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Tag: Genetics

  • Veterans and scientists fulfill ‘no man left behind,’ returning long-lost American remains from lonely Pacific WWII battlefield | CNN

    Veterans and scientists fulfill ‘no man left behind,’ returning long-lost American remains from lonely Pacific WWII battlefield | CNN

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    CNN
     — 

    On a remote Pacific sandbar, replete with the ravages of war, a small group of veterans, volunteers and archeologists are doing their best to keep the enduring promise of “no man left behind.”

    According to the Department of Defense, nearly half of the known American casualties from the Battle of Tarawa were never recovered. Approximately 1,000 Marines and sailors lost their lives on the small sandbar November 20-23, 1943, in the US military’s first offensive of the war in the central Pacific.

    Graves remained lost for decades, Pentagon historians write, because of bad record keeping, poor memories, and in some instances, war infrastructure inadvertently built over service members’ unmarked final resting places. DOD records show by 1950, a military board declared hundreds of Americans who fought and died on the island “non-recoverable,” leaving families without words, images or ideas of where the young men rested.

    After excavation efforts paused during the pandemic, teams will return to the lonely atoll, with the goal of returning as many remains of US service members as they can.

    “This is not a normal thing for somebody to be doing,” said Paul Schwimmer, a retired US Army Green Beret who searches for American remains with the non-profit group, History Flight, who added a new chapter of history is unfolding along the isolated and idyllic shore.

    “Don’t tell us these men are not recoverable, give us a chance to go after them.”

    Government figures show 72,627 Americans are currently classified as missing in action from World War II. There are more US troops missing from 1941-1945, than from all other wars with US involvement combined.

    In 2003, commercial pilot and World War II history aficionado Mark Noah founded History Flight. The group’s initial aim was to preserve American aviation history, an outgrowth of Noah’s love of antiquity, aircraft and his family tradition of scholarship.

    “My father was a diplomat for the State Department, a Harvard and MIT-trained sinologist,” Noah said in an interview with CNN. “I was born in China, where my dad was posted, and I was able to see the lingering effects of World War II up close. That was the beginning of a fascination with the Second World War.”

    Noah relates the multitude of missing service members to those missing in his own life.

    “Four of my close friends in Beijing disappeared during Tiananmen Square,” Noah said. “And I’ve always wondered where they fell into, this deep void, the unknown. And at a subconscious level, it’s one of the reasons why I’m driven to find our missing Americans, especially when we know where they are, on an island.”

    Noah said 2008 was a turning point, when History Flight’s mission changed from aviation to recovery missions.

    “I was doing research about a missing airplane that crashed in the lagoon of Tarawa, and I was shocked at just how many people were missing on this small island,” Noah said.

    “So, I self-funded what became our first Tarawa excavation, and with all of those people missing in such a small place, we chose Tarawa because we thought we could deliver a project with a high probability of success.” The cost was $25,000, with a team of 10 people.

    A cadre of veterans, scientists and students interviewed residents who found bones underneath their homes. The non-profit also used ground-penetrating radar on the atoll, ultimately finding scores of American graves buried within a working commercial seaport.

    In the decade since its first dig, History Flight has led to the identification of 96 American service members killed on Tarawa, according to the branch of the Pentagon charged with finding US military remains, the Defense POW/MIA Accounting Agency.

    “That number undoubtedly will go up,” agency spokesperson Johnie Webb said.

    In a cozy East Wenatchee, Washington, living room, twins Don and David McCannel held the crumbling and corroded helmet buried with their uncle, Gunnery Sgt. Arthur B. Summers, a Tarawa Marine once considered missing in action.

    Summers’ near-complete skeleton is among the latest remains discovered by History Flight. His return home for burial in America followed a now familiar ritual of repatriation: Delicately-handled bones are discovered on Tarawa, then flown to the US for positive identification, and finally, re-buried with full military honors.

    The McCannel twins are now 76 years old, born three years after a telegram told their mother Summers was killed in action, his body missing on a faraway Pacific island.

    “My most vivid memory is, when I was about 10 years old, my mother said to me, ‘my brother was killed in Tarawa and his body was never recovered,’” David McCannel described in an interview. “She didn’t cry. She just said he’s gone forever.”

    Schwimmer, the retired Green Beret with History Flight, said he was within the Tarawa excavation site when Summers’ remains were discovered in 2019, and attended Summers’ Washington funeral in August 2022.

    “To see this, to look over my shoulder, to put my hand on the casket and say, ‘Hey bud, I saw you in 2019. I took you from Tarawa to here.’ For me, that’s great,” Schwimmer said. “Now, put me back on an airplane, get me in the field, I got work to do.”

    Summers was killed on November 23, 1943, the final day of fighting on the island, and according to military records, the day Summers’ second enlistment extension was to expire.

    “I thank them eternally, and forever,” Don McCannel said of History Flight and those responsible for Summers’ identification. “My uncle Arthur did his duty, and these men and women today did theirs, truly.”

    Marine Corps Gunnery Sgt. Arthur B. Summers, 27. Summers' remains are among the latest to be discovered by History Flight on Tarawa and reburied in America.

    The Pentagon agency tasked with finding the remains of an astounding 81,500 Americans missing since World War I, contracts Tarawa excavation work with History Flight. But the agency itself is solely responsible for the process of DNA identification.

    There is no margin for error. Scientists and military personnel from Hawaii, Nebraska and Delaware finish the process of uniting stories, names, and family histories with the skeletal remains of US troops.

    The remains of Tarawa U.S. Marine 1st Lt. Alexander Bonnyman, discovered by History Flight, in a rare photo released publicly of how Tarawa remains are found.

    Dr. John Byrd, the agency’s laboratory director, explained the challenges of dealing with DNA from that era. “They’re highly degraded, there’s only a tiny amount of DNA left in there at all. And our DNA lab is the best in the world at extracting what little bit is left in there.”

    Byrd said the average time to identify an individual is 2.5 years, but can be as quickly as two weeks.

    “When none of the stars are aligned, it can take several years. We have ID’s we’ve made after more than 10 years, when we finally got enough evidence together to be able to prove the identity.”

    For Summers’ remains, delivered to the agency’s Pearl Harbor laboratory in July 2019, the DOD agency was able to make a positive DNA identification in a matter of months, on October 17, 2019.

    First, remains arrive at an agency laboratory in Honolulu, or Omaha, Nebraska. “They come from a variety of sources, from our own excavations, and from excavations from our partners … We also do a lot of disinterments of unknown remains, right from our national cemeteries,” Byrd explained.

    Next, as the remains are assigned to evidence managers, scientists determine which tests are needed to identify the remains. The majority will involve DNA testing, but other methods, such as dental records, can be used.

    DNA testing and other identification work then begins. Samples are sent to the Armed Forces DNA Identification Lab in Dover, Delaware, and a type of identification known as stable isotope analysis can also be performed at the agency’s Pearl Harbor lab. The isotope testing is used to trace remains’ geographic origin.

    Finally, test results are evaluated, and perhaps even more testing is needed.

    “You love it when the test results come back in, and they clearly direct you to one individual that these remains should be,” Byrd said. “But we also sometimes get results that aren’t strong enough to point to one person only. And then we have to find another way to try to resolve the case other than the testing we did in the first round … that is one of the most difficult steps for many of our cases.”

    History Flight estimates their Tarawa excavation efforts are halfway finished.

    “We believe about 250 sets of remains can still be found, and we want to keep going,” History Flight founder Mark Noah said.

    The non-profit’s vice president, retired U.S. Marine Corps Sgt. Maj. Justin LeHew, is currently walking across America, from Boston to Newport, Oregon, to donations for the group’s ongoing work in the Pacific.

    LeHew served in the 2nd Marine Division, the same (albeit modern day) combat element which engaged in the Battle of Tarawa in November 1943. His previous chapter of military service includes receiving the Navy Cross, awarded for his 2003 role in rescuing ambushed soldiers in Iraq, including Pfc. Jessica Lynch.

    “Team members are putting in the work for the missing,” LeHew wrote on Facebook, as his walk on U.S. Highway 20, America’s longest road, approached Yellowstone National Park.

    “This specific road was selected to highlight the long journey home that over 81,000 missing U.S. Servicemembers have been trying to make since World War II,” LeHew said.

    “We know that we can fulfill this promise of ‘no one left behind’ on Tarawa,” Noah added. “We simply need people to know we’re there, to know about us, put the financial resources in place, and help us carry on this sacred mission.”

    History Flight team on Tarawa, from left, archeologists Aundrea Thompson & Hillary Parsons, retired Korean War veteran John Craig Weatherell, archeologists Maddeline Voas & Heather Backo.

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  • Genome sequencing supports Nile rat animal model for diabetes research

    Genome sequencing supports Nile rat animal model for diabetes research

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    FOR IMMEDIATE RELEASE

     

    Newswise — MADISON — Model organisms are essential for biomedical research and have enabled many important scientific discoveries. The ability to sequence the genomes of these models is a powerful tool to study the genetic factors that impact human health.

    The house mouse (Mus musculus) and Norway rat (Rattus norvegicus) are widely used in research due to their genetic similarities to humans. But another rodent is rising through the ranks — Arvicanthis niloticus, the Nile rat.

    New research published today in BMC Biology provides a high-quality reference genome assembly for the Nile rat, expanding its potential as a model organism. 

    “We need research tools that will enable us to do the same things with the Nile rat that we are used to doing with the lab mouse,” says Yury Bukhman, a computational biologist in the Stewart Computational Biology Group at Morgridge and senior author on the project. “Having the reference genome is an advance toward that goal.”

    In particular, the Nile rat serves as an alternative model in two research areas where lab mice and rats have limitations — type 2 diabetes and disorders associated with a disrupted circadian rhythm.

