood samples collected the first week after diagnosis from 139 Covid-19 patients with all levels of disease found a sharp transition between mild and moderate illness. The ISB team found a molecular tug-of-war occurring in which inflammation promotes a stronger immune response while key nutrients required for building that response are depleted in the transition to moderate disease. This leads to dysfunctional immune responses and impairs the recovery of those with severe disease. The findings suggest therapeutic interventions in patients with moderate disease are likely to be most effective.

COVID’S LETHAL CYTOKINE STORM

A storm of tiny proteins called cytokines are responsible for severe effects of Covid-19, including lung damage, organ failure, and death. Scientists from St. Jude Children’s Research Hospital identified two of the many cytokines produced by immune cells during SARS-CoV-2 infection that together appear to be the main drivers of acute lung damage — TNF-alpha and IFN-gamma. In mice, these cytokines caused tissue damage and inflammation like that seen with Covid-19, and inhibition of them protected the animals from severe symptoms. The scientists hope their findings lead to testing of already-approved drugs that block these cytokines.

TESTING DRUG CARDIOTOXICITY

Heart toxicity is a major reason drugs are withdrawn from the market, and approved cancer drugs often have serious heart side effects, pointing to the need for improved preclinical screening methods. The UofL researchers developed a system for keeping human and pig heart slices functional for up to six days and showed they could be used to reliably identify known safety issues with three cancer drugs, including their effects on viability, structure, function, and gene expression. The technology is technically demanding and expensive, but the work shows the platform's potential for screening drugs, the authors write.

HUMAN BODY ON A CHIP

Drugs often fail in clinical trials because preclinical testing in mice and other animals doesn't reliably predict their effects in humans. The Wyss team developed “human-body-on-chips” to overcome this problem. These chips link together multiple organs-on-chips — USB-stick-sized devices containing cells from human organs and blood vessels — mimicking how the body's vasculature connects organs. Using this device, they showed they could predict how the human body processes the cancer drug cisplatin and how it affects organs.

SCENT AND OBESITY

The sense of smell is known to be associated with fat metabolism, but the underlying mechanism is unknown. Baylor researchers showed that specific scents can by themselves regulate fat storage in worms, without a change in eating habits, by interacting with specific neurons and receptors. In nature, this mechanism may enable worms to adjust metabolic activity in response to environmental changes — for example, after detecting certain odors released by bacteria during times of reduced availability of lipids.

BETA BLOCKER SURPRISE

People with type 2 diabetes are at high risk for cardiovascular disease, but diabetes drugs that lower blood glucose do not lower the incidence of heart disease, suggesting other pathways are involved. Cleveland Clinic and Stanford scientists discovered a metabolite produced by gut microbes was consistently found in patients with diabetes who experience heart attacks or strokes. They showed this metabolite promotes clotting and binds to the same receptor as beta blockers, and when mice were treated with the drug, it reversed the effects of the metabolite, pointing to a previously unrecognized way the common heart medication might protect patients.

AI PROMPTS CRITICAL CONVERSATION

Many cancer patients die without having talked to their doctor about their end-of-life preferences, resulting in unwanted care. University of Pennsylvania researchers developed an algorithm to predict which cancer patients were at the highest risk of dying within six months and prompt clinicians weekly to have conversations with them about their treatment goals and care wishes. The number of these conversations with high-risk patients quadrupled during the five-month trial. Giving clinicians such behavioral nudges might reduce the number of patients who die in the ICU or on a ventilator rather than at home.

DOMESTIC VIOLENCE DURING COVID-19

Early in the pandemic, the number of domestic violence victims treated for physical injuries at the Brigham increased 1.9 times compared with the same period in 2017-19; severe injuries also were higher. The findings suggest the victims, almost all women, were afraid to seek health care until the abuse had become more serious due to fear of the coronavirus, the researchers said. Abuse victims are hesitant to tell doctors about the violence, so the researchers are using X-rays and clinical notes to train an artificial intelligence system to predict the likelihood that injuries are the result of partner violence.

DRUGGING THE UNDRUGGABLE

Amgen has applied for FDA approval of sotorasib, which would be the first treatment targeting cancers caused by KRAS mutations, the most frequent genetic driver of cancer. The pill targets a variant found in 13% of non-small cell lung cancers and up to 3% of other cancers. Key data came from a Phase 1 trial of sotorasib led by MD Anderson and Memorial Sloan Kettering, in which 32% of lung cancer patients with this mutation saw tumors shrink, with median progression-free survival of about six months. It was less effective against colorectal cancer. Treatment-related adverse events occurred in 57% of patients, though most weren't serious.

LEARNING WHERE CANCER DRUGS GO

Cells compartmentalize proteins in the nucleus into droplets called condensates, a poorly studied organelle. Whitehead researchers discovered cancer drugs like cisplatin and tamoxifen also accumulate in specific condensates in cancer cells grown in a dish, and this affects how they well they work. The findings suggest cancer drugs could be designed to target specific condensates containing molecules crucial to tumor growth. The team found resistance to tamoxifen may sometime result from dilution of the drug in condensates, information that might help researchers devise a solution.

QUANTIFYING LONG-COVID

This project to track outcomes of Covid-19 patients across Michigan after hospital discharge was one of the first studies to quantify the impact of "long-Covid." The researchers found that 60 days after being released from the hospital, 15% of patients had been rehospitalized and 7% had died. Among patients reached for a follow-up phone survey, many reported symptoms such as labored breathing or cough and persistent loss of taste or smell. Nearly half of these patients reported they were emotionally affected by their health problems.

DIVERSITY IN COVID-19 MESSAGING

Few public health messages about Covid-19 directly address communities of color, and most feature white experts. To determine whether the race or ethnicity of the person delivering the message affects the Covid knowledge and behavior of Black and Latinx individuals, researchers from Mass. General, Harvard, and MIT showed participants three videos about Covid, delivered by a white, Black, or Latinx doctor. In a survey afterward, Black participants said they were more likely to socially distance or wear masks when a Black physician delivered the message, but the same was not true for Latinx participants when a Latinx doctor was featured.

