Publisher Health

Rice University synthetic biologists have found a way to piggyback on the glucose monitoring technology used in automated insulin dosing systems and make it universally applicable for the monitoring and dosing of virtually any drug.
In a recently published study in Nature Communications, researchers in the lab of Caroline Ajo-Franklin demonstrated the technique by modifying a blood-glucose sensor to detect the anticancer drug afimoxifene , an estrogen inhibitor that patient’s bodies also make after they take the chemotherapy tamoxifen.
By building on mature biosensing technology that’s commercially available at most drug stores for under $20, Ajo-Franklin’s team hopes to speed the development of automated dosing systems for chemotherapies and other drugs as well as other technologies for real-time monitoring of biomarkers in the blood.
“The dream is to have technology similar to what’s available today for monitoring and treating variations in blood glucose, and have that be true for basically any drug,” said Ajo-Franklin, a bioscientist, cancer researcher and director of the Rice Synthetic Biology Institute . “Millions of people use blood-glucose monitors every day. If we can use that same basic technology to monitor other drugs and biomarkers, we could move away from the one-size-fits-all dosing regimes that we’re stuck with today.”
The heart of blood-glucose monitoring technology is a biochemical reaction in which specific proteins bind to glucose molecules and release electrons. Millions of these reactions take place within seconds, creating a small electrical current that is proportional to the amount of glucose in the blood sample.
Rong Cai , a postdoctoral research associate and the lead author of the study, tested more than 400 slightly modified versions of the electron-releasing protein and found a version that reacted with afimoxifene, reducing the current output from the glucose reaction in the blood. This allowed the team to detect the presence of afimoxifene by comparing the current produced by the regular glucose test to the reduced current from the modified test.
To demonstrate the technology in an electronic device, Ajo-Franklin’s team worked with the research group of Rice engineer and materials scientist Rafael Verduzco to create an afimoxifene sensor that emitted a current when the drug was detected.

Ajo-Franklin said her lab is already working on both ways to improve the sensitivity of glucose-based drug tests and methods to rapidly identify glucose-oxidizing proteins that can detect drugs other than afimoxifene.
“The glucometer is the part that’s so well-developed,” Cai said. “While our target is different, it’s just a matter of engineering and changing the protein on the inside. On the outside, everything will still be the same. You can still do the test with a strip or on your arm.”
She said another key feature of the technology is that it produces an electrical output.
“If your signal is electrical, you can read it in your phone, store its data in your phone, send it to the cloud, whatever,” Cai said. “That’s the part, that marriage between electricity and biology, that is very attractive.”
Ajo-Franklin is a professor of biosciences in the Weiss School of Natural Sciences and a CPRIT Scholar in Cancer Research with the Cancer Prevention and Research Institute of Texas (CPRIT). Verduzco is a professor of chemical and biomolecular engineering and of materials science and nanoengineering in the George R. Brown School of Engineering .
The research was supported by CPRIT (RR190063), the National Science Foundation (1828869, 2223678) and the Army Research Office (W911NF-22-1-0239).

Among his accomplishments during a four-decade career in public health, he helped to pioneer programs providing bed nets in Africa.Kent Campbell, an instrumental figure in the global battle against malaria — most notably in Africa, where he led an innovative program providing bed nets to protect rural villagers from the mosquitoes carrying the disease — died on Feb. 20 in Oro Valley, Ariz., a suburb of Tucson. He was 80.His death, in a nursing care facility, was caused by complications of cancer, his children said.As chief of the malaria branch of the Centers for Disease Control and Prevention from 1981 to 1993, and later as an adviser to UNICEF and the Bill & Melinda Gates Foundation, Dr. Campbell is credited with helping to save lives on multiple continents.In Zambia, where he began working on a program with the Gates Foundation in 2005 distributing bed nets and newer antimalarial drugs, malaria cases were cut in half within three years. The program was later expanded to more than 40 other countries in Africa.“His legacy in my country is as one of the people who greatly contributed to the control and prevention of malaria,” Kafula Silumbe, a Zambian public health specialist who worked closely with Dr. Campbell, said in an interview. “It was a collective effort, but he definitely was part of that initial push.”Tall and lanky, with a Southern drawl that revealed his Tennessee upbringing, Dr. Campbell stumbled on what would become a four-decade-long career in public health.In 1972, during his pediatric residency in Boston, he joined the C.D.C. as a conscientious objector to the Vietnam War. Not long after, he was sent to Sierra Leone to help investigate an outbreak of Lassa fever, a virulent hemorrhagic virus.We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

