Friday, January 19, 2024

 

The extinction of the giant ape: a long-standing mystery solved



Peer-Reviewed Publication

MACQUARIE UNIVERSITY

Gigantopithecus blacki in a forest scene 

IMAGE: 

AN ARTIST IMPRESSION OF A GROUP OF G. BLACKI WITHIN A FOREST IN SOUTHERN CHINA

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CREDIT: GARCIA/JOANNES-BOYAU (SOUTHERN CROSS UNIVERSITY)





Giants once roamed the karst plains of southern China, three-metre tall apes weighing in at 250 kilograms. These very distant human ancestors – Gigantopithcus blacki – went extinct before humans arrived in the region, with few clues to why, and so far leaving around 2000 fossilised teeth and four jawbones as the only signs of their existence.

New evidence from this region published in Nature, uncovered by a team of Chinese, Australian and US researchers, demonstrates beyond doubt that the largest primate to walk the earth went extinct between 295,000 and 215,000 years ago, unable to adapt its food preferences and behaviours, and vulnerable to the changing climates which sealed its fate.

“The story of G. blacki is an enigma in palaeontology – how could such a mighty creature go extinct at a time when other primates were adapting and surviving? The unresolved cause of its disappearance has become the Holy Grail in this discipline,” says palaeontologist and co-lead author Professor Yingqi Zhang, from the Institute of Vertebrate Palaeontology and Palaeoanthropology at the Chinese Academy of Sciences (IVPP).

“The IVPP has been excavating for G. blacki evidence in this region for over 10 years but without solid dating and a consistent environmental analysis, the cause of its extinction had eluded us.”

Definitive evidence revealing the story of the giant ape’s extinction has come from a large-scale project collecting evidence from 22 cave sites spread across a wide region of Guangxi Province in southern China. The foundation of this study was the dating.

“It’s a major feat to present a defined cause for the extinction of a species, but establishing the exact time when a species disappears from the fossil record gives us a target timeframe for an environmental reconstruction and behaviour assessment,” says co-lead author, Macquarie University geochronologist Associate Professor Kira Westaway.

“Without robust dating, you are simply looking for clues in the wrong places.”

Six Australian universities contributed to the project. Macquarie University, Southern Cross University, Wollongong University and the University of Queensland used multiple techniques to date samples. Southern Cross also mapped G. blacki teeth to extract information on the apes’ behaviours. ANU and Flinders University studied the pollen and fossil bearing sediments in the cave respectively, to reconstruct the environments in which G. blacki thrived and then disappeared.

Six different dating techniques were applied to the cave sediments and fossils, producing 157 radiometric ages. These were combined with eight sources of environmental and behavioural evidence, and applied to 11 caves containing evidence of G blacki, and also to 11 caves of a similar age range where no G. blacki evidence was found.

Luminescence dating, which measures a light-sensitive signal found in the burial sediments that encased the G. blacki fossils, was the primary technique, supported by uranium series (US) and electron-spin resonance (US-ESR) dating of the G. blacki teeth themselves.

“By direct-dating the fossil remains, we confirmed their age aligns with the luminescence sequence in the sediments where they were found, giving us a comprehensive and reliable chronology for the extinction of G. blacki,” says Southern Cross University geochronologist Associate Professor Renaud Joannes-Boyau.

 

Using detailed pollen analysis, fauna reconstructions, stable isotope analysis of the teeth and a detailed analysis of the cave sediments at a micro level, the team established the environmental conditions leading up to when G blacki went extinct. Then, using trace element and dental microwear textural analysis (DMTA) of the apes’ teeth, the team modelled G. blacki’s behaviour while it was flourishing, compared to during the species’ demise.

 

“Teeth provide a staggering insight into the behaviour of the species indicating stress, diversity of food sources, and repeated behaviours,” says Associate Professor Joannes-Boyau

 

The findings show G.blacki went extinct between 295,000 and 215,000 years ago, much earlier than previously assumed. Before this time, G. blacki flourished in a rich and diverse forest.

