Day: February 10, 2023

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‘Love Hormone’ Oxytocin’s Role may be Overblown

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Disagreeing couple
Photo by Monstera from Pexels

The vital role of the ‘love hormone’ oxytocin for social attachments is being called into question. More than 40 years of pharmacological and behavioural research has pointed to oxytocin receptor signalling as an essential pathway for the development of social behaviours in prairie voles, humans, and other species, but a genetic study published in the journal Neuron shows that voles can form enduring attachments with mates and provide parental care without oxytocin receptor signalling.

Prairie voles are one of only a few monogamous mammalian species. After mating, they form lifelong partnerships known as “pair-bonds.” Pair-bonded voles share parental responsibilities, prefer the company of their partner over unknown members of the opposite sex, and actively reject potential new partners. Previous studies that used drugs to block oxytocin from binding to its receptor found that voles were unable to pair-bond when oxytocin signalling was blocked.

Neuroscientists Devanand Manoli of UCSF and Nirao Shah of Stanford University wanted to know whether pair-bonding was really controlled by oxytocin receptor signalling. To test this, they used CRISPR to generate prairie voles that lack functional oxytocin receptors. Then, they tested these mutant oxytocin-receptor-less voles to see whether they could form enduring partnerships with other voles. To their surprise, the mutant voles formed pair-bonds just as readily as normal voles.

“We were all shocked that no matter how many different ways we tried to test this, the voles demonstrated a very robust social attachment with their sexual partner, as strong as their normal counterparts,” says Manoli.

Next, the researchers wondered whether oxytocin receptor signaling is similarly dispensable for its other functions – parturition, parenting (which, in prairie voles, is a shared responsibility between the two parents), and milk release during lactation.

“We found that mutant voles are not only able to give birth, but actually nurse,” says Shah. Both male and female mutants engaged in the usual parental behaviours of huddling, licking, and grooming, and were able to rear pups to weaning age.

However, the mutant prairie voles did have limited milk release compared to normal voles. As a result, fewer of their pups survived to weaning age, and those that did survive were smaller compared to the pups of normal prairie voles. The fact that the voles could nurse at all is in contrast to equivalent studies in oxytocin receptor-deficient mice, who completely failed to lactate or nurse, and whose pups consequently died within a day or so of being born. The authors hypothesize that this species difference could be due to the inbred nature of laboratory mouse strains in contrast to the genetically heterogenous voles. “It could be that inbreeding in mice has selected for a large dependence on oxytocin signalling, or this may represent a species-specific role of oxytocin receptor signalling,” says Shah.

When asked why their results differ from previously published studies that used drugs to block oxytocin receptor signalling, the authors point to the key difference between genetic and pharmacological studies: precision. “Drugs can be dirty,” says Manoli, “in the sense that they can bind to multiple receptors, and you don’t know which binding action is causing the effect. From a genetics perspective, we now know that the precision of deleting this one receptor, and subsequently eliminating its signalling pathways, does not interfere with these behaviours.”

“For at least the last ten years people have been hoping for the possibility of oxytocin as a powerful therapeutic for helping people with social cognitive impairments due to conditions ranging from autism to schizophrenia,” Manoli says. “This research shows that there likely isn’t a magic bullet for something as complex and nuanced as social behaviour.”

Another key difference is that, whereas most pharmacological studies suppress oxytocin receptor signalling in adult animals, this study switched it off when the voles were embryos. “We’ve made a mutation that starts from before birth,” says Shah. “It could be that there are compensatory or redundant pathways that kick-in in these mutant animals and mask the deficits in attachment, parental behaviours, and milk let-down.”

Working with prairie voles presented an obstacle, but one worth overcoming. Because prairie voles are not commonly used in genetic studies like laboratory mice, the team needed to develop all of their molecular tools and protocols from scratch. Now that they have these vole-specific pipelines and tools, the authors are excited about the doorways this opens, both for them and for other researchers.

“We’re very happy to be part of a community and to have this technology that we can share,” says Manoli. “Now we have this trove that we can start to mine. There are so many other questions that prairie voles could be interesting and useful for answering, both in terms of potential clinical implications for models of anxiety or attachment and also for basic comparative biology.”