PILL THAT SAMPLES GUT MICROBES

Tufts scientists developed a pill-sized device that can be swallowed and sample gut microbes noninvasively and showed it faithfully recapitulated the gut microbiome of pigs and primates. The pill travels through the entire gastrointestinal tract, giving a more complete profile of the microbes inhabiting our gut than fecal samples, which only capture microbes in the colon. The "lab-on-a-pill" could improve understanding of the gut microbiome and eventually be used as a diagnostic tool and to monitor the body's response to treatments.

DIAGNOSING CANCER USING MICROBES

Researchers from UC San Diego reexamined thousands of cancer patient blood and tissue samples to create a comprehensive database of the cancer microbiome. Using machine learning, they identified unique patterns of microbial DNA for many types of cancer, and could distinguish people with cancer from those who were cancer-free based on microbial DNA found in blood. This new method could help with early detection of cancer, and the scientists have formed a company to develop and commercialize a diagnostic test.

SOLVING KEY ENZYME'S STRUCTURE

Abnormal production of triglycerides increases heart disease risk, but until now, the structure of a key enzyme involved in making triglycerides was unknown. A Stony Brook team deciphered the structure of lipin/Pah PAP, and showed how mutations in it lead to abnormal triglyceride production. Mutations in the enzyme can also cause diseases like the inflammatory disorder Majeed syndrome and nerve damage resulting in weakness or pain in hands or feet. Now, researchers can study how this enzyme contributes to these diseases.

REVIVING HEART PATIENTS

In a randomized trial testing a new strategy for resuscitating patients after an out-of-hospital cardiac arrest, a University of Minnesota team showed that use of a life support device known as ECMO (extracorporeal membrane oxygenation) significantly improved survival of patients whose hearts couldn't be shocked back into rhythm. Six of 14 patients treated with ECMO upon arrival at the hospital survived to discharge — and were still alive six months later — compared with 1 of 15 given standard care.

LUNGS-IN-A-DISH TO STUDY COVID

Duke and University of North Carolina researchers developed a lab-grown lung model using human lung stem cells isolated from patients. This “lung-in-a-dish” contains the air sacs where Covid-19 wreaks havoc in severe cases. When these lung organoids were infected with Covid-19, they reacted similarly to human lungs. Researchers think this model could help researchers understand what happens at the molecular level when SARS-CoV-2 infects lungs and potentially be used to screen for drug treatments.

COVID-19 RISK DURING PREGNANCY

Researchers at the University of Washington were the first in the U.S. to show that pregnant women are at high risk of developing severe Covid-19 symptoms if they have other risk factors like obesity, by analyzing the outcomes of all laboratory-confirmed cases of Covid during pregnancy from January to April 2020 in Washington state. The group is still working to understand the severity of the disease in pregnant women and the most effective treatments.

SAFER PSYCHEDELICS

There has been growing interest in treating neuropsychiatric disorders such as depression, PTSD, and addiction with psychedelics. One promising candidate is ibogaine, but it causes hallucinations lasting more than a day and it has been connected to several cardiac-related deaths. Researchers at UC Davis synthesized a variant of the drug that reduced drug-seeking behavior in mice and zebrafish without causing hallucinations or severe cardiac issues. This ibogaine variant is a promising candidate for a clinical trial evaluating it as a treatment for substance use disorder.

NANOPARTICLE DRUGS FOR INFLAMMATION

Researchers from Texas A&M developed pills to treat two different inflammatory diseases by encapsulating drugs that aren’t absorbed well by the body in a nanoparticle coating. They first showed in mice that encapsulated cyclosporine A, a fungal protein used to prevent organ rejection, can effectively treat lupus erythematosus, an autoimmune disease. Similarly, coated curcumin, an herbal supplement used to reduce inflammation, reduced eye inflammation in beagles. These studies provide a road map for transforming old drugs into treatments for new diseases.

BRAIN-PENETRATING NANOPARTICLE

Getting cancer drugs through the blood-brain barrier is a challenge for treatment of glioblastoma, but Michigan researchers engineered a synthetic protein nanoparticle able to reach tumors in the brain. The nanoparticle, packaged with siRNA that blocks a pathway related to tumor progression, was injected into eight mice with glioblastoma; seven were alive and tumor-free after 90 days, compared with a 44-day median survival for mice in a control group. When tumors were implanted in the brains of cured mice, their immune response prevented the cancer's regrowth without further treatment, suggesting the therapy’s potential to prevent recurrence.

PERSONALIZED GLIOBLASTOMA TREATMENT

Weill Cornell researchers showed that glioblastoma cerebral organoids — lentil-sized laboratory models of human brains injected with stem cells from a patient's tumor — were superior to other approaches for modeling these cancers and recreated the genetics and other key features of the actual tumors. They showed that the neuroanatomically accurate microenvironment of the brain organoids was critical for recapitulating the cellular states of the original tumor, though they can't be used to study interactions with blood vessels and immune cells. The findings show the potential of using organoids to screen drugs for individual patients' tumors.

MITOCHONDRIAL GENOME EDITOR

Scientists from the Broad Institute, University of Washington, and Massachusetts General Hospital developed the first genome editor for mitochondrial DNA, using a novel bacterial toxin. Mitochondria are the cell's power hub and they carry their own tiny genome. One small error in their genetic code causes rare but devastating disorders that are virtually untreatable. CRISPR doesn't penetrate mitochondria, but the new "base editor" precisely edited five genes in human mitochondria with up to about 40% efficiency. The scientists hope this tool can be used to make mouse models of mitochondrial diseases and, eventually, as a therapy.

GENOME EDITING FOR EYE DISEASES

UCI researchers used base editing, a form of CRISPR that in theory could correct most diseases caused by single-nucleotide mutations, to treat a retinal condition called Leber congenital amaurosis (LCA) in mice. In adult animals receiving injections of the base editor into the retina, the mutated gene was corrected with up to 29% efficiency, and vision and retinal function were restored to nearly normal. While a conventional gene therapy has been approved for LCA, this study provides evidence that base editing could be used for a range of inherited retinal diseases.

POSSIBLE MS TREATMENT TARGET

UT-Southwestern researchers showed that in a mouse model of multiple sclerosis, reducing levels of a protein called Reelin — which is elevated in people during MS relapse — prevented the leakage of a type of immune cell from blood vessels into the spinal cord and thus prevented neuroinflammation and progression of paralysis. If the findings are confirmed by further preclinical studies, Reelin could be a treatment target for people with progressive forms of MS, for which there are no effective therapies.

