Categories
COVID-19 Public Health

COVID Disease Severity Lower Than Ever, Most People Infected Unaware of Status

As the omicron BA.5 subvariant has become dominant, many countries are heading into their third wave of Omicron cases. Japan reports its largest-ever surge in cases, recording over 200,000 new cases in one day.

Though omicron BA.5 has become the most dominant subvariant of COVID (accounting for 88% of new cases in the US) and is highly contagious, CDC data shows disease severity at its lowest point ever.

Intensive Care Unit (ICU) admission among hospitalized COVID-19 patients. (cdc.gov)

Among hospitalized COVID patients, about 1 in 10 are admitted to the ICU as of July 2022. This figure was as high as 1 in 3 in March 2020, and 1 in 5 as recently as December 2021.

Mortality among hospitalized COVID-19 patients. (cdc.gov)

Similarly, mortality among hospitalized COVID patients has decreased appreciably from 1 in 5 in March 2020 to 1 in 40 in July 2022.

These decreases in COVID disease severity follow the emergence of the omicron variant in November 2021 and its ever-growing share of new infections. The omicron variant, while of high concern and contagion, does not appear to be of proportionally high consequence compared to earlier variants.

The most common symptoms of COVID include cough, fever, and chills. Many report symptoms resembling a common cold with symptoms like upper respiratory congestion. Most people (56%) who are infected with the omicron variant are not aware of their positive status according to a recent Cedars-Sinai study.

Multiple factors could explain omicron’s lower severity, including widespread vaccination or immunity gained from prior exposure and infection. It is also possible that omicron has mutations that decrease severity while favoring infectivity.

Categories
Genetics

Antisense Therapy Explained: How Blocking mRNA Can Treat Genetic Disorders

Antisense therapy has proven to be effective at treating previously untreated genetic disorders including Duchenne muscular dystrophy and familial hypercholesterolemia. The therapy has also demonstrated promising results in Phase III clinical trials for amyotrophic lateral sclerosis (ALS).

What is antisense therapy, and how are antisense oligonucleotides used to treat genetic disorders?

Background

Genetic Disorders and Proteins

Genetic disorders are diseases caused by abnormal changes in our DNA sequence (mutations). Many diseases have a genetic basis, with mutations either being a direct cause or one of many contributors to a disease’s proliferation.

Some people are born with genetic disorders, acquiring mutations from one or both parents, while others acquire them during their lifetime due to mistakes made by their own cells or exposure to viruses, radiation, or mutagenic chemicals. Most mutations do not result in genetic disorders.

The reason why mutations can affect biological processes is because our DNA provides our cells with the blueprints necessary to build proteins, which are complex molecules responsible for carrying out the chemical reactions that occur within our bodies.

Humans are believed to have 25,000 unique proteins (some copied trillions of times throughout our bodies) that have very specific tasks and functions pertaining to growth, maintenance, structure, metabolism, immune defense, and much more. It follows that a mutation, which creates an error in the genetic instructions to create a specific protein, can have profound impacts on our health.

Genetic disorders that cause the creation of harmful proteins are notoriously difficult to treat. New genes can be introduced into cells to result in the creation of non-mutated proteins, but it is not yet possible to completely stop the production of specific proteins.

This limitation even applies with the recently discovered CRISPR-Cas9 gene editing technology, which can add, remove, inhibit, and activate genes–but not in all cells of the body, meaning some cells will still produce the harmful target protein. Therefore, gene therapy that could inhibit the expression of harmful mutated genes would benefit patients with such disorders.

Antisense Therapy

How It Works

When cells use our DNA’s instructions to build new copies of a protein, it must first be processed into a form that can be read by the ribosome, which is the site of protein synthesis in our cells. Messenger RNA (mRNA) is the final form into which a part of the DNA sequence is processed before the ribosome uses its instructions to build new proteins.

Antisense oligonucleotides (ASOs) are strands of DNA or RNA that are complementary to an mRNA strand that encodes for a mutated protein. Due to this complementary nature, the ASO and the faulty mRNA strand will bind together. This prevents the ribosome from ever translating the specific mutated mRNA strand into the harmful, mutated protein that is the basis of the target genetic disorder.

Implications and Discussion

Many genetic disorders are caused by single mutated proteins that have harmful effects. Some of the most serious neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS) are caused by harmful mutated proteins.

Using ASOs to stop these proteins from being built by our cells can offer significant therapeutic effects in patients with this kind of genetic disorder.

For example, a mutation in the gene that encodes for the huntingtin protein causes the protein to take on an elongated shape. When metabolized, these mutated huntingtin proteins bind together and accumulate into increasingly large deposits in the brain, eventually becoming large enough to affect normal brain function. This is the basis for Huntington’s disease. Using ASOs to decrease expression of the mutated Huntingtin protein could provide therapeutic effects.

Antisense therapies could also treat diseases by inhibiting non-mutant proteins. For hypertriglyceridemia (excess triglycerides), ASOs could be used to inhibit the production of the APOC3 gene which encodes for a protein that regulates triglyceride metabolism.

Certain cancers could also be targeted by ASOs, as they could be used to block the production of proteins that facilitate the growth of a cancerous or precancerous mass of cells.

Solely using the antisense oligonucleotide is around 50% effective at preventing synthesis of a target protein. However, when combined with an enzyme that degrades the complex between the mRNA and ASO, this synthesis-blocking efficacy reaches 95%. This can slow the progression of or provide lasting relief from symptomatic disorder.

Limitations

Antisense therapy can not be used for all genetic disorders. Only those which are caused by a single protein mutated into a harmful form could theoretically be treated by the therapy. Also, stopping the production of an implicated protein could have unexpected side effects due to the discontinuation of normal functions of the protein. In one available ASO therapy, nusinersen (Spinraza), patients experienced varied side effects including increased risk of respiratory infection, congestion, constipation, and stunted growth in children–potentially related to the decreased presence of the target protein.

Another limitation of oligonucleotides is that it is very difficult to deliver them to the interior of our cells. However, surrounding them with fatty particles, like what is used to surround the mRNA in COVID-19 vaccines, can protect them from degradation and help them enter our cells. Though, it can still prove difficult to deliver antisense agents to places like the brain, where a drug must make it through the difficult-to-permeate ‘firewall’ that is the blood-brain barrier. For nusinersen (Spinraza), which has a target protein in the central nervous system, the antisense agent must be injected directly into the spinal canal.