Source: News-Medical.Net

Categories : GeneticsTags : Leave a comment

DNA Analysis can Cut Adverse Drug Reactions by 30%

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Genetics
Image source: Pixabay

Patients can experience 30% fewer serious adverse reactions if their drugs are tailored to their genes, reports a study published in The Lancet. A European collaboration involving researchers from Karolinska Institutet suggests that a genetic analysis prior to drug therapy could significantly reduce suffering and healthcare costs.

 A significant proportion of patients experience adverse reactions to their medication. Since we each carry a unique set of genes, we react differently to the same drugs. For example, some people break them down faster, meaning that they require a higher dose to obtain the desired effect.  

DNA pass that fits in the wallet

To overcome this problem, researchers from Leiden University Medical Center in the Netherlands, Karolinska Institutet and other collaborating institutions have developed the principle for a “DNA pass” that has been clinically validated in the recently published study.

“It’s basically a credit card-sized card with a magnetic strip containing all the important genetic data on a particular patient,” explains one of the study’s co-authors Magnus Ingelman-Sundberg, professor of molecular toxicology at the Department of Physiology and Pharmacology at Karolinska Institutet. 

“When a patient’s card is scanned, doctors and pharmacists can work out the optimal dose of a drug for that particular individual.”

The study included almost 7 000 patients from seven European countries between March 2017 and June 2020 all of whom were genotyped with respect to variations in twelve specific genes of significance to drug metabolism, transport and side-effects. All participants then received their drugs either conventionally or with a genotype-based modification.

Twelve weeks after their drug regimen began, the patients were contacted by a specialist nurse about any adverse reactions, such as diarrhoea, pain or loss of taste. The study concluded that such adverse reactions to drugs can be greatly reduced by analysing the genes that code for enzymes that metabolise them.

“The patients who’d received genotype-driven treatment had, on average, 30 per cent fewer adverse reactions than the controls,” says Professor Ingelman-Sundberg.  

Now sufficiently compelling data

Professor Ingelman-Sundberg, a long-standing expert at the European Medical Agency on the development of this method, believes that there is now sufficiently compelling data to warrant the widespread use of the DNA pass.

“I think we’ve come to the point where a genetic pass like this will be useful,” he says. 

Globally, the problem of adverse reactions is considerable. In the EU, they cause up to 128 000 fatalities a year and up to 9% of all hospital admissions, a figure that more than doubles to 20% in over 70s.

“Our results strongly suggest that an initial genotyping of the patients will deliver significant savings to society,” says Professor Ingelman-Sundberg. “The genotyping itself need only be done once per patient at a maximum cost of 6,000 SEK. The general introduction of this predictive system could therefore go a long way towards reducing public healthcare costs.”

Source: Karolinska Institutet

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ChatGPT can Now (Almost) Pass the US Medical Licensing Exam

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ChatGPT can score at or around the approximately 60% pass mark for the United States Medical Licensing Exam (USMLE), with responses that make coherent, internal sense and contain frequent insights, according to a study published in PLOS Digital Health by Tiffany Kung, Victor Tseng, and colleagues at AnsibleHealth.

ChatGPT is a new artificial intelligence (AI) system, known as a large language model (LLM), designed to generate human-like writing by predicting upcoming word sequences. Unlike most chatbots, ChatGPT cannot search the internet. Instead, it generates text using word relationships predicted by its internal processes.

Kung and colleagues tested ChatGPT’s performance on the USMLE, a highly standardised and regulated series of three exams (Steps 1, 2CK, and 3) required for medical licensure in the United States. Taken by medical students and physicians-in-training, the USMLE assesses knowledge spanning most medical disciplines, ranging from biochemistry, to diagnostic reasoning, to bioethics.

After screening to remove image-based questions, the authors tested the software on 350 of the 376 public questions available from the June 2022 USMLE release. 