    Mice and rats are nocturnal animals, and so they are less useful at modeling human circadian cycles. Additionally, they can develop pre-diabetes symptoms with a high-fat diet, but they rarely develop long-term diabetic complications like humans with the disease.

    “You can alter their genetics, you can give them exaggerated amounts of fat, or use chemicals to accelerate the process. But that’s a lot of additional confounding factors that you are pushing into the animal model to get what you want,” says first author Huishi Toh, an assistant project scientist at the University of California Santa Barbara who worked with Jamie Thomson, emeritus director of regenerative biology at Morgridge and professor at UCSB.

    The Nile rat is diurnal, active during the daytime like humans. It also has more photoreceptors in its eye in comparison to nocturnal rodents, which makes it relevant for studying human retinal disease — including diabetic retinopathy.

    “There is still room for a lot of discovery in type 2 diabetes, with questions that are difficult to answer. That’s why we thought that maybe it’s time to take a risk on a newer animal model,” Toh says. “Does it mean it’s more accurate or that you can replace other models? No, of course not. But you can find different information that can be useful, too.”

    Another benefit of the Nile rat is that it serves as an outbred model, meaning its genetics are reflective of a diverse population. Many laboratory mice strains have been inbred for generations, creating stable populations that are nearly genetically identical. This is useful for reducing experimental variability, but less useful when studying the complex genetic factors contributing to disease.

    “We also know that epigenetics is really important — the environment crossing with the genetic components — so we have to study both. That’s why we require a very high-quality genome to allow the ability to do that,” says Toh.

    The Nile rat genome is a product of a large international collaboration involving the Vertebrate Genomes Project, a consortium of researchers aiming to assemble reference-quality genomes of all vertebrate species.

    The technology to produce a complete and highly accurate genome sequence is relatively new. Typically, to sequence a large genome, the DNA sequence needs to be chopped into shorter lengths between 100-300 nucleotides and then reassembled into longer contiguous sequences (contigs). But this approach tends to leave lots of gaps.

    “An important genome quality measure is what’s the length of an average contig. Basically, the longer it is, the fewer gaps you have,” says Bukhman. “Ours is one of the longest.”

    The research team applied long-read sequencing technology to assemble longer contigs from reads of around 10,000 to 20,000 nucleotides in length. They also used multiple additional technologies to join contigs together into scaffolds that run the length of a chromosome. Finally, they were able to fully resolve two copies of the genome — the one that the sequenced individual inherited from its mother and the one from its father.

    “These technologies are developing very fast,” Bukhman says. “I think the holy grail would be to just be able to sequence a whole chromosome and do it accurately. However, that hasn’t happened yet.”

    Another measure is looking at the completeness of the genome. The team analyzed their Nile rat sequence through a database called BUSCO (benchmarking universal single copy orthologs), which provides a set of genes commonly found in the phylogenetic group of interest, in this case rodents.

    “We’re basically in the same league as the other rodent model organisms,” says Bukhman. “We find complete sequences of 99% of BUSCO genes, so we’re not missing a lot of protein coding sequence.”

    With a high-quality sequence in hand, the researchers looked for patterns in the genome, such as genes that have different number of copies in Nile rat compared to house mouse, that could be candidates for future study. 

    They also used Kinderminer and Serial KinderMiner (SKiM) — applications developed by the Stewart Computational Biology Group at Morgridge — to query PubMed abstracts and identify genes associated with type 2 diabetes.

    “We don’t have a ‘smoking gun’ at this point,” says Bukhman. “You can always get a list of genes. But then, how do you know that they’re really important in diabetes? That will take years and years of experimental work.”

    Now that the Nile rat has a high-quality reference genome, Bukhman and Toh both hope that the species will become more widely used in biomedical research.

    “People are resistant to using new animal models, because it’s a lot of money, a lot of effort, and a lot of risk,” says Toh. “But we decided to take the unconventional route. In research, I think, to survive is to find different flavors, different trajectories. And we’ve removed some of that risk.”

     

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    As an independent research organization, the Morgridge Institute for Research explores uncharted scientific territory to discover tomorrow’s cures. In affiliation with the University of Wisconsin-Madison, we support researchers who take a fearless approach to advancing human health in emerging fields such as regenerative biology, metabolism, virology and biomedical imaging. Through public programming, we work to inspire scientific curiosity in everyday life. Learn more at: morgridge.org

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    Morgridge Institute for Research

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  • DNA barcoding reveals cancer cells’ ability to evade the immune system

    DNA barcoding reveals cancer cells’ ability to evade the immune system

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    Newswise — Some cancer cells can deploy parallel mechanisms to evade the immune system’s defences as well as resist immunotherapy treatment, according to a new study from the Garvan Institute of Medical Research.  

    By suppressing the action of killer T-cells and hindering the ability of the immune system to flag tumour cells for destruction, breast cancer cells are able to replicate and metastasise, the researchers found.  

    “We know that breast cancer typically doesn’t respond well to immunotherapy, and we wondered if there’s an intrinsic mechanism enabling breast cancer cells to escape the immune system,” says first author Ms Louise Baldwin, who is a PhD student in Associate Professor Alex Swarbrick’s lab at Garvan. 

    The researchers used a technique called DNA barcoding, which tags cells with a known sequence and tracks the progression of tumour cells through time. 

    “We showed that there are rare cancer cells capable of escaping the immune system and escaping treatment with immunotherapy,” Ms Baldwin says. 

    The mechanisms could be used as potential targets for therapies, to stop tumorous cells from adapting and spreading. Another future application could be in prognosis, where a high number of cells could indicate which patients might not respond to immunotherapy. 

    The new study is published in Nature Communications.  

    While immunotherapy is an effective treatment in many cancers, in some people their cancer cells evolve to outplay the immune system defences. This process is known as immunoediting, where interaction between tumour cells and immune cells results in many cancerous cells being destroyed by the immune system, but leaving some undetected, which continue to grow and spread. 

    The researchers used mouse breast cancer cells tagged with a known DNA ‘barcode’, a sequence that was passed on from one generation of cells to the next.  

    The barcoding allowed the team to see where more aggressive, resistant cells came from, as they could trace it back to the original cell to see if it had grown or shrunk.  

    “Lead author Dr Simon Junankar wanted to understand whether resistance was adaptive – whether cancer cells duck and weave – or are they pre-programmed to evade the immune system,” says Associate Professor Alex Swarbrick, a laboratory head and Co-Lead of the Dynamic Cellular Ecosystems in Cancer Program at Garvan. 

    The team found that even before treatment, the cancer cells had diversified. “Some cells had already acquired the ability to evade immunity, meaning they have an innate ability to escape the immune system,” he says.  

    The cells seem to do this with parallel approaches. One way is to suppress the action of killer T-cells, which would usually destroy harmful cells. The other is to reduce the expression of MHC1 on cells, which act as a flag for the immune system to recognise harmful cells. 

    “Most tumour cells vanish when the immune system gets switched on, but a small proportion keep growing and expanding,” says Associate Professor Swarbrick. 

    “Tumours keep evolving and diversifying, and action by the immune system or treatment like chemotherapy is like pruning a tree – cancer cells get wiped out but the remaining branches on the tree continue to grow.” 

    The researchers also looked at the genetics of the cells, but there were no genes found to be associated, suggesting epigenetics might be at play.  

     

    –ENDS– 

     

    This research was supported by research grants from the National Breast Cancer Foundation (NBCF). Louise Baldwin is supported by an Australian Government research training (RTP) stipend and Associate Professor Swarbrick is the recipient of a research fellowship from the NHMRC. 

    Associate Professor Swarbrick is a Conjoint Associate Professor at St Vincent’s Clinical School, Faculty of Medicine and Health, UNSW Sydney.  

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    Garvan Institute of Medical Research

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  • Personalising whole genome sequencing doubles diagnosis of rare diseases

    Personalising whole genome sequencing doubles diagnosis of rare diseases

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    Newswise — Tailoring the analysis of whole genome sequencing to individual patients could double the diagnostic rates of rare diseases, finds a new study led by UCL researchers.

    In 2018, the UK’s department of health announced an NHS Genomic Medicine Service, which allows patients with rare diseases to have their entire genetic code read in the hope of providing a much-needed diagnosis.

    However, the interpretation of this data can be extremely challenging and many people with complex, rare genetic diseases still do not receive a molecular answer to the cause of their problems.

    In the study, published in Nature Communications, researchers at The London Mitochondrial Centre at UCL Queen Square Institute of Neurology and UCL Great Ormond Street Institute of Child Health sought to offer such patients an improved chance of receiving a genetic diagnosis.

    To do so, they tested how using a genomic medicine team of specialist doctors, bioinformaticians, and scientists could boost the capabilities of NHS diagnostic laboratories beyond the standard semi-automated analysis of data. The UCL team re-evaluated undiagnosed cases to identify clues that might help direct further, more personalised analysis. They subsequently applied additional bioinformatic approaches, using advanced computer technologies to identify genetic alterations in a patients’ DNA which may be causing disease but had been overlooked during routine testing.

    The work included 102 undiagnosed patients, suspected of having a primary mitochondrial disease (a large group of incurable genetic disorders that affect children and adults, associated with a broad spectrum of medical problems, severe disabilities, and reduced lifespan), who had undergone whole genome sequencing via the NHS’s 100,000 Genomes Project.

    This personalised approach increased the diagnostic rate from 16.7% to 31.4%. It also detected potential disease-causing variants in a further 3.9% of patients.

    Lead author, Dr Robert Pitceathly (co-lead for the London NHS Highly Specialised Service for Rare Mitochondrial Disorders and a research group leader at UCL Queen Square Institute of Neurology), said: “The NHS has invested heavily in advanced genetic technologies. Consequently, the UK has established itself at the forefront of diagnostic whole genome sequencing. That said, some people with rare genetic diseases remain without a molecular diagnosis after their genome is analysed.