In general, antisense therapy research faces an uphill battle. Since the prospect of using ASOs as drugs was first conceived by Harvard scientists in 1978, less than 10 antisense therapies have been approved by the FDA–the first was approved in 1998. Many antisense therapies have failed in the early phases of clinical trials due to low efficacy. Ionis Pharmaceuticals is the most notable biotechnology company researching antisense therapy, with nine current antisense drug candidates reaching Phase III trials as of June 2022.

Whether ASOs will play a wide role in the treatment of genetic disorders has yet to be determined, though recent innovations in drug delivery systems as well as dozens of such therapies being in advanced clinical trials makes them more promising than ever.

References
Categories
Cardiology

Neural Network Outperforms Physicians at Predicting Cardiac Arrest Risk

Intro

A study published by researchers from Johns Hopkins University highlights new artificial intelligence tools that could help physicians preemptively identify cardiac arrest in patients with the use of artificial intelligence. This new technology could change the way healthcare professionals approach preventative cardiac care, potentially saving patients from fatal outcomes.

Background

Cardiac arrest is one of the leading causes of death, causing hundreds of thousands of deaths per year in the United States. It is caused by a sudden, often arbitrary failure of the heart and can be attributed to factors such as genetics, diet, arrythmia (abnormal heartbeat), and underlying heart problems. They can be the result of chronic cardiovascular conditions but can also occur in healthy individuals. Despite the vast research regarding the disease, scientists are still not completely sure how cardiac arrest arises in patients. Cardiac arrest is nearly impossible to predict with accuracy, making it one of medicine’s deadliest and most confusing conditions.

Currently, physicians determine a patient’s likelihood of cardiac arrest by analyzing their vitals and heart scarring. Testing of vitals entails quantitative analysis of a patient’s blood, including but not limited to cholesterol and sugar levels. Heart scars are tiny marks in the heart which cause cardiovascular disease, and ultimately, cardiac arrest. However, heart scars are incredibly hard to detect because they are microscopic in size. The team of researchers from Johns Hopkins University sought to develop a solution that could accurately predict cardiac arrest risk.

Methods & Results

The team created an artificial intelligence (AI) program built on a neural network that can predict a patient’s probability of developing a cardiac arrest in the next ten years with statistically significant accuracy. The AI program views close-up images of patients’ cardiac tissues, and combined with the patient’s history, determines the probability of a cardiac arrest. The model was able to outperform human predictions of cardiac arrest, and the research team plans to implement the technology as a valuable tool available to physicians.

The research team modeled the AI after a neural network, which is a computer system modeled after the human brain. That is, “neural” pathways are strengthened by successful predictions of correlations in a given data set, enabling computers to make highly accurate predictions of increasingly complex and abstract concepts by applying its knowledge from these data sets.

The AI was programmed to conduct a personalized, patient-specific survival assessment, which analyzes a patients’ underlying conditions and vitals. Next, the team used contrast-enhanced cardiac scar images from and taught the AI to detect aspects of the image that are invisible to the naked eye by using neural network technology. Currently, cardiologists are only able to analyze parts of scar images such as volume, mass, shape, etc. These enhanced images are evaluated by the AI in quantitative ways that human doctors could simply never achieve. The AI was then tested on real patients and data from previous years to see if the neural network could use this data to reliably extrapolate it onto new data.

The researchers found that their algorithm could accurately predict cardiac arrest in real patients to a better extent than physicians. They also tested the AI at 60 different health centers around the US, indicating that this model could be replicated at other hospitals.

Discussion

The researchers concluded that the AI could be of major use to physicians. They plan to continue development of the program for both cardiac arrest and other heart-related diseases. The technology could also improve the accuracy of other diagnostics that rely solely on visual observation. These findings have grand implications on the future of healthcare, indicating a new role of specialized software and artificial intelligence. It may not be long before this novel application of artificial intelligence becomes widespread among physicians, enabling improved patient care by revealing the previously unnoticed.

References
Categories
Commentary Genetics

Dog Behavior Unrelated to Breed? Researchers Respond to Controversy, Misleading Media Coverage

Key Points

– A dog genomics study that found a smaller-than-expected relationship between dog breed and behavior has become widely controversial.
– Critics of the study’s methodology were not satisfied with its rationale for the use of dog-owner surveys to determine behavioral traits due to the possibility of rater bias.
– A well-known psychologist and dog behaviorist believes the study’s data actually proves that breed does, in fact, predict behavior to an appreciable extent–and that the researchers came to an erroneous conclusion.
– Media coverage of the study, even by the journal in which it was published, used absolute language that severely downplayed or outright denied any correlation that was established between breed and behavior.
– The researcher’s most significant finding that distinct genes were associated with individual behavior “at finer resolution than ever before” was largely overlooked.

Introduction

A recent dog genomics study from UMass Chan School of Medicine researchers claims to challenge popular breed stereotypes, concluding that dog breed is a poor predictor of individual behavior. According to the study, which was the feature article in the April 29 issue of Science, just 9% of variation in dog behavior can be explained by breed.

The study received widespread acclaim, making headlines in publications including The New York Times and The Associated Press. Many dog lovers were pleased with the results that showed a high degree of individuality in dogs. In fact, advocates for pit bull terriers largely rejoiced, as the study seemed to disprove negative stereotypes of the breed that might keep people from adopting them.

The CEO of Best Friends Animal Society said in a press release that “these findings could have far-reaching positive impacts in animal welfare,” and that the study’s findings “could be especially positive for pit bull type dogs, Rottweilers, Dobermans, German Shepherds and Chows, which often have an unfair stigma attached to their breed.”

Headlines of media reports of the study, including those from popular science publications, made generalizing claims that dog behavior is unrelated to breed.

They’re All Good Dogs, and It Has Nothing to Do With Their Breed

The New York Times

Massive study of pet dogs shows breed does not predict behaviour

Nature

Dog Breed Doesn’t Affect Behavior, According to New Genetic Research

Smithsonian Magazine

Even in Science, where the study was published, editors added the following generalization to the summary:

…dog breed is generally a poor predictor of individual behavior and should not be used to inform decisions relating to selection of a pet dog.

Science

While the study did receive positive acclaim, it also provoked significant controversy. Critics called into question the claims of the media as well as the methodology and conclusions of the study. After all, it is widely believed that breed is the most important factor in determining a dog’s behavior and temperament.

Is the criticism justified? Are the media’s generalizing claims supported by the study? First, it is important to understand the methods used by the researchers to come to their conclusion.

OneResearch dives headfirst into the media coverage, methodology, and critiques of the popular study, featuring quotes from an interview with the lead researcher.

Methodology of the Study

To determine whether dog breed could predict behavior, the research team sequenced the DNA of thousands of dogs, including pure-breds and mutts, and surveyed their owners with questions about their pet’s behavior.