BRAIN LIQUID BIOPSY

The "empty" space between your brain cells and blood capillaries is filled with a fluid that can be analyzed to identify specific markers of neurological disorders, aiding in diagnosis and monitoring of treatment. But those markers or proteins are often too big to capture using current methods. Working in rodents, a research group at MIT developed a new method to identify these large proteins. They plan to use this tool in rodent models of neurological disorders to find new disease biomarkers that could eventually be used to study and improve diagnosis of these disorders in people.

AVOIDING SURGERY ON NEWBORNS

Vascular malformations are birthmarks or masses resulting from abnormal development of blood vessels that are often pathogenic. Drugs are being developed to treat malformations caused by specific genetic variants, but newborns must undergo surgery to biopsy the malformation to determine if they’re candidates for the drugs. Researchers at Seattle Children's Research Institute developed a new diagnostic method that doesn't require surgery. They were able to analyze DNA obtained from patients' plasma for gene variants associated with different types of vascular malformations, making diagnosis easier for the clinician and the patient.

EXPANDING HEART VALVE

Children born with defective heart valves require up to five replacement operations before reaching adulthood because current prosthetic valves can't accommodate growth. A Boston Children's Hospital-led team developed a prototype inspired by the valves in veins, which have two leaflets instead of the three in traditional prosthetic valves, that could be expanded using an inflatable balloon catheter. Testing in the lab and in sheep validated the valve's performance and showed it could be expanded as lambs grew for up to 10 weeks. Long-term durability and safety testing is needed before moving into clinical trials.

“BACKPACKS” HELP CELLS ATTACK TUMORS

Macrophages are like the Pac-Man of immune cells — they gobble up bacteria and other harmful things like cancer cells. Cancer cells can fight back, however, by secreting a substance that switches macrophages into a tumor-protecting state instead. Researchers from Harvard's Wyss Institute made nanoparticle “backpacks” for macrophages, which are loaded with cytokines that keep the macrophages in attack mode. These backpack-bearing macrophages slowed tumor growth and reduced metastasis in mice with aggressive breast cancer without significant side effects, suggesting they could be a potential future cancer therapy.

PREVENTING CANCER SPREAD

Like a fast-turning Ferris wheel, a molecule called Rab11b transports recycled proteins to the surface of metastic breast cancer cells, helping them to adapt to the brain microenvironment and take root there. The Notre Dame scientists showed that this molecule was especially active during early brain metastasis, and that its activity could be inhibited with two statins that cross the blood-brain barrier. The statins also prevented tumor cell growth in lab dishes and decreased brain metastasis in mice. The research points to repurposing statins as a possible strategy for preventing breast cancer spread to the brain.

ARTHRITIS DRUG SPEEDS COVID-19 RECOVERY

Emory researchers tested the efficacy of the drug baricitinib, often used to treat rheumatoid arthritis, in combination with hydroxychloroquine to speed recovery of Covid-19 patients. Although they only treated 15 hospitalized patients, they saw improved recovery and reduced mortality. This small study led to the drug's inclusion in a larger multi-institutional NIH-funded clinical trial, which showed that treatment with baricitinib, when combined with remdesivir, reduced recovery time of hospitalized patients. The FDA subsequently authorized this combination as a Covid treatment.

REPURPOSING DRUGS AGAINST COVID-19:

Just four months after the first reports about the novel coronavirus, a UCSF-led international team mapped interactions between 26 SARS-CoV-2 proteins and human proteins, identifying 332 that the virus uses to enter and infect cells and multiply. They then sorted through chemical libraries looking for existing drugs that target these proteins, finding 69 compounds, of which 29 are FDA-approved treatments for other illnesses. The paper spawned numerous clinical trials, with two dozen of the drugs being studied as possible Covid-19 treatments.

HOPE AGAINST HOOKWORM INFECTIONS

Parasitic hookworms infect some half a billion people worldwide, stunting growth of children and causing cognitive impairment, malnutrition, and anemia, but current drugs are losing potency because of resistance. Seeking to develop an inexpensive, scalable, and safe new drug, UMass researchers engineered bacteria with a protein that forms crytals toxic to these gastrointestinal nematodes, inactivated the bacteria with food-grade essential oils, and formulated it as a powder, which was potent against human-hookworm infections in hamsters and nontoxic to the animals. This research lays the groundwork for clinical trials.

BLOCKING MOSQUITO-BORNE DISEASES

Filarial parasites that cause canine heartworm disease and lymphatic filariasis, which affects 120 million people and can result in the disfiguring and painful disease elephantiasis, are spread by mosquitoes. Penn researchers found that a strain of Aedes aegypti mosquito resistant to infection by the heartworm parasite has a hyper-charged immune response, and that activating the immune response of otherwise-susceptible mosquitoes blocked development of both parasites into a transmissible form. They propose creating genetically modified mosquito populations using gene-drive technology as a strategy for controlling these diseases. 

NEW ANTIVIRAL DRUG

Georgia State researchers identified a new antiviral drug that can treat several illnesses that mostly affect children, including measles and upper respiratory infections caused by several types of paramyxoviruses. Designing a clinical trial with mostly child volunteers is complicated, so identifying drug treatments has been challenging. This new drug, which inhibits the viral enzyme essential for replication of its genome, targets some types of paramyxoviruses that affect adults, simplifying clinical trial design.

GENE THERAPY FOR HERPES

Fred Hutch researchers eliminated more than 90% of latent herpes simplex virus (HSV) in the main cells they infect in mice, by editing the virus genome with a DNA-cutting enzyme. After an initial infection, HSV lives on in the peripheral nerves, and the infection occasionally ramps up and causes sores around the mouth, lips, or genitals. While current treatments reduce the frequency of flare-ups and their severity, none attacks the virus lingering in cells. If it can be optimized, the new treatment offers a potential strategy to attack HSV and other chronic infections, such as hepatitis B and HIV, at the source, potentially curing patients.

SAVING RHINOS FROM EXTINCTION

Northern white rhinos are on the verge of extinction; only two females, Najin and Fatu, remain, at the Kenya’s Ol Pejeta Conservancy. However, the San Diego Zoo has stored skin cells from this species at -196° C. Researchers from the zoo and Scripps Research created induced pluripotent stem cells from the skin and showed they could make precursors of rhino egg and sperm cells. The researchers are now working to turn these cells into functional eggs and sperm, perform in vitro fertilization, and implant the resulting embryos in surrogate mothers — closely related southern white rhinos. 