    “We believe investing in specialist genomic medicine teams is crucial, ensuring equitable access to dedicated multidisciplinary expertise and maximising diagnoses. On average, patients in our study waited over 30 years for a diagnosis – we now have the capability to solve such cases but need adequate workforce planning to support NHS diagnostic genetic laboratories in achieving this goal.”

    Receiving a genetic diagnosis is important as it allows patients to receive access to family planning, specialised IVF, and drugs trials. It can also permit targeted screening of known disease complications and access to drug studies.

    Dr Pitceathly said: “In this study, every new genetic diagnosis had a direct impact on patient care. This included additional check-ups for heart problems, hearing loss, and diabetes, and access to clinical trials.”

    Professor Michael Hanna, Director of UCL Queen Square Institute of Neurology said: “This work is a significant step forward in developing the best ways to maximise the benefits of genome analysis for patients. It clearly demonstrates that by combining automated approaches to genome analysis with data interpretation by a skilled multidisciplinary team the diagnostic rates doubles. This is an important finding that will influence how genomic medicine diagnostic services should evolve world-wide.”

    Co-author, Dr James Davison (Metabolic Medicine Department at Great Ormond Street Hospital and chair of the British Inherited Metabolic Diseases Group), said: “The journey to reaching a diagnosis for children and adults with rare, complex, medical conditions can be a very long process, and genomic medicine provides a transformative and powerful tool in helping reach that goal.

    “This study highlights the importance of the collaboration between specialist clinicians and genetic scientists in interpreting the results of genome sequencing to maximise the opportunity of reaching a diagnosis which can then help guide medical management and treatment options.”

    The researchers involved in this study are funded by the Medical Research Council.

    Patient story

    Rachel North was one of the patients involved in the trial and described getting a diagnosis as “life changing”. It has since allowed her to be screened for disease complications such as osteopenia, and these have been treated.

    She said: “I had attended so many hospitals over the past 20 years and had been searching so long, I never thought I’d get a diagnosis.

    “Wondering about it took up so much energy, and I was worried about my 12-year-old son, and if my condition would affect him. So, getting a rare recessive diagnosis was a relief and takes away fear of the unknown.

    “Having a diagnosis allows me to research my condition and be very proactive in managing it.

    “Anything that helps me understand and make sense of what is happening to my body helps me come to terms with it and gives me confidence that I am managing it as well as possible.”

    Notes to Editors

     

    William L. Macken, Micol Falabella, Caroline McKittrick, Chiara Pizzamiglio, Rebecca Ellmers, Kelly Eggleton, Cathy E. Woodward, Yogan Patel, Robyn Labrum, Genomics England Research Consortium, Rahul Phadke, Mary M. Reilly, Catherine DeVile, Anna Sarkozy, Emma Footitt, James Davison, Shamima Rahman, Henry Houlden, Enrico Bugiardini, Rosaline Quinlivan, Michael G. Hanna, Jana Vandrovcova, Robert D. S. Pitceathly. Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing, will be published in Nature Communications, on 7th November 2022 at 10:00 GMT / 05:00 ET.

     

    The DOI for this paper will be: 10.1038/s41467-022-32908-7

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    University College London

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  • Death in CRISPR gene therapy study sparks search for answers

    Death in CRISPR gene therapy study sparks search for answers

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    The lone volunteer in a unique study involving a gene-editing technique has died, and those behind the trial are now trying to figure out what killed him.

    Terry Horgan, a 27-year-old who had Duchenne muscular dystrophy, died last month, according to Cure Rare Disease, a Connecticut-based nonprofit founded by his brother, Rich, to try and save him from the fatal condition.

    Although little is known about how he died, his death occurred during one of the first studies to test a gene editing treatment built for one person. It’s raising questions about the overall prospect of such therapies, which have buoyed hopes among many families facing rare and devastating diseases.

    “This whole notion that we can do designer genetic therapies is, I would say, uncertain,” said Arthur Caplan, a medical ethicist at New York University who is not involved in the study. “We are out on the far edge of experimentation.”

    The early-stage safety study was sponsored by the nonprofit, led by Dr. Brenda Wong at the University of Massachusetts Chan Medical School and approved by the Food and Drug Administration. The hope was to use a gene-editing tool called CRISPR to treat Horgan’s particular form of Duchenne muscular dystrophy. The rare, genetic muscle-wasting disease is caused by a mutation in the gene needed to produce a protein called dystrophin. Most people with Duchenne die from lung or heart issues caused by it.

    At this point, it’s unclear whether Horgan received the treatment and whether CRISPR, other aspects of the study or the disease itself contributed to his death. Deaths are not unheard of in clinical trials, which test experimental treatments and sometimes involve very sick people.

    But trials involving CRISPR are relatively new. And Fyodor Urnov, a CRISPR expert at the Innovative Genomics Institute at University of California, Berkeley, said any death during a gene therapy trial is an opportunity for the field to have a reckoning.

    “Step one is to grieve for the passing of a brave human soul who agreed to be basically a participant in an experiment on a human being,” Urnov said. “But then, to the extent that we can, we must learn as much as we can to carve out a path forward.”

    FEW ANSWERS YET

    A statement from Cure Rare Disease said multiple teams across the country are looking into the details of the trial and its outcome, and the company intends to share findings with the scientific community.

    “It will probably be 3-4 months to come up with a full conclusion,” said spokesman Scott Bauman. “At this stage of the game, saying anything is pure speculation.”

    The company, which is also working on 18 other therapeutics, said in its statement that the teams’ work is essential not only to shed light on the study’s outcome but also “on the challenges of gene therapy broadly.” Meanwhile, it said, “we will continue to work with our researchers, collaborators, and partners to develop therapies for the neuromuscular diseases in our pipeline.”

    Bauman said the company has filed a report on death the with the FDA as required. The FDA declined to release or confirm the report.

    Sarah Willey, spokeswoman for Chan Medical School, said scientists there provided data to the company for the report. She later emailed to say no one there would comment further; out of respect for the family’s wishes, all information would come from Cure Rare Disease. Monkol Lek, a Yale genetics expert who has been collaborating on the effort, did not respond to a request for comment. Yale spokeswoman Bess Connolly asked a reporter for context on the story but didn’t respond to a follow-up email or phone call.

    A crucial question is whether CRISPR played a part in Horgan’s death.

    The chemical tool can be used to “edit” genes by making cuts or substitutions in DNA. The tool has transformed genetic research and sparked the development of dozens of experimental therapies. The inventors of the tool won a Nobel Prize in 2020.

    In this case, scientists used a modified form of CRISPR to increase the activity of a gene. The CRISPR therapeutic is inserted directly into the body and delivered to cells with a virus.

    But CRISPR is not perfect.

    “We know that CRISPR can miss its target. We know that CRISPR can be partially effective. And we also know that there may be issues with … viral vectors” that deliver the therapy into the body, Caplan said. “Red flags are flying here. We’ve got to make sure that they get addressed very, very quickly.”

    Safety issues have arisen in gene therapy studies before. Late last year, Pfizer reported the death of a patient in its early-stage trial for a different Duchenne muscular dystrophy gene therapy. And in a major earlier setback for the gene therapy field, 18-year-old Jesse Gelsinger died in 1999 during a study that involved placing healthy genes into his liver to combat a rare metabolic disease. Scientists later learned that his immune system overreacted to the virus used to deliver the therapy. Many recent studies, including the Cure Rare Disease trial, use a different virus that’s considered safer.

    Another difference? The recent trial involved just one person — a type of trial Caplan is skeptical about.

    Horgan’s recent death, he said, “may make us think whether we really do like studies that are just on one person, and do we want to say: ‘No, ethically, you’ve got to at least have a trial where you line up 5, 10, 20 people (and) you learn from the data.’ ”

    A ‘MEDICAL PIONEER’

    On the company’s web site, Horgan was described as a “medical pioneer” who “will be remembered as a hero.”

    In 2020, the Montour Falls, New York resident blogged that he was diagnosed with Duchenne at age 3. As a kid, he said, he loved computers — once building his own — and would play catch in the driveway with his family when he could still walk. Later in his life, he used a motorized wheelchair. He studied information science at Cornell University and went on to work at the school in the information science department.

    “As I grew up and began to understand what it meant to have DMD, my fears about this disease began to grow as it began to manifest,” Horgan wrote. “There weren’t many, or any, trials available to me through the years” — until this one brought the prospect of a customized drug.

    Horgan was enrolled in the study on Aug. 31. The plan was to suppress his immune system to prep his body for a one-time, gene-editing therapy delivered by IV at UMass medical school, followed by monitoring in the hospital. The company explained that the therapy is designed to increase the level of an alternate form of the dystrophin protein using CRISPR, with the goal of stabilizing or potentially reversing the progression of symptoms.

    Urnov, scientific director for technology and translation at the Berkeley genomics institute, said no other trial targeted this disease using this kind of virus to deliver this particular payload with its modified form of CRISPR.

    Some other gene therapy trials – such as those targeting the blood disorders sickle cell disease and beta thalassemia – involve removing stem cells from someone’s blood, using CRISPR in the lab, then putting the altered cells back into the person. The first time CRISPR was used to edit genes within the body was to address a blindness-causing mutation.

    Given the “exceptional distinctness” of the Cure Rare Disease approach, Urnov said he doesn’t think Horgan’s death will have a major impact on things like using gene therapy to fix blood diseases. But he said pinpointing the exact cause will help inform scientists throughout the field.

    “History teaches us that in the case of such fatalities – which have been rare – that a deep dive into what happened was critical for the field to move forward.”

