White House seeks input on tightening rules for risky pathogen research

 A panel’s recommendations earlier this year to tighten U.S. rules for funding research on dangerous pathogens sparked concerns that some of the changes would hamper routine studies important to public health. Now, the White House is looking at ways to narrow the swath of federally funded research that would undergo the heightened reviews proposed in a final report released in March by the National Science Advisory Board for Biosecurity (NSABB).

A notice posted today in the Federal Register by the Office of Science and Technology Policy (OSTP) seeks comments by 16 October on a range of issues, including the following.

Dual-use research

Current U.S. policy on pathogen research requires special reviews by local institutional committees and funding agencies if the proposed studies are considered “dual-use research of concern” (DURC)—the results from them could, in theory, be used to cause harm. The existing policy covers just seven types of experiments, such as those that would make a pathogen resistant to drugs, involving only 15 pathogens or their toxins.

But NSABB recommended expanding the reviews beyond those 15 “select agents” to cover proposals to study any human, animal, or plant pathogen in the seven types of experiments. One scientist has called this “a potential for disaster” because it would require reviews of routine, relatively low-risk studies, such as certain experiments on cold viruses and viruses modified to fight cancer.

Today’s White House notice suggests that, instead, institutions could limit DURC reviews to the standard select agents and other pathogens so risky that they must be studied in facilities with the highest biocontainment conditions, known as biosafety level-3 and biosafety level-4 laboratories.

Gain of function

An existing Department of Health and Human Services (HHS) policy, known as the Potential Pandemic Pathogen Care and Oversight (P3CO) framework, requires a high-level government review of potential gain-of-function (GOF) research, where the concern is that scientists may modify already dangerous pathogens in ways that make them riskier. It currently limits such reviews to pathogens that are likely to be both highly transmissible and highly virulent, such as certain experiments with H5N1 avian influenza

NSABB recommended expanding the HHS policy to include pathogens that are only “moderately” transmissible and/or virulent. Supporters of that idea note, for example, that the SARS-CoV-2 virus is not covered by the policy because it kills less than 1% of people it infects. Such examples underscore the idea that even moderately virulent pathogens can cause a global pandemic, backers of expanding the policy say. Like the DURC proposals, however, the recommendation has drawn an outcry from microbiologists concerned about overreach.

To limit the P3CO policy, the White House notice suggests including only respiratory pathogens, which can be spread through the air or in saliva droplets. But that change would exclude research on deadly viruses such as Ebola, which is transmitted by contact with body fluids, and the less potent but fast-spreading strain of mpox that spread globally this year mainly through sexual contact. (A proposed GOF experiment on mpox has stirred controversy in the past year.)

Vaccine and surveillance research

The current P3CO policy exempts from review GOF studies involving pathogen surveillance, such as monitoring of flu viruses in wildlife, and vaccine development or production. For example, vaccine developers must create versions of viruses that grow well in cells to make vaccines. And to find out whether SARS-CoV-2 vaccines will work against new variants, company researchers have added the surface protein from those variants to the original SAR-CoV-2 virus.

NSABB recommends removing this exemption. Critics of that move worry it would impede the public health response to pandemics. The White House notice asks for feedback on whether some exemptions should remain, for example for vaccine production.

The definition of “reasonably anticipated”

The current DURC and P3CO definitions cover studies “reasonably anticipated” to result in some undesirable outcome, such as creation of a potential pandemic pathogen. Some policy experts and a federal watchdog have said the “reasonably anticipated” standard is too vague.

The OSTP notice suggests a lengthy definition for “reasonably anticipated” that specifies that “an individual with scientific expertise relevant to the research in question would expect this outcome.” Although the definition would “not require high confidence that the outcome will definitely occur,” it would exclude “technically possible, but highly unlikely” outcomes.

The White House also seeks input on adding “in silico” research to the policies, which would cover efforts using computers to design a new, dangerous pathogen. The final DURC and P3CO policies are due out in December.