 

By 700,000 to 600,000 years ago, the environment became more variable due to the increase in the strength of the seasons, causing a change in the structure of the forest communities.

 

Orangutans (genus Pongo) – a close relative of G. blacki – adapted their size, behaviour and habitat preferences as conditions changed. In comparison, G. blacki relied on a less nutritious back up food source when its preferences were unavailable, decreasing the diversity of its food. The ape became less mobile, had a reduced geographic range for foraging, and faced chronic stress and dwindling numbers.

 

G. blacki was the ultimate specialist, compared to the more agile adapters like orangutans,  and this ultimately led to its demise,” says Professor Zhang.

 

Associate Professor Westaway says: “With the threat of a sixth mass extinction event looming over us, there is an urgent need to understand why species go extinct.

“Exploring the reasons for past unresolved extinctions gives us a good starting point to understand primate resilience and the fate of other large animals, in the past and future.”

 

  

Digging into the hard cemented cave sediments containing a wealth of fossils and evidence of G. blacki

Facing out of Zhang Wang Cave across the alluvial plain


A drones-eye view of Mulan Mountain 

 

A beating biorobotic heart aims to better simulate valves



Peer-Reviewed Publication

CELL PRESS

Scientists crafted a biorobotic heart simulator by replacing the heart muscle of a biological heart’s left chamber with a soft robotic pump 

IMAGE: 

SCIENTISTS CRAFTED A BIOROBOTIC HEART SIMULATOR BY REPLACING THE HEART MUSCLE OF A BIOLOGICAL HEART’S LEFT CHAMBER WITH A SOFT ROBOTIC PUMP

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CREDIT: MANISHA SINGH





Combining a biological heart and a silicone robotic pump, researchers created a biorobotic heart that beats like a real one, with a focus on a valve on the left side of the heart. The heart valve simulator, presented on January 10 in the journal Device, can mimic the structure, function, and motion of a healthy or diseased heart, allowing surgeons and researchers to demonstrate various interventions while collecting real-time data.

“The simulator has a huge benefit as a research tool for those who study different heart valve conditions and interventions,” says senior author and biomedical engineer Ellen Roche of the Massachusetts Institute of Technology. “It can serve as a surgical training platform for clinicians, medical students, and trainees, allow device engineers to study their new designs, and even help patients better understand their own disease and potential treatments.”

Before new interventions reach humans, they undergo rigorous testing in heart simulators and animal subjects. However, current heart simulators don’t completely capture the complexity of a heart and have a short shelf-life of two to four hours. Animal studies are expensive and time consuming, and the findings may not always translate to humans. The biorobotic heart can bridge these gaps as a less expensive method with a shelf life of months.

The researchers focused on mitral regurgitation, a disorder in which the valve between the left heart chambers doesn’t close properly—resulting in a leaky heart valve where blood can flow backwards. This condition, affecting about 24.2 million people worldwide, can cause shortness of breath, swelling in the limbs, and heart failure. Given the intricacy of the valve’s structure, surgeries to correct the disorder are highly complex, highlighting a need for effective technology and precise surgical techniques.

To better understand the mitral valve in healthy and diseased states, the team built a biorobotic heart based on a pig heart. The researchers replaced the heart muscle in the left chamber with a silicone-made soft robotic pump system actuated by air. When inflated, the system twists and squeezes the heart like real heart muscle, pumping artificial blood through a mock circulation system and simulating the beat of a biological heart.

When the team damaged the mitral valve in the biorobotic heart, it showed characteristics of a leaky heart valve. The team then had cardiac surgeons correct the damage with three different techniques: anchoring the flailing valve leaflet tissue with artificial chords, replacing the valve with a prosthetic valve, and implanting a device to help valve leaflet closing.

All three procedures were successful, bringing the pressure, flow, and heart function to normal. The system also enabled the research team to collect real-time data during surgery and is compatible with current imaging technologies used in the clinics. Because the artificial blood used in the system is clear, it also allows direct visualization of the procedure. The findings demonstrated the device as a new heart model.