CLOTTING IN COVID-19 PATIENTS

The Michigan researchers found that about half of hospitalized Covid-19 patients had autoimmune antibodies targeting phospholipids, and higher levels of these antibodies were associated with hyperactive neutrophils and activation of clotting pathways. When these antibodies from some patients were injected into mice, they promoted clotting. The findings suggest such antibodies might play a role in causing blood clots in many Covid-19 patients and targeting the autoantibodies with therapies used for autoimmune diseases might be a treatment strategy.

GLIOBLASTOMA’S ACHILLES' HEEL

Glioblastoma is the most common and aggressive brain tumor and current therapeutic options such as surgery and chemotherapy are ineffective; only 10% of patients survive past three years. UVA researchers determined that a gene called advillin is often highly expressed in patient tumors and that its overexpression is crucial for glioblastoma proliferation and migration. Conversely, reducing the amount of advillin in glioblastoma cells in a dish and in a mouse slowed cell proliferation and reduced tumor formation. The researchers conclude that advillin is a "bona fide oncogene" and promising target for glioblastoma therapeutics.

ALS TREATMENT

A randomized, placebo-controlled clinical trial showed that a combination drug treatment for ALS modestly slowed the rate of decline in a measure of ability to perform daily activities over a 24-week period. When patients were followed for up to 35 months, a significant survival benefit emerged: There was a 44% lower chance of dying in the group originally assigned to the drug compared to the original placebo group. The results suggest that this drug combination might be the first to positively affect both physical function and survival in ALS.

NEW TECHNIQUE FINDS KEY AUTISM GENES

Researchers from MIT's McGovern Institute, Harvard, and the Broad Institute developed a technique to simultaneously identify the function of numerous disease-risk genes in living animals, and to confirm whether they have a causal role in particular diseases. The team used CRISPR genome editing to mutate 35 suspected autism genes and introduced all of them into the brains of developing mice. Nine of the mutations had significant effects in a variety of brain cell types. This "Perturb-Seq" technique can be used in many other diseases and tissues.

ONE-DOSE COVID-19 VACCINE

The BIDMC team, working with Johnson & Johnson, developed and conducted preclinical testing of a single-dose Covid-19 vaccine, which is one of three authorized in the U.S. The others require two doses. The researchers tested seven versions of the vaccine, each a different variant of the virus spike protein, and identified one that generated the strongest immune response in monkeys. The candidate vaccine induced four times the level of neutralizing antibodies seen in patients recovered from Covid-19 and fully protected five of six animals from infection — paving the way for clinical trials that led to its approval.

TARGETING TAU IN ALZHEIMER'S

With the failure of Alzheimer's drug candidates targeting beta-amyloid, researchers are pivoting to target tau, another toxic protein that clumps together inside brain cells of Alzheimer's patients. A Boston Children's Hospital team found that tau is chemically modified as the disease progresses, and that specific changes correlate with disease severity. The changes they characterized could be useful for designing antibody and small-molecule drugs, as well as imaging reagents and diagnostics, that better target the protein at specific stages of Alzheimer's.

HIV GENE THERAPY

The isolation of anti-HIV antibodies from rare individuals able to generate them has inspired hope they can be used to treat or prevent HIV infections. Repeated large doses would be required, but a one-time gene therapy is another possible strategy. University of Miami scientists report that six years after a monkey was injected with a gene therapy encoding for an antibody against a monkey version of HIV, its muscle cells were still pumping out high levels of the antibody, the animal was infection-free, and it had produced no "anti-drug antibodies" against the delivered antibody, a frequent hurdle to such treatments.

COVID DOWN THE DRAIN

Tracking the spread of Covid-19 infection in communities has been hampered by gaps in testing, so researchers from the Brigham, MIT, and Biobot Analytics found a way to test entire towns — by checking for SARS-CoV-2 in sewer water. They developed a sampling device to measure viral load at wastewater treatment plants and in manholes around Massachusetts. Levels were higher than expected based on clinically confirmed cases and they found viral levels peaked in wastewater five days before the onset of cases requiring medical care. The group is now providing data to cities, businesses, and schools across the U.S.

WHY MITOCHONDRIA LOSE POWER

Diminished function of the mitochondria, the cell's power plants, underlies many age-related and metabolic diseases. Utah researchers uncovered an important role for the amino acid cysteine in driving this decline during aging, showing that cellular pools of cysteine are mishandled in aged cells. While normally beneficial for cells, too much cysteine leads to mitochondrial impairment by altering the availability of intracellular iron, a critical cofactor for many mitochondrial processes. Cysteine-driven mitochondrial decline can be suppressed by iron supplementation, pointing to a new avenue for treating age-related disorders such as Parkinson's and Alzheimer's.

NEW CANCER IMMUNOTHERAPY

At MD Anderson, chimeric antigen receptor (CAR)-modified natural killer (NK) cells are being developed as a new type of immunotherapy for blood cancers, using cells obtained from umbilical cord blood and genetically engineered to recognize certain cancer targets. In an ongoing Phase 1/2a clinical trial of this therapy, 7 of 11 patients went into remission and none had major side effects, such as the life-threatening cytokine release syndrome or neurotoxicity seen in some patients treated with CAR-T cell therapies. If further research confirms these early results, this new approach could provide an easier-to-manufacture, off-the-shelf treatment.

PRESCRIPTION VIDEO GAMES

Children with ADHD significantly improved their performance on a test of attention after playing a therapeutic video game designed by Akili Interactive Labs, showed a company-sponsored study led by Duke researchers. The study led to FDA approval of EndeavorRx, the first of a prescription video game as a treatment. Medication and behavioral therapy for ADHD have issues including inaccessibility, side effects, and poor adherence. In this study, 83% of children played at least 25 minutes a day for as much as five days a week. Additional research is exploring the durability of the benefits.

ANTIFUNGAL FROM SEA SQUIRTS

New antifungal agents are urgently needed to combat spreading drug-resistant fungal pathogens. University of Wisconsin researchers, using advanced tools to screen the microbiomes of marine animals, identified a series of antifungal molecules. The most promising, turbinmicin — from a sea squirt — showed potent efficacy toward multiple-drug-resistant human fungal pathogens, including C. auris, in experiments in mice and lab dishes. The compound's safety profile and highly selective mechanism of action make it a promising drug candidate, the authors say.