    ———

    The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute’s Department of Science Education. The AP is solely responsible for all content.

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  • Man arrested in connection with 42-year-old homicide cold case using new DNA technology | CNN

    Man arrested in connection with 42-year-old homicide cold case using new DNA technology | CNN

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    CNN
     — 

    The Las Vegas Metropolitan Police Department has arrested a man in connection with the killing of 25-year-old Sandra DiFelice, nearly 42 years after her death.

    Paul Nuttall, 64, was arrested on charges of “open murder” with the use of a deadly weapon, sexual assault with the use of a deadly weapon and burglary while in possession of a deadly weapon, police said in a statement Monday.

    In Nevada, a person accused of murder will generally be charged with “open murder,” meaning a general allegation of murder which includes, “Murder in the First Degree and all necessarily included offenses. These would include Murder in the Second Degree and possibly Voluntary Manslaughter and Involuntary Manslaughter based upon the specific facts of the case,” according to Clark County’s website.

    CNN has reached out to Nuttall’s public defender but has not yet heard back.

    DiFelice was allegedly brutally raped and murdered inside her home on December 26, 1980, according to police.

    In February 2021, DiFelice’s daughter – who at the time of the incident was three years old and at her grandparents’ house – called cold case detectives at the police department to ask for an update on the investigation.

    Detectives reviewed the investigation, and “upon a review of that investigation, in conjunction with our DNA forensics lab, they were able to determine that there was additional evidence that could be submitted for processing using new DNA technology. During that processing of the evidence, DNA recovered from under the fingernails of Sandra DiFelice identified the suspect of Sandra DiFelice’s murder as Paul Nuttall,” Lt. Jason Johansson said during a news conference.

    Nuttall was originally named as a person of interest during the initial stages of the investigation, police said during the news conference. Authorities said his fingerprint was found in DiFelice’s home, but it was determined that Nuttall knew DiFelice’s roommate and that explained why his fingerprint was there, police said during the news conference.

    Nuttall is currently in custody at the Clark County Detention Center, according to online records.

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  • Do Pancreatic Cysts Become Cancerous?

    Do Pancreatic Cysts Become Cancerous?

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    Newswise — New Brunswick, N.J., November 1, 2022 – It’s not unusual for cysts to form in the pancreas,  an important organ that produces enzymes that help digest food, and it secretes hormones—such as insulin—that help regulate metabolism. Although some pancreas cysts are benign, the majority are pre-cancerous and are the most common identifiable precursor to pancreatic cancer. Russell Langan, MD, FACS, FSSO, surgical oncologist at Rutgers Cancer Institute of New Jersey,  the state’s leading cancer center and only NCI-designated Comprehensive Cancer Center, chief of Surgical Oncology and Hepatopancreatobiliary Surgery at Cooperman Barnabas Medical Center, an RWJBarnabas Health facility, and assistant professor of surgery at Rutgers Robert Wood Johnson Medical School, shares more information on monitoring pancreatic cysts and pancreatic cancer.

    The Difference between Pancreatic Cancer and Cysts

    According to the National Cancer Institute, pancreatic cancer is the fourth leading cause of cancer death in the United States. A history of smoking, diabetes and chronic pancreatitis and obesity are risk factors for developing the disease. Further, the risk of pancreatic cancer is higher if there is either a family history of pancreatic cancer or a history of certain genetic syndromes. Pancreatic cysts are fluid-filled growths that develop in the pancreas. Most develop for no apparent reason are incidentally identified but do require surveillance.

    Their Link to Pancreatic Cancer

    Unlike other cysts such as those on the ovaries, liver or kidneys, pancreatic cysts do have the potential to progress to pancreatic cancer over time. It is widely believed that certain pancreatic cysts represent a field defect of the pancreas and that the risk of developing a pancreas cancer is not only within the cyst but rather the entire gland itself. 

    Finding Pancreatic Cysts

    Pancreatic cysts often don’t cause symptoms, so they’re frequently found during an imaging scan for something else. Once identified, patients and doctors are encouraged to refer to pancreatic care teams where the characteristics of the cyst, pancreas, family history and other risk factors can all be assessed by a pancreas multidisciplinary team.

    Preventative Medicine at its Best

    When pancreatic cysts are followed and surveyed appropriately, intervening at appropriate times can reduce the risk of developing pancreas cancer. Cooperman Barnabas Medical Center has pioneered one of the first cloud-based data management platforms in the nation to identify, track and monitor patients with pancreatic cysts. Through the program, patients are identified and offered consultation with our pancreas care team.  In doing this, the appropriate evidence based follow-up imaging or endoscopy is performed regularly to monitor the cysts and the surrounding pancreas.

    To learn more visit rwjbh.org/beatcancer or call 844-CANCERNJ (844-226-2376).

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    Rutgers Cancer Institute of New Jersey

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  • Use of DNA Biomarkers for Detecting Early-Stage HPV-Positive Oropharynx Cancers Has Limitations

    Use of DNA Biomarkers for Detecting Early-Stage HPV-Positive Oropharynx Cancers Has Limitations

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    Newswise — Oropharynx cancers caused by human papillomavirus (HPV) have risen dramatically over the years, superseding tobacco use and heavy drinking as the primary driver of new cases. Fortunately, HPV-positive oropharynx cancers have an improved survival rate compared to other head and neck cancers, allowing for less intensive treatment options, especially if diagnosed at early stages. One promising biomarker for early diagnosis and predicting reoccurrence, circulating tumor HPV DNA (ctHPV DNA), is found in the blood of almost 90% of patients with HPV-positive oropharynx cancer and can be detected using commercially available blood assays measuring HPV DNA from tumor cells (TTMV-HPV DNA). However, in a study of 110 HPV-positive oropharynx cancer patients, investigators from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, found that TTMV-HPV DNA levels are linked to the presence of cancer in the lymph nodes and are often indetectable in patients without neck masses. This has a tremendous impact on how the test is interpreted and applied for early-stage disease and may mean it is not as effective for screening and early diagnosis of this increasingly common disease. 

    “ctHPV DNA testing is emerging as a powerful tool in the diagnosis, treatment, and post-treatment surveillance of HPV-positive oropharynx cancer,” said first author Eleni M. Rettig, MD, of Brigham and Women’s Hospital Division of Otolaryngology-Head and Neck Surgery and Dana-Farber Cancer Institute. Rettig is also an affiliated faculty member in the Center for Surgery and Public Health. “It’s increasingly critical to understand both the strengths and limitations of this test.”

    Read more in JAMA-Otolaryngology Head and Neck Surgery.

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    Brigham and Women’s Hospital

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  • Breast Cancer Drug Benefits Broader Group of Patients, Trial Shows

    Breast Cancer Drug Benefits Broader Group of Patients, Trial Shows

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    Newswise — DALLAS – Oct. 28, 2022 – A drug approved to treat breast cancer patients with mutations in the BRCA1 or BRCA2 genes may also benefit people who have other genetic mutations.

    Researchers at UT Southwestern reported in the journal Nature Cancer that talazoparib successfully shrank the tumors of breast cancer patients with mutations in the PALB2 gene. Patients with this mutation would not have previously qualified for treatment with talazoparib, a type of cancer drug known as a PARP inhibitor.

    “These patients would otherwise have very limited treatment options,” said Joshua Gruber, M.D., Ph.D., Assistant Professor of Internal Medicine at UT Southwestern and a member of the Harold C. Simmons Comprehensive Cancer Center. “This study expands the patient population that can benefit from PARP inhibitors.”

    Like other PARP inhibitors, talazoparib works by blocking a protein that usually helps cells repair damaged DNA. Without the ability to repair their DNA, cancer cells accumulate damage and eventually die. In cancers that have other defects in this process – including those with BRCA1/2 mutations – the drug is particularly effective, dealing a fatal second blow to the DNA repair machinery.

    In a landmark 2018 study, researchers focused on advanced breast cancer patients with BRCA mutations – which account for 5% to 10% of all breast cancer cases – and found that talazoparib increased their survival time. The Food and Drug Administration approved the drug for that group, and follow-up studies have found that talazoparib also works for prostate and pancreatic cancer patients with BRCA mutations.

    In the new phase 2 trial, Dr. Gruber and colleagues tested the effectiveness of talazoparib in advanced cancer patients with less common gene mutations associated with DNA repair. Previous data has suggested that more than 17% of all cancers have such mutations.

    Twenty patients were enrolled in the trial at Stanford University, where Dr. Gruber previously served. Thirteen had breast cancer, three had pancreatic cancer, and four had other tumor types. The patients had mutations in eight DNA repair genes. On average, they took a daily talazoparib pill for 23.8 weeks.

    Among all patients, the average survival time was 5.6 months, and 20% had at least partial shrinkage of tumors. Because this was a phase 2 trial, there was not a control group to compare these data to, but the results were especially striking for patients with the PALB2 mutations: They survived 6.9 months on average, and all six patients (five with breast cancer, one with pancreatic cancer) had tumor shrinkage.

    The findings underscore the increasing importance of genetic testing to guide treatment for cancer patients, Dr. Gruber said. The team is planning a follow-up trial at UT Southwestern to further understand which patients gain the most benefit from talazoparib.

    About UT Southwestern Medical Center

    UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 24 members of the National Academy of Sciences, 18 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,900 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 100,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits a year.

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  • Defect in Gene Caused Massive Obesity in Mice Despite Normal Food Intake

    Defect in Gene Caused Massive Obesity in Mice Despite Normal Food Intake

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    Newswise — DALLAS – Oct. 28, 2022 – A faulty gene, rather than a faulty diet, may explain why some people gain excessive weight even when they don’t eat more than others, UT Southwestern researchers at the Center for the Genetics of Host Defense have discovered.