“It was really interesting for the surgeons to see every step,” says Roche. “When you’re working with patients, you can’t visualize the process because there’s blood in the heart.” She foresees their heart model as a realistic environment for cardiac surgery training and practice.

Next, the team aims to optimize the current biorobotic heart system by shortening the production time and lengthening the shelf life even more. Instead of using a pig heart, they’re also exploring 3D printing technology to recreate a synthetic human heart for the system.

“Our biorobotic heart may help improve the device design cycle, allow rapid iterations, get things approved by regulatory bodies, and launch them into the market quickly,” says Roche. “Expediting and improving these processes will ultimately benefit patients.”

###

This work was supported by the National Science Foundation, the Philips/MIT award, and the MathWorks Fellowship. Please see the text for conflict-of-interest information.

Device, Park et al. “Biorobotic hybrid heart as a benchtop cardiac mitral valve simulator” https://www.cell.com/device/fulltext/S2666-9986(23)00357-5

Device (@Device_CP), is a physical science journal from Cell Press along with ChemJoule, and MatterDevice aims to be the breakthrough journal to support device- and application-oriented research from all disciplines, including applied physics, applied materials, nanotechnology, robotics, energy research, chemistry, and biotechnology, under a single title that focuses on the integration of these diverse disciplines in the creation of the cutting-edge technology of tomorrow. Visit http://www.cell.com/device/home. To receive Cell Press media alerts, contact press@cell.com.

Joking apart: What men and women find funny


Humor preferences may reflect how social worlds of the sexes are organized, study finds


Peer-Reviewed Publication

DE GRUYTER




Men rate visual jokes more highly than women do, whereas women prefer jokes that involve political commentary or the dynamics of close relationships, a new study of print cartoons dating from 1930-2010 finds.

The research, led by Professor Robin Dunbar of the University of Oxford and published in the De Gruyter journal Humor, also found some similarities, with both sexes enjoying cartoons that delve into the complexities of romance. 

Study data was collected from 3,380 people attending an exhibit of print cartoons by well-known artists at The Cartoon Museum, London. The humor of such cartoons is strongly visual and often uses a verbal caption to add context and, in many instances, the punchline.

The researchers arranged cartoons of varying complexity in 18 pairs and asked study participants to rate which joke was funnier. The responses were then analyzed according to the ‘mentalizing’ content of the cartoons, participants' age and sex, and when the cartoon was first published.  

More complex jokes with more ‘mindstates’ (“I know what she’s thinking about what he’s saying”) were considered funnier than those that relied on simpler, more slapstick humor. However, such jokes only worked up to a limit of three levels with additional mindstates falling flat: the 2D medium cannot ably handle more detailed reveals like moving 3D images with an additional time perspective.

“Like verbal jokes, cartoons are funnier the more mindstates, essentially characters, they involve,” says Professor Dunbar. "But there is a limit after which they become incomprehensible.”

Participant age didn’t significantly affect the humor rating given to a cartoon, and nor did the time since its publication.

Both sexes clearly considered visual jokes using puns or wordplay and social commentary jokes about domestic marital relationships funnier than any other topic. Men and women were least enthusiastic about political jokes.

However, some modest differences were found between the sexes with women indicating a greater preference for jokes about domestic situations and political commentary while men preferred situational (slapstick) and visual jokes.

This finding may reflect how men and women manage their relationships, the authors surmise. “We argue that these differences in humor preference arise from the remarkable differences in social style of the two sexes,” Professor Dunbar says. “This explanation has previously been overlooked because psychologists and others have concentrated on IQ-type differences, which are minimal.”

 

Survey finds majority of Americans think bariatric surgery is a shortcut to losing pounds, should only be a last resort


Experts stress the need for surgery to improve obesity-related health issues and help patients improve their lives


Reports and Proceedings

ORLANDO HEALTH

News package 

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A NEW SURVEY BY ORLANDO HEALTH REVEALS COMMON STIGMAS AROUND WEIGHT LOSS PROCEDURES THAT MAY DETER PATIENTS FROM PURSUING EFFECTIVE TREATMENT FOR OBESITY.