COATING THE GUT

Researchers at MIT and Brigham and Women's Hospital devised a non-invasive way to temporarily coat the small intestine with an adhesive polymer that, with further development, might improve medication delivery and treat diseases. Their key insight was that the polymer could be created within the gut, simply by drinking a solution that would react with an enzyme in the intestinal lining. In pigs, they showed that the coating might be useful to treat lactose intolerance, help people with diabetes reduce glucose uptake after meals, and slow absorption of medications, allowing for drugs to be dosed less frequently.

COVID’S LETHAL CYTOKINE STORM

A storm of tiny proteins called cytokines are responsible for severe effects of Covid-19, including lung damage, organ failure, and death. Scientists from St. Jude Children’s Research Hospital identified two of the many cytokines produced by immune cells during SARS-CoV-2 infection that together appear to be the main drivers of acute lung damage — TNF-alpha and IFN-gamma. In mice, these cytokines caused tissue damage and inflammation like that seen with Covid-19, and inhibition of them protected the animals from severe symptoms. The scientists hope their findings lead to testing of already-approved drugs that block these cytokines.

TESTING DRUG CARDIOTOXICITY

Heart toxicity is a major reason drugs are withdrawn from the market, and approved cancer drugs often have serious heart side effects, pointing to the need for improved preclinical screening methods. The UofL researchers developed a system for keeping human and pig heart slices functional for up to six days and showed they could be used to reliably identify known safety issues with three cancer drugs, including their effects on viability, structure, function, and gene expression. The technology is technically demanding and expensive, but the work shows the platform's potential for screening drugs, the authors write.

BETA BLOCKER SURPRISE

People with type 2 diabetes are at high risk for cardiovascular disease, but diabetes drugs that lower blood glucose do not lower the incidence of heart disease, suggesting other pathways are involved. Cleveland Clinic and Stanford scientists discovered a metabolite produced by gut microbes was consistently found in patients with diabetes who experience heart attacks or strokes. They showed this metabolite promotes clotting and binds to the same receptor as beta blockers, and when mice were treated with the drug, it reversed the effects of the metabolite, pointing to a previously unrecognized way the common heart medication might protect patients.

DOMESTIC VIOLENCE DURING COVID-19

Early in the pandemic, the number of domestic violence victims treated for physical injuries at the Brigham increased 1.9 times compared with the same period in 2017-19; severe injuries also were higher. The findings suggest the victims, almost all women, were afraid to seek health care until the abuse had become more serious due to fear of the coronavirus, the researchers said. Abuse victims are hesitant to tell doctors about the violence, so the researchers are using X-rays and clinical notes to train an artificial intelligence system to predict the likelihood that injuries are the result of partner violence.

LEARNING WHERE CANCER DRUGS GO

Cells compartmentalize proteins in the nucleus into droplets called condensates, a poorly studied organelle. Whitehead researchers discovered cancer drugs like cisplatin and tamoxifen also accumulate in specific condensates in cancer cells grown in a dish, and this affects how they well they work. The findings suggest cancer drugs could be designed to target specific condensates containing molecules crucial to tumor growth. The team found resistance to tamoxifen may sometime result from dilution of the drug in condensates, information that might help researchers devise a solution.

DIVERSITY IN COVID-19 MESSAGING

Few public health messages about Covid-19 directly address communities of color, and most feature white experts. To determine whether the race or ethnicity of the person delivering the message affects the Covid knowledge and behavior of Black and Latinx individuals, researchers from Mass. General, Harvard, and MIT showed participants three videos about Covid, delivered by a white, Black, or Latinx doctor. In a survey afterward, Black participants said they were more likely to socially distance or wear masks when a Black physician delivered the message, but the same was not true for Latinx participants when a Latinx doctor was featured.

PILL THAT SAMPLES GUT MICROBES

Tufts scientists developed a pill-sized device that can be swallowed and sample gut microbes noninvasively and showed it faithfully recapitulated the gut microbiome of pigs and primates. The pill travels through the entire gastrointestinal tract, giving a more complete profile of the microbes inhabiting our gut than fecal samples, which only capture microbes in the colon. The "lab-on-a-pill" could improve understanding of the gut microbiome and eventually be used as a diagnostic tool and to monitor the body's response to treatments.

SOLVING KEY ENZYME'S STRUCTURE

Abnormal production of triglycerides increases heart disease risk, but until now, the structure of a key enzyme involved in making triglycerides was unknown. A Stony Brook team deciphered the structure of lipin/Pah PAP, and showed how mutations in it lead to abnormal triglyceride production. Mutations in the enzyme can also cause diseases like the inflammatory disorder Majeed syndrome and nerve damage resulting in weakness or pain in hands or feet. Now, researchers can study how this enzyme contributes to these diseases.

COVID-19 RISK DURING PREGNANCY

Researchers at the University of Washington were the first in the U.S. to show that pregnant women are at high risk of developing severe Covid-19 symptoms if they have other risk factors like obesity, by analyzing the outcomes of all laboratory-confirmed cases of Covid during pregnancy from January to April 2020 in Washington state. The group is still working to understand the severity of the disease in pregnant women and the most effective treatments.

NANOPARTICLE DRUGS FOR INFLAMMATION

Researchers from Texas A&M developed pills to treat two different inflammatory diseases by encapsulating drugs that aren’t absorbed well by the body in a nanoparticle coating. They first showed in mice that encapsulated cyclosporine A, a fungal protein used to prevent organ rejection, can effectively treat lupus erythematosus, an autoimmune disease. Similarly, coated curcumin, an herbal supplement used to reduce inflammation, reduced eye inflammation in beagles. These studies provide a road map for transforming old drugs into treatments for new diseases.

BRAIN-PENETRATING NANOPARTICLE

Getting cancer drugs through the blood-brain barrier is a challenge for treatment of glioblastoma, but Michigan researchers engineered a synthetic protein nanoparticle able to reach tumors in the brain. The nanoparticle, packaged with siRNA that blocks a pathway related to tumor progression, was injected into eight mice with glioblastoma; seven were alive and tumor-free after 90 days, compared with a 44-day median survival for mice in a control group. When tumors were implanted in the brains of cured mice, their immune response prevented the cancer's regrowth without further treatment, suggesting the therapy’s potential to prevent recurrence.