    The findings, published in Cell Metabolism, describe how a defect in a gene called Ovol2 caused mice with normal activity levels and food intake to become obese as they reached adulthood due to problems generating body heat. If the same holds true in humans, who share a nearly identical gene and its protein product, the findings could eventually help identify potential treatments for obesity.

    “Most cases of obesity are caused by overeating or by lack of physical activity, but our research has shown that a mutation of a little-studied gene called Ovol2 causes massive obesity – due solely to a defect in thermogenesis, or heat production,” said study leader Zhao Zhang, Ph.D., Assistant Professor of Internal Medicine who co-led this study with Nobel Laureate Bruce Beutler, M.D., Professor of Immunology and Director of the Center for the Genetics of Host Defense.

    About 42% of people in the U.S. are obese, a condition that drives up the risk of many other health problems including heart disease, stroke, Type 2 diabetes, and certain types of cancer. Although researchers agree obesity appears to stem from an interplay between a person’s genes and his or her environment, the genes that play important roles in the most common forms of obesity aren’t well understood, and the most famous obesity mutations in mice and humans cause a voracious appetite.

    To learn more about basic mechanisms of obesity, Drs. Zhang and Beutler and their colleagues used a chemical to generate random mutations in the DNA of mice. In a particular family of mice, obesity began at about 10 weeks of age – young adulthood for the rodents – and continued until the animals were massively overweight. The researchers identified the responsible mutation in a gene called Ovol2.

    “No one had associated this gene with obesity before,” Dr. Beutler said, “because it’s essential for life. The mutation we created was mild enough to allow survival but damaging enough to reveal a striking metabolic defect.”

    The obese mice experienced a 556% increase in fat weight, accompanied by a 20% reduction in lean weight, compared to littermates who had not undergone mutagenesis. Experiments showed the obese animals weren’t able to maintain their core body temperature when exposed to cold, which appeared to result from an inability to effectively use a type of tissue called brown fat, the primary function of which is to generate heat. Further tests suggested that the healthy Ovol2 gene suppressed development of white fat, the main tissue responsible for energy storage.

    When the researchers overexpressed the normal Ovol2 protein, they found that animals gained far less weight than wild-type controls in mice fed a high-fat diet. The authors said these findings suggest Ovol2 is a key player in energy metabolism – which probably holds true for humans since the human Ovol2 protein is very similar to the mouse version. Eventually, said Dr. Zhang, doctors may be able to treat obesity by giving patients drugs that drive up Ovol2 function.

    Drs. Beutler and Zhang are inventors on a patent related to these findings.

    UT Southwestern is a Nutrition Obesity Research Center, one of 12 in the nation funded by the National Institutes of Health and the only one in Texas. The Center supports work by more than 150 UT Southwestern scientists to investigate the causes, prevention, and treatment options for obesity.

    Dr. Beutler is a Regental Professor who holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie, Sr. He received the 2011 Nobel Prize in Physiology or Medicine for his discovery of how the innate immune system is activated.

    Other UTSW researchers who contributed to this study include Yiao Jiang, Lijing Su, Sara Ludwig, Xuechun Zhang, Miao Tang, Xiaohong Li, Priscilla Anderton, Xiaoming Zhan, Mihwa Choi, Jamie Russell, Chun-Hui Bu, Stephen Lyon, Darui Xu, Sara Hildebrand, Lindsay Scott, Jiexia Quan, Rochelle Simpson, Qihua Sun, Baifang Qin, Tiffany Collie, Meron Tadesse, and Eva Marie Y. Moresco.

    This work was supported by the National Institutes of Health (K99 DK115766, R00 DK115766, R01 AI125581, and U19 AI100627) and the Lyda Hill Foundation.

    About UT Southwestern Medical Center

    UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 24 members of the National Academy of Sciences, 18 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,900 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 100,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits a year.

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  • The Origin-of-Life Molecule, a Key to Cancer Research

    The Origin-of-Life Molecule, a Key to Cancer Research

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    Newswise — RNA, the molecule that gave rise to life, has been shown to be essential for repairing human genetic material and preventing mutations that might lead to developing cancer. Recent advances in research, such as those published by the research team of Daniel Gómez Cabello at the University of Seville, propose this compound as a therapeutic target for developing tailored strategies for treating cancer.

    The RNA polymerase enzyme, the RNA production machine in cells, is essential for repairing breakages in human DNA safely and reliably. RNA production is essential for healthy cells but especially for tumour cells, which require much more activity by this enzyme to grow uncontrolled.

    The study revealed that RNA synthesis inhibition with the THZ1 compound and analogues after therapies that cause DNA breakages, such as radiation therapy, greatly increases tumour cells’ sensitivity to death. “This study provides clues on how to improve conventional therapies and achieve a higher success rate with treatments. Although there is still a long way to go to be able to use these RNA polymerase inhibitors in the clinical setting, clinical trials are currently underway based on this enzyme for treating cancer”, explained the Principal Investigator, Daniel Gómez-Cabello. “Increasing the knowledge on how to use these compounds in a safer and more tailored manner allows us to address as best as possible the treatment of cancer”, added the researcher Diana Aguilar-Morante, the study’s co-author.

    This research by the Biomedical Institute of Seville and the University of Seville, in collaboration with the Danish Cancer Society, has been published in the prestigious journal Nature Communications. Both researchers return to Spain from Denmark and have been able to continue their research thanks to contracts funded by the Government of Andalusia and the Spanish Association against Cancer (AECC). “Thanks to the AECC, we have been able to continue with these studies and move this project forward”, explained the author.

    Currently, these researchers are working on the mechanisms of how RNA, the original molecule that enables life, can serve as a tool for treating diseases. “Once we have observed that selectively inhibiting RNA production boosts the utility of radiation therapy in cancer cells and does not drastically affect the rest of the cells, we will start researching it in various types of cancer, such as glioblastoma and paediatric neuroblastoma”, commented Diana Aguilar-Morante. “At this point, our challenge will be to improve the efficiency of these new RNA production inhibitors and reduce the side effects that can occur in patients with cancer”, stated Gómez-Cabello.

    RNA, the molecule that gave rise to life, has been shown to be essential for repairing human genetic material and preventing mutations that might lead to developing cancer. Recent advances in research, such as those published by the research team of Daniel Gómez Cabello at the University of Seville, propose this compound as a therapeutic target for developing tailored strategies for treating cancer.

    The RNA polymerase enzyme, the RNA production machine in cells, is essential for repairing breakages in human DNA safely and reliably. RNA production is essential for healthy cells but especially for tumour cells, which require much more activity by this enzyme to grow uncontrolled.

    The study revealed that RNA synthesis inhibition with the THZ1 compound and analogues after therapies that cause DNA breakages, such as radiation therapy, greatly increases tumour cells’ sensitivity to death. “This study provides clues on how to improve conventional therapies and achieve a higher success rate with treatments. Although there is still a long way to go to be able to use these RNA polymerase inhibitors in the clinical setting, clinical trials are currently underway based on this enzyme for treating cancer”, explained the Principal Investigator, Daniel Gómez-Cabello. “Increasing the knowledge on how to use these compounds in a safer and more tailored manner allows us to address as best as possible the treatment of cancer”, added the researcher Diana Aguilar-Morante, the study’s co-author.

     

    This research by the Biomedical Institute of Seville and the University of Seville, in collaboration with the Danish Cancer Society, has been published in the prestigious journal Nature Communications. Both researchers return to Spain from Denmark and have been able to continue their research thanks to contracts funded by the Government of Andalusia and the Spanish Association against Cancer (AECC). “Thanks to the AECC, we have been able to continue with these studies and move this project forward”, explained the author.

    Currently, these researchers are working on the mechanisms of how RNA, the original molecule that enables life, can serve as a tool for treating diseases. “Once we have observed that selectively inhibiting RNA production boosts the utility of radiation therapy in cancer cells and does not drastically affect the rest of the cells, we will start researching it in various types of cancer, such as glioblastoma and paediatric neuroblastoma”, commented Diana Aguilar-Morante. “At this point, our challenge will be to improve the efficiency of these new RNA production inhibitors and reduce the side effects that can occur in patients with cancer”, stated Gómez-Cabello.

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    University of Seville

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  • MD Anderson’s Guillermina Lozano Receives AAMC Award for Distinguished Research in the Biomedical Sciences

    MD Anderson’s Guillermina Lozano Receives AAMC Award for Distinguished Research in the Biomedical Sciences

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    Newswise — HOUSTON ― In recognition of her trailblazing work uncovering the mechanisms of the p53 tumor suppressor, Guillermina “Gigi” Lozano, Ph.D., chair of Genetics at The University of Texas MD Anderson Cancer Center, has received the 2022 Award for Distinguished Research in the Biomedical Sciences by the Association of American Medical Colleges (AAMC).

    Since its inception in 1947, the AAMC Award for Distinguished Research in the Biomedical Sciences has annually honored an individual or team of two individuals whose research has contributed to significant scientific discoveries benefitting human health and well-being, who participate in research beyond their own work through mentorship or review panels, and whose standards of professional ethics and scientific integrity are of the highest caliber. Lozano is the second MD Anderson researcher to be selected for this award, with James Allison, Ph.D., honored in 2014.

    “Gigi’s key discoveries in the field of cancer biology are of tremendous importance, enabling a deeper understanding of the mechanisms that drive tumor development and treatment response. These breakthroughs are necessary for advancing the field and improving the care we bring to our patients,” said Giulio Draetta, M.D., Ph.D., chief scientific officer. “Her commitment to research excellence strengthens our entire MD Anderson community, and we applaud her for this well-deserved recognition.”