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CREDIT: ORLANDO HEALTH





Orlando, Fla - More than two in five U.S. adults suffer from obesity, an epidemic that continues to trend upward. While bariatric surgery is an extremely effective treatment option, a new national survey by Orlando Health reveals common stigmas that may deter those who qualify for surgery from pursuing the treatment they need.

“Treatment plans for obesity are tailored to each individual patient based on things like body mass index and existing medical conditions and may include medication, lifestyle changes, counseling and bariatric surgery,” said Andre Teixeira, MD, medical director and bariatric surgeon at Orlando Health Weight Loss and Bariatric Surgery Institute. “By taking this personalized approach, we are extremely successful in reversing health issues caused by obesity, from diabetes to heart disease. But if someone’s decision is affected by those who think they don’t need surgery or that make them feel like a failure if they have surgery, that greatly diminishes their chances of losing weight and maintaining a healthy lifestyle long term.”

The survey, conducted by Ipsos, found 79% of Americans believe weight loss surgery should only be pursued as a last resort, and 60% agree that bariatric surgery is a shortcut to shedding pounds, something Dr. Teixeira says couldn’t be further from the truth.

“Bariatric surgery is by no means an easy way out. If you have the courage to ask for help and commit to doing the hard work of changing your diet and improving your life, you’re a champion in my book.” Dr. Teixeira said. “Surgery is simply a tool to jumpstart that change. After surgery, it is up to the patient to learn how to eat well, implement exercise into their routine and shift their mindset to maintain their health for the rest of their lives.”

Guidelines by the American Society of Metabolic and Bariatric Surgery (ASMBS) and International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) were recently updated for the first time since 1991 to expand access to bariatric surgery, which is less invasive and safer than ever, thanks to advancements in laparoscopic and robotic surgery techniques. Yet only 1% of those who are clinically eligible undergo surgical treatment for obesity.

The survey also found that 61% of respondents believe exercise and diet should be enough.

“Because of the stigma around obesity and bariatric surgery, so many of my patients feel defeated if they can’t lose weight on their own,” said Muhammad Ghanem, MD, a bariatric surgeon at Orlando Health Weight Loss and Bariatric Surgery Institute. “But when I tell them obesity is a disease and that many of its causes are outside of their control, you can see their relief. They often even shed a tear because they’ve struggled with their weight all their lives and finally have some validation.”

That was the case for Maritza Cruz Rivera, 64, who lived with pain and fatigue for years and finally hit a breaking point during a routine visit to her primary care physician.

“When they weighed me before my appointment, I looked at the scale and started to cry. There it was: 227,” Cruz Rivera said. “Something triggered in me in that moment to finally do something about my weight and get some help.”

Upon learning that bariatric surgery was a good option for her, she spoke with friends and family. While many supported her decision to undergo surgery, she also heard a lot of misconceptions. She says it’s best to get the facts from your doctor and make a decision based on what is best for your health.

Following surgery, Cruz Rivera changed her relationship with food and began prepping healthy salads and soups that she enjoys. A year later, she is at a healthy weight and is living the life she’s always strived to live, riding her bicycle with her grandchildren, going for long walks in her neighborhood and even doing one of her favorite things: dancing.

“I haven’t been able to dance like this in 20 years. I didn’t go into this to look like Barbie, I just wanted to live a healthy life with my family, and now I can do that,” Cruz Rivera said. “For anyone struggling with obesity who feels depressed or stuck like I did, don't bury yourself in that dark hole. Understand and know that there's always a solution.”

B-ROLL, SOUND BITES, WEB ELEMENTS & HI-RES STILL PHOTOS - Including HD video available for free/unrestricted use by the news media: https://bit.ly/3N3mVsI

CourtesyOrlando Health

For assistance in downloading, or if you have any questions, contact: ben@mediasourcetv.com or call:  419.345.5478.

 

About Orlando Health

Orlando Health, headquartered in Orlando, Florida, is a not-for-profit healthcare organization with $9.6 billion of assets under management that serves the southeastern United States and Puerto Rico.