The researchers used the survey responses to measure eight factors:

  • Human sociability (less sociable to highly sociable)
  • Arousal level (aroused to composed)
  • Toy-directed motor patterns (toy-directed to not toy-directed)
  • Biddability [responsiveness to human direction] (biddable to independent)
  • Agonistic threshold (assertive to diffident)
  • Dog sociability (less sociable to highly sociable)
  • Environmental engagement (engaged to not engaged)
  • Proximity seeking (affectionate to aloof)

Then, correlations were calculated to determine to what extent breed explains the values of these factors in individual dogs. They also measured physical traits like size, ear shape, and fur length as well as motor pattern behaviors like howling, retrieving, and pointing.

Another aspect of the study, which will be discussed later in this article, sought to link distinct genes with behaviors.

Discussion of Methodology

Rater Bias

Perhaps the most common critique of the study is the use of pet owner surveys to determine dog behavior. Specifically, the possibility of rater bias did not go unnoticed to skeptics of the study.

Voluntary self reporting is unscientific. Anyone who owns a pitbull is going to know the stereotypes and resist them. Questions about aggression they’ll decide to interpret how they want in their responses.

Reddit comment

Of course, nobody would assess the behavior of schoolchildren by asking their mommies, so the whole enterprise strikes me as less than scientific.

Gene Lyons for the Vallejo Times-Herald

Rater bias is addressed within the study. First, the authors claimed that by using mutts and determining their breed composition via DNA sequencing, breed-stereotype biases of surveyed owners should not largely affect the results. This claim was supported by other data within the study which shows that people are inaccurate at guessing the breed composition of mutts. Though, pure-bred dogs were also used in the study.

The authors admit to the limitation that pet owner survey responses “are susceptible to rater bias, including the influence of breed stereotypes.” Also, the authors prefaced findings regarding the relationship between breed and human sociability factor with a disclaimer that owner survey data “may be influenced by breed stereotypes and other factors, and differences are not necessarily genetic in origin.”

Kathleen Morrill, a Ph.D. candidate at UMass Chan Medical School, is the first author of the study. Morrill told OneResearch in a written interview that rater bias “can never be fully mitigated,” elaborating further:

Rather, we expect to overcome noise generated from rater bias by larger and larger samples. Strong effects are the first to appear at any given sample size. Real but small effects become more and more evident and supported at larger sample sizes.

…nor does rater bias need to be fully accounted for us to achieve our initial goal for the project: to genetically map behavioral traits.

Kathleen Morrill for OneResearch

It was not clear how larger samples would decrease the effect of rater bias. When seeking to genetically map behavioral traits, it seems that only traits not affected by rater bias could be reliably mapped.

Survey Validation

Further concerns regarding the survey focused on the validation of the questions for the context of determining large-scale trends in dog behavior and temperament. Readers wondered how they determined which questions to ask, and how accurately those questions could quantify personality traits and behaviors.

In a Reddit AMA (Q&A), Morrill addressed this concern.

Owner surveys are a widely accepted method of assessing a dog’s behavior in its home environment and allow us to achieve the scale necessary to study traits that derive from the interaction of genetics and environment. They are generally considered to be reliable, and previous work comparing survey data and professional assessments confirm this. They are widely used in veterinary medicine. Dog behaviorists will often implement these prior to in-person consultations, because a dog can behave differently in a clinical context.

Kathleen Morrill via Reddit

Though owner surveys are considered to be reliable in the context of veterinary medicine, they may not be as reliable when seeking to determine large-scale, long-term personality and behavioral trends of groups rather than making simple assessments about individuals.

A columnist for the Vallejo Times-Herald was not convinced.

Limiting a behavioral study to suburban backyard behavior tells you very little about what dogs really are.

Gene Lyons for the Vallejo Times-Herald

In terms of deciding which questions to ask, Morrill said that they chose to use previously validated questionnaires, including the Dog Personality Questionnaire (DPQ), Dog Impulsivity Assessment Scale (DIAS), Quality of Life assessment (CHQLS-15), and Canine Cognitive Dysfunction Rating (CCDR). The researchers also used questions added by dog behavior consultants.

The use of such surveys remains controversial in biological and medical research, in general, due to the myriad of biases that can compromise data. These specific surveys were not validated for the novel purpose used in the study. It can’t be determined with the available data whether this affected the results of the study.

Still, survey use is at least insightful as a starting point for generating new hypotheses that can be tested more thoroughly in follow-up validation studies. This is supported by previous use of digital phenotyping in genetic studies of human diseases.

The Dog Personality Questionnaire, developed to assess individual dog’s personality and temperament, is a good starting point for assessing the personality and temperament of individual dogs, as our project sought to do.

Kathleen Morrill for OneResearch

Results & Conclusions of the Study

The study found that for all eight factors, breed explained more of the behavioral variance than size, sex, or age. However, only 3% to 25% of variance in factor scores could be explained by breed, averaging only 9% across all tested factors. The majority of breeds scored within one standard deviation of the average for all behavioral factors, with few breeds over- or underrepresented in the highest-scoring quartiles.

Behavioral factors show high variability within breeds, suggesting that although breed may affect the likelihood of a particular behavior to occur, breed alone is not, contrary to popular belief, informative enough to predict an individual’s disposition.

Morrill et al.

The researchers hypothesized that this surprising conclusion could be due to the lack of breeding for function in favor of appearance during the past few centuries since modern dog breeds were established.

Interestingly, when grouping breeds by their historically given working roles according to characterizations by the American Kennel Club, more behavioral correlations could be drawn. For example, breeds known for herding were found to be more interested in toys, more biddable, more engaged, and more aloof. Working breeds were more dog social. Toy breeds were more independent and less dog social.

Heritability explained more behavioral variance than breed. The authors found that certain behaviors were up to 67% heritable, averaging 25% across behaviors. Motor pattern behaviors like howling, retrieving, and pointing were among the most heritable behaviors, while human sociability was the most heritable factor. 46% of the behavioral questions from the survey could be explained mostly by heritability.

Physical traits were found to be much more heritable than behavioral traits, as most measured physical traits exceeded 85% heritability.

Discussion of Conclusions

Dr. Stanley Coren Article

As quoted above from the study, the authors concluded that even though breed can affect the likelihood of certain behaviors to occur, breed alone does not provide enough information to reliably predict behavior. The study’s conclusion expanded upon past research that noted “mixed consistency” between empirical evidence and widely-recognized breed standards.

