And researchers are discovering why. The SARS-CoV-2 virus, like many viruses before it, is bad news for the brain. In a study published Dec.16 in Nature Neuroscience, researchers found that the spike protein, often depicted as the red arms of the virus, can cross the blood-brain barrier in mice.

This strongly suggests that SARS-CoV-2, the cause of COVID-19, can enter the brain.

The spike protein, often called the S1 protein, dictates which cells the virus can enter. Usually, the virus does the same thing as its binding protein, said lead author William A. Banks, a professor of medicine at the University of Washington School of Medicine and a Puget Sound Veterans Affairs Healthcare System physician and researcher. Banks said binding proteins like S1 usually by themselves cause damage as they detach from the virus and cause inflammation.

“The S1 protein likely causes the brain to release cytokines and inflammatory products,” he said.

In science circles, the intense inflammation caused by the COVID-19 infection is called a cytokine storm. The immune system, upon seeing the virus and its proteins, overreacts in its attempt to kill the invading virus. The infected person is left with brain fog, fatigue and other cognitive issues.

Banks and his team saw this reaction with the HIV virus and wanted to see if the same was happening with SARS CoV-2.

Banks said the S1 protein in SARS-CoV2 and the gp 120 protein in HIV-1 function similarly. They are glycoproteins — proteins that have a lot of sugars on them, hallmarks of proteins that bind to other receptors. Both these proteins function as the arms and hand for their viruses by grabbing onto other receptors. Both cross the blood-brain barrier and S1, like gp120, is likely toxic to brain tissues.

“It was like déjà vu,” said Banks, who has done extensive work on HIV-1, gp120, and the blood-brain barrier.

The Banks’ lab studies the blood-brain barrier in Alzheimer’s, obesity, diabetes, and HIV. But they put their work on hold and all 15 people in the lab started their experiments on the S1 protein in April. They enlisted long-time collaborator Jacob Raber, a professor in the departments of Behavioral Neuroscience, Neurology, and Radiation Medicine, and his teams at Oregon Health & Science University.

The study could explain many of the complications from COVID-19.

“We know that when you have the COVID infection you have trouble breathing and that’s because there’s infection in your lung, but an additional explanation is that the virus enters the respiratory centers of the brain and causes problems there as well,” said Banks.

Raber said in their experiments transport of S1 was faster in the olfactory bulb and kidney of males than females. This observation might relate to the increased susceptibility of men to more severe COVID-19 outcomes.

As for people taking the virus lightly, Banks has a message:

“You do not want to mess with this virus,” he said. “Many of the effects that the COVID virus has could be accentuated or perpetuated or even caused by virus getting in the brain and those effects could last for a very long time.”

This study was partially supported by a National Institute on Aging-funded COVID-19 supplement to a shared RF1 grant of Banks and Raber.?

“You don’t get big fish,” said UC Santa Barbara biogeochemist Morgan Raven. “You don’t even get charismatic zooplankton.” But although anoxic oceans may seem alien to organisms like ourselves that breathe oxygen, they’re full of life, she said.

These strange ecosystems are expanding, thanks to climate change — a development that is of concern for fisheries and anyone who relies on oxygen-rich oceans. But what piques Raven’s interest is the changing chemistry of the oceans — the Earth’s largest carbon sink — and how it could move carbon from the atmosphere to long-term reservoirs like rocks.

“What happens to our carbon cycle as we get these large areas of the ocean that are oxygen-free?” she said. This question was central to research conducted by Raven and colleagues Rick Keil (University of Washington) and Samuel Webb (Stanford Linear Accelerator Laboratory) in a paper published in the journal Science.

‘A spinning wheel’

In oxygen-rich oceans, carbon is moved around largely by food web processes that begin with carbon dioxide-fixing phytoplankton that photosynthesize at the water’s surface.