After indeterminate responses were removed, ChatGPT scored between 52.4% and 75.0% across the three USMLE exams. The passing threshold each year is approximately 60%. ChatGPT also demonstrated 94.6% concordance across all its responses and produced at least one significant insight (something that was new, non-obvious, and clinically valid) for 88.9% of its responses. Notably, ChatGPT exceeded the performance of PubMedGPT, a counterpart model trained exclusively on biomedical domain literature, which scored 50.8% on an older dataset of USMLE-style questions.

While the relatively small input size restricted the depth and range of analyses, the authors note their findings provide a glimpse of ChatGPT’s potential to enhance medical education, and eventually, clinical practice. For example, they add, clinicians at AnsibleHealth already use ChatGPT to rewrite jargon-heavy reports for easier patient comprehension.

“Reaching the passing score for this notoriously difficult expert exam, and doing so without any human reinforcement, marks a notable milestone in clinical AI maturation,” say the authors.

Author Dr Tiffany Kung added that ChatGPT’s role in this research went beyond being the study subject: “ChatGPT contributed substantially to the writing of [our] manuscript… We interacted with ChatGPT much like a colleague, asking it to synthesise, simplify, and offer counterpoints to drafts in progress…All of the co-authors valued ChatGPT’s input.”

Source: EurekAlert!

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Transforming the Way Cancer Vaccines are Designed and Made

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Photo by Louise Reed on Unsplash

A new way to significantly increase the potency of almost any vaccine has been developed by researchers from the International Institute for Nanotechnology (IIN) at Northwestern University, which they describe in Nature.

The scientists used chemistry and nanotechnology to change the structural location of adjuvants and antigens on and within a nanoscale vaccine, greatly increasing vaccine performance. The antigen targets the immune system, and the adjuvant is a stimulator that increases the effectiveness of the antigen. 

“The work shows that vaccine structure and not just the components is a critical factor in determining vaccine efficacy,” said lead investigator Chad A. Mirkin, director of the IIN. “Where and how we position the antigens and adjuvant within a single architecture markedly changes how the immune system recognises and processes it.”

This new heightened emphasis on structure has the potential to improve the effectiveness of conventional cancer vaccines, which historically have not worked well, Mirkin said. 

Mirkin’s team has studied the effect of vaccine structure in the context of seven different types of cancer to date, including triple-negative breast cancer, papillomavirus-induced cervical cancer, melanoma, colon cancer and prostate cancer to determine the most effective architecture to treat each disease.   

Conventional vaccines take a blender approach   

With most conventional vaccines, the antigen and the adjuvant are simply blended and injected into a patient, giving no control over the vaccine structure, and, consequently, limited control over trafficking and processing of the vaccine components. Thus, there is no control over how well the vaccine works.  

“A challenge with conventional vaccines is that out of that blended mish mosh, an immune cell might pick up 50 antigens and one adjuvant or one antigen and 50 adjuvants,” said study author and former Northwestern postdoctoral associate Michelle Teplensky, who is now an assistant professor at Boston University. “But there must be an optimum ratio of each that would maximise the vaccine’s effectiveness.” 

Enter SNAs (spherical nucleic acids), which are the structural platform, invented and developed by Mirkin, used in this new class of modular vaccines. SNAs allow scientists to pinpoint exactly how many antigens and adjuvants are being delivered to cells. SNAs also enable scientists to tailor how these vaccine components are presented, and the rate at which they are processed. Such structural considerations, which greatly impact vaccine effectiveness, are largely ignored in conventional approaches.  

Vaccines developed through ‘rational vaccinology’ offer precise dosing for maximum effectiveness

Mirkin came up with this approach to systematically control antigen and adjuvant locations within modular vaccine architectures, and called it ‘rational vaccinology’. It is based on the concept that the structural presentation of vaccine components matters as much as the components themselves in driving efficacy.   

“Vaccines developed through rational vaccinology deliver the precise dose of antigen and adjuvant to every immune cell, so they are all equally primed to attack cancer cells,” said Mirkin. “If your immune cells are soldiers, a traditional vaccine leaves some unarmed; our vaccine arms them all with a powerful weapon with which to kill cancer. Which immune cell ‘soldiers’ do you want to attack your cancer cells?”