Published1 hour agoShareclose panelShare pageCopy linkAbout sharingBy Michael BuchananBBC NewsA group of doctors offered a controversial medical technique which allegedly put kidney patients’ health at risk.At least 20 patients at Queen Alexandra Hospital (QA) in Portsmouth have been using the procedure, which is not recommended in UK guidelines.A consultant was wrongly sacked from the hospital in 2018 after objecting to the practice. The hospital trust said the safety and care of its patients was its priority.Jasna Macanovic, who worked at the QA for 17 years, had raised concerns about the way the trust was allowing some staff to deliver the dialysis technique – known as buttonholing. “I don’t think they’re fit to practise medicine,” Dr Macanovic told the BBC.All patients using a dialysis machine – which cleans their blood because their kidneys can no longer do this – need to have a special strengthened blood vessel made for them, to connect to the machine. Usually this is a fistula, made by joining an artery with a vein, but for a small number of patients whose veins are fragile, a piece of plastic tubing called an arterio-venous graft is used instead. Needles connect the graft to the machine, and are normally inserted into different places on the graft each time – a technique known as rope-laddering. Buttonholing, on the other hand, involves putting needles into the same hole each time. This is safe for those with fistulas, but for those using grafts, it “has always been avoided… due to the risk of infection and graft degradation”, according to the UK Kidney Association guidelines which are used throughout the NHS. It says only rope-laddering is recommended for grafts. International guidelines, and the grafts’ manufacturer, go further, describing the practice as contraindicated, meaning it may be harmful to patients. Nonetheless a small team at Portsmouth – including consultants Paul Gibbs and Nick Sangala, as well as nurse Sarah Kattenhorn – championed the procedure. When Dr Macanovic examined the records of 15 patients using the buttonholing technique at the QA, she found infection rates four times higher than they experienced using the standard technique. One of the patients featured in Dr Macanovic’s audit was Amanda Kelsey, who died in April 2020, aged 50. Image source, Family handoutHer death certificate gave the cause of death as a stroke, end-stage renal failure and Covid-19. Her husband repeatedly asked the hospital to investigate why her blood pressure had suddenly increased in the months before her death. He says he never got an answer on this, and both he and Dr Macanovic now wonder if it was linked in some way to the complications she had been experiencing with her kidney dialysis. “We were told it’s less aggressive on your skin and on the point of entry into your vein,” recalls her husband Mark. But Mrs Kelsey’s medical records, which BBC News has seen, show she suffered a great deal after she started buttonholing. There are repeated references to her graft clotting, with various surgeries to repair it. “I would say that the buttonhole needling technique destroyed her life, certainly destroyed her health,” says Dr Macanovic. “No human body should be put through that trauma.” Dr Macanovic’s audit found that Mrs Kelsey’s complication rate during buttonholing was almost six times higher than it had been previously, and that in the three years after she started buttonholing, Mrs Kelsey had had at least 18 interventions related to problems with her graft. In the three previous years, when she had been using the standard rope-laddering technique, she had needed just one intervention. In a statement, the Portsmouth Hospitals University NHS Trust said it wasn’t able to comment on Mrs Kelsey’s case because of patient confidentiality. It said her death was reviewed by an independent medical examiner, in accordance with the law, and the examiner agreed with the cause of death given by the reporting doctor.But it did acknowledge that it was “not aware” of any other NHS organisation using buttonholing and that a medical paper evidencing the merits of the technique – that a staff member had publicly promised in 2020 – had not been written or published. File on 4 – Whistling in the windThe NHS whistleblowers punished for raising concerns.Listen now on BBC SoundsDr Macanovic says she drew her colleagues’ attention to several sets of guidelines which outlined the dangers of buttonholing, wrote to the grafts’ manufacturers who confirmed that “the buttonhole technique… cannot be used”, and reported her colleagues’ actions to regulators – the Care Quality Commission (CQC) and the General Medical Council (GMC).Though the regulators’ reviews found there had been problems – for example a CQC inspection found the procedure had been introduced without patients being informed of the dangers of the technique – they didn’t stop the procedure. They said safety concerns were taken into account. It also cleared those involved of any misconduct.An external review commissioned by the trust also found no evidence of direct patient harm, but Dr Macanovic remains unconvinced.”It’s very important for society to understand how weak the regulatory bodies are when it comes to patient safety,” she said.The trust, for its part, said it “does not accept that Dr Macanovic raised evidenced concerns of patient harm” but said her claims had been “fully reviewed by clinicians” at the trust and considered alongside existing reviews and the medical history of each patient.Dr Macanovic was dismissed in March 2018, but subsequently won £219,000 in compensation for unfair dismissal after taking legal action. The judge in her employment tribunal ruled she had been sacked as a result of her whistleblowing. Portsmouth Hospitals University NHS Trust told the BBC that while UK vascular access guidelines do not recommend buttonholing, they “do not specifically state that it is contraindicated”. It added that other options were always “explored and offered” before this technique was discussed with patients.The trust added that “Dr Gibbs did not persuade or encourage patients or other clinicians to use the buttonholing AV graft technique” and that he “at all times, properly set out the known advantages and disadvantages of the technique to patients”. It added that Dr Gibbs had always “acted properly, in accordance with his obligations as a medical practitioner, and with patient safety in mind”.The trust acknowledged that Dr Sangala and Ms Kattenhorn were supportive of the buttonholing technique and had spoken about it at national and international conferences. It said their 2016 and 2017 conference presentations had also referred to two patient deaths and an excised infected graft, “providing a balanced view of the technique and not misrepresenting the outcomes at these meetings”.”The safety and care of our patients is our priority”, said the trust, and “we took the concerns raised by Dr Macanovic in 2016 very seriously”. It said it had now stipulated further oversight, including “a comprehensive letter of consent… rigorous surveillance of the patients and recording of complications via our incident recording system”.It added that it “is in full support” of its staff, and is confident in their credibility and ability to practise. More on this story’I am at the mercy of someone’s kindness to live’Published1 March’Wearable kidney’ could help those on dialysisPublished19 October 2023