The American Society for Microbiology, which has raised concerns about the NSABB recommendations, “welcomes the RFI [request for information] and the opportunity it offers for the community to weigh in on how the NSABB recommendations could be implemented and how current policies, grounded in science, should be updated to enable vital research on pathogens in the U.S. to continue while ensuring appropriate oversight and security guardrails,” says Mary Lee Watts, director of federal affairs for the society.

https://www.science.org/content/article/white-house-seeks-input-tightening-rules-risky-pathogen-research

New breakthrough in obesity research

 A significant development  brings hope to the one billion individuals with obesity worldwide. Researchers led by Director C. Justin LEE from the Center for Cognition and Sociality (CCS) within the Institute for Basic Science (IBS) have discovered new insights into the regulation of fat metabolism. The focus of their study lies within the star-shaped non-neuronal cells in the brain, known as 'astrocytes'. Furthermore, the group announced successful animal experiments using the newly developed drug 'KDS2010', which allowed the mice to successfully achieve weight loss without resorting to dietary restrictions.

The complex balance between food intake and energy expenditure is overseen by the hypothalamus in the brain. While it has been known that the neurons in the lateral hypothalamus are connected to fat tissue and are involved in fat metabolism, their exact role in fat metabolism regulation has remained a mystery. The researchers discovered a cluster of neurons in the hypothalamus that specifically express the receptor for the inhibitory neurotransmitter 'GABA (Gamma-Aminobutyric Acid)'. This cluster has been found to be associated with the α5 subunit of the GABAA receptor and was hence named the GABRA5 cluster.

In a diet-induced obese mouse model, the researchers observed significant slowing in the pacemaker firing of the GABRA5 neurons. Researchers continued with the study by attempting to inhibit the activity of these GABRA5 neurons using chemogenetic methods. This in turn caused a reduction in heat production (energy consumption) in the brown fat tissue, leading to fat accumulation and weight gain. On the other hand, when the GABRA5 neurons in the hypothalamus were activated, the mice were able to achieve a successful weight reduction. This suggests that the GABRA5 neurons may act as a switch for weight regulation.

In a new surprising and unexpected turn of events, the research team discovered that the astrocytes in the lateral hypothalamus regulate the activity of the GABRA5 neurons. The numbers and sizes of the reactive astrocytes are increased, and they begin to overexpress the MAO-B enzyme (Monoamine Oxidase B). This enzyme plays a crucial role in the metabolism of neurotransmitters in the nervous system and is more predominantly expressed in reactive astrocytes. This ends up in the production of a large amount of tonic GABA (Gamma-Aminobutyric Acid), which inhibits the surrounding GABRA5 neurons.

It was also discovered that suppressing the expression of the MAO-B gene in reactive astrocytes can decrease GABA secretion, thereby reversing the undesirable inhibition of the GABRA5 neurons. Using this approach the researchers were able to increase the heat production in the fat tissue of the obese mice, which allowed them to achieve weight loss even while consuming a high-calorie diet. This experimentally proves that the MAO-B enzyme in reactive astrocytes can be an effective target for obesity treatment without compromising appetite.

Furthermore, a selective and reversible MAO-B inhibitor, 'KDS2010', which was transferred to a biotech company Neurobiogen in 2019 and is currently undergoing Phase 1 clinical trials, was tested on an obese mouse model. The new drugs yielded remarkable results, demonstrating a substantial reduction in fat accumulation and weight without any impacts on the amount of food intake.

Postdoctoral researcher SA Moonsun said, "Previous obesity treatments targeting the hypothalamus mainly focused on neuronal mechanisms related to appetite regulation." She added, "To overcome this, we focused on the non-neuronal 'astrocytes' and identified that reactive astrocytes are the cause of obesity."

Center Director C. Justin LEE also said, "Given that obesity has been designated by the World Health Organization (WHO) as the '21st-century emerging infectious disease,' we look to KDS2010 as a potential next-generation obesity treatment that can effectively combat obesity without suppressing appetite."