    Lozano is internationally recognized as one of the world’s foremost cancer researchers. She was the first to establish p53 as a transcriptional activator of other genes and highlighted its mutation or deletion as a hallmark of more than 90% of cancers. She also identified the physiological roles of the Mdm2 and Mdm4 proteins as gatekeepers in cancer development and in regulating p53, providing the backbone for potentially using Mdm2/4 inhibitors as a novel targeted therapy approach .

    “I am flattered to be recognized for our work on the p53 tumor suppressor pathway and want to thank members of my laboratory for all of their contributions,” Lozano said. “I look forward to continuing our exciting research and advancing new discoveries that will bring us closer to our mission to end cancer.”

    Lozano also discovered the key mechanism through which breast cancers with mutant p53 respond better to chemotherapy than those with wild-type p53, and she led the development of laboratory models of mutant p53 that more accurately represent breast and pancreatic cancers. The Lozano laboratory at MD Anderson remains focused on understanding the effects of wild-type or mutant p53 on the tumor microenvironment and on genomic stability in cancer development and progression.

    Lozano graduated magna cum laude with degrees in biology and mathematics from The University of Texas Rio Grande Valley. She received her Ph.D. in biochemistry from Rutgers University and the University of Medicine and Dentistry of New Jersey, continuing to Princeton University for a postdoctoral fellowship. She joined MD Anderson in 1987 and has published 261 articles in peer-reviewed journals, reviews and book chapters over the course of her 35 years at the institution, rising to her current position as chair of the department of Genetics. She has also mentored many young scientists, with 33 graduate students receiving their M.S. and Ph.D. degrees under her direction and 29 postdoctoral fellows having trained in her lab.

    Lozano is an elected fellow of the American Association for the Advancement of Science (AAAS) and the American Association for Cancer Research (AACR) Academy. She has been elected to the National Academy of Medicine, the National Academy of Sciences, and the American Academy of Arts and Sciences. Among her many honors, she has received the Hubert L. Olive Stringer Distinguished Chair in Oncology in Honor of Sue Gribble Stringer in 2018, the AACR-Minorities in Cancer Research Jane Cooke Wright Lectureship and AACR-Women in Cancer Research Charlotte Friend Lectureship awards, and the 2018 MD Anderson President’s Leadership Award for Advancing Women and Minority Faculty.

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    University of Texas M. D. Anderson Cancer Center

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  • United BioChannels Acquires ORFLO Technologies to Expand Market Share and Enhance Customer Engagement

    United BioChannels Acquires ORFLO Technologies to Expand Market Share and Enhance Customer Engagement

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    Newswise — SAN DIEGO, Oct. 27, 2022 /PRNewswire/ — United BioChannels (UBC), a commercial strategy consultancy, announced its acquisition of ORFLO Technologies, LLC, from Gemini Bioproducts. The acquisition represents an opportunity for both ORFLO and UBC to collaboratively increase the commercial presence of ORFLO and build market share using UBC’s Modular Method of developing commercial strategy and tactical execution. ORFLO, a leading manufacturer of cell counting and characterization technologies, will be led by Varshal Davé, UBC’s Managing Partner, who will assume the role of Chief Executive Officer. The acquisition is funded through a collaboration between UBC and BroadOak Capital Partners.

    United BioChannels (UBC) Acquires ORFLO Technologies to Expand Market Share and Enhance Customer Engagement

    “We are very excited to bring ORFLO Technologies into the United BioChannels family,” said UBC’s President Jeff Whitmore. “ORFLO has historically lacked a strong commercial focus, so our expertise presents an opportunity for a synergistic relationship. We believe that our processes will lead to increased visibility and revenue for ORFLO.”

    “We have been tracking the progress of ORFLO Technologies for quite some time,” added Bill Snider, Partner at BroadOak Capital Partners, “and we see some great potential that the UBC team can unlock. ORFLO has a strong market presence and we think UBC’s leadership can only help the company grow.”

    Cell and gene therapy, amongst other bioprocessing applications, require robust instrumentation as integral components of their workflow. Cell counters in particular serve critical quality control functions in multiple stages of these complex processes. Ketchum, Idaho, based ORFLO Technologies has excelled in these processes, having been implemented as standard instruments in regulated workflows for many leading bioprocessing companies. With a strong market presence having over 3,000 instruments installed worldwide, ORFLO has an established customer base that the company can build upon under UBC’s leadership.

    About United BioChannels

    United BioChannels is a global network of life sciences sales and executive professionals in strategic locations and science hubs. We are an experienced team with a diverse background in launching new technologies and with decades of commercial experience. We use a validated approach to get solutions to the right people. Through extensive due diligence to understand our clients’ unique situations, we can pinpoint the correct market segments to maximize success. We test market hypotheses and build messaging and sales tools, creating “win-win” relationships.

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    United BioChannels

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  • Speeding Up DNA Computation with Liquid Droplets

    Speeding Up DNA Computation with Liquid Droplets

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    Newswise — Recent studies have shown that liquid-liquid phase separation – akin to how oil droplets form in water – leads to formation of diverse types of membraneless organelles, such as stress granules and nucleoli, in living cells. These organelles, also called biomolecular condensates, are liquid droplets performing specific cellular functions including gene regulation and stress response.

    Now, a joint research team led by Professor Yongdae Shin and Do-Nyun Kim at Seoul National University announced that they harnessed the unique properties of the self-assembling DNA molecules to build synthetic condensates with programmable compositions and functionalities.

    The researchers designed DNA scaffolds with motifs for self-association as well as specific recruitment of DNA targets. In a proper range of salt concentration and temperature, the engineered DNA scaffolds underwent liquid-liquid phase separation to form dense condensates, organized in a highly similar manner to those in living cells. The synthetic DNA condensates can recruit specific target DNA molecules, and the researchers demonstrated that the degree of recruitment can be precisely defined at the DNA sequence level.

    They then endowed the synthetic condensates with functionalities by using DNA computation components as targets. DNA computing has been widely implemented for various bioengineering and medical applications, due to its intrinsic capacity of parallel computation. However, the slow speed of individual computation process has been a major drawback. With the synthetic DNA condensates, Shin and his team showed that DNA computation including logic gate operations were drastically sped up, by more than tenfold, when coupled to the condensates.

    The architecture of DNA scaffolds also allowed selective recruitment of specific computing operations among many others running in parallel, which enabled a novel kinetics-based gating mechanism. The researchers expected that their system could be widely applied to diverse DNA circuits for disease diagnostics, biosensing, and other advanced molecular computations.

    The results of this study were published in Science Advances.

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    Seoul National University

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  • Ancient DNA gives rare snapshot of Neanderthal family ties

    Ancient DNA gives rare snapshot of Neanderthal family ties

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    NEW YORK — A new study suggests Neanderthals formed small, tightknit communities where females may have traveled to move in with their mates.

    The research used genetic sleuthing to offer a rare snapshot of Neanderthal family dynamics — including a father and his teenage daughter who lived together in Siberia more than 50,000 years ago.

    Researchers were able to pull DNA out of tiny bone fragments found in two Russian caves. In their study, published Wednesday in the journal Nature, they used the genetic data to map out relationships between 13 different Neanderthals and get clues to how they lived.

    “When I work on a bone or two, it’s very easy to forget that these are actually people with their own lives and stories,” said study author Bence Viola, an anthropologist at the University of Toronto. “Figuring out how they’re related to each other really makes them much more human.”

    Our ancient cousins, the Neanderthals, lived across Europe and Asia for hundreds of thousands of years. They died out around 40,000 years ago, shortly after our species, the Homo sapiens, arrived in Europe from Africa.

    Scientists have only recently been able to dig around in these early humans’ DNA. New Nobel laureate Svante Paabo — who is an author on this latest study — published the first draft of a Neanderthal genome a little over a decade ago.

    Since then, scientists have sequenced 18 Neanderthal genomes, said lead author Laurits Skov, a geneticist at the Max Planck Institute for Evolutionary Anthropology. But it’s rare to find bones from multiple Neanderthals from the same time and place, he said — which is why these cave discoveries were so special.

    “If there was ever a chance to find a Neanderthal community, this would be it,” Skov said.

    The caves, located in remote foothills above a river valley, have been a rich source of materials from stone tools to fossil fragments, Viola said. With their prime view of migrating herds in the valley below, researchers think the caves might have served as a short-term hunting stop for Neanderthals.

    Archaeologists excavating the caves have found remains from at least a dozen different Neanderthals, Viola said. These remains usually come in small bits and pieces — “a finger bone here, a tooth there” — but they’re enough for scientists to extract valuable DNA details.

    The researchers were able to identify a couple of relatives among the group. Along with the father and daughter, there was a pair of other relatives — maybe a boy and his aunt, or a couple of cousins.

    Overall, the analysis found that everyone in the group had a lot of DNA in common. That suggests that at least in this area, Neanderthals lived in very small communities of 10 to 20 individuals, the authors concluded.

    But not everyone in these groups stayed put, according to the study.

    Researchers looked at other genetic clues from mitochondrial DNA, which is passed down on the mother’s side, and the Y chromosome, which is passed down on the father’s side.

    The female side showed more genetic differences than the male side — which means females may have moved around more, Skov said. It’s possible that when a female Neanderthal found a mate, she would leave home to live with his family.

    University of Wisconsin anthropologist John Hawks, who was not involved in the study, said the research was an exciting application of ancient DNA evidence, even as many questions remain about Neanderthal social structures and lifestyles.

    Figuring out how early humans lived is like “putting together a puzzle where we have many, many missing pieces,” Hawks said. But this study means “somebody’s dumped a bunch more pieces on the table.”

    ———

    The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute’s Department of Science Education. The AP is solely responsible for all content.