What’s in the $24.99 tub, exactly? Lindsay Moyer, a nutritionist, reviews the contents of the movie-snack “vessel.”In the “Dune” movies, a gigantic sandworm can rise from the desert and devour soldiers and military vehicles in its gaping maw. In real life, humans watching movies devour popcorn. These two ideas have been combined to spawn the “Dune” popcorn bucket, a sandworm-shaped tub that is having a cultural moment. The bucket arrives on the heels of other recent popcorn collectibles, like the 16-inch Barbie Corvette snack holder. But is there more to these vessels than meets the eye?Lindsay Moyer thinks about popcorn. She is the senior nutritionist at the Center for Science in the Public Interest, a nonprofit consumer advocacy group focused on food systems and healthy eating. She sat down with The New York Times to discuss what she sees when she considers “Dune: The Popcorn Bucket.” This interview has been edited and condensed for clarity.Have you seen the “Dune” popcorn bucket?I’ve seen photos. I haven’t seen it in real life.First impressions?It looks pretty wild. It looks like it would actually slow you down in terms of eating. It doesn’t seem ideally designed to serve yourself popcorn out of.Because it is shaped like a worm’s mouth?Yeah, because of all the stuff sticking out of it.Do you like popcorn?We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

Published19 minutes agoShareclose panelShare pageCopy linkAbout sharingBy Dominic Hughes & Natalie WrightHealth correspondent, BBC News”Hugging my mum again. I’d love that. That would be special.” Tears are streaming down Paul Earnshaw’s face as he talks to us.He has struggled for years with alcohol, but is now trying to break free from his addiction. It is going to be a tough journey.The road to recoveryThe enormity of what lies ahead is sinking in.Paul is about to start a detox course, followed by what could be up to six months of rehab.”I need to do it. I won’t let nobody down. I won’t let myself down.”Sitting on a sofa in the Blackpool offices of the charity Empowerment, Paul is reflecting on where he has ended up.”I don’t want to be picking a can up every single day, walking around the streets, people thinking, ‘oh, look at him, he’s drinking again, still doing this, still doing that’.”Nah, I don’t want to do that. I’m 40 years old, I’m not getting any younger. It’s time to move on, it’s time to live my life a different way. It’s an opportunity – if I don’t take it, I’ll never get it again, but I’m taking it, I’m doing it.”At one point Dave, Paul’s support worker, gives him a huge hug, and for a moment you feel Paul may never let go.’Deaths of despair’Blackpool is a town plagued by too many preventable fatalities linked to alcohol, drug abuse and suicide – collectively described by the bleakly poetic phrase “deaths of despair”.A study of deaths recorded at coroners’ courts across England suggests that between 2019 and 2021, about 46,200 people lost their lives in this way – the equivalent of 42 people every day.And research suggests Paul’s hometown of Blackpool has the highest rate of these deaths.In Blackpool the rate is 83.8 for every 100,000 deaths. Compare that to the area with the lowest rate, Barnet in Greater London, where the figure stands at 14.5 deaths per 100,000.Steven Brown, a senior member of the Empowerment team, has lived a similar life to Paul, and against the odds, has somehow come out the other side.”I’m from a council estate in Layton in Blackpool, and I started hanging around with older people, my brother, and most of us started taking drugs, and then a lot of us couldn’t stop taking drugs,” he said.”I was stuck in that revolving door cycle that I couldn’t get out [of].” The drugs led to crime, which led to prison, but after more than 20 years spent in and out of jail, a key moment came when Steven went to a prison talk by a former addict who was running a charity for ex-offenders.”I didn’t know that people recovered. You either