A prominent critique of this conclusion was published in Psychology Today by Dr. Stanley Coren, a psychology professor and neuropsychological researcher who is well known for his books about dog behavior.

Dr. Coren alleged that the researchers “misread” their own data. Using the study’s data, he found that breed is a “pretty good” indication of behavioral differences between groups of dogs, but that it is not a guarantee for the behavior of any particular individual.

To support his own conclusion from the data, Dr. Coren mentioned the following statistics from the study’s supplemental materials:

  • 62% of golden retrievers will fall into the highest quartile for human sociability
  • 72% of border collies fall into the top quartile for biddability (responsiveness to human direction)

While Dr. Coren noted that 16% of border collies will actually fall into the lowest quartile for biddability, he said that the data means that your odds are still “better than 4 to 1” that any given border collie will be highly intelligent and trainable. Thus, he believes that breed can, in fact, be a useful indicator of a dog’s behavior for prospective dog owners.

Dr. Jessica Hekman, who co-authored the study, expressed an idea similar to Dr. Coren’s in a statement to the American Kennel Club.

…you’ll definitely improve your chances of getting the right dog for you if you are also thoughtful about what breed you bring home.

Dr. Jessica Hekman for American Kennel Club

Since Dr. Coren concluded from the data that breed can be a useful predictor of a dog’s behavior, why did the study conclude otherwise?

Kathleen Morrill, first author of the study, answered questions from OneResearch about Dr. Coren’s article.

The data [visualization] tool explored by Dr. Coren indeed supports that for assertions of one or two facets of canine behavior, breed can be informative. Though, it depends on the breed and the behavior, as the relationship is far from extensive.

Kathleen Morrill for OneResearch

Morrill then brought attention to a figure in the study that shows instances in which age is “just as informative” as breed. She mentioned how the data shows that the benefits that breed offers when determining behaviors “quickly dissolve given a wider array of behaviors asserted.”

She then invoked an excerpt from the study itself–the first conclusion drawn in the Discussion, which highlights the inconsistency and “modest value” of using breed to predict behaviors in individual dogs. It states that for heritable and more breed-differentiated traits like biddability, breed can make predictions “somewhat more accurate” for purebred dogs. Though, for other factors, like agonistic threshold, they found breed to be “almost uninformative.”

Aggressive Breeds

Internet comments on news websites reporting on the study widely criticized the paper’s conclusion due to their belief that breed strongly determines behavior. Among countless anecdotes, many commentors questioned how the study could find that breed did not explain behavior despite certain breeds dominating the charts for the most bites–implying that these breeds are highly or disproportionately prone to aggression compared to others.

Pit bulls are reportedly the top breed responsible for fatal dog attacks on humans. A 2020 study from a level 1 trauma center also found that for dog bite incidents, pit bulls were much more likely than other breeds to bite without provocation and to go off property to attack. Dog bite data collected by the government of New York City shows that pit bull bites are by far the most commonly reported.

These facts caused internet users to doubt the study’s conclusions that breed can’t predict individual dog’s disposition and that breed did not explain agonistic threshold, which the study’s authors defined as “how easily [a] dog is provoked by a frightening, uncomfortable, or annoying stimulus.”

Dr. Benjamin Hart, animal behaviorist and professor emeritus at the UC Davis School of Veterinary Medicine, told SFGate that pit bulls often show no signs of aggression before an attack.

It’s quite common for a pit bull to show no signs of aggression. People will call it a nice dog, a sweet dog, even the neighbors–and then all of a sudden something triggers the dog, and it attacks a human in a characteristic way of biting and hanging on until a lot of damage is done.

Dr. Benjamin Hart for SFGate

Alarmingly, this means that owner surveys could never indicate the possibility that certain breeds are predisposed to such spontaneous dangerous behaviors. Notably, the researchers did not attempt to account for such behavior.

Morrill said that aggression was not measured because it is not a unitary behavior and can’t be well-defined scientifically, or even colloquially. Also, she explained that agonistic threshold is distinctly a fear response unrelated to predation, meaning spontaneous aggressive behaviors could not have been well accounted for, anyway.

When asked if the study had anything to say about the role of genetics or breed in predatory biting leading to severe or fatal injuries, Morrill responded succinctly, “No.”

Thus, the widely held beliefs regarding dangers of the pit bull terrier cannot be discounted by the study, regardless of conclusions that breed is not usually a reliable indicator of individual behavior.

Discussion of Media Coverage

Best Friends Animal Society Press Release

Best Friends Animal Society, an animal welfare nonprofit, is perhaps the largest advocacy group for stigmatized dog breeds. The nonprofit strongly believes that “all dogs are individuals,” and according to their latest press release, “this study proves it.” BFAS lobbies government bodies to end breed-specific legislation and prevent insurance from denying homeowners coverage due to “dangerous dog” ownership, disgustingly likening this “discrimination” to racism (see: Human races are not like dog breeds: refuting a racist analogy).

They use this study to claim that there is no such thing as a dangerous dog breed in order to support their positions against breed-specific legislation. Importantly for BFAS and its donors, this study should not influence breed-specific legislation.

We did not seek to address the validity of breed-specific legislation and its effectiveness for meeting public health goals to minimize dog bites and attacks on people. We don’t study dangerous interactions or dog bites.

Kathleen Morrill for OneResearch

Morrill did note that the limited predictive value of breed for inferring individual behavior could still have some relevance to breed-specific legislation. Nevertheless, the reason why pit bull terriers attack at much higher rates than other breeds was not elucidated by the study, possibly because it could not be measured using survey-based methodology. Additionally, the basis of the pit bull terrier’s relatively frequent and severe attacks is likely to be independent from the tested personality factors.

It follows that neither supporters nor detractors of breed-specific legislation should look to this study to support their position.

Breed Completely Unrelated to Behavior?

Absolute statements that breed has nothing to do with behavior are widespread across media coverage of the study. As established within the study and this article, this is not the case.

The study itself mentions not only through data but explicitly in the very beginning of the discussion that there is at least a correlation between breed and certain behaviors–but these correlations might not be strong enough to reliably predict behavior from breed. As Dr. Coren pointed out, the data shows that any given border collie has a 4 to 1 chance of scoring high in biddability. Still, as Morrill said, this is a narrow use case for predicting behaviors from breed.

Regardless, the media’s portrayal of the study’s results as showing that breed has no effect on behavior is not supported by the study. Morrill agreed with this in a statement to OneResearch.

Any headline that suggests no effects on behavior would be a misrepresentation. Headlines with scale qualifiers like “little effect” walk the delicate line of nonspecific enough to be technically in line with our findings and attention-grabbing to a large audience, whether they agree with the scale of “little” or not.