Journal Reference:

1. Moonsun Sa, Eun-Seon Yoo, Wuhyun Koh, Mingu Gordon Park, Hyun-Jun Jang, Yong Ryoul Yang, Mridula Bhalla, Jae-Hun Lee, Jiwoon Lim, Woojin Won, Jea Kwon, Joon-Ho Kwon, Yejin Seong, Byungeun Kim, Heeyoung An, Seung Eun Lee, Ki Duk Park, Pann-Ghill Suh, Jong-Woo Sohn, C. Justin Lee. Hypothalamic GABRA5-positive neurons control obesity via astrocytic GABA. Nature Metabolism, 2023; DOI: 10.1038/s42255-023-00877-w

https://www.sciencedaily.com/releases/2023/08/230831121624.htm

Radiologists must monitor novel Alzheimer's treatment side effect

 A new article published in RadioGraphics, a journal of the Radiological Society of North America (RSNA), examines the use of monoclonal antibody therapies for treating Alzheimer disease and alerts physicians to be on the lookout for a potential side effect: amyloid-related imaging abnormalities (ARIA).

Alzheimer disease is a progressive, irreversible brain disorder that slowly degrades memory and cognitive function. It is the most common form of dementia worldwide. While previous treatment methods focused on addressing Alzheimer disease symptoms, recent approvals of monoclonal antibodies have provided a path to target the underlying disease itself.

The main pathologic feature of Alzheimer disease is a buildup of toxic amyloid-B. Disease-modifying drugs like monoclonal antibodies work by clearing toxic amyloid-B protein from the brain. In June 2021, the U.S. Food and Drug Administration (FDA) gave accelerated approval for aducanumab (Aduhelm) as a treatment for Alzheimer disease. The FDA has determined that there is substantial evidence that aducanumab reduces amyloid-B plaques in the brain and that the reduction in these plaques is likely to result in benefits to patients.

"FDA-approved drugs such as aducanumab, as well as upcoming newer-generation drugs, have provided an exciting new therapy focused on reducing the amyloid plaque burden in Alzheimer disease," said Amit K. Agarwal, M.B.B.S., M.D., lead author of the article and neuroradiologist at Mayo Clinic in Jacksonville, Florida.

Although this groundbreaking new therapy has shown benefits in Alzheimer's patients, it is not without complications. Increased use of monoclonal antibodies led to the discovery of amyloid-related imaging abnormalities (ARIA). The abnormalities have been further classified into two categories, ARIA-E, representing edema (swelling) and/or effusion, and ARIA-H, representing hemorrhage. ARIA is thought to be caused by increased vascular permeability following an inflammatory response, leading to the leakage of blood products and fluid into surrounding tissues.

Patients with ARIA sometimes have headaches, but they are usually asymptomatic and only diagnosable with MRI.

"It is essential for the radiologist to recognize and monitor ARIA," Dr. Agarwal said. "As the use of monoclonal antibodies becomes more widespread, close collaboration between neurologists and radiologists is needed before and during therapy to plan for image monitoring per established guidelines."

ARIA-E is the most common side effect of monoclonal antibody treatment. In two phase III trials, 35% of patients on the approved dose had ARIA-E. These trials also showed that most ARIA-E cases were clinically asymptomatic and that 98% were resolved at follow-up imaging. ARIA-E occurred most frequently between three and six months of treatment, with incidence sharply dropping after the first nine months. ARIA-H typically occurs in about 15 to 20% of patients treated with monoclonal antibodies. Unlike ARIA-E, ARIA-H is not transient and does not resolve over time.

Most patients with asymptomatic ARIA meeting specific radiographic and clinical criteria may continue to receive treatment. The vast majority of patients with ARIA-E can continue therapy either with or without temporary suspension. However, in ARIA-H patients, therapy decisions depend on the severity of ARIA-H and whether it is stabilized. The detection of 10 or more new microhemorrhages requires permanent discontinuation of therapy.

"Immunotherapy is becoming more prevalent in managing dementia, and the recently approved monoclonal antibody therapy offers an exciting new frontier," Dr. Agarwal said. "Identifying and monitoring ARIA plays a vital role in safety monitoring and management decisions in anti-amyloid monoclonal antibody trials and clinical practice."

According to Dr. Agarwal, when ARIA is present, a conservative monitoring plan should be established with a multidisciplinary approach that includes neurologists and radiologists familiar with the clinical and imaging aspects of the condition.