Building an (even) better vaccine  

The team developed a cancer vaccine that reduced tumour growth by more than four times compared to checkpoint inhibitor monotherapy, and led to a 40% extension in median survival.  

By reconfiguring the architecture of a vaccine containing multiple targets, the SNA enables the immune system to find tumour cells. The team investigated differences in how well two antigens were recognised by the immune system depending on their placement, on the core or perimeter, of the SNA structure. For an SNA with optimum placement, they could increase the immune response and how quickly the nanovaccine triggered cytokine (an immune cell protein) production to boost T cells attacking the cancer cells. The scientists also studied how the different placements affected the immune system’s ability to remember the invader, and whether the memory was long-term.  

“Where and how we position the antigens and adjuvant within a single architecture markedly changes how the immune system recognises and processes it,” Mirkin said. 

The most powerful structure throws two punches to outsmart the tumour  

The study data show that attaching two different antigens to an SNA comprising a shell of adjuvant was the most potent approach for a cancer vaccine structure. These engineered SNA nanostructures stalled tumour growth in multiple animal models.   

“It is remarkable,” Mirkin said. “When altering the placement of antigens in two vaccines that are nearly identical from a compositional standpoint, the treatment benefit against tumours is dramatically changed. One vaccine is potent and useful, while the other is much less effective.”  

Many current cancer vaccines are designed to primarily activate cytotoxic T cells, only one defence against a cancer cell. Because tumour cells are always mutating, they can easily escape this immune cell surveillance, quickly rendering the vaccine ineffective. The odds are higher that the T cell will recognise a mutating cancer cell if it has more antigens to recognise it.   

“You need more than one type of T cell activated, so you can more easily attack a tumour cell,” Teplensky said. “The more types of cells the immune system has to go after tumours, the better. Vaccines consisting of multiple antigens targeting multiple immune cell types are necessary to induce enhanced and long-lasting tumour remission.”  

Another advantage of the rational vaccinology approach, especially when used with a nanostructure like an SNA, is that it’s easy to alter the structure of a vaccine to go after a different type of disease. Mirkin said they simply switch out a peptide, a snippet of a cancer protein with a chemical handle that “clips” onto the structure, not unlike adding a new charm to a bracelet.   

Towards the most effective vaccine for any cancer type 

“The collective importance of this work is that it lays the foundation for developing the most effective forms of vaccine for almost any type of cancer,” Teplensky said. “It is about redefining how we develop vaccines across the board, including ones for infectious diseases.” 

In a previously published paper, Mirkin, Teplensky and colleagues demonstrated the importance of vaccine structure for SARS-CoV-2 by creating vaccines that exhibited protective immunity in 100% of animals against a lethal viral infection.  

“Small changes in antigen placement on a vaccine significantly elevate cell-to-cell communication, cross-talk and cell synergy,” Mirkin said. “The developments made in this work provide a path forward to rethinking the design of vaccines for cancer and other diseases as a whole.”   

Source: Northwestern University

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Strep A Toxin Serves as Both Weapon and Shield

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Streptococcus pyrogenese bound to human neutrophil
Streptococcus pyogenese bound to a human neutrophil. Credit: National Institute of Allergy and Infectious Diseases, National Institutes of Health

Griffith University researchers have unlocked one of the secrets as to why some forms of Streptococcus Group A (Strep A) are associated with severe invasive infection. The results, published in mBio, suggest that a toxin it secretes not only damages cells but helps Strep A resist host defence.

Around the world, invasive Strep A diseases are responsible for more than 163 000 deaths annually and a recent increase in cases of invasive Strep A disease has been observed internationally.

For the past 10 years, Institute for Glycomics Associate Professor Manisha Pandey and Professor Michael Good have been researching the pathways in which Strep A can spread through the body.

“The findings from this study will have far-reaching implications as Strep A is responsible for a significant number of invasive and non-invasive infections which cause significant morbidity and mortality globally,” Associate Professor Pandey said.

“The reason for this is that invasive organisms express significantly more of the toxin, streptolysin O (SLO), which was the main focus of this study.

“SLO exerts potent cell and tissue destructive activity and promotes Strep A resistance to clearance by white cells in the body which is the critical first element of host defence against invasive Strep A infection.”