Kathleen Morrill for OneResearch

Misleading statements were not limited to headlines, either.

Breed means very little in predicting the behavior and personality of an individual dog, the researchers found. That appears to be especially true for traits that are most commonly associated with a dog’s personality, qualities such as cuddliness, friendliness toward strangers and aggression.

The Washington Post

Of course, aggression was not measured by the study. In fact, the word “aggression” is not written at all in the text.

The summary of the study that appears before its text on Science concludes that “dog breed is generally a poor predictor of individual behavior and should not be used to inform decisions relating to selection of a pet dog.” Dr. Hekman clarified to the Cog Dog Radio podcast that this take was written by Science editors, not the authors of the study.

I don’t want to speak for anybody else but myself, but I disagree with that statement. And I have no power to have it taken down.

Dr. Jessica Hekman for Cog Dog Radio

Media Coverage Overview

Dr. Elinor Karlsson, another key researcher and co-author of the paper, said that she was “for the most part quite happy” with the media coverage. “Our assertion that breed is not a reliable predictor of behavior in dogs was pretty clearly stated in our paper.” Dr. Karlsson clarified that even if breed is not a reliable predictor, there can still be differences between breeds. Also, traits can be heritable without being different between breeds. The study does not say that behavior lacks genetic basis.

Dr. Karlsson said she would expect more behaviorally distinct results from working dogs instead of the pet dogs used in the study, since they were more recently bred for performance rather than aesthetics.

Unfortunately, some sensationalist journalists and special interest groups misrepresented the results of the study to establish a narrative that no dog behaviors can be explained or predicted by breed. Popular science coverage is highly prone to cherry picking of data as journalists offer incomplete evidence to draw conclusions that scientists often don’t have the opportunity to correct or dispute before it’s too late.

The Buried Lede

Morrill expressed similar dismay that publications covering her study did not focus on–or even mention, in most cases–one of her most important findings.

The buried lede of our publication–one which didn’t get nearly as much media attention–is that we do successfully find genes associated with individual behavior, at finer resolution than ever before, largely thanks to all the mixed-breed dogs. 

Kathleen Morrill for OneResearch

The researcher’s ability to pinpoint these genes marks an apparent methodological success that could have implications on the study of human genetics. Improvements in methodology could perhaps reveal more genes associated with distinct individual behaviors.

In human genetics, we are always thinking about genes through the lens of “What goes wrong?”–it’s all very disorder-focused.

Kathleen Morrill for OneResearch

Morrill mentioned how, in laboratory settings, researchers must “break” genes and then measure the behavioral effects in order to understand their functions.

In dog genetics, we gain a new perspective on genetic variation and its behavioral effects, which is often more subtle. In this way, we can learn more about the biological functions of genes and gene regulators.

For example, we map common genetic variation that correlates with howling frequency in dogs. This variation exists nearby a gene that, in people, mutations in the same gene causes developmental disorders. In laboratory animals, mutations in that gene cause defects in the cortical regions of the brain pertaining to speech development. But, in dogs? We might get a better sense for how vocalization varies — it’s less all-or-nothing.

Kathleen Morrill for OneResearch

This finding also has implications on studies of human genetics and subsequent medical applications.

Human susceptibility to neuropsychiatric conditions is shaped by many genes and gene regulators, and large interactive effects of genes, environment, and life experiences. We have a limited understanding of the normal functions of genes that we do find associated with human disorders, and we’re also severely under-equipped to treat and manage neuropsychiatric conditions, like obsessive compulsive disorder or severe agoraphobia, with existing psychotropic medications. Comparative medicine and genomics in dogs has highlighted many genetic contributions to disease already, and will offer the opportunity to treat canine and human disorders in tandem.

Kathleen Morrill for OneResearch
Categories
COVID-19

CRISPR Test Detects All Variants of COVID-19, Could Run on Mobile Phones

During the pandemic, laboratories across the world worked hard to improve current diagnostic testing methods. The main method, quantitative polymerase chain reaction (qPCR) turns a small quantity of DNA into a larger amount and uses fluorescent dyes to indicate the presence or absence of viral genetic material. However, this method falls short in the following ways:

  1. It requires expensive equipment and reagents, along with trained personnel.
  2. It requires temperature cycles, so it cannot be performed at a single temperature.
  3. It takes time. Depending on the initial amount of target present, a qPCR test can take as long as 90 minutes.

At the University of Florida, PhD student Long T. Nguyen, working under Dr. Piyush Jain, has developed a rapid, single temperature COVID-19 diagnostic test that provides results in under 30 minutes. Amazingly, the test distinguishes between five COVID variants, achieves amplification, and RNA to DNA conversion all in one “pot.” Finally, the results can be read on a mobile phone.

The system they used is based on a detection system found in bacteria. Bacteria contain natural immune systems called CRISPR Cas, which function to create both a memory of past viral infections, along with a defense system once these viruses come back. Cas is a protein which is sometimes described as “a pair of molecular scissors,” capable of cutting DNA or RNA fragments, while CRISPR contains complementary sequences to attacking viruses and acts as a “molecular GPS,” helping Cas find a certain target. For this reason, it is also called a Guide RNA.

DNA sequence matching the guide RNA and being cut by a Cas protein into two slices. / Javier Zarracina via vox.com

Some Cas proteins locate their target and only make cuts around the target DNA/RNA; this is called cis cleavage. Others go on a “cutting frenzy.” After finding the target and cutting, the Cas protein starts cutting up other DNA or RNA fragments surrounding it, termed trans cleavage. Cas9 proteins, famous for genetic engineering, employ cis cleavage and only cut DNA. Cas12 and Cas13 proteins utilize trans cleavage, cutting DNA and RNA respectively. All bacteria have adapted their own systems, with slight variations, allowing scientists to harness each’s individual powers.

Cas12 and Cas13 proteins are at the forefront of diagnostic research. Their cutting frenzy may not be great for gene editing, but recent innovation has found that FQ reporters, or fluorescent quenchers, can be used to detect a signal with light. These reporters are dampened by a piece of RNA or DNA located between the fluorescent and quencher. Once cut, they glow and show a light on a fluorescent reader. If a Cas12 or Cas13 protein detects its target, it will cut the target then rapidly start cutting the FQ reporters nearby.

CRISPR RNA, shortened as crRNA, can be “programmed” to target any part of a target sequence. Specifically for the virus that causes COVID-19, there is a highly conserved region called the N gene. Since this same sequence is found across all variants, it can indicate the presence of the virus, but does not distinguish between mutated strains. The Jain lab identified mutated regions on each of the five variants: Alpha, Beta, Gamma, Delta, and Omicron, and created crRNAs which were complementary to each of these mutated regions. 