GENOME EDITING FOR EYE DISEASES

UCI researchers used base editing, a form of CRISPR that in theory could correct most diseases caused by single-nucleotide mutations, to treat a retinal condition called Leber congenital amaurosis (LCA) in mice. In adult animals receiving injections of the base editor into the retina, the mutated gene was corrected with up to 29% efficiency, and vision and retinal function were restored to nearly normal. While a conventional gene therapy has been approved for LCA, this study provides evidence that base editing could be used for a range of inherited retinal diseases.

POSSIBLE MS TREATMENT TARGET

UT-Southwestern researchers showed that in a mouse model of multiple sclerosis, reducing levels of a protein called Reelin — which is elevated in people during MS relapse — prevented the leakage of a type of immune cell from blood vessels into the spinal cord and thus prevented neuroinflammation and progression of paralysis. If the findings are confirmed by further preclinical studies, Reelin could be a treatment target for people with progressive forms of MS, for which there are no effective therapies.

AVOIDING SURGERY ON NEWBORNS

Vascular malformations are birthmarks or masses resulting from abnormal development of blood vessels that are often pathogenic. Drugs are being developed to treat malformations caused by specific genetic variants, but newborns must undergo surgery to biopsy the malformation to determine if they’re candidates for the drugs. Researchers at Seattle Children's Research Institute developed a new diagnostic method that doesn't require surgery. They were able to analyze DNA obtained from patients' plasma for gene variants associated with different types of vascular malformations, making diagnosis easier for the clinician and the patient.

“BACKPACKS” HELP CELLS ATTACK TUMORS

Macrophages are like the Pac-Man of immune cells — they gobble up bacteria and other harmful things like cancer cells. Cancer cells can fight back, however, by secreting a substance that switches macrophages into a tumor-protecting state instead. Researchers from Harvard's Wyss Institute made nanoparticle “backpacks” for macrophages, which are loaded with cytokines that keep the macrophages in attack mode. These backpack-bearing macrophages slowed tumor growth and reduced metastasis in mice with aggressive breast cancer without significant side effects, suggesting they could be a potential future cancer therapy.

REPURPOSING DRUGS AGAINST COVID-19:

Just four months after the first reports about the novel coronavirus, a UCSF-led international team mapped interactions between 26 SARS-CoV-2 proteins and human proteins, identifying 332 that the virus uses to enter and infect cells and multiply. They then sorted through chemical libraries looking for existing drugs that target these proteins, finding 69 compounds, of which 29 are FDA-approved treatments for other illnesses. The paper spawned numerous clinical trials, with two dozen of the drugs being studied as possible Covid-19 treatments.

HOPE AGAINST HOOKWORM INFECTIONS

Parasitic hookworms infect some half a billion people worldwide, stunting growth of children and causing cognitive impairment, malnutrition, and anemia, but current drugs are losing potency because of resistance. Seeking to develop an inexpensive, scalable, and safe new drug, UMass researchers engineered bacteria with a protein that forms crytals toxic to these gastrointestinal nematodes, inactivated the bacteria with food-grade essential oils, and formulated it as a powder, which was potent against human-hookworm infections in hamsters and nontoxic to the animals. This research lays the groundwork for clinical trials.

GENE THERAPY FOR HERPES

Fred Hutch researchers eliminated more than 90% of latent herpes simplex virus (HSV) in the main cells they infect in mice, by editing the virus genome with a DNA-cutting enzyme. After an initial infection, HSV lives on in the peripheral nerves, and the infection occasionally ramps up and causes sores around the mouth, lips, or genitals. While current treatments reduce the frequency of flare-ups and their severity, none attacks the virus lingering in cells. If it can be optimized, the new treatment offers a potential strategy to attack HSV and other chronic infections, such as hepatitis B and HIV, at the source, potentially curing patients.

SAVING RHINOS FROM EXTINCTION

Northern white rhinos are on the verge of extinction; only two females, Najin and Fatu, remain, at the Kenya’s Ol Pejeta Conservancy. However, the San Diego Zoo has stored skin cells from this species at -196° C. Researchers from the zoo and Scripps Research created induced pluripotent stem cells from the skin and showed they could make precursors of rhino egg and sperm cells. The researchers are now working to turn these cells into functional eggs and sperm, perform in vitro fertilization, and implant the resulting embryos in surrogate mothers — closely related southern white rhinos. 

GLIOBLASTOMA’S ACHILLES' HEEL

Glioblastoma is the most common and aggressive brain tumor and current therapeutic options such as surgery and chemotherapy are ineffective; only 10% of patients survive past three years. UVA researchers determined that a gene called advillin is often highly expressed in patient tumors and that its overexpression is crucial for glioblastoma proliferation and migration. Conversely, reducing the amount of advillin in glioblastoma cells in a dish and in a mouse slowed cell proliferation and reduced tumor formation. The researchers conclude that advillin is a "bona fide oncogene" and promising target for glioblastoma therapeutics.

NEW TECHNIQUE FINDS KEY AUTISM GENES

Researchers from MIT's McGovern Institute, Harvard, and the Broad Institute developed a technique to simultaneously identify the function of numerous disease-risk genes in living animals, and to confirm whether they have a causal role in particular diseases. The team used CRISPR genome editing to mutate 35 suspected autism genes and introduced all of them into the brains of developing mice. Nine of the mutations had significant effects in a variety of brain cell types. This "Perturb-Seq" technique can be used in many other diseases and tissues.

TARGETING TAU IN ALZHEIMER'S

With the failure of Alzheimer's drug candidates targeting beta-amyloid, researchers are pivoting to target tau, another toxic protein that clumps together inside brain cells of Alzheimer's patients. A Boston Children's Hospital team found that tau is chemically modified as the disease progresses, and that specific changes correlate with disease severity. The changes they characterized could be useful for designing antibody and small-molecule drugs, as well as imaging reagents and diagnostics, that better target the protein at specific stages of Alzheimer's.

COVID DOWN THE DRAIN

Tracking the spread of Covid-19 infection in communities has been hampered by gaps in testing, so researchers from the Brigham, MIT, and Biobot Analytics found a way to test entire towns — by checking for SARS-CoV-2 in sewer water. They developed a sampling device to measure viral load at wastewater treatment plants and in manholes around Massachusetts. Levels were higher than expected based on clinically confirmed cases and they found viral levels peaked in wastewater five days before the onset of cases requiring medical care. The group is now providing data to cities, businesses, and schools across the U.S.