went to prison – you got locked up – or you died.”Having some hope from someone like me, who hadn’t been to college and wasn’t educated – and I knew that they’d walked in the steps that I’d walked in – they was talking my language.”And it’s that hope of, ‘how have you done it? I want what you have. How do I follow you?’ and I guess that little bit of hope changed my life.”While he was in recovery, someone told Steven he only needed to change one thing in his life: “Everything – people, places and things.” Steven understood what his friend meant.Everyone in the Empowerment team has what is known as “lived experience”, meaning they have all lived the chaotic and dangerous lives of the addicts, homeless people and alcoholics they are now helping.Clean for more than seven years, Steven’s life now could not be more different from the one he left behind – a steady job that he loves, a partner, a child, a home.Wealthy but unequalA new study, led by academics from Health Equity North, the University of Manchester and the National Institute for Health and Care Research, mapped the deaths to local council areas and calculated what factors increased the risk of dying this way.So being from the north, being white, male and working class, working in a manual job, having a lower level of education – all these are risk factors.Image source, BBC NewsBut as report author Christine Camacho explains, these factors combine to become more than the sum of their parts.”It’s a bit like some of the effects that we saw in Covid where the pandemic exacerbated some of those underlying inequalities,” she said.And the bad news for Blackpool, a northern seaside town, is that it has a higher rate of these deaths than anywhere else in England.”The UK is a wealthy country, but it’s also quite an unfair country – our resources are not equally distributed. And deaths of despair are one avoidable consequence of that unequal distribution,” she added.Breaking the cycleThere are 25 members of the Empowerment charity working in and around Blackpool, trying to offer that tiny bit of hope that transformed Steven’s life.They operate alongside social workers, the town council and the local NHS, trying to find housing, healthcare and support, and offering practical help for the homeless, including supplying clothing and essential toiletries.Helping prevent overdoses is also a crucial part of the work, with workers distributing the anti-overdose drug Naloxone, a treatment that Steven says saved his own life more than once. Support workers also build relationships of trust with people whose lives have descended into chaos.Kate – not her real name – is now in her 30s, and said: “I started drink and drugs at a very young age, to the point of oblivion sometimes.” For a while she was in rehab but dropped out and last autumn, she found herself pregnant, homeless and still in the grip of her addiction. However, Kate’s support worker from Empowerment stuck with her and never gave up.Kate has been clean for more than 100 days and said: “It was extremely difficult, but I’d just had enough of living on the streets, being around needles in abandoned hotels, it was horrible. “It was the change and the support from these guys that got me to where I am today, as well as myself. For someone to be there, and to have that support from when I was really bad in addiction, to now being clean, and having someone there regardless of whether I’m there or not, and still trying to support me, is an amazing feeling. “If it hadn’t been for her, I wouldn’t be where I am today.”Kate and Paul were both at risk of becoming statistics, but with the help of the Empowerment team they are beginning the long and difficult road to recovery. More on this storyEasier to get crack than takeaway, says ex-addictPublished14 FebruaryFormer addict goes ‘full circle’ to help othersPublished8 JanuaryRelated Internet LinksEmpowerment CharityThe BBC is not responsible for the content of external sites.