The N gene encodes for the nucleocapsid region on the COVID-19 virus. It is found in all variants of COVID-19.(Kubina & Dziedzic, 2020)

They then had to choose the optimal Cas protein, which could withstand higher temperatures. This was necessary because amplification occurs at high temperatures, ranging from 55-70°C. BrCas12b comes from a thermophilic bacterium found in hot springs and was the optimal choice.

They combined this Cas protein, along with a crRNA and finally, a master mix of RT-LAMP (Reverse Transcription Loop Mediated Isothermal Amplification). This is a very complex sounding term, but it can be broken down fairly easily. Reverse transcription is the process of converting RNA into DNA. Isothermal means it works at a single temperature and amplification implies the amount of DNA increases greatly. This amplification also provides a checkpoint. Researchers were able to first see if the patient sample was amplified; if so, COVID must be present. Then, using the CRISPR Cas system, they can determine exactly what variant is present. 

Image showing all of the components used in the Jain lab’s one-pot detection. (Nguyen et al., 2022)

Detection is completed in under 30 minutes and patient samples with a higher viral load (i.e., they had more SARS-CoV-2 virions present in their sample), exhibited 100% accuracy with about 95% sensitivity in distinguishing variants. The figure below, from Long et. al shows the incredible accuracy which comes from this detection. The colored titles, “Alpha, Beta, etc.” are the variant present in the patient sample, while the x-axis shows the crRNA used. For instance, it was expected that if a patient contained the Beta strain, only the Beta crRNA would show high signal.

Detection results for variants, showing high sensitivity. (Nguyen et al., 2022)

Most studies combining RT-LAMP with a CRISPR reaction have extremely low sensitivity and difficulty distinguishing a positive sample. The use of specifically BrCas12b, a less studied Cas protein, allowed the Jain lab to circumvent many of the problems others have had combining the two. The applicability of this research extends far beyond COVID-19 detection. Any RNA or DNA detection could be done utilizing this research, simply by changing the sequence located on the crRNA.

Moreover, the Jain lab aims to create portable and cheap methods for testing. They proposed an inexpensive lens which can be attached to any mobile phone camera. In a dark setting, the lens, which costs less than $5 can shine light of a specific wavelength on a sample with the added CRISPR Cas reagent and glow in the presence of COVID-19.

Potential for at-home testing using a specialized lens. Positive samples will glow in the dark once subjected to the light. (Nguyen et al., 2022)
References
  • Kubina, R., & Dziedzic, A. (2020, June 26). Molecular and serological tests for COVID-19. A comparative review of SARS-Cov-2 coronavirus laboratory and point-of-care diagnostics. MDPI. https://doi.org/10.3390/diagnostics10060434
  • Nguyen, L. T., et al. (2022, March 1). A Thermostable Cas12b from Brevibacillus Leverages One-pot Detection of SARS-CoV-2 Variants of Concern. eBioMedicine, The Lancet Discovery Science. https://doi.org/10.1016/j.ebiom.2022.103926
Categories
Neurology

Social Media Use During Pandemic Linked to Increased Tic Severity in Adolescents with Tourette’s

A study being conducted at the University of Florida is investigating a correlation between the use of social media during the COVID-19 pandemic and a change in tic severity for adolescents with Tourette syndrome.

Background

Tourette syndrome is a type of tic syndrome often present at a young age even as early as 2 years old. Tics are sudden movements, jolts, or sounds that those with tic syndromes feel the urge or are compelled to do. Often times it is compared to the urge of a sneeze where the person will feel great discomfort if they do not perform the tic. That being said, tics have the urge to be suppressed but not without causing discomfort to the individual.

Often times, people confuse and associate Tourette’s syndrome with coprolalia. Coprolalia is a specific type of phonic or vocal tic in which people shout obscene language. This specific type of tic is very rare and only affects around 10% of those diagnosed with Tourette’s Syndrome.

Study

After analysis of a patient population of surveys completed by adolescent individuals (n=20) with ages ranging from 11 to 21 years old, the researchers found statistically significant data showing that social media use, and increased social media use during the pandemic, causes an increase in tic severity and frequency.

  • 90% reported using social media more frequently during the pandemic
  • 65% reported using social media for an average of 6 hours per day
  • 50% reported that social media negatively impacted their tics
  • 85% reported that their tic frequencies worsened during the pandemic

This study was recently highlighted by both the University of Florida and the American Academy of Neurology (AAN) for its findings related to the implications of the pandemic on the mental health of adolescents. The researchers plan to add new participants to the study to strengthen the data and gain new insights.

This research is important as it can help to identify possible stressors for those with tics and work towards providing relief from tic symptoms for those with Tourette’s.

This article is based on the following sources

– American Academy of Neurology. (2022, February 28). Study: Tic severity linked with social media use for teens during pandemichttps://www.aan.com/PressRoom/Home/PressRelease/4961
– Centers for Disease Control and Prevention. (2020, May 13). Five Things You May Not Know About Tourette Syndromehttps://www.cdc.gov/ncbddd/tourette/features/tourette-five-things.html
– Mayo Clinic. (2018, August 8). Tourette syndrome – Symptoms and causeshttps://www.mayoclinic.org/diseases-conditions/tourette-syndrome/symptoms-causes/syc-20350465
– Tourette Association of America. (2016, May 21). Understanding coprolalia: A misunderstood symptomhttps://tourette.org/resource/understanding-coprolalia/
– University of Florida News. (2022, March). Heavy social media use may be linked to increase in tic severityhttps://news.ufl.edu/2022/03/social-media-use-and-tic-severity/

Categories
Neuroscience

Mouse Study: Follicle-Stimulating Hormone Is a Key Instigator of Alzheimer’s Disease

A study published in Nature reports that Follicle-Stimulating Hormone (FSH) may be a key instigator of Alzheimer’s disease (AD). Treatment including gene therapy and anti-FSH antibodies reversed and prevented AD-related pathologies in mice.

Background

Alzheimer’s disease (AD) is the 7th leading annual cause of death in the United States and is typically caused by an abnormal buildup of two proteins: amyloid and tau. Amyloid proteins help with neuron growth and repair but can destroy nerve cells later in life due to abnormal buildups referred to as plaques. Tau is intended to stabilize neurons by providing them with a  neurofibrillary structure. When unregulated, tau proteins can dysfunctionally aggregate into neurofibrillary tangles (NFTs), causing AD.