Journal Reference:

1. Amit Agarwal, Vivek Gupta, Pavan Brahmbhatt, Amit Desai, Prasanna Vibhute, Nelly Joseph-Mathurin, Girish Bathla. Amyloid-related Imaging Abnormalities in Alzheimer Disease Treated with Anti–Amyloid-β Therapy. RadioGraphics, 2023; 43 (9) DOI: 10.1148/rg.230009

https://www.sciencedaily.com/releases/2023/08/230831142812.htm

Antioxidants stimulate blood flow in tumors

 Vitamin C and other antioxidants stimulate the formation of new blood vessels in lung cancer tumours, a new study from Karolinska Institutet published in The Journal of Clinical Investigation shows. The discovery corroborates the idea that dietary supplements containing antioxidants can accelerate tumour growth and metastasis.

"We've found that antioxidants activate a mechanism that causes cancer tumours to form new blood vessels, which is surprising, since it was previously thought that antioxidants have a protective effect," says study leader Martin Bergö, professor at the Department of Biosciences and Nutrition and vice president of Karolinska Institutet in Sweden. "The new blood vessels nourish the tumours and can help them grow and spread."

Antioxidants neutralise free oxygen radicals, which can damage the body, and are therefore commonly found in dietary supplements. But overly high doses can be harmful.

"There's no need to fear antioxidants in normal food but most people don't need additional amounts of them," says Professor Bergö. "In fact, it can be harmful for cancer patients and people with an elevated cancer risk."

Previously unknown mechanism

Professor Bergö's research group has previously shown that antioxidants like vitamin C and E accelerate the growth and spread of lung cancer by stabilising a protein called BACH1. BACH1 is activated when the level of free oxygen radicals drops, which happens, for example, when extra antioxidants are introduced via the diet or when spontaneous mutations in the tumour cells activate endogenous antioxidants. Now the researchers have been able to show that the activation of BACH1 induces the formation of new blood vessels (angiogenesis).

While low oxygen levels (hypoxia) are known to be required for angiogenesis to occur in cancer tumours, the new mechanism identified by the researchers demonstrates that tumours can form new blood vessels in the presence of normal oxygen levels as well. The study also shows that BACH1 is regulated in a similar way as the HIF-1α protein -- a mechanism that was awarded the 2019 Nobel Prize in Physiology or Medicine and that allows cells to adapt to changes in oxygen levels. HIF-1α and BACH1 work together in the tumours, the new research shows.Hoping for more effective drugs

"Many clinical trials have evaluated the efficacy of angiogenesis inhibitors, but the results have not been as successful as anticipated," says Ting Wang, doctoral student in Professor Bergö's group at Karolinska Institutet. "Our study opens the door to more effective ways of preventing angiogenesis in tumours; for example, patients whose tumours exhibit high levels of BACH1 might benefit more from anti-angiogensis therapy than patients with low BACH1 levels."

The researchers used a range of cell-biological methods and concentrated most of their work on lung cancer tumours by studying organoids -- small cultivated microtumours from patients. But they also studied mice and samples of human breast and kidney tumours. Tumours in which BACH1 was activated, either via ingested antioxidants or by overexpression of the BACH1 gene, produced more new blood vessels and were highly sensitive to angiogenesis inhibitors.

"The next step is to examine in detail how levels of oxygen and free radicals can regulate the BACH1 protein, and we will continue to determine the clinical relevance of our results," says Ting Wang. "We'll also be doing similar studies in other cancer forms such as breast, kidney and skin cancer."

The study was conducted in close collaboration with KI researchers Susanne Schlisio, Staffan Strömblad and Eckardt Treuter and researchers at the First Affiliated Hospital of Zhengzhou University. The research was financed primarily by grants from the Swedish Cancer Society, the Swedish Research Council, the Sjöberg Foundation, the Knut and Alice Wallenberg Foundation, the Centre for Innovative Medicine (CIMED) and Karolinska Institutet. There are no reported conflicts of interest.

Journal Reference:

1. Ting Wang, Yongqiang Dong, Zhiqiang Huang, Guoqing Zhang, Ying Zhao, Haidong Yao, Jianjiang Hu, Elin Tüksammel, Huan Cai, Ning Liang, Xiufeng Xu, Xijie Yang, Sarah Schmidt, Xi Qiao, Susanne Schlisio, Staffan Strömblad, Hong Qian, Changtao Jiang, Eckardt Treuter, Martin O. Bergo. Antioxidants stimulate BACH1-dependent tumor angiogenesis. Journal of Clinical Investigation, 2023; DOI: 10.1172/JCI169671

https://www.sciencedaily.com/releases/2023/08/230831142816.htm

Red blood cells exposed to oxygen deficiency protect against myocardial infarction

Red blood cells exposed to oxygen deficiency protect against myocardial infarction, according to a new KI study published in the Journal of Clinical Investigation. The study also shows that the protective effect is enhanced by a nitrate-rich vegetable diet.