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  • Increased Risk for Stillbirth Passed Down Through Fathers, Male Relatives

    Increased Risk for Stillbirth Passed Down Through Fathers, Male Relatives

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    Newswise — (Salt Lake City) – Newly published research is the first to show that stillbirth can be inherited and tends to be passed down through male members of the family. That risk preferentially comes from the mother’s or father’s male relatives—their brothers, fathers, grandfathers, uncles, or male cousins. But the odds of a couple losing a baby to stillbirth are even greater when the condition comes from the father’s side of the family.

    “Stillbirth is one of those problems that is so tragic and life-changing,” says Jessica Page, MD, an assistant professor in the Department of Obstetrics & Gynecology at University of Utah Health and Intermountain Healthcare. “It is especially frustrating when you don’t have a good answer for why it happens. This knowledge may give us the opportunity to change how we risk stratify people and reduce their risk through prevention.”

    The results, published in BJOG, come from the largest study of its kind to examine the health histories of families over multiple generations. Page is co-author on the study led by Tsegaselassie Workalemahu, PhD, and senior author Robert Silver, MD, both of whom are faculty in the Department of Obstetrics & Gynecology at U of U Health.

    “Studying pregnancy provides the opportunity to improve the health of future generations,” Workalemahu explains. He says that understanding patterns of stillbirth in families may help genetic counselors advise their patients about their risk. It is also an important step toward identifying specific genes that increase the risk of stillbirth, which could one day lead to better diagnosis and prevention.

    Searching for risk factors of stillbirth

    In the U.S., stillbirth is more common than many people realize, occurring in 1 in 165 births among babies that are 20 weeks or older. The risk goes up when the mother has certain health conditions such as gestational hypertension, preeclampsia, or diabetes, but the causes of as many as 1 in 3 cases still go unexplained.

    To understand other risk factors contributing to stillbirth, the scientists examined 9,404 stillbirth cases and 18,808 live birth controls between 1978 and 2019 that were represented in the Utah Population Database, a genealogical resource linked to health, birth, and death records. They found that 390 families had an excess number of stillbirths over multiple generations, suggesting there are genetic causes of stillbirth.

    By comparing incidence of stillbirth among first-, second-, and third-degree relatives of babies from affected families with the equivalent relatives from unaffected families, the scientists identified familial risk in related individuals. Their analysis revealed that an increased risk for stillbirth was passed down through male family members, a trend that had not been seen before.

    “We were able to evaluate multigenerational trends in fetal death as well as maternal and paternal lineages to increase our ability to detect a familial aggregation of stillbirth,” Workalemahu says. “Not many studies have examined inherited genetic risk for stillbirth because of a lack of data. The Utah Population Database (UPDB) allows for a more rigorous evaluation than has been possible in the past.”

    The population in the UPDB has similar genetic diversity to the U.S. population of northern European descent and may not be generalizable to the general U.S. population. Future studies will need to determine whether the trends hold true among people of different races and ethnicities.

    “Stillbirth rate reduction has been slow in the U.S. and we think many stillbirths may be potentially preventable,” Page says. “This is motivating us to look for those genetic factors so we can achieve more dramatic rate reduction.”

    # # #

    The research published as, “Familial aggregation of stillbirth: A pedigree analysis of a matched case–control study” and is supported by grants from the National Institutes of Health.

    About University of Utah Health

    University of Utah Health provides leading-edge and compassionate care for a referral area that encompasses Idaho, Wyoming, Montana, and much of Nevada. A hub for health sciences research and education in the region, U of U Health has a $458 million research enterprise and trains the majority of Utah’s physicians and health care providers at its Colleges of Health, Nursing, and Pharmacy and Schools of Dentistry and Medicine. With more than 20,000 employees, the system includes 12 community clinics and five hospitals. U of U Health is recognized nationally as a transformative health care system and provider of world-class care.

     

     

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  • New mitochondrial disease identified in identical twins

    New mitochondrial disease identified in identical twins

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    Key Takeaways

    • In a set of identical twins, investigators have discovered a disease that affects the mitochondria, or the specialized compartments within cells that produce energy
    • Unlike in other mitochondrial diseases, mitochondria were hyperactive in these cases, so that even though the siblings had a high intake of calories, their body weights remained very low

    Newswise — BOSTON – In a set of identical twins, investigators led by researchers at Massachusetts General Hospital (MGH) and Children’s Hospital Philadelphia (CHOP) have identified a mitochondrial disease not previously reported.

    Diseases that affect mitochondria—specialized compartments within cells that contain their own DNA and convert the food we eat into energy needed to sustain life—typically interfere with mitochondrial function, but in these two patients, mitochondria were hyperactive.

    So, as reported in the New England Journal of Medicine, even though the siblings were eating far more calories than needed, their body weights remained very low.

    “This is a highly unusual mitochondrial phenotype. There are more than 300 rare genetic mitochondrial diseases, and nearly all of them are associated with an interruption of mitochondria,” says senior author Vamsi K. Mootha, MD, a Professor of Systems Biology and Medicine at MGH.

    Genome sequencing revealed a mutation in an enzyme called the mitochondrial ATP synthase, which is required by cells to generate the energy storage molecule ATP.

    Experiments indicated that this mutation creates “leaky” mitochondria that dissipate energy—a process called mitochondrial uncoupling.

    “We propose a new name—mitochondrial uncoupling syndrome—that presents with hypermetabolism and uncoupled mitochondria,” says Mootha. “These cases are very important for the field of rare disease genetics, mitochondrial biology, and metabolism.”

    The authors note that additional studies on mitochondrial uncoupling syndromes may provide insights into differences in energy metabolism in the general population.

    “These twins represent the first disorder of mitochondrial uncoupling where we have been able to find the genetic cause,” said Rebecca D. Ganetzky, MD, an attending physician in Mitochondrial Medicine program at CHOP and co-author of the study.

    “By discovering that pathogenic variants in the ATP synthase itself can cause mitochondrial uncoupling, these twins may be the first identified patients in a whole class of diseases of mitochondrial coupling.”

    Additional co-authors include Andrew L. Markhard, BA, Irene Yee, BS, Sheila Clever, MSc, Alan Cahill, PhD, Hardik Shah, MS, Zenon Grabarek, PhD, and Tsz-Leung To, PhD.

    This work was supported by the National Institutes of Health and others.

    About the Massachusetts General Hospital

    Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In July 2022, Mass General was named #8 in the U.S. News & World Report list of “America’s Best Hospitals.” MGH is a founding member of the Mass General Brigham healthcare system.

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    Massachusetts General Hospital

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  • Gene activity in a test tube

    Gene activity in a test tube

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    Newswise — Pathological processes are usually characterised by altered gene activity in the cells affected. So, gaining an accurate picture of gene activity can provide the key to the development of new, targeted therapies. Whether these therapies then work as we would want them to can also be verified by looking at genes and the processes they initiate.

    It is no wonder that research is focused on methods and techniques that provide detailed information about the genetic activity of individual cells. A research team at the University of Würzburg (JMU) has now developed a technique that is a significant improvement on the methods used to date. Scientists from the Institute for Molecular Infection Biology (IMIB) and the Helmholtz Institute for RNA-based Infection Research (HIRI) were involved. They have presented the results of their work in the current issue of the journal Nucleic Acids Research.

    Analysis of a synthetic transcriptome

    “We have developed a technique that can be used to analyse the translational landscape of a fully customisable synthetic transcriptome, in other words one outside the cell,” is how Jörg Vogel explains the central outcome of the study. Vogel heads the Institute for Molecular Infection Biology at JMU and is also the Director of HIRI as well as the principal author of the study. The new technique has been given the scientific name INRI-seq, which is short for in vitro Ribo-seq.

    A transcriptome is a collection of all the genes that are active in a cell at a given point in time. It consists of the sum of the existing mRNA – the transporters of the blueprints for proteins from the cell nucleus to the ribosomes. Ribosomes are the “protein factories” of the cell; this is where translation of the nucleotide sequence of the mRNA into the amino acid sequence of a protein takes place.

    Refinement of comparable methods

    In principle, INRI-seq is a refinement of comparable methods that pursue the same goal but provide less accurate results or have other disadvantages. For example, RNA sequencing (RNA-seq) determines the concentration of mRNA in cells, allowing conclusions to be drawn about their active genes. However, the final protein abundance does not always correlate with the respective mRNA concentrations.

    A more accurate technique is ribosome profiling (Ribo-seq). Over the past ten years, this has become one of the main methods for measuring protein synthesis directly in a transcriptome-wide manner. “While Ribo-seq has greatly advanced the study of translation-related processes, the method has not been without limitations,” says Jörg Vogel.

    Numerous limitations of Ribo-seq

    For instance, it is a major challenge to detect weakly expressed genes with Ribo-seq, preventing many genes from being recorded in common study designs. Similarly, a Ribo-seq study of microbes from important ecological habitats such as the human gut is difficult since many of them cannot be cultured in the laboratory.

    A further shortcoming, as Vogel explains, is the fact that “on the mechanistic level, Ribo-seq-based studies of molecules affecting translation, such as special antibiotics, can be hampered by cellular responses”. Since Ribo-seq is performed on living cells, it can be difficult to distinguish between direct and indirect effects on translation.

    To overcome some of these limitations, the scientists from Würzburg have developed INRI-seq for the global study of translation in a cell-free environment. INRI-seq uses a commercially available in vitro translation system combined with an in vitro-synthesised, fully customisable transcriptome that allows better control of individual mRNA levels. “With INRI-seq, for example, it is no longer necessary for translation-modulating substances to traverse cellular membranes or to extract ribosomes from a large number of living cells,” says Vogel, outlining the advantages of the technique. “You also need a lot less of the often expensive substance that you want to study, such as a new antibiotic that can only be produced on a small scale. INRI-seq therefore also saves time and money.”