Elevated follicle-stimulating hormone (FSH) levels are often associated with menopause and, when regulated, the hormone’s intended purpose in the human body is to stimulate egg and sperm development. Both low and high levels of FSH are associated with infertility and sexual defects.

Scientists have long suspected that menopause plays a role in the pathogenesis of AD. During menopause, females have elevated levels of FSH, which—among other hormones—can lead to bone decay, weight gain, tiredness, and cognitive defects like those observed in AD patients. Women have a three-times higher rate of disease progression.

Method & Results

To determine if FSH is linked to the development of AD, researchers from Emory University and Icahn School of Medicine conducted an experiment in which they manipulated FSH levels in mice and then examined cognitive function and plaque formation.

In mice injected with extra FSH for three months, researchers already observed amyloid plaques and and tau NFTs, as well as inflammation and destruction of neurons—all symptoms of AD. Specifically, the damage, plaques, and NFTs occurred largely in hippocampal and cortical neurons. Further, these mice showed impaired spatial memory as demonstrated by comparatively poor performance in a water maze test. These changes were observed in both male and female mice.

The researchers then administered an antibody drug that lowers FSH levels. After treatment, they identified that the same AD symptoms identified in the FSH-supplemented mice had nearly disappeared. Their anti-FSH antibody (FSH-Ab) inhibited amyloid plaque and NFT formation while also reversing cognitive decline. As FSH-Ab inhibits all functions of FSH, the mice would also experience increased bone mass, decreased body fat, and increased energy expenditure.

The researchers believe excess FSH causes an increase in the expression of a gene that regulates an enzyme called arginine endopeptidase. This enzyme ultimately keeps amyloid and tau proteins in check, but once overproduced, clumping and tangling can begin. Experimentation revealed that either the deletion of this gene via gene therapy or FSH-Ab treatment successfully reduced amyloid plaques and tau NFTs and improved water maze performance.

While increased FSH levels in menopausal women is implied in the pathogenesis of AD, the researchers tested how male mice would respond to FSH-Ab. They found that the antibody “at the very least” prevented amyloid accumulation in the male mice.

Discussion

The researchers concluded that extremely high FSH levels can impact protein regulation pathways, eventually leading to AD-related pathologies in mice. Also, antibody therapy targeting FSH can reverse and prevent formation of amyloid plaques and NFTs. Mice had recovered performance in cognitive tests following FSH-Ab treatment.

These findings have serious implications if the findings translate to humans. FSH concentrations could be used as an assay in patients to determine pathology and treatment. Antibody and gene therapies that proved to reverse and prevent AD symptoms in mice could also be used in humans with FSH-induced AD.

References
  • Abbott, A. (2022, March 9). Could drugs prevent Alzheimer’s? These trials aim to find out. Nature. https://www.nature.com/articles/d41586-022-00651-0
  • Murphy, S. L., et al. (2021, December). https://www.cdc.gov/nchs/data/databriefs/db427.pdf. National Center for Health Statistics. https://www.cdc.gov/nchs/data/databriefs/db427.pdf
  • Orlowski, M., & Sarao, M. S. (2021, May 9). Physiology, follicle stimulating hormone. National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/books/NBK535442/#NBK535442_pubdet
  • Xiong, J., Kang, S., et al. (2022, March 2). FSH blockade improves cognition in mice with Alzheimer’s disease. Nature. https://www.nature.com/articles/s41586-022-04463-0
Categories
Immunotherapy Public Health

How Bacteriophages Could Save Humanity from Antibiotic Resistance

“Thanks to penicillin… he will come home!” pronounced a Life magazine advertisement published in 1944. At this time, penicillin, the first true antibiotic drug, had just been discovered and made commercially available.

Antibiotics are drugs that prevent or treat bacterial infections. Before the advent of penicillin, the leading causes for death were bacterial infections resulting in pneumonia, tuberculosis, diarrhea, and enteritis, causing one third of all deaths in the United States. Since then, the idea of deaths by bacterial infection have largely faded into the past—until the evolution of antibiotic-resistant bacteria has now threatened this status quo.

In antibiotic or antimicrobial resistance, antibiotics are no longer effective against bacteria that have evolved to survive it, particularly using beta-lactamase enzymes. This resistance is further accelerated by excessive, unnecessary use of antibiotics, mainly in industrial livestock production and over-prescription. This increased use contributes to the evolutionary pressure on microbes to develop resistance to antibiotics.

Alexander Fleming, who discovered penicillin, was receiving the Nobel Prize in medicine and physiology when he ominously predicted antibiotic resistance: “It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them.” Fleming himself was hesitant of widespread antibiotic use, recognizing its resistant capabilities from the year they were released. In 2019, the CDC reported more than 2.8 million antibiotic-resistant infections in the US.

Antibiotics have very specific mechanisms of action to target bacteria. For example, penicillin binds to an enzyme on the bacteria and removes it, which breaks an important barrier in the cell. If one certain bacteria has a mutated enzyme, the antibiotic will be rendered ineffective, and that mutation will become prevalent in that bacterial species.

A key difference between bacteria and most other organisms is their ability to transmit genes to nearby bacteria in a process called horizontal gene transfer. This is why bacterial resistance has quickly become an epidemic as it spreads quickly and efficiently. Unfortunately, it would take almost a decade to modify the antibiotics necessary to combat these “superbug” bacteria.

Bacteriophages, meaning “bacteria eaters,” are viruses that only infect bacteria. Most are lytic, meaning that when infecting a host, they inject their genes into the host, utilize the host to rapidly replicate, and destroy the cell walls by bursting through, essentially creating a “phage-producing factory” from a bacteria. A small number are lysogenic, which means they coexist with bacteria.

Consequently, bacteriophages have provoked the interest of researchers as a potential replacement for traditional antibiotics, which are obtained from fungi. While there are a little over 100 known traditional antibiotic drugs to fight the near-infinite supply of bacteria in the world, estimates show that there exist about 10 phages for each bacterium. This indicates that there may be many more potentially therapeutic bacteriophages than traditional antibiotics. Bacteriophages are the most abundant “organism” in the biosphere, either living harmoniously with bacteria in the lysogenic cycle or destroying about 40% of the ocean’s bacteria every day, amounting to 10²³ phage infections in only one second.

Though, phages have drawbacks as potential antibiotic therapies. For one, they are extremely specific. While a single traditional antibiotic can target a multitude of bacteria, bacteriophages target one bacteria. A working solution for this is the use of “phage cocktails,” which combine multiple natural and synthetic bacteriophages to more effectively treat patients.