Professor Good said: “We found SLO alters interactions with host cell populations and increases Strep A viability at sites in the body such as the blood and spleen, and that its absence results in significantly less virulence.”

“Essentially, the less SLO present, the less severe the case of Strep A.”

SLO is secreted by nearly all Strep A isolates, but those that secrete the most SLO are the most virulent.

This work underscores the importance of SLO in Strep A virulence while highlighting the complex nature of Strep A pathogenesis.

This improved insight into host-pathogen interactions will enable a better understanding of host immune evasion mechanisms and inform streptococcal vaccine development programs.

Dr Pandey said a key finding was the presence of SLO in invasive organisms did not impair the ability of the Strep A vaccine candidate developed by Griffith University’s Institute for Glycomics and which is now in a clinical trial.

The Strep A virulence study was part of a PhD project undertaken by Dr Emma Langshaw.

Source: Griffith University

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Genetic Variations Influence Drug Metabolism in Patients of African Descent

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Photo by Agung Pandit Wiguna

Investigators have identified new genetic variations that affect gene expression in the liver cells of patients of African ancestry, findings that provide insight into how drugs are metabolised differently in different populations, according to a study published in The American Journal of Human Genetics.

Expression quantitative locus (eQTL) studies use an individual’s genomic and transcriptomic data to uncover unique genetic variants that regulate gene expression. However, people of African descent have not been well represented in these databases.

Having this comprehensive, multiomic data is key to uncovering the mechanisms that regulate an individual’s genome and understanding how different groups of people respond to drugs differently, which can improve treatment strategies, according to Minoli Perera, PharmD, PhD, associate professor of Pharmacology and senior author of the study.

“We don’t have data from any historically excluded populations to run these analyses, so a big motivation of my lab is to create data in African ancestry populations so that they are represented in multiomics,” said Perera.

In the current study, the investigators treated hepatocytes from liver tissue samples from African American patients with six FDA approved drugs: Rifampin, Phenytoin, Carbamazepine, Dexamethasone, Phenobarbital and Omeprazole.

The investigators then performed whole-genome genotyping and RNA sequencing on primary hepatocytes treated both with and without the drugs. They also mapped eQTLs, or single-nucleotide polymorphisms (SNPs) affecting gene expression, in the liver cells.

From this comprehensive analysis, they uncovered varying transcriptional changes in the cell lines across the different drug treatments and identified NRF2 as a potential gene transcription regulator.

“NRF2 has been already identified as a very important transcription factor for drug metabolism, but this is a much more comprehensive way to look at it,” Perera said.

The investigators also discovered nearly 3000 genetic variants that affect how well hepatocytes respond to external stimuli, including drugs, which the investigators called drug response eQTLs, or reQTLs. Notably, they discovered reQTLs for drug-metabolising genes such as CYP3A5.

Most individuals of European ancestry carry a specific genetic variant in CYP3A5 which results in no/low CYP3A5 enzyme, whereas individuals of African ancestry carry that variant at a lower frequency. According to Perera, this is a problem because most participants that are recruited for clinical trials are of European ancestry, and the findings from these trials directly inform how often and how much of a drug should be prescribed to all patients, regardless of their ancestry.

“When you test drugs in a group of people with limited diversity, and then say this is the dose, this is how fast it’s metabolised, this is how often you dose the drug and then you give this medication to the entire U.S. population, we don’t know for sure how accurate those measures are, and that’s just with one variant. Other variants that may influence how much or how little we up-regulate these important enzymes,” Perera said.

Perera said her team is now expanding their work by increasing the number of hepatocytes from African American participants they’re studying and incorporating other types of omics techniques, such as epigenetic profiling.

“Almost exclusively we’ve done epigenetic screenings in European populations, so what can we find in the epigenome that’s important for African Americans. Also, because there’s more genetic variation in individuals of African descent, would that change the epigenome in ways that we aren’t able to see in Europeans,” Perera said. “We hope that what we’re doing can help annotate new studies coming along for African ancestry populations.”

Source: Northwestern University