Managing circadian rhythms through intense light and chronologically timed therapy can help prevent or treat a variety of circulatory system conditions including heart disease, according to a new study from researchers at the University of Colorado Anschutz Medical Campus.
The study was published today in Circulation Research, an official journal of the American Heart Association.
“The impact of circadian rhythms on cardiovascular function and disease development is well established,” said the study’s lead author Tobias Eckle, MD, PhD, professor of anesthesiology at the University of Colorado School of Medicine. “However, translational preclinical studies targeting the heart’s circadian biology are just now emerging and are leading to the development of a novel field of medicine termed circadian medicine.”
The senior author is Professor Tami A. Martino, PhD, distinguished chair in molecular and cardiovascular research at the University of Guelph in Ontario, Canada.
The study reviews current circadian medicine research, focusing on the use of intense light therapy following surgery, utilizing light to treat cardiac injury, exploring how cardiovascular disease can differ between men and women and administering drugs at specific times of day to coincide with the body’s internal clock to speed healing.
It also urges more aggressive use of this therapy in humans, rather than relying on mostly animal models.
“There are literally millions of patients who could benefit from this,” Eckle said. “The treatments are almost all low-risk. Some involve using light boxes and others use drugs that are already on the market.”
Circadian rhythms significantly influence how the cardiovascular system operates. Timing is everything. Blood pressure and heart rates follow distinct patterns, peaking during the day and ebbing at night. When this is disrupted, it leads to worse cardiovascular disease outcomes including myocardial infarction and heart failure.

Light is critical in maintaining the proper balance and functioning of the body. Shift employees who may work night hours then day hours often have worse cardiac outcomes.
Eckle, who has studied circadian rhythm and health for years, said intense light can help heal the body after heart surgery while protecting it from injury during surgery, including reducing the chances of cardiac ischemia.
According to the researchers, when light hits the human eye it is transmitted to the suprachiasmatic nucleus, a structure in the brain’s hypothalamus that regulates most circadian rhythms in the body. Intense light stabilizes the PER2 gene and increases levels of adenosine, which blocks electrical signals in the heart that cause irregular rhythms, making it cardiac protective.
Eckle has used light therapy with patients after surgery and seen positive results including lower levels of troponin, a key protein whose elevation can signal a heart attack or stroke.
Given the mounting evidence that intense light and timed drug treatments are effective, he said, it is time to move forward with more clinical trials.
“Circadian rhythms play a crucial role in cardiovascular health, influencing the timing of onset and severity of cardiovascular events and contributing to the healing process from disease,” Eckle said. “Studies in humans are clearly required. Regarding intense light therapy, chronotherapy and restricted feeding are low-risk strategies that should be tested sooner than later.”

Inhaling nontuberculous mycobacteria is common for most people. The bacteria are found in water systems, soil and dust worldwide and, for many, cause no harm.
For those with underlying conditions, nontuberculous mycobacteria (NTM) can infect the lungs, causing symptoms similar to tuberculosis. Inflammation can cause a chronic and sometimes bloody cough as well as scarring, which can make respiratory infections like bronchitis and pneumonia more common. Due to the slow growth of the bacteria, proper diagnosis and treatment can take months.
In a new study, Tulane University researchers have developed a CRISPR-based platform for diagnosing NTM infections where blood testing can yield results in as little as two hours.
The preliminary findings, published in the American Journal of Respiratory and Critical Care Medicine, showed that the blood test was able to accurately identify more than 93% of patients with an NTM infection. Rapid, accurate diagnosis has never been more important as cases of NTM infections have continued to increase annually, spreading from subtropical regions to more temperate zones in part due to global climate change.
“NTM infection is highly underestimated, and due to the slow diagnosis of it, patients with NTM infection are not effectively treated,” said Bo Ning, corresponding author and assistant professor of molecular biology at Tulane University School of Medicine. “Importantly, our blood test can analyze NTM DNA fragments in the bloodstream, thereby inferring a drug response, which is crucial for rapidly determining treatment plans, capabilities traditional diagnostic approaches cannot achieve.”
The blood test is specifically designed to detect mycobacteria avium complex (MAC), one of the most common types of NTM and the most common cause of NTM-induced pulmonary disease.
To identify an infection, the test detects fragments of NTM DNA in the bloodstream. Current diagnosis methods rely on analysis of long-term cultures of the slow-growing bacteria, which can lead to delays in diagnosis and treatment. And with more than 190 species of NTM, correctly diagnosing an infection can be difficult.

