Studying Mental Illness by Using Artificial 3D Human “Mini-Brains”

A better understanding of mental illness allows for more effective treatments of it, and this highly complex research looks to be a positive contribution to that.

Article: 3-D human ‘mini-brains’ shed new light on genetic underpinnings of major mental illness

Major mental illnesses such as schizophrenia, severe depression and bipolar disorder share a common genetic link. Studies of specific families with a history of these types of illnesses have revealed that affected family members share a mutation in the gene DISC1. While researchers have been able to study how DISC1 mutations alter the brain during development in animal models, it has been difficult to find the right tools to study changes in humans. However, advancements in engineering human stem cells are now allowing researchers to grow mini-organs in labs, and gene-editing tools can be used to insert specific mutations into these cells.

Researchers from Brigham and Women’s Hospital are leveraging these new technologies to study the effects of DISC1 mutations in cerebral organoids — “mini brains” — cultured from human stem cells. Their results are published in Translational Psychiatry.

“Mini-brains can help us model brain development,” said senior author Tracy Young-Pearse, PhD, head of the Young-Pearse Lab in the Ann Romney Center for Neurologic Diseases at BWH. “Compared to traditional methods that have allowed us to investigate human cells in culture in two-dimensions, these cultures let us investigate the three-dimensional structure and function of the cells as they are developing, giving us more information than we would get with a traditional cell culture.”

The researchers cultured human induced pluripotent stem cells (iPSCs) to create three-dimensional mini-brains for study. Using the gene editing tool CRISPR-Cas9, they disrupted DISC1, modeling the mutation seen in studies of families suffering from these diseases. The team compared mini-brains grown from stem cells with and without this specific mutation.

DISC1-mutant mini-brains showed significant structural disruptions compared to organoids in which DISC1 was intact. Specifically, the fluid-filled spaces, known as ventricles, in the DISC1-mutant mini-brains were more numerous and smaller than in controls, meaning that while the expected cells are present in the DISC1-mutant, they are not in their expected locations. The DISC1-mutant mini-brains also show increased signaling in the WNT pathway, a pathway known to be important for patterning organs and one that is disrupted in bipolar disorder. By adding an inhibitor of the WNT pathway to the growing DISC1-mutant mini-brains, the researchers were able to “rescue” them — instead of having structural differences, they looked similar to the mini-brains developed from normal stem cells. This suggests that the WNT pathway may be responsible for the observed structural disruption in the DISC1-mutants, and could be a potential target pathway for future therapies.

Metallodrug Effective in “Taming” Antibiotic Resistant Superbugs

Metallodrugs are pharmaceuticals that use metal as an active ingredient, and according to the research, this one is able to substantially reduce the dangerous advancement of antibiotic resistance. More hospitals and medical researchers should therefore know about this.

Antimicrobial resistance posed by “superbugs” has been a major public health issue of global concern. Drug-resistant infections kill around 700,000 people worldwide each year. The figure could increase up to ten million by 2050, exceeding the number of deaths caused by cancers, according to figures of the World Health Organization (WHO).

Current clinical options for treating antibiotic resistant infections include increasing the prescribed antibiotic dose or using a combination therapy of two or more antibiotics. This might potentially lead to overuse of antibiotics, producing superbugs more resistant to antibiotics. Nevertheless, the development of antibiotic resistance far outruns the approvals of new antibacterial agents. While it may take a decade and cost an unusual high investment of USD 1 billion in average to bring a new drug to market, generating resistance to a new drug only requires a short couple of years by bacteria. Scientists and clinicians are in desperate need to discover an economic, effective, safe alternative strategy to meet the global public health challenge of antimicrobial resistance.

A research team led by Professor Sun Hongzhe of the Department of Chemistry, Faculty of Science and Dr Richard Kao Yi-Tsun of the Department of Microbiology, Li Ka Shing Faculty of Medicine, the University of Hong Kong (HKU) discovered an alternative strategy by repositioning colloidal bismuth subcitrate (CBS), an antimicrobial drug against Helicobacter pylori (H. pylori) -related ulcer.