NEW CANCER IMMUNOTHERAPY

At MD Anderson, chimeric antigen receptor (CAR)-modified natural killer (NK) cells are being developed as a new type of immunotherapy for blood cancers, using cells obtained from umbilical cord blood and genetically engineered to recognize certain cancer targets. In an ongoing Phase 1/2a clinical trial of this therapy, 7 of 11 patients went into remission and none had major side effects, such as the life-threatening cytokine release syndrome or neurotoxicity seen in some patients treated with CAR-T cell therapies. If further research confirms these early results, this new approach could provide an easier-to-manufacture, off-the-shelf treatment.

COATING THE GUT

Researchers at MIT and Brigham and Women's Hospital devised a non-invasive way to temporarily coat the small intestine with an adhesive polymer that, with further development, might improve medication delivery and treat diseases. Their key insight was that the polymer could be created within the gut, simply by drinking a solution that would react with an enzyme in the intestinal lining. In pigs, they showed that the coating might be useful to treat lactose intolerance, help people with diabetes reduce glucose uptake after meals, and slow absorption of medications, allowing for drugs to be dosed less frequently.

TESTING DRUG CARDIOTOXICITY

Heart toxicity is a major reason drugs are withdrawn from the market, and approved cancer drugs often have serious heart side effects, pointing to the need for improved preclinical screening methods. The UofL researchers developed a system for keeping human and pig heart slices functional for up to six days and showed they could be used to reliably identify known safety issues with three cancer drugs, including their effects on viability, structure, function, and gene expression. The technology is technically demanding and expensive, but the work shows the platform's potential for screening drugs, the authors write.

BETA BLOCKER SURPRISE

People with type 2 diabetes are at high risk for cardiovascular disease, but diabetes drugs that lower blood glucose do not lower the incidence of heart disease, suggesting other pathways are involved. Cleveland Clinic and Stanford scientists discovered a metabolite produced by gut microbes was consistently found in patients with diabetes who experience heart attacks or strokes. They showed this metabolite promotes clotting and binds to the same receptor as beta blockers, and when mice were treated with the drug, it reversed the effects of the metabolite, pointing to a previously unrecognized way the common heart medication might protect patients.

DIVERSITY IN COVID-19 MESSAGING

Few public health messages about Covid-19 directly address communities of color, and most feature white experts. To determine whether the race or ethnicity of the person delivering the message affects the Covid knowledge and behavior of Black and Latinx individuals, researchers from Mass. General, Harvard, and MIT showed participants three videos about Covid, delivered by a white, Black, or Latinx doctor. In a survey afterward, Black participants said they were more likely to socially distance or wear masks when a Black physician delivered the message, but the same was not true for Latinx participants when a Latinx doctor was featured.

PILL THAT SAMPLES GUT MICROBES

Tufts scientists developed a pill-sized device that can be swallowed and sample gut microbes noninvasively and showed it faithfully recapitulated the gut microbiome of pigs and primates. The pill travels through the entire gastrointestinal tract, giving a more complete profile of the microbes inhabiting our gut than fecal samples, which only capture microbes in the colon. The "lab-on-a-pill" could improve understanding of the gut microbiome and eventually be used as a diagnostic tool and to monitor the body's response to treatments.

NANOPARTICLE DRUGS FOR INFLAMMATION

Researchers from Texas A&M developed pills to treat two different inflammatory diseases by encapsulating drugs that aren’t absorbed well by the body in a nanoparticle coating. They first showed in mice that encapsulated cyclosporine A, a fungal protein used to prevent organ rejection, can effectively treat lupus erythematosus, an autoimmune disease. Similarly, coated curcumin, an herbal supplement used to reduce inflammation, reduced eye inflammation in beagles. These studies provide a road map for transforming old drugs into treatments for new diseases.

GENOME EDITING FOR EYE DISEASES

UCI researchers used base editing, a form of CRISPR that in theory could correct most diseases caused by single-nucleotide mutations, to treat a retinal condition called Leber congenital amaurosis (LCA) in mice. In adult animals receiving injections of the base editor into the retina, the mutated gene was corrected with up to 29% efficiency, and vision and retinal function were restored to nearly normal. While a conventional gene therapy has been approved for LCA, this study provides evidence that base editing could be used for a range of inherited retinal diseases.

AVOIDING SURGERY ON NEWBORNS

Vascular malformations are birthmarks or masses resulting from abnormal development of blood vessels that are often pathogenic. Drugs are being developed to treat malformations caused by specific genetic variants, but newborns must undergo surgery to biopsy the malformation to determine if they’re candidates for the drugs. Researchers at Seattle Children's Research Institute developed a new diagnostic method that doesn't require surgery. They were able to analyze DNA obtained from patients' plasma for gene variants associated with different types of vascular malformations, making diagnosis easier for the clinician and the patient.

REPURPOSING DRUGS AGAINST COVID-19:

Just four months after the first reports about the novel coronavirus, a UCSF-led international team mapped interactions between 26 SARS-CoV-2 proteins and human proteins, identifying 332 that the virus uses to enter and infect cells and multiply. They then sorted through chemical libraries looking for existing drugs that target these proteins, finding 69 compounds, of which 29 are FDA-approved treatments for other illnesses. The paper spawned numerous clinical trials, with two dozen of the drugs being studied as possible Covid-19 treatments.

GENE THERAPY FOR HERPES

Fred Hutch researchers eliminated more than 90% of latent herpes simplex virus (HSV) in the main cells they infect in mice, by editing the virus genome with a DNA-cutting enzyme. After an initial infection, HSV lives on in the peripheral nerves, and the infection occasionally ramps up and causes sores around the mouth, lips, or genitals. While current treatments reduce the frequency of flare-ups and their severity, none attacks the virus lingering in cells. If it can be optimized, the new treatment offers a potential strategy to attack HSV and other chronic infections, such as hepatitis B and HIV, at the source, potentially curing patients.