Red blood cells carry oxygen from the lungs to all of the body's cells and carbon dioxide back to the lungs. A new study, conducted at Karolinska Institutet in collaboration with Karolinska University Hospital, now shows that red blood cells have an intrinsic function of protecting against heart injury caused by myocardial infarction.

The effect is enhanced by a diet containing nitrate-rich vegetables, such as arugula and other green leafy vegetables.

"This effect was also shown in a clinical study in patients with high blood pressure who were randomly assigned to eat nitrate-rich vegetables or a diet low in nitrates," says John Pernow, Professor of Cardiology at the Department of Medicine, Karolinska Institutet in Solna and senior physician at Karolinska University Hospital, and the study's corresponding author together with Jon Lundberg, professor at the Department of Physiology and Pharmacology, Karolinska Institutet.

Part of the study was conducted through experiments with red blood cells from mice that were added to a myocardial infarction model with hearts from mice. Before the experiment, the red blood cells were exposed to low oxygen pressure, while nitrate was added to the drinking water.

In a clinical study, red blood cells were collected from patients with high blood pressure who were randomly assigned a nitrate-rich diet with green leafy vegetables or a diet with nitrate-poor vegetables. These red blood cells were given to the corresponding myocardial infarction model with hearts from rats.

"The results show both that the red blood cells convey protection against injury in the heart in the event of low oxygen levels, and how that protection can be enhanced through a simple dietary advice. This may be of great importance for patients at risk of myocardial infarction," says the study's first author Jiangning Yang, a researcher at the Department of Medicine, Solna, Karolinska Institutet.

The next step in the research is to develop additional drugs that can activate the protective signalling mechanism in red blood cells to provide protection to the body's tissues and cells in the event of oxygen deficiency.

"In addition, we need to map how the blood cells transmit their protective signal to the heart muscle cells," says John Pernow.

The study is a collaboration between researchers from, among others, Karolinska Institutet, Karolinska University Hospital, Tohoku University, Japan, Heinrich-Heine-University, Germany, and Ruhr-University Bochum, Germany.

The research was funded by the Swedish Heart-Lung Foundation, the Swedish Research Council and Region Stockholm's ALF project funds. Jon Lundberg and Eddie Weitzberg hold patents related to therapies based on inorganic nitrate. Other researchers report no conflicts of interest.

Journal Reference:

1. Jiangning Yang, Michaela L. Sundqvist, Xiaowei Zheng, Tong Jiao, Aida Collado, Yahor Tratsiakovich, Ali Mahdi, John Tengbom, Evanthia Mergia, Sergiu-Bogdan Catrina, Zhichao Zhou, Mattias Carlström, Takaaki Akaike, Miriam M. Cortese-Krott, Eddie Weitzberg, Jon O. Lundberg, John Pernow. Hypoxic erythrocytes mediate cardioprotection through activation of soluble guanylate cyclase and release of cyclic GMP. Journal of Clinical Investigation, 2023; 133 (17) DOI: 10.1172/JCI167693

https://www.sciencedaily.com/releases/2023/09/230901124039.htm

Link between memory and appetite in human brain may help explain obesity

 Disrupted connections between memory and appetite regulating brain circuits are directly proportional to body mass index (BMI), notably in patients who suffer from disordered or overeating that can lead to obesity, such as binge eating disorder (BED), according to new research from the Perelman School of Medicine at the University of Pennsylvania. Published today in Nature, the research notes that individuals who are obese have impaired connections between the dorsolateral hippocampus (dlHPC) and the lateral hypothalamus (LH), which may impact their ability to control or regulate emotional responses when anticipating rewarding meals or treats.