They found the bismuth-based metallodrug to effectively paralyze multi-resistant superbugs, e.g. Carbapenem-resistant Enterobacteriaceae (CRE) and Carbapenem-resistant Klebsiella pneumoniae (CRKP) and significantly suppress the development of antibiotic resistance, allowing the lifespan of currently-used antibiotic to be largely extended. CRE and CRKP can cause deadly infections such as bacteremia, pneumonia, and wound infections.

The team is the first globally to link the “resistance-proof” ability of metallo-drug to the treatment of superbugs. This bismuth drug-based therapy looks set to become the last-line strategy against superbugs infections apart from development of new antibiotics. Since CBS is a US Food and Drug Administration (FDA)-approved drug, it will hopefully be rapidly ready for human clinical trials.

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More importantly, the brand-new therapy allows the dose of antibiotics to be reduced by 90% to attain the same level of effectiveness, and the development of NDM-1 resistance to be significantly slowed down, which will largely extend the life cycle of currently used antibiotics.

In the mouse model of NDM-1 bacterial infection, combination therapy comprising CBS and Carbapenem significantly prolonged the life expectancy and raised the eventual survival rate of infected mice by more than 25 percentage points compared to Carbapenem monotherapy. The research team now concentrates on using CBS-based therapy in other animal infection models, e.g. urinary tract infection (UTI), hoping to offer a more extensive approach to combat with antibiotic resistant superbugs.

Dr Ho found the results very encouraging, he said: “There is currently no effective approach to overcome the NDM superbug. Bismuth has been used clinically for decades. Knowing that it can tame the NDM is like “a good rain after a long drought” for the scientific community.”

Artificial Mole as Early Cancer Detection in Development

For those of you who aren’t enthused about some of the other modern methods of cancer screenings, this artificial mole will possibly provide another avenue sometime in the next several years or so.

Alongside cardiovascular disease, cancer has become the top cause of death in industrialised countries. Many of those affected are diagnosed only after the tumour has developed extensively. This often reduces the chance of recovery significantly: the cure rate for prostate cancer is 32 percent and only 11 percent for colon cancer. The ability to detect such tumours reliably and early would not only save lives, but also reduce the need for expensive, stressful treatment.

Researchers working with Martin Fussenegger, Professor at the Department of Biosystems Science and Engineering at ETH Zurich in Basel, have now presented a possible solution for this problem: a synthetic gene network that serves as an early warning system. It recognises the four most common types of cancer — prostate, lung, colon and breast cancer — at a very early stage, namely when the level of calcium in the blood is elevated due to the developing tumour.

The early warning system comprises a genetic network that biotechnologists integrate into human body cells, which in turn are inserted into an implant. This encapsulated gene network is then implanted under the skin where it constantly monitors the blood calcium level.

As soon as the calcium level exceeds a particular threshold value over a longer period of time, a signal cascade is triggered that initiates production of the body’s tanning pigment melanin in the genetically modified cells. The skin then forms a brown mole that is visible to the naked eye.

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The researchers used calcium as the indicator of the development of the four types of cancer, as it is regulated strongly in the body. Bones serve as a buffer that can balance out concentration differences. However, when too much calcium is detected in the blood, this may serve as a sign for one of the four cancers.

“Early detection increases the chance of survival significantly,” says Fussenegger. For example, if breast cancer is detected early, the chance of recovery is 98 percent; however, if the tumour is diagnosed too late, only one in four women has a good chance of recovery. “Nowadays, people generally go to the doctor only when the tumour begins to cause problems. Unfortunately, by that point it is often too late.”

The implant also has an additional advantage: “It is intended primarily for self-monitoring, making it very cost effective,” explains the ETH professor.

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So far, this early warning implant is a prototype; the associated work recently published in the journal Science Translational Medicine is a feasibility study. The researchers have tested their early warning system in a mouse model and on pig skin. It functioned reliably during these tests. Moles developed only when the calcium concentration reached a high level.

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The concept of the “biomedical tattoo,” as Fussenegger describes this new finding, would also be applicable to other gradually developing illnesses, such as neurodegenerative diseases and hormonal disorders. In principle, the researchers could replace the molecular sensor to measure biomarkers other than calcium.