“Currently, correct diagnosis and treatment can last more than six months,” Ning said. “Not only can our blood test provide same-day results, this test can be quickly performed in any clinics where blood can be drawn and does not require specialized training or equipment needed to analyze bacteria cultures.”
Ning said the United States may face rising NTM infections in the future and that accessible tests like this one are vital to staying ahead of it.
Going forward, he hopes to expand the types of NTM that CRISPR can detect and develop point-of-care tests for NTM detection.
“The goal is to reduce barriers to testing and diagnosis and prepare for a potential surge of NTM infections,” Ning said.
The study was conducted in collaboration with Oregon Health & Science University.

Cell division is the generative spark of nearly every lifeform on Earth. But if healthy growth goes unchecked, cell division can turn lethal, overwhelming the organism. Such is the case with so-called oncogenes. When altered by a mutation, these growth-moderating genes go haywire, producing a geyser of cancer cells as a result. Oncogenes are also insidiously adept at generating tumors that over time become genetically “independent” from their origin, so it has been exceedingly difficult for scientists to shut down their replication at the source.
Now Rockefeller University researchers have discovered a new way to target the oncogene behind a rare and often deadly liver disease using small interfering RNAs (siRNAs), an innate mechanism for silencing gene expression. As described in Molecular Therapy, the researchers slipped siRNAs inside fibrolamellar hepatocellular carcinoma (FLC) cells through a surface receptor, where they blocked the oncogene from producing illness-inducing proteins that lead to tumor formation.
It’s the first time that siRNAs have been used to hobble the progression of FLC, says first author Christoph Neumayer, a Ph.D. student in Rockefeller’s Laboratory of Cellular Biophysics, headed by Sanford M. Simon.
But the findings have wider applications as well. “That’s the really exciting part,” says Neumayer. “This is proof of concept that siRNAs can be used for FLC, as well as adult liver cancers, which are much more common, and other tumor types elsewhere in the body.”
The fusion oncogene
FLC is caused by the fusion of two genes located on chromosome 19: DNAJB1, which produces heat-shock proteins that encourage cell homeostasis, and PRKACA, which produces an enzyme called kinase A that’s key to cellular metabolic function. The resulting fusion, known as DNAJB1::PRKACA, brings together the proteins and a catalytic subunit of the kinase. This dysfunctional union promotes FLC formation, but how, exactly, is still unknown.
Researchers in Simon’s lab discovered that this fusion caused FLC in 2014, several years after Simon’s own teenage daughter, Elana, was diagnosed with liver disease. After having the resulting tumor removed — the only treatment option available to people with FLC — Elana went on to collaborate with her father to unearth its cause, publishing the results in Science.

Since then, Simon and his group have continued to reveal the mechanisms behind the disease as well as develop therapeutics. The siRNA research is part of a three-part strategy which also includes repurposing drugs for treating FLC and using molecules known as PROTACs to selectively degrade the DNAJB1::PRKACA protein that drives FLC. The drug repurposing is in advanced preparation for a clinical trial, and some of the PROTAC work is part of an international collaboration that was just awarded a $25 million Cancer Grand Challenges grant to develop treatments for high-risk, oncogene-driven cancers in children.
Recently, Simon’s lab discovered that they could completely stop FLC tumor growth in mice using shRNAs, short sequences of RNA that can be engineered to disrupt mRNA. The approach also caused many tumors to shrink or disappear.
Having shown that quelling the fused oncogene killed tumor cells, they decided to experiment with derailing kinase A activity, which research indicated was driving tumor growth.
Unlocking the cell door
The problem was, fused kinase A and its “wild type” form are nearly identical, so “any drug you developed that blocks fused kinase A activity would affect all kinase A, including in normal cells,” Neumayer says. “In other words, you would incur a host of problematic side effects.”
They had to find a way to disable toxic kinase while containing the impact so that kinase in other cells weren’t affected. To do that, they specifically designed siRNAs to aim at the fusion. But because siRNAs cannot cross cell membranes, the researchers needed to figure out a way to get the siRNA inside.