Also, phages are not entirely shielded from bacterial resistance. Bacteria can fight back with certain immune responses, specifically CRISPR Cas  systems. However, unlike antibiotics, phages are continually adapting and responding to such defensive systems. This continual mutation of phages poses a risk for FDA approval, but some researchers are working on machine learning  systems to predict these changes.

Still, bacteriophages show promise as an alternative therapy to traditional antibiotics. Scientists hope that phages will become an alternative defense against bacteria that could help ease antimicrobial resistance.

References
Categories
Pharmacology

Clascoterone, First Novel Acne Therapy in 38 Years, Treats Acne By Blocking Facial Androgen Receptors

In 1982, the FDA approved isotretinoin (Accutane), a Vitamin A derivative, for use in patients with acne. No new methods of acne medication had been approved from 1982 until the approval of topical clascoterone in August 2020, almost 40 years later.

Topical clascoterone is a cream that is applied directly to the skin of areas affected by acne. Clascoterone is an antiandrogen, which is a class of drug that blocks androgen receptors. The drug is the first antiandrogen to be approved by the FDA for acne medication, earning it the title of first-in-class medication. Androgens, which are male sex hormones present in males and lower levels in females, play an important role in the pathogenesis of acne.

During puberty, both males and females have increased levels of androgens like testosterone or dihydrotestosterone (DHT). Higher levels of testosterone can cause increased production of sebum, an oily substance secreted by sebaceous glands under the skin. Excessive amounts of sebum in a skin pore can cause a blockage (known as a comedo, blackhead, or whitehead) that may become infected.

Clascoterone was shown in vitro to have higher affinity for androgen receptors than DHT. This blockage of local androgen receptors by clascoterone was then shown by clinical trials to reduce the acne-causing effects of androgens.

The Investigator’s Global Assessment Scale (IGA) is a scale of acne severity that goes from 0 (clear) up to 4 (severe). Two clinical trials found that at least 18% of patients achieved a drop of at least 2 points on the IGA scale (resulting in a score of 0 or 1) at 12 weeks into treatment with topical clascoterone. One trial showed that patients, on average, saw a 39% decrease in total lesion count after 12 weeks of treatment.

The FDA listed the most common side effects of topical clascoterone as reddening, itching, and scaling or dryness of treated skin. The FDA-approved brand of topical clascoterone is Winlevi.

References
  • Piszczatoski, C. (2021, October 2). Topical Clascoterone: The First Novel Agent for Acne Vulgaris in 40 Years. https://doi.org/10.1016/j.clinthera.2021.08.007
  • U.S. Food and Drug Administration. (2020, September 3). Drug trial snapshot: Winlevi. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-winlevi
Categories
Neuroscience

Transparent Zebrafish Study Reveals How Sleep Repairs Damaged Neuronal DNA

Using transparent zebrafish, Israeli researchers were able to confirm neuronal DNA repair as a function of sleep, also identifying a protein that triggers both DNA repair and sleep.

Background

The functions of sleep, though widely researched, have largely remained a mystery. It is known that sleep influences cognition, benefitting learning and memory, but proposed physiological functions have had little strong evidence. Proposed functions of sleep include removing toxic byproducts in the brain caused by wakefulness, replenishing energy and supplies for cells, and remediating neural damage and cellular stress.

Prior research showed that wakefulness and neuronal activity causes DNA double-strand breaks. These lesions are accumulated during wakefulness, contributing to homeostatic sleep drive (the pressure to sleep that builds up as time awake increases). Sleep has been demonstrated to decrease this DNA damage.

Researchers from Israel’s Bar-Ilan University and Tel Aviv University used zebrafish to study neuronal DNA repair as a potential novel function of sleep. The zebrafish is a tiny freshwater fish that has been widely used as a model organism due to their 70% genetic homology (similarity) to humans. Among other parallel physiologies, zebrafish exhibit a diurnal sleep cycle with states closely resembling mammalian slow-wave sleep (SWS) and rapid eye movement (REM) sleep. A mutated type of zebrafish is transparent, enabling researchers to observe the previously unobservable.

Confocal microscopy image showing the developing face of a 6 day old zebrafish larva. / Oscar Ruiz and George Eisenhoffer, University of Texas MD Anderson Cancer Center

By inducing neuronal DNA damage in zebrafish, they were able to determine its relation to sleep as well as causal proteins.

Results

First, the researchers confirmed a significant positive correlation between levels of neuronal DNA damage and total sleep time (R = 0.76). During wakefulness, zebrafish larvae were treated with pentylenetetrazol, which stimulated their neuronal activity. Consequently, the larvae had increased neuronal DNA damage and a 5-fold increase in total sleep time.

Because neuronal DNA damage is not only caused by cell activity, the researchers then exposed the larvae to UV radiation, which damaged their DNA without increasing their neuronal activity. Their subsequent increased sleep further confirmed that DNA damage was the cause.

By testing the rates at which genes involved in the DNA damage response (DDR) were expressed during sleep, they found that the RAD52 and Ku80 proteins were responsible for repairing double-strand breaks during sleep.

Further analysis uncovered that the PARP1 protein, a DNA damage detector that organizes the DDR, was immediately recruited and activated upon neuronal DNA damage.

When the researchers provoked greater expression of PARP1, total sleep time and depth increased—demonstrating that the protein is what connects the DNA damage response to homeostatic sleep drive. PARP1 was also shown to promote sleep regardless of damage.

Discussion

The study confirms in multiple experiments that neuronal DNA repair is a function of sleep regulated by the PARP1 enzyme and carried out by the DNA repair proteins RAD52 and Ku80.

Triggering neuronal DNA damage via cellular excitation and UV light both caused the expected result of increased sleep, with PARP1 as the protein responsible for detecting the damage, provoking a repair response, and causing increased sleep drive.

The study authors noted their intrigue that FDA-approved PARP1 inhibitors used as antitumor agents all caused fatigue as the prominent side effect, suggesting that inhibiting PARP1 masks its sleep-promoting signals. The use of PARP1 inhibitors was also found to cause increased DNA damage. These results, separate from their study, align with their findings regarding the functions of PARP1 as observed in zebrafish.

References
  • Frank, M. G. (2006, August 1). The mystery of sleep function: Current perspectives and future directions. De Gruyter. https://doi.org/10.1515/revneuro.2006.17.4.375
  • Yourgenome. (2021, July 21). Why use the zebrafish in research? https://www.yourgenome.org/facts/why-use-the-zebrafish-in-research
  • Zada, D., et al. (2021, December 16). Parp1 promotes sleep, which enhances DNA repair in neurons. Molecular Cell. https://doi.org/10.1016/j.molcel.2021.10.026