Ketamine Nasal Spray Shows Effectiveness at Treating Major Depression and Suicidal Thoughts

There’s definitely something to be said about ketamine’s apparent effectiveness at immediately making many suicidal people no longer want to end their lives. The importance of caution in using it should be noted though.

A nasal spray formulation of ketamine shows promise in the rapid treatment of symptoms of major depression and suicidal thoughts, according to a new study published online today in The American Journal of Psychiatry (AJP).

The double-blind study compared the standard treatment plus an intranasal formulation of esketamine, part of the ketamine molecule, to standard treatment plus a placebo for rapid treatment of symptoms of major depression, including suicidality, among individuals at imminent suicide risk. The study involved 68 participants randomly assigned to one of two groups — either receiving esketamine or placebo twice a week for four weeks. All participants continued to receive treatment with antidepressants throughout. The researchers looked at effects at four hours after first treatment, at 24 hours and at 25 days.

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The results of the study support nasal spray esketamine as a possible effective rapid treatment for depressive symptoms in patients assessed to be at imminent risk for suicide, according to the authors. Esketamine could be an important treatment to bridge the gap that exists because of the delayed effect of most common antidepressants. Most antidepressants take four to six weeks to become fully effective.

This study was a proof-of-concept, phase 2, study for esketamine; it must still go through a phase 3 study before possible FDA approval. It was funded by Janssen Research and Development, LLC.

The authors caution that more research is needed on the potential for abuse of ketamine. That caution is also the focus of an accompanying AJP editorial also published online today. In the editorial, AJP Editor Robert Freedman, M.D., along with members of the AJP Editorial Board, note the known potential for abuse and existing reports of abuse of prescribed ketamine. They discuss the need for additional research relating to the abuse potential of ketamine during phase 3 trials, such as monitoring of patients’ craving and potential ketamine use from other sources.

While it is the responsibility of physicians to provide a suicidal patient with the fullest range of effective interventions, the AJP Editor’s note, “protection of the public’s health is part of our responsibility as well, and as physicians, we are responsible for preventing new drug epidemics.” The Editors suggest the need for broad input in the development of effective controls on the distribution and use of ketamine.

Raw Fruits and Vegetables May Provide Better Mental Health Outcomes

Mental health problems are a really significant undercurrent issue in countries across the world today, and so even more minor studies like this can be helpful at addressing them.

Seeking the feel good factor? Go natural.

That is the simple message from University of Otago researchers who have discovered raw fruit and vegetables may be better for your mental health than cooked, canned and processed fruit and vegetables.

Dr Tamlin Conner, Psychology Senior Lecturer and lead author, says public health campaigns have historically focused on aspects of quantity for the consumption of fruit and vegetables (such as 5+ a day).

However, the study, just published in Frontiers in Psychology, found that for mental health in particular, it may also be important to consider the way in which produce was prepared and consumed.

“Our research has highlighted that the consumption of fruit and vegetables in their ‘unmodified’ state is more strongly associated with better mental health compared to cooked/canned/processed fruit and vegetables,” she says.

Dr Conner believes this could be because the cooking and processing of fruit and vegetables has the potential to diminish nutrient levels.

“This likely limits the delivery of nutrients that are essential for optimal emotional functioning.”

For the study, more than 400 young adults from New Zealand and the United States aged 18 to 25 were surveyed. This age group was chosen as young adults typically have the lowest fruit and vegetable consumption of all age groups and are at high risk for mental health disorders.

The group’s typical consumption of raw versus cooked and processed fruits and vegetables were assessed, alongside their negative and positive mental health, and lifestyle and demographic variables that could affect the association between fruit and vegetable intake and mental health (such as exercise, sleep, unhealthy diet, chronic health conditions, socioeconomic status, ethnicity, and gender).

“Controlling for the covariates, raw fruit and vegetable consumption predicted lower levels of mental illness symptomology, such as depression, and improved levels of psychological wellbeing including positive mood, life satisfaction and flourishing. These mental health benefits were significantly reduced for cooked, canned, and processed fruits and vegetables.

“This research is increasingly vital as lifestyle approaches such as dietary change may provide an accessible, safe, and adjuvant approach to improving mental health,” Dr Conner says.