Luckily, a door into the cell had already been identified: a receptor called ASGR1 that’s only expressed in liver cells. Its key had been too: a binding molecule known as GalNAc. Together, the duo function as a waste disposal team.
GalNAc conjugate therapies, which attach siRNA molecules to the ligand to deliver therapies inside cells, are already on the market for conditions such as hereditary transthyretin-mediated amyloidosis and atherosclerotic cardiovascular disease. The team wondered if they could use the same approach to thwart the kinase driving FLC tumors.
Stabilization and shrinkage
To test their theory, the researchers attached a custom siRNA to the receptor’s ligand and studied the method in a variety of tumor models in mice and in human cell cultures. The conjugate therapy was not only successfully delivered into the cells in all contexts, but it also caused a reduction of mRNA in the oncogene, preventing the production of the protein and resulting in the tumors stagnating or shrinking, unable to grow. They also did not detect any liver toxicity in the mice, indicating the animals tolerated the siRNAs well.
“What we saw was tumor inhibition, when we had hoped to outright kill the tumor,” Neumayer notes. “Our future direction will be to try to figure out how to improve that.”
They also tested the specificity of the siRNA by injecting it into tumor cells of another type of liver cancer. It had no toxic impact on them — exactly as the researchers hoped. “We wanted to show that our siRNA is so targeted to the FLC fusion oncogene that it has no side effects on other cells — even on other cancer cells,” he notes.
Neumayer says the findings suggest that siRNAs may be effective beyond FLC, capable of treating tumors throughout the body with a high degree of specificity: “I think siRNA medicines as a class will have a big impact over time as a new kind of genetic therapy.”

A recent study from the lab of Dr. Hugo J. Bellen, distinguished service professor at Baylor College of Medicine and investigator at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) links the FRYL gene to a new neurodevelopmental disorder in humans. They used fruit flies to establish that the loss of a functional copy of the FRY-like transcription coactivator (FRYL) gene is the underlying cause of this new disorder in fourteen individuals. The study was published in the American Journal of Human Genetics.
FRYL belongs to the Furry protein family which is evolutionarily conserved from yeast to humans. The functions of FRYL in mammals are largely unknown, and variants in FRYL have not previously been associated with a genetic disorder.
“This foundational study paves the way for not only a better understanding of the biological role of this gene but also opens avenues to study this new disorder,” Dr. Bellen said.
Finding a cohort of 14 patients with FRYL variants
In collaboration with Dr. Wendy Chung, who was initially at Columbia and later at Boston Children’s Hospital, the team recruited fourteen unrelated individuals through the Pediatric Cardiac Genomics Consortium, the SPARK consortium, and the GeneMatcher website. The individuals presented with developmental delay, intellectual disability, dysmorphic features, and other congenital anomalies in multiple systems including heart and gastrointestinal issues. A few also had autism, seizures, and low muscle tone.
To find the genetic cause for their symptoms, they analyzed the DNA of these individuals. Upon examining their exome (i.e. the protein-coding part of the genome), they found that a majority of individuals were missing portions of the FRYL gene and the remaining individuals had missense mutations that are akin to misspellings in the gene, all of which result in a FRYL protein that is either non-functional or has a reduced function. Further, they found that FRYL variants were not genetically inherited but arose spontaneously in all individuals except one.
Using fruit flies to identify the cellular location and function of FRYL
“To understand in which cells and how this protein functions, we turned to the fruit fly model,” said lead author Dr. Xueyang Pan, who is a postdoctoral fellow in the Bellen lab. Humans have two Furry genes, FRY and FRY-like, whereas flies have one furry (fry) gene which bears close sequence resemblance to its human counterparts.