Founded more than 100 years ago, the healthcare system is recognized around the world for Central Florida’s only pediatric and adult Level I Trauma program as well as the only state-accredited Level II Adult Trauma Center in Pinellas County. It is the home of the nation’s largest neonatal intensive care unit under one roof, the only system in the southeast to offer open fetal surgery to repair the most severe forms of spina bifida, the site of an Olympic athlete training facility and operator of one of the largest and highest performing clinically integrated networks in the region. Orlando Health has pioneered life-changing medical research and its Graduate Medical Education program hosts more than 350 residents and fellows.

The 3,429-bed system includes 29 hospitals and emergency departments – 25 of which are currently operational with four coming soon. The system also includes nine specialty institutes, skilled nursing facilities, an in-patient behavioral health facility under the management of Acadia Healthcare, and more than 375 outpatient facilities that include physician clinics, imaging and laboratory services, wound care centers, home healthcare services in partnership with LHC Group, and urgent care centers in partnership with FastMed Urgent Care. More than 4,750 physicians, representing more than 100 medical specialties and subspecialties have privileges across the Orlando Health system, which employs more than 27,000 team members and more than 1,500 physicians.

In FY 23, Orlando Health cared for 197,000 inpatients and 6.6 million outpatients.  The healthcare system provided nearly $1.3 billion in total impact to the communities it serves in the form of community benefit programs and services, Medicare shortfalls, bad debt, community-building activities and capital investments in FY 22, the most recent period for which this information is available.

Additional information can be found at http://www.orlandohealth.com, or follow us on LinkedInFacebookInstagram and Twitter @orlandohealth.

Survey method

This survey was conducted online within the United States by Ipsos on the KnowledgePanel® from November  9 to November 12, 2023, and surveyed 1,017  U.S. adults ages 18 and older.  This poll is based on a nationally representative probability sample and has margin of sampling error of plus or minus 3.3 percentage points at the 95% confidence level, for results based on the entire sample of adults. For complete survey methodology, including weighting variables and subgroup sample sizes, please contact: christopher.moessner@ipsos.com.


Maritza Cruz Rivera discusses progress with bariatric surgeon Andre Teixeira, MD, a year after undergoing bariatric surgery (IMAGE)

ORLANDO HEALTH

Maritza Cruz Rivera looks at photos of herself before she underwent bariatric surgery. (IMAGE)

ORLANDO HEALTH


Some mosquitoes like it hot


Mosquito heat tolerance varies by population, according to a new study; findings could change estimates of vector-borne disease risk


Peer-Reviewed Publication

WASHINGTON UNIVERSITY IN ST. LOUIS

mosquitoes 

IMAGE: 

VIALS CONTAINING THE GLOBALLY INVASIVE TIGER MOSQUITO AEDES ALBOPICTUS.

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CREDIT: LAWTON BLANCHARD




Certain populations of mosquitoes are more heat tolerant and better equipped to survive heat waves than others, according to new research from Washington University in St. Louis.

This is bad news in a world where vector-borne diseases are an increasingly global health concern. Most models that scientists use to estimate vector-borne disease risk currently assume that mosquito heat tolerances do not vary. As a result, these models may underestimate mosquitoes’ ability to spread diseases in a warming world.

Researchers led by Katie M. Westby, a senior scientist at Tyson Research Center, Washington University’s environmental field station, conducted a new study that measured the critical thermal maximum (CTmax), an organism’s upper thermal tolerance limit, of eight populations of the globally invasive tiger mosquito, Aedes albopictus. The tiger mosquito is a known vector for many viruses including West Nile, chikungunya and dengue.

“We found significant differences across populations for both adults and larvae, and these differences were more pronounced for adults,” Westby said. The new study is published Jan. 8 in Frontiers in Ecology and Evolution.

Westby’s team sampled mosquitoes from eight different populations spanning four climate zones across the eastern United States, including mosquitoes from locations in New Orleans; St. Augustine, Fla.; Huntsville, Ala.; Stillwater, Okla.; St. Louis; Urbana, Ill.; College Park, Md.; and Allegheny County, Pa.