GLIOBLASTOMA’S ACHILLES' HEEL

Glioblastoma is the most common and aggressive brain tumor and current therapeutic options such as surgery and chemotherapy are ineffective; only 10% of patients survive past three years. UVA researchers determined that a gene called advillin is often highly expressed in patient tumors and that its overexpression is crucial for glioblastoma proliferation and migration. Conversely, reducing the amount of advillin in glioblastoma cells in a dish and in a mouse slowed cell proliferation and reduced tumor formation. The researchers conclude that advillin is a "bona fide oncogene" and promising target for glioblastoma therapeutics.

NEW TECHNIQUE FINDS KEY AUTISM GENES

Researchers from MIT's McGovern Institute, Harvard, and the Broad Institute developed a technique to simultaneously identify the function of numerous disease-risk genes in living animals, and to confirm whether they have a causal role in particular diseases. The team used CRISPR genome editing to mutate 35 suspected autism genes and introduced all of them into the brains of developing mice. Nine of the mutations had significant effects in a variety of brain cell types. This "Perturb-Seq" technique can be used in many other diseases and tissues.

NEW CANCER IMMUNOTHERAPY

At MD Anderson, chimeric antigen receptor (CAR)-modified natural killer (NK) cells are being developed as a new type of immunotherapy for blood cancers, using cells obtained from umbilical cord blood and genetically engineered to recognize certain cancer targets. In an ongoing Phase 1/2a clinical trial of this therapy, 7 of 11 patients went into remission and none had major side effects, such as the life-threatening cytokine release syndrome or neurotoxicity seen in some patients treated with CAR-T cell therapies. If further research confirms these early results, this new approach could provide an easier-to-manufacture, off-the-shelf treatment.

COATING THE GUT

Researchers at MIT and Brigham and Women's Hospital devised a non-invasive way to temporarily coat the small intestine with an adhesive polymer that, with further development, might improve medication delivery and treat diseases. Their key insight was that the polymer could be created within the gut, simply by drinking a solution that would react with an enzyme in the intestinal lining. In pigs, they showed that the coating might be useful to treat lactose intolerance, help people with diabetes reduce glucose uptake after meals, and slow absorption of medications, allowing for drugs to be dosed less frequently.

DIVERSITY IN COVID-19 MESSAGING

Few public health messages about Covid-19 directly address communities of color, and most feature white experts. To determine whether the race or ethnicity of the person delivering the message affects the Covid knowledge and behavior of Black and Latinx individuals, researchers from Mass. General, Harvard, and MIT showed participants three videos about Covid, delivered by a white, Black, or Latinx doctor. In a survey afterward, Black participants said they were more likely to socially distance or wear masks when a Black physician delivered the message, but the same was not true for Latinx participants when a Latinx doctor was featured.

PILL THAT SAMPLES GUT MICROBES

Tufts scientists developed a pill-sized device that can be swallowed and sample gut microbes noninvasively and showed it faithfully recapitulated the gut microbiome of pigs and primates. The pill travels through the entire gastrointestinal tract, giving a more complete profile of the microbes inhabiting our gut than fecal samples, which only capture microbes in the colon. The "lab-on-a-pill" could improve understanding of the gut microbiome and eventually be used as a diagnostic tool and to monitor the body's response to treatments.

GENOME EDITING FOR EYE DISEASES

UCI researchers used base editing, a form of CRISPR that in theory could correct most diseases caused by single-nucleotide mutations, to treat a retinal condition called Leber congenital amaurosis (LCA) in mice. In adult animals receiving injections of the base editor into the retina, the mutated gene was corrected with up to 29% efficiency, and vision and retinal function were restored to nearly normal. While a conventional gene therapy has been approved for LCA, this study provides evidence that base editing could be used for a range of inherited retinal diseases.

GENE THERAPY FOR HERPES

Fred Hutch researchers eliminated more than 90% of latent herpes simplex virus (HSV) in the main cells they infect in mice, by editing the virus genome with a DNA-cutting enzyme. After an initial infection, HSV lives on in the peripheral nerves, and the infection occasionally ramps up and causes sores around the mouth, lips, or genitals. While current treatments reduce the frequency of flare-ups and their severity, none attacks the virus lingering in cells. If it can be optimized, the new treatment offers a potential strategy to attack HSV and other chronic infections, such as hepatitis B and HIV, at the source, potentially curing patients.

GLIOBLASTOMA’S ACHILLES' HEEL

Glioblastoma is the most common and aggressive brain tumor and current therapeutic options such as surgery and chemotherapy are ineffective; only 10% of patients survive past three years. UVA researchers determined that a gene called advillin is often highly expressed in patient tumors and that its overexpression is crucial for glioblastoma proliferation and migration. Conversely, reducing the amount of advillin in glioblastoma cells in a dish and in a mouse slowed cell proliferation and reduced tumor formation. The researchers conclude that advillin is a "bona fide oncogene" and promising target for glioblastoma therapeutics.

COATING THE GUT

Researchers at MIT and Brigham and Women's Hospital devised a non-invasive way to temporarily coat the small intestine with an adhesive polymer that, with further development, might improve medication delivery and treat diseases. Their key insight was that the polymer could be created within the gut, simply by drinking a solution that would react with an enzyme in the intestinal lining. In pigs, they showed that the coating might be useful to treat lactose intolerance, help people with diabetes reduce glucose uptake after meals, and slow absorption of medications, allowing for drugs to be dosed less frequently.

DIVERSITY IN COVID-19 MESSAGING

Few public health messages about Covid-19 directly address communities of color, and most feature white experts. To determine whether the race or ethnicity of the person delivering the message affects the Covid knowledge and behavior of Black and Latinx individuals, researchers from Mass. General, Harvard, and MIT showed participants three videos about Covid, delivered by a white, Black, or Latinx doctor. In a survey afterward, Black participants said they were more likely to socially distance or wear masks when a Black physician delivered the message, but the same was not true for Latinx participants when a Latinx doctor was featured.

GENE THERAPY FOR HERPES

Fred Hutch researchers eliminated more than 90% of latent herpes simplex virus (HSV) in the main cells they infect in mice, by editing the virus genome with a DNA-cutting enzyme. After an initial infection, HSV lives on in the peripheral nerves, and the infection occasionally ramps up and causes sores around the mouth, lips, or genitals. While current treatments reduce the frequency of flare-ups and their severity, none attacks the virus lingering in cells. If it can be optimized, the new treatment offers a potential strategy to attack HSV and other chronic infections, such as hepatitis B and HIV, at the source, potentially curing patients.