"These findings underscore that some individual's brains can be fundamentally different in regions that increase the risk for obesity," senior author, Casey Halpern, MD, an associate professor of Neurosurgery and Chief of Stereotactic and Functional Neurosurgery at Penn Medicine and the Corporal Michael J. Crescenz Veterans Affairs Medical Center. "Conditions like disordered eating and obesity are a lot more complicated than simply managing self-control and eating healthier. What these individuals need is not more willpower, but the therapeutic equivalent of an electrician that can make right these connections inside their brain."

The dlHPC is located in the region of the brain that processes memory, and the LH is in the region of the brain that is responsible for keeping the body in a stable state, called homeostasis. Previous research has found an association with loss of function in the human hippocampus in individuals with obesity and related disordered eating, like BED. However, outside of imaging techniques such as magnetic resonance imaging (MRI), the role of the hippocampus has been difficult to study in humans with obesity and related eating disorders.

In this study, researchers were able to evaluate patients whose brains were already being monitored electrically in the Epilepsy Monitoring Unit. Researchers monitored brain activity as patients anticipated and then received a sweet treat (a chocolate milkshake). They found that both the dlHPC and the LH activated simultaneously when participants anticipated receiving the rewarding meal. These researchers confirmed using stimulation techniques pioneered by coauthors, Kai Miller, MD, PhD, and Dora Hermes Miller, PhD, from Mayo Clinic, that this specific zone of the hippocampus, the dlHPC, and LH exhibited extremely strong connectivity, as well.

In individuals with obesity, researchers found that the impairment of this hypothalamus-hippocampus circuit was directly proportional to their BMI. That is, in participants with a high BMI, the connection was even more disturbed.

To further validate the connection, Halpern's team used a technique called "brain clearing," to analyze brain tissue. The technique revealed melanin-concentrating hormone, a hormone known to regulate feeding behavior that is produced in the LH. They found the presence of MCH in the dlHPC, and nowhere else, confirming a link between the two regions.

"The hippocampus has never been targeted to treat obesity, or the disordered eating that can sometimes cause obesity," said Halpern. "We hope to be able to use this research to both identify which individuals who are likely to develop obesity later in life, and to develop novel therapies -- both invasive and not -- to help improve function of this critical circuit that seems to go awry in patients who are obese."

This research was funded by the Foundation for OCD Research, the National Institute of Health (R01 MH124760, K23 MH106794, R01 NS095985), the Natural Sciences and Engineering Research Council of Canada (#40306) and the Canadian Institutes of Health Research (#41916).

Journal Reference:

1. Daniel A. N. Barbosa, Sandra Gattas, Juliana S. Salgado, Fiene Marie Kuijper, Allan R. Wang, Yuhao Huang, Bina Kakusa, Christoph Leuze, Artur Luczak, Paul Rapp, Robert C. Malenka, Dora Hermes, Kai J. Miller, Boris D. Heifets, Cara Bohon, Jennifer A. McNab, Casey H. Halpern. An orexigenic subnetwork within the human hippocampus. Nature, 2023; DOI: 10.1038/s41586-023-06459-w

https://www.sciencedaily.com/releases/2023/08/230830131943.htm

'Dem hopes for Michelle Obama in 2024 another sign of Biden’s vulnerability'

Michelle Obama’s name keeps surfacing on the wish list of some Democrats as an alternative to President Biden in 2024, an aberration that conservatives say is partly driven by fear among liberals and the media that probes of Hunter Biden will turn up more damaging information about the Biden family’s finances before the election.

Polls consistently show at least half of Democratic voters don’t want Mr. Biden, at age 80 already the nation’s oldest president, to run for a second term. The level of dissatisfaction has remained high as fresh allegations emerge that he may have been involved in pay-to-play influence through his son’s foreign business deals.

Even if Mr. Biden does drop out, there’s no emerging consensus on who should replace him. Even less support exists in the party for alternatives such as California Gov. Gavin Newsom, Vice President Kamala Harris and Transportation Secretary Pete Buttigieg.

Some anxious Democrats keep returning to the notion of Mrs. Obama, who was generally more popular among Democrats than her husband during their eight years in the White House.

She remains a favorite among Democrats, more so than Mr. Biden, as shown in a poll last month.

https://www.washingtontimes.com/news/2023/sep/1/some-democrats-keep-hoping-for-michelle-obama-in-2/