“Most of the time they just get eaten by zooplankton,” Raven said. But if they aren’t eaten by larger animals, they head to the depths where they respire carbon dioxide and excrete organic carbon.

“It’s like a spinning wheel — CO₂ goes to plankton, goes to CO₂,” Raven said.

In the absence of zooplankton and fish, however, more of the sinking organic carbon can survive and be deposited at depth, she said. In fact, sediments under these anoxic zones generally have more organic carbon deposits than their oxygen-rich counterparts. But, according to the researchers, we lack a “full mechanistic understanding” of how this occurs.

“It’s been a bit of a mystery,” Raven said.

The team did have a clue in the form of a hypothesis formed about a decade ago by University of Southern Denmark geologist Don Canfield and colleagues.

“They put out this idea that maybe inside of these zones, microbes are still eating organic carbon, but respiring sulfate,” Raven said. Called “cryptic sulfur cycling,” the idea was somewhat difficult to accept largely because the products of this microbial sulfate reduction (MSR) were difficult to detect, and because other compounds in the area, such as nitrates, were more energetically favorable to metabolize.

However, according to the study, “there is emerging molecular and geochemical evidence that suggests MSR may occur in (oxygen-deficient zones) despite plentiful dissolved nitrate.”

The researchers tested whether this enigmatic process might be hiding inside of large (>1mm), fast-sinking organic particles by collecting particles from the Eastern Tropical North Pacific oxygen-deficient zone, roughly located off the northwestern coast of Mexico.

“It really is just this polymeric, sticky stuff,” Raven said of the aggregations of mostly dead phytoplankton, fecal matter, other small organisms and bits of sand and clay that get glued together in a “fluffy” matrix. Collection of these particles is itself an accomplishment for researchers combing the vast oceans for relatively small, diffuse particles.

“My colleagues from the University of Washington had this collection device that was really the thing that made it possible to do this,” she said. The collected particles were sent to the Stanford Synchotron Radiation Lightsource for analysis.

Pickled phytoplankton

Results of the analysis, such as evidence of the production of organic sulfur within the samples, demonstrate what Raven calls a “pickling” of the dead phytoplankton, as they sink through the anoxic area.

“Phytoplankton grow in the surface ocean, but due to gravity, they sink,” she said. As they fall through the anoxic region, these organic aggregates undergo sulfurization, which has the effect of shielding the carbon at their core from enzymes or other substances that would otherwise wear them away.

“Even when it gets to the sediment, bacteria there can’t eat these organic particles,” noted Raven. And just like the pickles we know and love, the preservation process makes the organic particle resistant to bacteria, she said, which could explain why more organic carbon is found in the sediments below anoxic ocean zones.

Sulfurization of organic carbon particles in anoxic ocean zones, while newly confirmed in modern-day oceans, is actually an ancient process, Raven explained.

“It’s the same process that can also make petroleum,” she said, pointing out that where oilbeds are found, so, too, is sulfur. This process may have been widespread during the Cretaceous period (145.5 to 65.5 million years ago), when the Earth was consistently tropical and the ocean was subject to geologic and mass extinction events that resulted in the burial of massive amounts of carbon, and anoxic waters throughout the Atlantic.

“What we didn’t know is whether this was also going on in these less extreme modern environments,” Raven said.

What remains to be seen is how these growing oxygen depleted zones will interact with climate change.

“Potentially as these zones expand, there could be a negative feedback — more CO₂ in the atmosphere makes higher temperatures, which makes these zones bigger,” Raven said. “These bigger zones then trap more CO₂ and put it in the sediment and rocks.” This feedback might help the Earth balance its carbon cycle over time, she said, “but we need to know how this connects to everything else.”

The new approach uses natural cancer-targeting immune cells, known as natural killer cells, that have been modified to selectively target lymphoma. As described in their study, published in the journal Angewandte Chemie, the modified natural killer cells brought about a dramatic reduction of lymphoma in a mouse.

“We found a way to achieve selectivity in targeting lymphoma cells, which is an important departure from existing therapies,” says co-senior author Peng Wu, PhD, an associate professor in the Department of Molecular Medicine at Scripps Research.

Wu and his lab collaborated in the study with the lab of co-senior author James Paulson, PhD, the Cecil H. and Ida Green Professor and Chair of the Department of Molecular Medicine at Scripps Research.

More than 20,000 people in the United States die of lymphomas annually, while approximately 85,000 people are newly diagnosed. Most lymphomas arise from B cells, an important type of lymphocyte whose primary function is to make antibodies.

Some existing lymphoma treatments, including B-cell-killing antibodies and so-called CAR-T cell therapies, work by targeting B cells indiscriminately, largely wiping them out. However, this strategy brings many adverse side effects, including months of immunosuppression due to low antibody levels.

Wu, Paulson and their teams have developed a more specific approach using natural killer cells, which are immune cells that normally patrol the bloodstream and tissues, seeking and destroying virus-infected or cancerous cells. These immune-system warriors, also known as NK cells, are able to recognize certain tell-tale surface molecules that signify serious damage or malignancy within a cell; they can then kill that target cell through a variety of means, including by secreting proteins that punch holes in the cell’s outer membrane.

Creating a super-powered NK cell

In the early 1990s, Canadian researchers developed a special type of NK cell, NK-92, from a patient with a rare NK-cell cancer. NK-92 cells are relatively easy to grow and multiply in the lab, compared with normal NK cells found in human blood.

The Canadian researchers and others have since shown that NK-92 cells are good at killing different kinds of cancerous cells, and can bring about dramatic results in some patients, with minimal side effects. NK-92MI cells, an easier-to-multiply version of NK-92 cells, are now being widely investigated for use against various cancers.

On their own, NK-92MI cells may not be ideal cancer-fighters, especially not for advanced malignancies, in part because they are dispersed throughout the body when infused into the bloodstream. In the new study, however, Wu and his team used chemistry techniques to modify NK-92MI cells to concentrate their cancer-fighting power against lymphoma.

Steering powerful cells where they’re needed most

In an initial set of experiments, the Scripps Research scientists re-engineered NK-92MI cells to include a surface molecule that binds to a B-cell surface receptor called CD22, which is normally abundant on B-cell-derived lymphoma cells. Thus, in principle, the NK-92MI cells would selectively recognize cancerous B cells.

In cell-culture tests, the modification brought a big improvement in the NK cells’ ability to kill lymphoma cells, and these killer cells did not harm healthy cells. In a mouse model of lymphoma, however, the strategy didn’t work so well, apparently because the NK cells still did not go where they were needed.

“We found that after being injected, these NK cells tend to be found in the lungs and throughout the bloodstream — whereas in this mouse model and in human lymphoma patients, the lymphoma cells are mostly in the bone marrow,” Wu says.

The team then added to their NK cells a new molecule called Sialyl-Lewis X, which made the cells gather in bone marrow amid the lymphoma cells. This led to a dramatic delay in the development of lymphoma in the mice. With this promising result, Wu and his lab now are continuing to develop this and related strategies for clinical use.

Wu and Paulson suspect that in general, adding homing molecules such as Sialyl-Lewis X to cell-based anticancer treatments enhances the cancer-killing power at the site of the cancer, and may be a key to these treatments’ future success — particularly against solid tumors and other highly localized cancers.

Wu notes, too, that Sialyl-Lewis X, which made the NK-92MI cells gather in bone marrow, as well as the CD22-binding molecule that directed the cells to malignant B cells, are both sugar-like “glycan” molecules. Although such molecules are found on virtually all cells, and often have essential biological functions as well as crucial roles in disease, they are difficult to study and thus have been relatively neglected.

“People are only starting to appreciate the importance of glycans,” says Senlian Hong, PhD, the first author of the study and a postdoctoral research associate in the Wu lab at Scripps Research.

Funding was provided by the National Institutes of Health (R01AI143884, R01GM113046, P41GM103390, P01GM107012, R01GM130915, R01AI050143, P01HL107151, U19AI136443) and the Danish National Research Foundation (DNRF107).

In a new study, Scripps Research scientists have devised a way to deactivate these designer drugs after they’ve been administered — offering a potential path for treating addiction and overdose.

The research appears today in the American Chemical Society’s open access journal JACS Au, with findings from the laboratory of Kim Janda, PhD, the Ely R. Callaway, Jr. professor of chemistry at Scripps Research. Janda and his team developed a vaccine that was able to broadly counter the effects of synthetic cannabinoids in rodents, sequestering the drug molecules before they could interact with the central nervous system. Importantly, the approach worked in models that simulated smoking and vaping, which is how the drugs are most commonly used in real life.

“Synthetic cannabinoids are much more powerful and toxic than users often realize, and their rising prevalence has led to serious health issues among young people and adults,” Janda says. “We found a way to negate the dangerous effects of these drugs, even when they’re consumed in impure forms, as is often the case. Our hope is that this may one day help treat cannabinoid use disorders or accelerate recovery for people who overdosed.”

Not to be confused with marijuana

Synthetic cannabinoids act on the same brain cell receptors as THC, the mind-altering ingredient in marijuana. However, they’re human-made in a laboratory, with chemical structures that don’t look anything like THC. Moreover, their actual effects can be unpredictable and, in some cases, fatal, Janda says.

The synthetic drugs are often sprayed on dried plant materials so they can be smoked, or sold as vaping liquids to be inhaled using e-cigarettes. Manufacturers tend to sell the products in colorful foil packages and plastic bottles under a wide variety of brand names, including Spice, K2, Joker, Black Mamba and hundreds of others.

Synthetic cannabinoids are also sometimes mixed with other dangerous drugs such as fentanyl, which can make them more deadly. Overdoses are on the upswing, as evidenced by calls to poison control centers.

“The drugs often called synthetic marijuana are, in reality, very different from marijuana,” the American Association of Poison Control Centers says. “They contain powerful chemicals and can cause severe, life-threatening health effects: severe agitation and anxiety, nausea, vomiting, seizures and hallucinations. The drugs are made specifically to be abused. Like many other illegal drugs, synthetic marijuana is not tested for safety, and users don’t know exactly what chemicals they are putting into their bodies.”

Expanding on a proven method

For the study, Janda says first author Mingliang Lin, a graduate student, wanted to explore whether a vaccine could work against synthetic cannabinoids, just as they have shown to do against some other drugs of abuse. Janda already has developed vaccine-based approaches to combat heroin, fentanyl and cocaine.

As an addiction treatment, Janda believes vaccines provide benefits over other therapeutics, as they don’t require taking a daily pill and can reduce the risk of an overdose if the user relapses.

The newest vaccine differs from Janda’s previous work in that it’s composed of multiple drug-like antigens that stimulate “broadly neutralizing” antibodies within the body, which disable many types of cannabinoids. This is key, as synthetic cannabinoids encompass a wide range of human-made chemicals.

In behavioral experiments involving mice, the team found that even when exposed to a large amount of the drug, the vaccine offered broad protection against the psychoactive effects. The team also developed a version of the vaccine that could be inhaled, which could offer greater convenience.

“This work provides a solid foundation for future therapeutic development against synthetic cannabinoid abuse,” Janda says. “The ultimate goal is to provide prolonged protection for those who may be struggling with substance abuse.”

The study, “Broadly Neutralizing Synthetic Cannabinoid Vaccines,” is authored by Mingliang Lin, Jinny Claire Lee, Steven Blake, Beverly Ellis, Lisa Eubanks and Kim Janda.

The project was supported by the Skaggs Institute for Chemical Biology at Scripps Research.