* The top 10 raw foods related to better mental health were: carrots, bananas, apples, dark leafy greens such as spinach, grapefruit, lettuce, citrus fruits, fresh berries, cucumber, and kiwifruit.

Quality of Audio Recordings is Possibly Important for Assessing Scientific Information

Kind of daunting if significantly true, but truth tellers should be aware of this as they face well-funded corporate propaganda machines. From what I know about sound quality, the rooms that are recorded in can actually make a substantial difference based on the texture of the floors and walls. That’s probably why rooms specifically designed for audio recording can easily cost thousands of dollars, but I do also think that a lot of people have a better BS detector than this study would suggest.

Separating fact from fiction in the age of alternate facts is becoming increasingly difficult, and now a new study has helped reveal why. Research by Dr Eryn Newman of The Australian National University (ANU) has found that when people listen to recordings of a scientist presenting their work, the quality of audio had a significant impact on whether people believed what they were hearing, regardless of who the researcher was or what they were talking about.

Dr Newman, of the ANU Research School of Psychology, said the results showed when it comes to communicating science, style can triumph over substance.

“When people are assessing the credibility of information, most of the time people are making a judgement based on how something feels,” Dr Newman said. “Our results showed that when the sound quality was poor, the participants thought the researcher wasn’t as intelligent, they didn’t like them as much and found their research less important.”

The study used experiments where people viewed video clips of scientists speaking at conferences. One group of participants heard the recordings in clear high-quality audio, while the other group heard the same recordings with poor-quality audio.

Participants were then asked to evaluate the researchers and their work. Those who listened to the poorer quality audio consistently evaluated the scientists as less intelligent and their research as less important.

In a second experiment, researchers upped the ante and conducted the same experiment using renowned scientists discussing their work on the well-known US Science Friday radio program. This time the recordings included audio of the scientists being introduced with their qualifications and institutional affiliations.”It made no difference,” she said. “As soon as we reduced the audio quality, all of a sudden the scientists and their research lost credibility.”

As with the first experiments, participants thought the research was worse, the scientists were less competent and they also reported finding their work less interesting.

Dr Newman said in a time when genuine science is struggling to be heard above fake news and alternate facts, researchers need to consider not only the content of their messages, but features of the delivery.

“Another recent study showed false information travels six times faster than real information on Twitter,” she said.”Our results show that it’s not just about who you are and what you are saying, it’s about how your work is presented.”

Vaccines to Treat Opioid Abuse and Prevent Overdoses in Development

It should be beneficial once it’s developed. For today, it’s not widely known, but needles aren’t the only way to deliver Narcan (what’s used to respond to opioid overdoses) — there’s actually a nasal spray that exists now too.

Heroin and prescription opioid abuse and fatal overdoses are a public health emergency in the United States. Vaccines offer a potential new strategy to treat opioid abuse and prevent fatal opioid overdoses.
A team of scientists from the University of Minnesota Medical School and Minneapolis Medical Research Foundation at Hennepin Healthcare is developing vaccines against heroin and prescription opioids, such as oxycodone and fentanyl. These vaccines function by using the immune system to produce molecules (antibodies) that target, bind, and prevent opioids from reaching the brain (the site of drug action).
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Pre-clinical studies show that both heroin and oxycodone vaccines are effective in blocking heroin and oxycodone distribution to the brain when subjects are challenged with clinically-relevant opioid doses. Vaccination prevents addiction-relevant behaviors, including opioid self-administration that models human abuse patterns. These vaccines appear to be safe and may help in preventing opioid-induced respiratory depression, a hallmark of an opioid fatal overdose.

Importantly, vaccination does not prevent use of currently approved addiction treatment medications such as methadone, naltrexone, buprenorphine, and naloxone.

The research team is also working on biologics against other opioid targets, such as fentanyl, and developing more effective next-generation vaccine formulations.

“Opioid vaccines show promising pre-clinical efficacy, but the road from the laboratory to the clinic is still long,” said Principal Investigator Marco Pravetoni, Ph.D., Minneapolis Medical Research Foundation senior investigator and associate professor of medicine at the University of Minnesota Medical School.