    Higher success rate in the experiment

    The research team demonstrated how well the system works using a synthetically generated transcriptome of the bacterium Escherichia coli. Compared to a technically similar study on living cells, INRI-seq identified almost four times more sites where translation processes are initiated, demonstrating its high sensitivity.

    Therefore, Vogel and his team are in no doubt that “INRI-seq bears great potential as an alternative method for studying translation process and thus also substances that can influence these processes”.

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  • Is ‘frozen shoulder’ a genetic condition? Study finds links to specific genes

    Is ‘frozen shoulder’ a genetic condition? Study finds links to specific genes

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    Newswise — October 14, 2022 – Frozen shoulder, or adhesive capsulitis, is a common cause of shoulder pain and immobility. New findings point to specific genes associated with an increased risk of this condition, reports The Journal of Bone & Joint Surgery. The journal is published in the Lippincott portfolio in partnership with Wolters Kluwer.

    The risk genes are associated with nearly a sixfold increase in the odds of developing frozen shoulder – a stronger association for most known clinical risk factors, according to the new research by Mark T. Langhans, MD, PhD, of Hospital for Specialty Surgery, New York. The authors believe their findings may lend new insights into the causes, prevention, and treatment of adhesive capsulitis.

    Genome-wide association study finds ‘significant loci’ affecting frozen shoulder risk

    Patients with adhesive capsulitis develop painful and progressive loss of shoulder motion with associated pain. Frozen shoulder is one of the most common shoulder conditions, occurring in up to 10% of people at some time in their lives. Although the exact cause is unclear, frozen shoulder sometimes occurs after an injury, surgery, or other condition that reduces shoulder mobility. Loss of motion results from fibrosis (scarring or thickening) of the capsule around the shoulder joint.

    Certain clinical factors are associated with an increased risk of frozen shoulder, including diabetes, thyroid disease, and smoking. Recent studies have suggested that risk is also higher in people with affected relatives – suggesting a possible genetic predisposition. Dr. Langhans and colleagues performed a genome-wide association study to identify specific genes that might be related to the risk of frozen shoulder.

    Data studied from large British database

    The study used data from a large British database, the UK Biobank, which includes genetic and health data on approximately 500,000 patients. The analysis focused on 2,142 patients with adhesive capsulitis compared to those without this diagnosis. Possible genetic associations were adjusted for other factors, including sex, diabetes, thyroid disease, history of shoulder dislocation, and smoking.

    The study identified three significant loci for frozen shoulder. The strongest association was found for gene variants located at a site called WNT7B. This finding was consistent with previous studies that reported a possible link between WNT7B and frozen shoulder, along with several other orthopaedic-related conditions. Weaker associations were also found for two previously unreported genetic loci located near genes for POU1F1 and MAU2.

    All three associations remained significant after adjustment for other factors. Together, the three variants carried nearly a sixfold increase in the odds of developing frozen shoulder. That was greater than the risk associated with diabetes (about four-fold) or thyroid disease (less than two-fold), and second only to smoking (about 11-fold).

    New insights could lead to a new development

    The findings may lend new insights into the development of adhesive capsulitis. In particular, genes located at WNT7B have been shown to be expressed in bone-forming cells (osteoblasts) and to be involved in regulating fibrosis, along with a wide range of other functions. The two newly reported loci, POU1F1 and MAU2, are involved with cell division, which might lend clues into the cellular mechanism by which frozen shoulder develops.

    The researchers note some key limitations of their analysis, including the need for further studies of genetic associations in groups other than the white, British population that predominates in the UK Biobank.

    Meanwhile, the new study identifies several gene loci with the ability to predict a clinically relevant risk of frozen shoulder. Dr. Langhans and colleagues conclude: “Refining the genetic risk metric and including it in a larger clinical model could allow patients at risk for future adhesive capsulitis to be identified, leading to efforts at prevention, early diagnosis, and ultimately improved outcomes.”

    Click here to read “Genome-Wide Association Study of Adhesive Capsulitis Suggests Significant Genetic Risk Factors“

    DOI: 10.2106/JBJS.21.01407

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    About The Journal of Bone & Joint Surgery

    The Journal of Bone & Joint Surgery (JBJS) has been the most valued source of information for orthopaedic surgeons and researchers for over 125 years and is the gold standard in peer-reviewed scientific information in the field. A core journal and essential reading for general as well as specialist orthopaedic surgeons worldwide, The Journal publishes evidence-based research to enhance the quality of care for orthopaedic patients. Standards of excellence and high quality are maintained in everything we do, from the science of the content published to the customer service we provide. JBJS is an independent, non-profit journal.

    About Wolters Kluwer

    Wolters Kluwer (WKL) is a global leader in professional information, software solutions, and services for the clinicians, nurses, accountants, lawyers, and tax, finance, audit, risk, compliance, and regulatory sectors. We help our customers make critical decisions every day by providing expert solutions that combine deep domain knowledge with advanced technology and services.

    Wolters Kluwer reported 2021 annual revenues of €4.8 billion. The group serves customers in over 180 countries, maintains operations in over 40 countries, and employs approximately 19,800 people worldwide. The company is headquartered in Alphen aan den Rijn, the Netherlands.

    Wolters Kluwer provides trusted clinical technology and evidence-based solutions that engage clinicians, patients, researchers and students in effective decision-making and outcomes across healthcare. We support clinical effectiveness, learning and research, clinical surveillance and compliance, as well as data solutions. For more information about our solutions, visit https://www.wolterskluwer.com/en/health and follow us on LinkedIn and Twitter @WKHealth.

    For more information, visit www.wolterskluwer.com, follow us on Twitter, Facebook, LinkedIn, and YouTube.

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    Wolters Kluwer Health: Lippincott

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  • Gene Therapy Rapidly Improves Night Vision in Adults with Congenital Blindness

    Gene Therapy Rapidly Improves Night Vision in Adults with Congenital Blindness

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    Newswise — PHILADELPHIA—Adults with a genetic form of childhood-onset blindness experienced striking recoveries of night vision within days of receiving an experimental gene therapy, according to researchers at the Scheie Eye Institute in the Perelman School of Medicine at the University of Pennsylvania.

    The patients had Leber Congenital Amaurosis (LCA), a congenital blindness caused by mutations in the gene GUCY2D. The researchers, whose findings are reported in the journal iScience, delivered AAV gene therapy, which carries the DNA of the healthy version of the gene, into the retina of one eye for each of the patients in accordance with the clinical trial protocol. Within days of being treated, each patient showed large increases, in the treated eye, of visual functions mediated by rod-type photoreceptor cells. Rod cells are extremely sensitive to light and account for most of the human capacity for low-light vision.

    “These exciting results demonstrate that the basic molecular machinery of phototransduction remains largely intact in some cases of LCA, and thus can be amenable to gene therapy even after decades of blindness,” said study lead author Samuel G. Jacobson, MD, PhD, a professor of Ophthalmology at Penn.

    LCA is one of the most common congenital blindness conditions, affecting roughly one in 40,000 newborns. The degree of vision loss can vary from one LCA patient to another but all such patients have severe visual disability from the earliest months of life. There are more than two dozen genes whose dysfunction can cause LCA.

    Up to 20 percent of LCA cases are caused by mutations in GUCY2D, a gene that encodes a key protein needed in retinal photoreceptor cells for the “phototransduction cascade”—the process that converts light to neuronal signals. Prior imaging studies have shown that patients with this form of LCA tend to have relatively preserved photoreceptor cells, especially in rod-rich areas, hinting that rod-based phototransduction could work again if functional GUCY2D were present. Early results with low doses of the gene therapy, reported last year, were consistent with this idea.

    The researchers used higher doses of the gene therapy in two patients, a 19- year-old man and a 32-year-old woman, who had particularly severe rod-based visual deficits. In daylight, the patients had some, albeit greatly impaired, visual function, but at night they were effectively blind, with light sensitivity on the order of 10,000 to 100,000 times less than normal.

    The researchers administered the therapy to just one eye in each patient, so the treated eye could be compared to the untreated eye to gauge treatment effects. The retinal surgery was performed by Allen C. Ho, MD, a professor of Ophthalmology at Thomas Jefferson University and Wills Eye Hospital. Tests revealed that, in both patients, the treated eyes became thousands of times more light-sensitive in low-light conditions, substantially correcting the original visual deficits. The researchers used, in all, nine complementary methods to measure the patients’ light sensitivity and functional vision. These included a test of room navigation skills in low-light conditions and a test of involuntary pupil responses to light. The tests consistently showed major improvements in rod-based, low-light vision, and the patients also noted functional improvements in their everyday lives, such as “can [now] make out objects and people in the dark.”

    “Just as striking was the rapidity of the improvement following therapy. Within eight days, both patients were already showing measurable efficacy,” said study co-author Artur V. Cideciyan, PhD, a research professor of Ophthalmology at Penn.

    To the researchers, the results confirm that GUCY2D gene therapy to restores rod-based photoreceptor functions—and suggest that GUCY2D–LCA patients with more severe rod-based dysfunction are likely to benefit most dramatically from the therapy. The practical message is that there should be an emphasis on rod vision measurements at screening of LCA candidates and in monitoring them throughout a treatment trial.

    The findings, the researchers said, also underscore the remarkable fact that in some patients with severe congenital vision loss, the retinal cell networks that mediate vision remain largely alive and intact, and need only the resupply of a missing protein to start working again, more or less immediately.

    The ongoing clinical trial is registered at clinicaltrials.gov as trial NCT03920007.

    Support for the research was provided by Atsena Therapeutics, Inc., the developer of the GUCY2D gene therapy; the National Institutes of Health (R01 EY11522); and by a CURE Formula grant from the Pennsylvania Department of Health.

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    Perelman School of Medicine at the University of Pennsylvania

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