First, they found that this gene is expressed in multiple tissues in flies including the central nervous system where it is present in neurons but not in glia, a cell type that provides physical and chemical support to the neurons.
Next, they found that the loss of both copies of this gene was lethal at the embryonic or larval stage, which gave a clue that it plays a critical role during development. Dr. Pan and others then created mutant clones lacking fry in the wings and eyes of flies with a normal genetic background outside the clones. The loss of fry causes developmental defects such as multiple wing hairs in the mutant wing clones as well as small, rough eyes caused by cell death in the mutant eye clones.
Modeling human FRYL variants in fruit flies
The team then created transgenic flies with the four missense variants found in affected individuals using two different genetic methods. One of the variants exhibited traits characteristic of severe functional loss of the protein, whereas two others behave as partial loss-of-function variants.
In summary, these findings support the idea that fry is critical for the proper development of various organs in fruit flies, and insufficient functional levels of its human counterpart FRYL cause a previously unknown neurodevelopmental disorder. This study sets the stage for future explorations to discover gene mechanisms and explore potential therapies for this condition.

Scientists love a challenge. Or a friendly competition.
Scientists at La Jolla Institute for Immunology (LJI) recently published the results of a competition that put researchers to the test. For the competition, part of the NIH-funded Computational Models of Immunity network, teams of researchers from different institutions offered up their best predictions regarding B. pertussis (whooping cough) vaccination.
Each team tried to answer the same set of questions about vaccine responses in a diverse set of clinical study participants. Which study participants would show the highest antibody response to B. pertussis toxin 14 days post-vaccination? Which participants would show the highest increase of monocytes in their blood one day post-vaccination? And so on.
The teams were given data on the study participant’s age, sex, and characteristics of their immune status prior to vaccination. The teams then developed computational models to predict vaccine responses in different patient groups.
“We asked, ‘What do you think is the most important factor that drives vaccination outcome?'” says LJI Professor Bjoern Peters, Ph.D., who led the recent Cell Reports Methodsstudy. “The idea was to make the teams really put their money where their mouth is.”
Multiple computational models to predict vaccine responses have been developed previously, many of them based on complex patterns in immune state before and after vaccination. Surprisingly, the best predictor in the competition was based on a very simple correlation: antibody responses decrease with the calendar age of study participants.
The result may seem anti-climactic, but the competition sheds light on where more vaccine research is needed. “We know calendar age is important, but we still see a lot of variability in vaccination responses that we can’t explain,” says Peters.

The competition has also helped rally scientists around further B. pertussis vaccine research. In the United States, B. pertussis vaccines were reformulated in the 1990s to address relatively minor adverse side effects. Research suggests the newer (aP vaccine) design may not be as effective as the older (wP vaccine) design in preventing disease transmission and infection.
“We don’t know what’s missing from this current vaccine,” says Peters. “That’s an open question.”
The prediction competition is shaping up to be an annual event, and previous entrants have gone back to the data to further hone their predictions. Perhaps, Peters hopes, this closer look at exactly what drives higher antibody responses in younger people can lead to better vaccines for all patient groups.
“We are hoping to use this competition not just as a way to examine the capacity of people to predict vaccination outcomes, but also as a way to address an important public health question,” says Peters.
The Peters Lab and the CMI-PB Team are currently finishing up their second invited challenge. They will host a public contest in or around August 2024. Researchers can join them at https://www.cmi-pb.org/
Additional authors of the study, “A multi-omics systems vaccinology resource to develop and test computational models of immunity,” include Pramod Shinde, Ferran Soldevila, Joaquin Reyna, Minori Aoki, Mikkel Rasmussen, Lisa Willemsen, Mari Kojima, Brendan Ha, Jason A Greenbaum, James A Overton, Hector Guzman-Orozco, Somayeh Nili, Shelby Orfield, Jeremy P. Gygi, Ricardo da Silva Antunes, Alessandro Sette, Barry Grant, Lars Rønn Olsen, Anna Konstorum, Leying Guan, Ferhat Ay, and Steven H. Kleinstein.
This study was supported by the National Institutes of Health’s (NIH) National Institute of Allergy and Infectious Diseases (NIAID; grants U01AI150753, U01AI141995 and U19AI142742.)