The scientists collected eggs in the wild and raised larvae from the different geographic locations to adult stages in the lab, tending the mosquito populations separately as they continued to breed and grow. The scientists then used adults and larvae from subsequent generations of these captive-raised mosquitoes in trials to determine CTmax values, ramping up air and water temperatures at a rate of 1 degree Celsius per minute using established research protocols.

The team then tested the relationship between climatic variables measured near each population source and the CTmax of adults and larvae. The scientists found significant differences among the mosquito populations.

The differences did not appear to follow a simple latitudinal or temperature-dependent pattern, but there were some important trends. Mosquito populations from locations with higher precipitation had higher CTmax values. Overall, the results reveal that mean and maximum seasonal temperatures, relative humidity and annual precipitation may all be important climatic factors in determining CTmax.

“Larvae had significantly higher thermal limits than adults, and this likely results from different selection pressures for terrestrial adults and aquatic larvae,” said Benjamin Orlinick, first author of the paper and a former undergraduate research fellow at Tyson Research Center. “It appears that adult Ae. albopictus are experiencing temperatures closer to their CTmax than larvae, possibly explaining why there are more differences among adult populations.”

“The overall trend is for increased heat tolerance with increasing precipitation,” Westby said. “It could be that wetter climates allow mosquitoes to endure hotter temperatures due to decreases in desiccation, as humidity and temperature are known to interact and influence mosquito survival.”

Little is known about how different vector populations, like those of this kind of mosquito, are adapted to their local climate, nor the potential for vectors to adapt to a rapidly changing climate. This study is one of the few to consider the upper limits of survivability in high temperatures — akin to heat waves — as opposed to the limits imposed by cold winters.

“Standing genetic variation in heat tolerance is necessary for organisms to adapt to higher temperatures,” Westby said. “That’s why it was important for us to experimentally determine if this mosquito exhibits variation before we can begin to test how, or if, it will adapt to a warmer world.”

Future research in the lab aims to determine the upper limits that mosquitoes will seek out hosts for blood meals in the field, where they spend the hottest parts of the day when temperatures get above those thresholds, and if they are already adapting to higher temperatures. “Determining this is key to understanding how climate change will impact disease transmission in the real world,” Westby said. “Mosquitoes in the wild experience fluctuating daily temperatures and humidity that we cannot fully replicate in the lab.”

 

Researchers engineer in vivo delivery system for prime editing, partially restoring vision in mice


By adapting virus-like particles to carry the machinery for a type of gene editing called prime editing, scientists have corrected disease-causing mutations in animals and increased editing efficiency.

Peer-Reviewed Publication

BROAD INSTITUTE OF MIT AND HARVARD





Prime editing, a versatile form of gene editing that can correct most known disease-causing genetic mutations, now has a new vehicle to deliver its machinery into cells in living animals.

A team of researchers at the Broad Institute of MIT and Harvard has engineered virus-like particles to deliver prime editors to cells in mice at a high enough efficiency to rescue a genetic disorder. In the new work published today in Nature Biotechnology, the team adapted engineered virus-like particles (eVLPs) that they had previously designed to carry base editors — another type of precision gene editor that makes single-letter changes in DNA. 

Now the researchers describe how they re-engineered both eVLPs and parts of the prime editing protein and RNA machinery to boost editing efficiency up to 170 times in human cells compared to the previous eVLPs that deliver base editors. The team used their new system to correct disease-causing mutations in the eyes of two mouse models of genetic blindness, partially restoring their vision. They also delivered prime editors to the mouse brain, and did not detect any off-target editing.

“This study represents the first time to our knowledge that delivery of protein-RNA complexes has been used to achieve therapeutic prime editing in an animal,” said David Liu, senior author of the study and Richard Merkin Professor and director of the Merkin Institute of Transformative Technologies in Healthcare at the Broad. Liu is also a Howard Hughes Medical Institute investigator and a professor at Harvard University.

Delivery dilemma

Gene editing approaches promise to treat a range of diseases by precisely correcting genetic mutations that cause disease. Prime editing, described in 2019 by Liu’s group, can make longer and more diverse types of DNA changes than other types of editing. However, delivering the complex gene editing machinery to cells in living animals has been challenging.

The prime editing system has three components: a Cas9 protein that can nick DNA; an engineered prime editing guide RNA (pegRNA) that specifies the location of the edit and also contains the new edited sequence to install at that location; and a reverse transcriptase that uses the pegRNA as a template to make specific changes to the DNA.

Researchers have used a variety of methods to deliver these molecular machines to cells, including lipid nanoparticles and viruses. Virus-like particles (VLPs), composed of a shell of viral proteins that carry cargo but lack any viral genetic material, have also been of particular interest. But VLPs have traditionally yielded modest delivery outcomes in animals, and have to be specifically engineered for each different type of cargo to efficiently deliver to cells.

“We initially hoped that we could just take the eVLPs that we had painstakingly developed and optimized for base editing and apply them to prime editors,” said Meirui An, a graduate student in the Liu lab and first author of the new paper. “But when we tried that, we observed almost no prime editing at all.”

Bottleneck breakthroughs

In the new work, the researchers extensively re-engineered both the eVLP proteins and the prime editing machinery itself so that both the delivery and editing systems worked more efficiently. For instance, they improved how the prime editing cargo was packaged in the eVLPs, how it was separated from the delivery vehicle, and how it was delivered into the target cells’ nuclei.

“The prime editor cargo must be efficiently packaged into eVLPs when the particles form but must also be efficiently released from the particles after target cell entry,” said Aditya Raguram, a former Liu lab graduate student and co-author of the study. “All of these steps have to be carefully orchestrated in order to achieve efficient eVLP-mediated prime editing.”

While each individual improvement led to small jumps in the efficiency of the prime editors, the changes together had a much larger impact.

“When we combined everything together, we saw improvements of roughly 100-fold compared to the eVLPs that we started with,” said Liu. “That kind of improvement in efficiency should be enough to give us therapeutically relevant levels of prime editing, but we didn’t know for sure until we tested it in animals.”

In vivo tests

Liu and his colleagues, in collaboration with Krzysztof Palczewski of the University of California, Irvine, first tested the system in mice to correct two different genetic mutations in the eyes. One mutation, in the gene Mfrp, causes a disease called retinitis pigmentosa that leads to progressive retinal degeneration. The other, in the gene Rpe65, is associated with blindness seen in the condition known as Leber congenital amaurosis (LCA) in humans.

In both instances, the eVLPs corrected the mutation in up to 20 percent of the animals’ retina cells, partially restoring their vision.

The research group also showed that the eVLPs loaded with prime editing machinery could effectively edit genes in the brains of living mice. Nearly half of all cells in the cortex of the brain that received the editing machinery showed a gene edit.

“The gene editing field largely agrees that, moving into the future, gene editing machinery should ultimately be delivered as proteins to minimize potential side effects and we’ve now shown an effective way to do that,” said Liu. “We plan to continue to actively work on improving eVLPs and adapting the technology to target other tissue types within the body.”

 

Funding:

Support for the study was provided in part by the National Institutes of Health, the Bill and Melinda Gates Foundation, the Howard Hughes Medical Institute, Foundation Fighting Blindness, the UC Irvine School of Medicine Dean’s office, a Research to Prevent Blindness unrestricted grant, and a National Science Foundation Graduate Research Fellowship.

Paper cited:

An, M. et al. Engineered virus-like particles for transient delivery of prime editor ribonucleoprotein complexes in vivoNature Biotechnology. Online January 8, 2024. DOI: 10.1038/s41587-023-02078-y 

 

About Broad Institute of MIT and Harvard

Broad Institute of MIT and Harvard was launched in 2004 to empower this generation of creative scientists to transform medicine. The Broad Institute seeks to describe the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community.

 

Founded by MIT, Harvard, Harvard-affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide.