thescientist--2020-10-14--Decoy Cells Trick SARS-CoV-2, Reduce Cytokines In Vitro

ABOVE : This illustration shows SARS-CoV-2 ( right ) binding to a genetically engineered vesicle ( left ) that has many ACE2 receptors , which the virus uses to gain entry into human cells .
LANG RAO & XIAOYUAN CHEN , NATIONAL INSTITUTES OF HEALTH Scientists have summoned every trick in the book to develop a COVID-19 treatment over the last few months , from stem cells and synthetic antibodies to common over-the-counter medications and tried-and-true steroids .
Some have even attempted to lure SARS-CoV-2 away from human cells by using molecular decoys .
But few have tried to distract @ @ @ @ @ @ @ .
Scientists reported in PNAS last week ( October 6 ) that genetically engineered cells can bind and neutralize the coronavirus in vitro .
They envision that such cellular decoys could be deployed to combat infections .
Xiaoyuan Chen , a senior investigator at the National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health ( NIH ) , pivoted from developing nanotechnology to diagnose and treat cancers to study SARS-CoV-2 when the virus began spreading around the world early this year .
He had seen previous reports of using @ @ @ @ @ @ @ HIV and was curious if the emerging technique might work against SARS-CoV-2.
“ It ’ s a very elegant study , ” says Karolinska Institute molecular toxicologist Bengt Fadeel , who was not involved in this study .
“ Provided that you know the receptor of a given virus , you could , in principle , adopt this approach to intercept any virus.
” By embedding monocytic vesicles , which have cytokine receptors , into the engineered cells , the decoys can bind with inflammatory cytokines such as IL-6 , preventing them from @ @ @ @ @ @ @ overreactive immune responses thought to contribute to more severe COVID-19.To find out , Chen and his collaborators at Wuhan University fused vesicles from human monocytic THP-1 cells , a cell line derived from leukemia , with human embryonic kidney cells that overproduce the ACE2 receptors that SARS-CoV-2 grabs hold of to infiltrate cells .
Chen says they hoped that , if the hybrid vesicles were injected in vivo , the virus would ignore unmodified human cells and instead home in on the decoys .
Once attached to the engineered cells ’ ACE2 , @ @ @ @ @ @ @ , according to Chen .
The idea of a decoy to thwart SARS-CoV-2 infection is not a new one .
One team of scientists created a decoy using engineered , free-floating ACE2 receptors that bind especially well with the virus .
Their decoys , which the developers propose can “ significantly block early stages of SARS-CoV-2 infections , ” are now in a Phase 2 clinical trial run by Apeiron Biologics .
In a July preprint , pharmacologist Gaurav Sahay of Oregon State University described a method that delivers engineered mRNA that codes @ @ @ @ @ @ @ using lipid nanoparticles , causing ACE2 decoys to be translated and secreted into the blood .
He found that the method successfully led to an increase of ACE2 decoys in vivo and they inhibited a modified , nonpathogenic version of SARS-CoV-2 in vitro .
Chen ’ s new spin on the concept is to couple the decoys with cytokine receptors .
“ The combination of [ ACE2 and cytokine receptors in ] the vesicle structure is something new , ” says Sahay , who was not involved in Chen ’ s study .
@ @ @ @ @ @ @ development.
” Researchers tested the nanodecoys by incubating both SARS-CoV , responsible for the 2003 SARS outbreak , and SARS-CoV-2 , which causes COVID-19 , in human and monkey cells , and found that the decoys significantly inhibited viral infection , regardless of cell or virus type .
To test whether the decoys could work outside a petri dish , researchers induced acute lung inflammation in mice by having them inhale lipopolysaccharide , an irritant .
Four hours later , the mice inhaled the nanodecoys , and after eight hours , the researchers @ @ @ @ @ @ @ lungs .
They found that the decoys successfully mopped up cytokines compared to mice that did not receive decoys .
“ This study is rather straightforward , ” says Chen .
“ It ’ s surprising that such a simple approach is able to neutralize the virus , at least at the cellular level , and in vivo neutralize cytokines within hours .
For COVID-19 , a rapid response is essential , and these nanodecoys do just that.
” While these results suggest that these decoys can neutralize cytokines in mice ’ s @ @ @ @ @ @ @ SARS-CoV-2 infection was not tested in mice .
Chen cited a shortage of the transgenic mice bearing human ACE2 that would be needed to conduct such experiments .
Mice that received the nanodecoys showed no adverse reaction to the treatment , which is encouraging , says Fadeel , but he says he wonders if that would hold true in humans as well , particularly because the engineered cells use material from human cancer cells .
“ I would be cautious about administering small bits of cancer cells , especially into the lungs , @ @ @ @ @ @ @ that cell membranes in the lungs , arteries , heart , kidney , and intestines produce ACE2 for a reason—it cleaves angiotensin , a protein that raises blood pressure .
He questions if the decoys might impair the body ’ s ability to regulate blood pressure , as angiotensin may bind to the decoys .
Neither Chen nor his colleagues at Wuhan University currently have plans to test the decoys in humans , but he filed a patent for their design through the NIH .
“ It ’ s a very simple approach—almost @ @ @ @ @ @ @ “ That ’ s the beauty of this study.
” L. Rao et al.
, “ Decoy nanoparticles protect against COVID-19 by concurrently adsorbing viruses and inflammatory cytokines , ” PNAS , doi:10.1073/pnas.2014352117 , 2020 .

ABOVE: This illustration shows SARS-CoV-2 (right) binding to a genetically engineered vesicle (left) that has many ACE2 receptors, which the virus uses to gain entry into human cells.
LANG RAO & XIAOYUAN CHEN, NATIONAL INSTITUTES OF HEALTH
Scientists have summoned every trick in the book to develop a COVID-19 treatment over the last few months, from stem cells and synthetic antibodies to common over-the-counter medications and tried-and-true steroids. Some have even attempted to lure SARS-CoV-2 away from human cells by using molecular decoys. But few have tried to distract the novel coronavirus with fake human cells. Scientists reported in PNAS last week (October 6) that genetically engineered cells can bind and neutralize the coronavirus in vitro. They envision that such cellular decoys could be deployed to combat infections.
“It’s a very elegant study,” says Karolinska Institute molecular toxicologist Bengt Fadeel, who was not involved in this study. “Provided that you know the receptor of a given virus, you could, in principle, adopt this approach to intercept any virus.”
Xiaoyuan Chen, a senior investigator at the National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health (NIH), pivoted from developing nanotechnology to diagnose and treat cancers to study SARS-CoV-2 when the virus began spreading around the world early this year. He had seen previous reports of using decoy receptors to trick pathogens such as HIV and was curious if the emerging technique might work against SARS-CoV-2.
To find out, Chen and his collaborators at Wuhan University fused membranes from human monocytic THP-1 cells, a cell line derived from leukemia, with membranes from human embryonic kidney cells that overproduce the ACE2 receptors that SARS-CoV-2 grabs hold of to infiltrate cells. Chen says they hoped that, if the hybrid vesicles were injected in vivo, the virus would ignore unmodified human cells and instead home in on the decoys. Once attached to the engineered cells’ ACE2, the virus would be absorbed and neutralized, according to Chen.
By embedding monocytic membranes, which have cytokine receptors, into the engineered vesicles, the decoys can bind with inflammatory cytokines such as IL-6, preventing them from building up and causing cytokine storms, overreactive immune responses thought to contribute to more severe COVID-19.
The idea of a decoy to thwart SARS-CoV-2 infection is not a new one. One team of scientists created a decoy using engineered, free-floating ACE2 receptors that bind especially well with the virus. Their decoys, which the developers propose can “significantly block early stages of SARS-CoV-2 infections,” are now in a Phase 2 clinical trial run by Apeiron Biologics. In a July preprint, pharmacologist Gaurav Sahay of Oregon State University described a method that delivers engineered mRNA that codes for ACE2 to the liver of mice using lipid nanoparticles, causing ACE2 decoys to be translated and secreted into the blood. He found that the method successfully led to an increase of ACE2 decoys in vivo and they inhibited a modified, nonpathogenic version of SARS-CoV-2 in vitro.
Chen’s new spin on the concept is to couple the decoys with cytokine receptors. “The combination of [ACE2 and cytokine receptors in] the vesicle structure is something new,” says Sahay, who was not involved in Chen’s study. “It’s a very exciting development.”
Researchers tested the nanodecoys by incubating both SARS-CoV, responsible for the 2003 SARS outbreak, and SARS-CoV-2, which causes COVID-19, in human and monkey cells, and found that the decoys significantly inhibited viral infection, regardless of cell or virus type.
To test whether the decoys could work outside a petri dish, researchers induced acute lung inflammation in mice by having them inhale lipopolysaccharide, an irritant. Four hours later, the mice inhaled the nanodecoys, and after eight hours, the researchers collected fluid from the mice’s lungs. They found that the decoys successfully mopped up cytokines compared to mice that did not receive decoys.
“This study is rather straightforward,” says Chen. “It’s surprising that such a simple approach is able to neutralize the virus, at least at the cellular level, and in vivo neutralize cytokines within hours. For COVID-19, a rapid response is essential, and these nanodecoys do just that.”
While these results suggest that these decoys can neutralize cytokines in mice’s lungs, their ability to block a SARS-CoV-2 infection was not tested in mice. Chen cited a shortage of the transgenic mice bearing human ACE2 that would be needed to conduct such experiments.
Mice that received the nanodecoys showed no adverse reaction to the treatment, which is encouraging, says Fadeel, but he says he wonders if that would hold true in humans as well, particularly because the engineered cells use material from human cancer cells. “I would be cautious about administering small bits of cancer cells, especially into the lungs,” he says.
Sahay also notes that cell membranes in the lungs, arteries, heart, kidney, and intestines produce ACE2 for a reason—it cleaves angiotensin, a protein that raises blood pressure. He questions if the decoys might impair the body’s ability to regulate blood pressure, as angiotensin may bind to the decoys.
Neither Chen nor his colleagues at Wuhan University currently have plans to test the decoys in humans, but he filed a patent for their design through the NIH. “It’s a very simple approach—almost too simple,” says Chen. “That’s the beauty of this study.”
L. Rao et al., “Decoy nanoparticles protect against COVID-19 by concurrently adsorbing viruses and inflammatory cytokines,” PNAS, doi:10.1073/pnas.2014352117, 2020.


thescientist--2020-10-14--US Tops List of COVID-19 and All-Cause Death Rates Since May

The COVID-19 pandemic has wreaked havoc on the US , with more than 216,000 confirmed deaths attributed to the disease and much of the population still vulnerable to the virus .
A new report in JAMA released this week ( October 12 ) compares how 19 countries that have employed different virus response strategies have fared since early May , finding that the US has the highest COVID-19 death rate .
“ It ’ s shocking .
It ’ s horrible , ” Ezekiel Emanuel , a former White House health adviser who chairs the department of medical ethics and @ @ @ @ @ @ @ and a coauthor of the report , tells NPR .
“ The United States really has done remarkably badly compared to other countries .
I mean , remarkably badly.
” Emanuel and his Harvard University colleague looked at COVID-19 death rates through mid-September in 19 countries that have a population greater than 5 million and a gross domestic product of at least $ 25,000 per capita .
They also tabulated the rates of death from any cause , which accounts for those that may have been due to the coronavirus but were never @ @ @ @ @ @ @ data through July 25 .
The report showed that the US had more deaths per 100,000 people than other high-mortality countries such as Italy and Sweden , and the most deaths per capita from any cause since May among all 14 countries .
Adjusting for population , US overall deaths this year are more than 85 percent higher than Germany and Canada and more than 29 percent higher than Sweden , “ which ignored everything for so long , ” Emanuel tells NPR .
Sweden took an unconventional approach to the virus and @ @ @ @ @ @ @ “ We have 29 % more mortality than we should have if we ’ d followed Sweden ’ s path and Sweden virtually did nothing , ” Emanuel says .
The authors also concluded that if the US COVID-19 death rate after May 10 were similar to that of Italy ’ s , the US would have had 91,604 fewer deaths .
“ Italy didn ’ t have anything special or different in terms of treatment , vaccines , diagnostics compared to the United States , ” Emanuel tells CNBC .
“ What @ @ @ @ @ @ @ public health measures , and that actually could have saved tens of thousands of lives in the United States.
” Another study published in JAMA October 12 found that the overall US death rate rose 20 percent in the time period from March to August compared to expected deaths , with 67 percent of the excess deaths arising from the virus .

ABOVE: © ISTOCK.COM,
MAMMUTH
The COVID-19 pandemic has wreaked havoc on the US, with more than 216,000 confirmed deaths attributed to the disease and much of the population still vulnerable to the virus. A new report in JAMA released this week (October 12) compares how 19 countries that have employed different virus response strategies have fared since early May, finding that the US has the highest COVID-19 death rate.
“It’s shocking. It’s horrible,” Ezekiel Emanuel, a former White House health adviser who chairs the department of medical ethics and health policy at the University of Pennsylvania and a coauthor of the report, tells NPR. “The United States really has done remarkably badly compared to other countries. I mean, remarkably badly.”
Emanuel and his Harvard University colleague looked at COVID-19 death rates through mid-September in 19 countries that have a population greater than 5 million and a gross domestic product of at least $25,000 per capita. They also tabulated the rates of death from any cause, which accounts for those that may have been due to the coronavirus but were never confirmed, for 14 countries with available data through July 25.
The report showed that the US had more deaths per 100,000 people than other high-mortality countries such as Italy and Sweden, and the most deaths per capita from any cause since May among all 14 countries.
Adjusting for population, US overall deaths this year are more than 85 percent higher than Germany and Canada and more than 29 percent higher than Sweden, “which ignored everything for so long,” Emanuel tells NPR. Sweden took an unconventional approach to the virus and imposed few restrictions and no lockdown. “We have 29% more mortality than we should have if we’d followed Sweden’s path and Sweden virtually did nothing,” Emanuel says.
The authors also concluded that if the US COVID-19 death rate after May 10 were similar to that of Italy’s, the US would have had 91,604 fewer deaths.
“Italy didn’t have anything special or different in terms of treatment, vaccines, diagnostics compared to the United States,” Emanuel tells CNBC. “What they had is better implementation of the public health measures, and that actually could have saved tens of thousands of lives in the United States.”
Another study published in JAMA October 12 found that the overall US death rate rose 20 percent in the time period from March to August compared to expected deaths, with 67 percent of the excess deaths arising from the virus.


thescientist--2020-10-14--Gene Therapy Workflow from Production to Quality Control

Gene therapy is a treatment strategy that addresses a disease condition by introducing new genes or modulating gene expression , @ @ @ @ @ of the issue .
To ensure high efficacy and patient safety , rigorous vector purification @ @ @ @ @ Learn more about some of the instruments used in this workflow at beckman.com/resources .

Gene therapy is a treatment strategy that addresses a disease condition by introducing new genes or modulating gene expression, to address the root cause of the issue. To ensure high efficacy and patient safety, rigorous vector purification and characterization are crucial. Learn more about some of the instruments used in this workflow at beckman.com/resources.


thescientist--2020-10-15--Argentinian Field Site Devastated by Fire

ABOVE : Two fires in Argentina burned 90 percent of the San Cayetano Provincial Park , which houses a field station that has carried out long-term monitoring of local primates for decades .
BELEN NATALINI Editor ’ s note : The following story contains graphic images of animals that died in the fires .
Amid a record year for fires across South America , two blazes have spiraled out of control in Argentina , scorching a state park in the northeastern province of Corrientes .
Within the park , an ecological field station that has carried out long-term primate research @ @ @ @ @ @ @ but roughly half of the park ’ s resident howler monkeys have likely died .
San Cayetano Provincial Park was only established in 2015 , but the Estación Biológica Corrientes ( EBCo ) —a field station managed by the country ’ s National Council for Scientific and Technical Research—first opened in 1975 .
While it has previously changed hands and names , since 2001 the station has served as an educational and research facility .
The first fire began on August 23 , within San Cayetano itself .
Over the next 24 hours @ @ @ @ @ @ @ of the 76-hectare park to ashes .
Several weeks later , in late September , a separate fire just outside the preserve scorched more than 1,000 hectares before entering the boundaries of San Cayetano on October 1 , claiming a further 30 percent of the park ’ s total area .
The patches left untouched include some fragmented forest as well as the research station ’ s main complex of buildings .
Martin Kowalewski , a primate ecologist and the field station ’ s director , was on hand to fight the fires @ @ @ @ @ @ @ where the fires are all around and you understand that you can do nothing , but you ’ re still there.
” Because there are many fires burning throughout the region , help was slow to arrive , and within the park the fires were fought primarily by rangers , conservationists , researchers , and locals from the nearby town .
Both fires are thought to have been started intentionally by cattle ranchers before spreading out of control .
The practice of burning grasslands each spring to prompt fresh growth is common .
@ @ @ @ @ @ @ of land to support a handful of cows , large ranching operations sometimes burn vast tracts of land , despite the practice being banned during extremely dry weather , Kowalewski says .
As ranching , logging , and agriculture have encroached on the field station , primatologists have documented these changes to the land through the resident population of black and gold howler monkeys ( Alouatta caraya ) .
This group represents the southernmost distribution for the species , and researchers have been tracking them for more than 30 years ; Kowalewski himself @ @ @ @ @ @ @ 1993 .
When the fires were finally extinguished , he and his team entered the park to assess the damage .
What they found , as documented through a series of posts on social media , caused Kowalewski profound anguish that he says ultimately turned to fury .
Of the 20 different groups of howler monkeys being monitored from the field station , 10 were able to shelter in forests that did not burn .
Half of the remaining groups , totaling between 40 and 50 animals , have died , while the @ @ @ @ @ @ @ “ It ’ s difficult because we are doing science , looking for patterns in nature .
But you can have this connection with your study animals too because we have been following them for 30 years , ” Kowalewski tells The Scientist .
“ All these groups that we found , I knew everything about them .
I knew who was the son , the daughter , the mother .
The first [ few days ] I was crying all the time.
” In addition to primates that died in the fires @ @ @ @ @ @ @ came across monkeys that had been struck by cars or attacked by dogs as they fled .
Others were electrocuted by power lines .
Speaking to The Guardian , Kowalewski tallied other animals killed by the flames : otters , foxes , deer , caiman , turtles , snakes , and capybaras .
While the park itself is protected from development , the surrounding forest is fragmented , leaving few spaces for animals to retreat to and fewer protections for them outside the park ’ s boundaries .
Kowalewski describes such preserves as @ @ @ @ @ @ @ world .
Those who carried out their research there recall what a unique oasis it was .
“ It was pretty amazing to wake up to howler monkey booms coming from the forest surrounding the field station , ” Sahana Kuthyar , a PhD student at the University of California , San Diego , who previously carried out research on howler monkeys at the station , tells The Scientist in an email .
“ My experience at EBCo was definitely unique , and I made long-lasting friendships and scientific collaborations for which I @ @ @ @ @ @ @ of San Cayetano burned , the future of the field station is uncertain .
The forests may recover , but it ’ s unknown whether an intact ecosystem could ever reestablish itself without help .
Kowalewski intends to continue documenting the recolonization of the area by howlers ; with so little forest remaining , he says , he expects to see increased conflict between groups .
Other researchers planning to visit the station are having to reassess .
Carson Black , a master ’ s student at Central Washington University , would have @ @ @ @ @ @ @ her thesis , which will look at the gut microbiome of howlers along a gradient of habitat health .
Hearing about the fires , she says she felt “ sheer and utter devastation.
” The pandemic had already paused her trip , and now she will have to rely on previously collected samples sent to her from collaborators in Argentina .
“ We heard so much about Australia burning last year and the Amazon , and I feel like a lot of people don ’ t realize that other places are at risk @ @ @ @ @ @ @ “ It ’ s extremely disheartening , but I just hope that .
.
.
we can get the word out that we ’ ve got to make a change , or we ’ re going to lose a lot more than what we ’ ve lost in Argentina .
”

ABOVE: Two fires in Argentina burned 90 percent of the San Cayetano Provincial Park, which houses a field station that has carried out long-term monitoring of local primates for decades.
BELEN NATALINI
Editor’s note: The following story contains graphic images of animals that died in the fires.
Amid a record year for fires across South America, two blazes have spiraled out of control in Argentina, scorching a state park in the northeastern province of Corrientes. Within the park, an ecological field station that has carried out long-term primate research for decades narrowly escaped the flames, but roughly half of the park’s resident howler monkeys have likely died.
San Cayetano Provincial Park was only established in 2015, but the Estación Biológica Corrientes (EBCo)—a field station managed by the country’s National Council for Scientific and Technical Research—first opened in 1975. While it has previously changed hands and names, since 2001 the station has served as an educational and research facility.
The first fire began on August 23, within San Cayetano itself. Over the next 24 hours, that blaze burned roughly 60 percent of the 76-hectare park to ashes. Several weeks later, in late September, a separate fire just outside the preserve scorched more than 1,000 hectares before entering the boundaries of San Cayetano on October 1, claiming a further 30 percent of the park’s total area. The patches left untouched include some fragmented forest as well as the research station’s main complex of buildings.
Martin Kowalewski, a primate ecologist and the field station’s director, was on hand to fight the fires, calling it a “strange universe where the fires are all around and you understand that you can do nothing, but you’re still there.” Because there are many fires burning throughout the region, help was slow to arrive, and within the park the fires were fought primarily by rangers, conservationists, researchers, and locals from the nearby town.
Both fires are thought to have been started intentionally by cattle ranchers before spreading out of control. The practice of burning grasslands each spring to prompt fresh growth is common. But while most landowners burn small plots of land to support a handful of cows, large ranching operations sometimes burn vast tracts of land, despite the practice being banned during extremely dry weather, Kowalewski says.
All these groups that we found, I knew everything about them. I knew who was the son, the daughter, the mother. The first [few days] I was crying all the time. —Martin Kowalewski, CONICET-Argentina
As ranching, logging, and agriculture have encroached on the field station, primatologists have documented these changes to the land through the resident population of black and gold howler monkeys (Alouatta caraya). This group represents the southernmost distribution for the species, and researchers have been tracking them for more than 30 years; Kowalewski himself has been working in the area since 1993.
When the fires were finally extinguished, he and his team entered the park to assess the damage. What they found, as documented through a series of posts on social media, caused Kowalewski profound anguish that he says ultimately turned to fury. Of the 20 different groups of howler monkeys being monitored from the field station, 10 were able to shelter in forests that did not burn. Half of the remaining groups, totaling between 40 and 50 animals, have died, while the other five groups remain unaccounted for.
“It’s difficult because we are doing science, looking for patterns in nature. But you can have this connection with your study animals too because we have been following them for 30 years,” Kowalewski tells The Scientist. “All these groups that we found, I knew everything about them. I knew who was the son, the daughter, the mother. The first [few days] I was crying all the time.”
Two howler monkeys and a caiman that died during the fires at the San Cayetano Provincial Park in northeast Argentina Marita Romero | Parque Provincial San Cayetano
In addition to primates that died in the fires, Kowalewski says, his team also came across monkeys that had been struck by cars or attacked by dogs as they fled. Others were electrocuted by power lines. Speaking to The Guardian, Kowalewski tallied other animals killed by the flames: otters, foxes, deer, caiman, turtles, snakes, and capybaras.
While the park itself is protected from development, the surrounding forest is fragmented, leaving few spaces for animals to retreat to and fewer protections for them outside the park’s boundaries. Kowalewski describes such preserves as “islands” in an increasingly urbanized world.
Those who carried out their research there recall what a unique oasis it was. “It was pretty amazing to wake up to howler monkey booms coming from the forest surrounding the field station,” Sahana Kuthyar, a PhD student at the University of California, San Diego, who previously carried out research on howler monkeys at the station, tells The Scientist in an email. “My experience at EBCo was definitely unique, and I made long-lasting friendships and scientific collaborations for which I am very grateful.”
With 90 percent of San Cayetano burned, the future of the field station is uncertain. The forests may recover, but it’s unknown whether an intact ecosystem could ever reestablish itself without help. Kowalewski intends to continue documenting the recolonization of the area by howlers; with so little forest remaining, he says, he expects to see increased conflict between groups.
Other researchers planning to visit the station are having to reassess. Carson Black, a master’s student at Central Washington University, would have traveled to EBCo to collect data for her thesis, which will look at the gut microbiome of howlers along a gradient of habitat health. Hearing about the fires, she says she felt “sheer and utter devastation.” The pandemic had already paused her trip, and now she will have to rely on previously collected samples sent to her from collaborators in Argentina.
“We heard so much about Australia burning last year and the Amazon, and I feel like a lot of people don’t realize that other places are at risk,” Carson tells The Scientist. “It’s extremely disheartening, but I just hope that . . . we can get the word out that we’ve got to make a change, or we’re going to lose a lot more than what we’ve lost in Argentina.”


thescientist--2020-10-15--Lipid Droplets Are Intracellular Bacteria-Fighting Machines

ABOVE : Human cells with lipid droplets ( blue ) containing cathelicidin ( green ) MARTA BOSCH Once thought to be little more than blobs of fat inside eukaryotic cells , lipid droplets may in fact provide a first line of defence against invading pathogens , according to evidence published today ( October 15 ) in Science .
When a bacterium enters a cell ’ s cytoplasm , intracellular lipid droplets close in , bringing with them an arsenal of antimicrobial proteins , the research shows .
“ This is the first evidence that there ’ s a direct [ @ @ @ @ @ @ @ intracellular pathogens , and I thought that was just fascinating , ” says Stacey Gilk of the University of Nebraska Medical Center who studies microbial pathology and was not involved in the research .
“ We ’ ve known about lipid droplets for over 100 years , but still don ’ t know much about them , ” adds virologist Sue Crawford at Baylor College of Medicine who also did not participate in the study .
“ This is a fantastic paper , ” she says .
It “ really pinpointed some of @ @ @ @ @ @ @ an antibacterial function.
” Lipid droplets are a type of organelle that exists in all eukaryotic cells .
They are jam-packed full of fats , as the name would suggest , and surrounded by a phospholipid monolayer ( as opposed to the classic bilayer membrane surrounding most other organelles ) .
Historically lipid droplets have been thought of as sites for storing excess fats and supplying them when and where needed—for instance , to the mitochondria for energy production .
More recently , research has shown that certain cell-invading viruses , bacteria , @ @ @ @ @ @ @ survival and growth , says Crawford .
But , there ’ s also evidence that the cell laces lipid droplets with antimicrobial proteins , just as a person might lace cheese with poison to rid their house of invading rodents .
Lipid droplets in mouse cells , for example , contain the antiviral compound viperin and a protein involved in activating the immune response against foreign antigens , while those in fruit fly cells contain proteins with antibacterial properties .
The new study , from University of Barcelona cell biologist Albert Pol and @ @ @ @ @ @ @ showing definitively that lipid droplets in mammalian cells can contain a wealth of immune proteins and have antibacterial activity against a number of bacterial species .
The team simulated a bacterial infection in live mice by injecting the animals with lipopolysaccharide ( LPS ) , a bacterial molecule that stimulates the innate immune response .
This led to an increase in the number of lipid droplets within cells of the animals ’ liver , explains Marta Bosch , a postdoctoral researcher in the laboratory of Pol .
Lipid droplets isolated from these animals @ @ @ @ @ @ @ , could inhibit the growth of E. coli in vitro , but the antibacterial capacity of the LPS-induced droplets was significantly more potent .
This indicates that immune signals driven by LPS might prime the droplets for antibacterial action , the team argues .
Lipid droplets isolated from mice with an actual bacterial infection had similar antibacterial potency to those of LPS-treated animals .
The team also analyzed the protein content of the lipid droplets from LPS-treated and control animals , and found that LPS treatment reduced the amount of proteins involved in @ @ @ @ @ @ @ immune factors such as cathelicidin , a broad-spectrum antimicrobial protein .
Cathelicidin was also present on the lipid droplets of human macrophages , the team showed , and when these cells were infected with E. coli , the droplets increased in number and appeared to localize with the bacteria .
When the macrophages were incubated with fatty acids to boost lipid droplet abundance prior to infection , they were better able to inhibit E. coli growth .
Such antibacterial capacity was impaired in macrophages where cathelicidin production was switched off , but enhanced @ @ @ @ @ @ @ of cathelicidin in their lipid droplets .
Indeed , cells with enhanced cathelicidin were more effective than control cells at reducing the growth of E. coli , Listeria monocytogenes , and methicillin-resistant Staphylococcus aureus .
“ Since most studies thus far demonstrate the importance of lipid droplets in the context of pathogen-mediated exploitation .
.
.
the demonstration of lipid droplet antibacterial capacity is exciting and promising , ” Minal Mulye a microbiologist and immunologist at Marian University , who was not involved in the work , writes in an email to The @ @ @ @ @ @ @ explored further in different bacterial pathogen infection models , ” she adds , “ and could eventually be targeted as an alternative antibacterial treatment.
” M. Bosch et al.
, “ Mammalian lipid droplets are innate immune hubs integrating cell metabolism and host defense , ” Science , 370 : eaay8085 , 2020 .

ABOVE: Human cells with lipid droplets (blue) containing cathelicidin (green)
MARTA BOSCH
Once thought to be little more than blobs of fat inside eukaryotic cells, lipid droplets may in fact provide a first line of defence against invading pathogens, according to evidence published today (October 15) in Science. When a bacterium enters a cell’s cytoplasm, intracellular lipid droplets close in, bringing with them an arsenal of antimicrobial proteins, the research shows.
“This is the first evidence that there’s a direct [immune] mechanism between lipid droplets and intracellular pathogens, and I thought that was just fascinating,” says Stacey Gilk of the University of Nebraska Medical Center who studies microbial pathology and was not involved in the research.
“We’ve known about lipid droplets for over 100 years, but still don’t know much about them,” adds virologist Sue Crawford at Baylor College of Medicine who also did not participate in the study. “This is a fantastic paper,” she says. It “really pinpointed some of the mechanisms by which lipid droplets have an antibacterial function.”
Lipid droplets are a type of organelle that exists in all eukaryotic cells. They are jam-packed full of fats, as the name would suggest, and surrounded by a phospholipid monolayer (as opposed to the classic bilayer membrane surrounding most other organelles). Historically lipid droplets have been thought of as sites for storing excess fats and supplying them when and where needed—for instance, to the mitochondria for energy production. More recently, research has shown that certain cell-invading viruses, bacteria, and parasites exploit these fuel-rich droplets for survival and growth, says Crawford.
But, there’s also evidence that the cell laces lipid droplets with antimicrobial proteins, just as a person might lace cheese with poison to rid their house of invading rodents. Lipid droplets in mouse cells, for example, contain the antiviral compound viperin and a protein involved in activating the immune response against foreign antigens, while those in fruit fly cells contain proteins with antibacterial properties.
The new study, from University of Barcelona cell biologist Albert Pol and colleagues, adds to this evidence, showing definitively that lipid droplets in mammalian cells can contain a wealth of immune proteins and have antibacterial activity against a number of bacterial species.
The team simulated a bacterial infection in live mice by injecting the animals with lipopolysaccharide (LPS), a bacterial molecule that stimulates the innate immune response. This led to an increase in the number of lipid droplets within cells of the animals’ liver, explains Marta Bosch, a postdoctoral researcher in the laboratory of Pol.
Lipid droplets isolated from these animals, or from saline-injected, control animals, could inhibit the growth of E. coli in vitro, but the antibacterial capacity of the LPS-induced droplets was significantly more potent. This indicates that immune signals driven by LPS might prime the droplets for antibacterial action, the team argues. Lipid droplets isolated from mice with an actual bacterial infection had similar antibacterial potency to those of LPS-treated animals.
The team also analyzed the protein content of the lipid droplets from LPS-treated and control animals, and found that LPS treatment reduced the amount of proteins involved in lipid metabolism and boosted levels of innate immune factors such as cathelicidin, a broad-spectrum antimicrobial protein.
Cathelicidin was also present on the lipid droplets of human macrophages, the team showed, and when these cells were infected with E. coli, the droplets increased in number and appeared to localize with the bacteria. When the macrophages were incubated with fatty acids to boost lipid droplet abundance prior to infection, they were better able to inhibit E. coli growth.
Such antibacterial capacity was impaired in macrophages where cathelicidin production was switched off, but enhanced in cells engineered to have higher levels of cathelicidin in their lipid droplets. Indeed, cells with enhanced cathelicidin were more effective than control cells at reducing the growth of E. coli, Listeria monocytogenes, and methicillin-resistant Staphylococcus aureus.
“Since most studies thus far demonstrate the importance of lipid droplets in the context of pathogen-mediated exploitation. . . the demonstration of lipid droplet antibacterial capacity is exciting and promising,” Minal Mulye a microbiologist and immunologist at Marian University, who was not involved in the work, writes in an email to The Scientist. “This effect should be explored further in different bacterial pathogen infection models,” she adds, “and could eventually be targeted as an alternative antibacterial treatment.”
M. Bosch et al., “Mammalian lipid droplets are innate immune hubs integrating cell metabolism and host defense,” Science, 370:eaay8085, 2020.


thescientist--2020-10-15--Nucleus Is Key to How Cells Sense Personal Space

In a pair of papers published in the same issue of Cell in 2015 , two groups showed that putting physical pressure on cells—by confining them , for instance—causes previously stationary cells to start moving quickly .
But it wasn ’ t clear how cells translated being squished into relocating .
Many of the same researchers , again working in two independent teams , have now found that the nucleus is responsible for sensing changes in pressure and triggering the signaling cascade that leads cells to get moving .
Both studies were published today ( October 15 ) in Science @ @ @ @ @ @ @ people would shake their heads that the nucleus is nothing but a bowling ball inside of a snake .
It was just this big , dense , unnecessary thing the cell had to drag along out of desperation because it had the DNA inside of it , ” says Kris Dahl , a chemical engineer at Carnegie Mellon University who was not involved in either study .
While there had been prior evidence indicating that the nucleus can pass mechanical forces from one side of the cell to the other , she adds @ @ @ @ @ @ @ to really show that .
.
.
it ’ s actively contributing , sending signals to the cell to allow it to do things.
” “ Similar to people , cells that make up tissues and organs in the human body are actually able to understand and protect their sort of personal space , ” explains Alexis Lomakin , a cell biologist at the St. Anna Children ’ s Cancer Research Institute in Vienna and a coauthor of one of the new studies .
After the 2015 studies , both research groups wanted @ @ @ @ @ @ @ start to move when they ’ re confined .
They ’ d shown in the earlier papers that contractility of myosin-II proteins just inside the cell membrane in the area known as the cell cortex triggered the movement , but what was sensing the cellular deformation and then activating myosin II was an open question .
See “ May the Force Be with You ” Lomakin became a guest scientist in the lab of Matthieu Piel at Institut Curie in Paris in 2015 .
He wanted to tackle this question of why cells @ @ @ @ @ @ @ a collaboration with Cédric Cattin , then a graduate student in the lab of Daniel Müller , a biophysicist at ETH Zürich .
Cattin , Müller , and colleagues had described a technique in 2015 in which they used microscopic cantilevers to confine cells .
Lomakin and Cattin worked together to apply the technique to precisely quantify cell responses to external pressure .
Meanwhile , Verena Ruprecht , a developmental biologist at the Centre for Genomic Regulation in Barcelona , and her colleagues were working on a similar goal .
“ The key @ @ @ @ @ @ @ does the cell actually feel that it is deformed ?
” says Ruprecht , a coauthor of the other new paper .
“ And how can it activate this program of cytoskeletal changes that then lead to the sudden migration that is like an escape reflex ?
” Ruprecht , Stefan Wieser , a biophysicist at the Institute of Photonic Sciences in Barcelona , and their team focused on proteins from the outer surface of zebrafish cells confined beneath coverslips in culture to see if any of these proteins were responsible for the @ @ @ @ @ @ @ They didn ’ t find a role for adhesion proteins or ion channels that sense mechanical deformation .
So they turned their attention to the nucleus .
“ The nucleus is a very large and prominent organelle .
.
.
and when you squish the cells , it is very clear that the intracellular organelles were affected , so we were then thinking , ‘ Maybe the sensor is not at the surface , but it ’ s in fact inside the cell , ’ ” says Ruprecht .
They noticed that myosin @ @ @ @ @ @ @ cells were compressed enough that the nucleus would be affected .
Using their microscopic cantilevers , Lomakin and colleagues made a similar observation and proposed that the nucleus is working as a sensor that , when deformed , signals to cells to seek more elbow room .
To connect nuclear deformation with cell motility , the researchers performed a small-molecule screen in human cancer cells and determined that intracellular calcium , stretch-sensitive proteins in the nuclear envelope , and an enzyme called cytosolic phospholipase A2 ( cPLA2 ) were involved .
Ruprecht ’ @ @ @ @ @ @ @ In a 2016 study , Philipp Niethammer ’ s group at Memorial Sloan Kettering Cancer Center showed that nuclear swelling during inflammation or osmotic stress , along with calcium signaling , could activate cPLA2 .
After seeing that study , Ruprecht ’ s team tested the role of cPLA2 in the zebrafish cell culture system .
Both groups found that when the nucleus gets squeezed , its envelope stretches and unfolds , releasing calcium and recruiting cPLA2 from within the nucleoplasm to the inner nuclear membrane .
This movement of the enzyme activates @ @ @ @ @ @ @ principle cleavage product , arachidonic acid , which then sends a cascade of signals in the cytoplasm that eventually trigger myosin II activity , thereby linking nuclear compression and cell movement .
“ Two independent groups using different approaches ended up with the same conclusions .
It ’ s nice to see a lot of the commonalities that they point out using different experimental systems , ” says Jan Lammerding , a biomedical engineer at Cornell University who did not participate in either study .
“ It really advances our understanding of how @ @ @ @ @ @ @ ” The groups have found a key mechanism , Lammerding tells The Scientist , but in the future , “ it would still be interesting to see if there are other mechanisms , and , if so , are they independent ?
How much interaction and crosstalk is there potentially between different nuclear mechanosensing mechanisms , but also between nuclear and cytoplasmic mechanisms ?
” In addition to more questions about how it all works , the researchers are excited about possible applications .
Cancer cells use “ this mechanism to escape crowded @ @ @ @ @ @ @ ” says Lomakin , which means that it could be targeted for cancer treatment .
“ Preliminary data show that down regulating the activity of cPLA2 [ with ] small molecule inhibitors could interfere with the ability of tumor cells to break free from the primary tumor and to metastasize to distant organs.
” A.J .
Lomakin et al.
, “ The nucleus acts as a ruler tailoring cell responses to spatial constraints , ” Science , doi:10.1126/science.aba2894 , 2020 .
V. Venturini et al.
, “ The nucleus measures shape changes for @ @ @ @ @ @ @ , ” Science , doi:10.1126/science.aba2644 , 2020 .

ABOVE: © ISTOCK.COM,
ERANICLE
In a pair of papers published in the same issue of Cell in 2015, two groups showed that putting physical pressure on cells—by confining them, for instance—causes previously stationary cells to start moving quickly. But it wasn’t clear how cells translated being squished into relocating. Many of the same researchers, again working in two independent teams, have now found that the nucleus is responsible for sensing changes in pressure and triggering the signaling cascade that leads cells to get moving. Both studies were published today (October 15) in Science.
“Even five years ago, people would shake their heads that the nucleus is nothing but a bowling ball inside of a snake. It was just this big, dense, unnecessary thing the cell had to drag along out of desperation because it had the DNA inside of it,” says Kris Dahl, a chemical engineer at Carnegie Mellon University who was not involved in either study. While there had been prior evidence indicating that the nucleus can pass mechanical forces from one side of the cell to the other, she adds, “these are the first papers to really show that . . . it’s actively contributing, sending signals to the cell to allow it to do things.”
“Similar to people, cells that make up tissues and organs in the human body are actually able to understand and protect their sort of personal space,” explains Alexis Lomakin, a cell biologist at the St. Anna Children’s Cancer Research Institute in Vienna and a coauthor of one of the new studies.
After the 2015 studies, both research groups wanted to understand what signals cause cells to start to move when they’re confined. They’d shown in the earlier papers that contractility of myosin-II proteins just inside the cell membrane in the area known as the cell cortex triggered the movement, but what was sensing the cellular deformation and then activating myosin II was an open question.
See “May the Force Be with You”
Lomakin became a guest scientist in the lab of Matthieu Piel at Institut Curie in Paris in 2015. He wanted to tackle this question of why cells contracted when confined, so he initiated a collaboration with Cédric Cattin, then a graduate student in the lab of Daniel Müller, a biophysicist at ETH Zürich. Cattin, Müller, and colleagues had described a technique in 2015 in which they used microscopic cantilevers to confine cells. Lomakin and Cattin worked together to apply the technique to precisely quantify cell responses to external pressure.
A human cervical cancer cell squeezes through a microfluidic channel. Nuclear stretch (magenta) precedes cell contractility driven by myosin II (green). Alexis Lomakin, St. Anna Children's Cancer Research Institute Vienna
Meanwhile, Verena Ruprecht, a developmental biologist at the Centre for Genomic Regulation in Barcelona, and her colleagues were working on a similar goal. “The key question that we asked is, how does the cell actually feel that it is deformed?” says Ruprecht, a coauthor of the other new paper. “And how can it activate this program of cytoskeletal changes that then lead to the sudden migration that is like an escape reflex?”
Ruprecht, Stefan Wieser, a biophysicist at the Institute of Photonic Sciences in Barcelona, and their team focused on proteins from the outer surface of zebrafish cells confined beneath coverslips in culture to see if any of these proteins were responsible for the switch from not moving to moving. They didn’t find a role for adhesion proteins or ion channels that sense mechanical deformation. So they turned their attention to the nucleus.
“The nucleus is a very large and prominent organelle . . . and when you squish the cells, it is very clear that the intracellular organelles were affected, so we were then thinking, ‘Maybe the sensor is not at the surface, but it’s in fact inside the cell,’” says Ruprecht. They noticed that myosin II only seemed to be enriched when cells were compressed enough that the nucleus would be affected.
Using their microscopic cantilevers, Lomakin and colleagues made a similar observation and proposed that the nucleus is working as a sensor that, when deformed, signals to cells to seek more elbow room. To connect nuclear deformation with cell motility, the researchers performed a small-molecule screen in human cancer cells and determined that intracellular calcium, stretch-sensitive proteins in the nuclear envelope, and an enzyme called cytosolic phospholipase A2 (cPLA2) were involved.
Ruprecht’s group also converged on cPLA2. In a 2016 study, Philipp Niethammer’s group at Memorial Sloan Kettering Cancer Center showed that nuclear swelling during inflammation or osmotic stress, along with calcium signaling, could activate cPLA2. After seeing that study, Ruprecht’s team tested the role of cPLA2 in the zebrafish cell culture system.
In this illustration, when cell confinement gets smaller than the nucleus’s resting diameter, the nucleus is deformed (I). Then, the nuclear envelope stretches and unfolds, resulting in tension that triggers calcium release, activation of cPLA2, and subsequent production of arachidonic acid (II). Downstream signaling generates actomyosin forces (III) and increased cell motility (IV). Alexis Lomakin, St. Anna Children's Cancer Research Institute Vienna
Both groups found that when the nucleus gets squeezed, its envelope stretches and unfolds, releasing calcium and recruiting cPLA2 from within the nucleoplasm to the inner nuclear membrane. This movement of the enzyme activates it, resulting in release of its principle cleavage product, arachidonic acid, which then sends a cascade of signals in the cytoplasm that eventually trigger myosin II activity, thereby linking nuclear compression and cell movement.
“Two independent groups using different approaches ended up with the same conclusions. It’s nice to see a lot of the commonalities that they point out using different experimental systems,” says Jan Lammerding, a biomedical engineer at Cornell University who did not participate in either study. “It really advances our understanding of how the nucleus helps to sense mechanical stress.”
The groups have found a key mechanism, Lammerding tells The Scientist, but in the future, “it would still be interesting to see if there are other mechanisms, and, if so, are they independent? How much interaction and crosstalk is there potentially between different nuclear mechanosensing mechanisms, but also between nuclear and cytoplasmic mechanisms?”
In addition to more questions about how it all works, the researchers are excited about possible applications. Cancer cells use “this mechanism to escape crowded environments, or mechanically constrictive environments,” says Lomakin, which means that it could be targeted for cancer treatment. “Preliminary data show that down regulating the activity of cPLA2 [with] small molecule inhibitors could interfere with the ability of tumor cells to break free from the primary tumor and to metastasize to distant organs.”
A.J. Lomakin et al., “The nucleus acts as a ruler tailoring cell responses to spatial constraints,” Science, doi:10.1126/science.aba2894, 2020.
V. Venturini et al., “The nucleus measures shape changes for cellular proprioception to control dynamic cell behavior,” Science, doi:10.1126/science.aba2644, 2020.


thescientist--2020-10-15--Bio-Rad Announces the Global Launch of the CFX Opus 96 and CFX Opus 384 Real-Time PCR Systems and BR

Bio-Rad Announces the Global Launch of the CFX Opus 96 and CFX Opus 384 Real-Time PCR Systems and BR.io, Web-Based Data Management and Analysis Software

The CFX Opus 96 and CFX Opus 384 Real-Time PCR Systems represent the next generation of the company ’ s CFX Real-Time PCR Systems that are used in research and genomic testing as well as in pathogen detection and infectious disease testing .
The CFX Opus 96 and CFX Opus 384 Real-Time PCR Systems employ the same optical design used across Bio-Rad ’ s portfolio of CFX products and offer enhanced usability with features designed for academic , commercial , and biopharma labs to conduct basic and translational research , process development , and quality control .
`` The CFX @ @ @ @ @ @ @ life science tools , helping our customers find answers to complex biological questions , '' said Annette Tumolo , Bio-Rad Executive Vice President and President Life Science Group .
`` The addition of BR.io cloud connectivity offers customers a simplified qPCR experience and demonstrate Bio-Rad ’ s commitment to developing robust solutions to meet customers ’ needs within the ever-evolving landscape of genomics research and diagnostics , '' she said .
Along with the launch , Bio-Rad also announces early access to BR.io , a cloud-based software that enables users to design experiments @ @ @ @ @ @ @ experiments remotely .
The integration with BR.io provides seamless data transfer and the ability for users to monitor instrument status anywhere from the cloud .
Bio-Rad 's entire line of CFX systems have been instrumental to the company ’ s global response to the COVID-19 pandemic .
The CFX Opus 96 and CFX Opus 384 Real-Time PCR Systems will further strengthen our contribution as we continue to work with our customers and governments around the world to fight this disease .
About the CFX Opus 96 and CFX Opus 384 Real-Time PCR Systems @ @ @ @ @ @ @ options provide an intuitive and efficient experience for real-time PCR users

The CFX Opus 96 and CFX Opus 384 Real-Time PCR Systems represent the next generation of the company’s CFX Real-Time PCR Systems that are used in research and genomic testing as well as in pathogen detection and infectious disease testing. The CFX Opus 96 and CFX Opus 384 Real-Time PCR Systems employ the same optical design used across Bio-Rad’s portfolio of CFX products and offer enhanced usability with features designed for academic, commercial, and biopharma labs to conduct basic and translational research, process development, and quality control.
"The CFX Opus Systems expand the Bio-Rad family of life science tools, helping our customers find answers to complex biological questions," said Annette Tumolo, Bio-Rad Executive Vice President and President Life Science Group. "The addition of BR.io cloud connectivity offers customers a simplified qPCR experience and demonstrate Bio-Rad’s commitment to developing robust solutions to meet customers’ needs within the ever-evolving landscape of genomics research and diagnostics," she said.
Along with the launch, Bio-Rad also announces early access to BR.io, a cloud-based software that enables users to design experiments, analyze data, and access their experiments remotely. The integration with BR.io provides seamless data transfer and the ability for users to monitor instrument status anywhere from the cloud.
Bio-Rad's entire line of CFX systems have been instrumental to the company’s global response to the COVID-19 pandemic. The CFX Opus 96 and CFX Opus 384 Real-Time PCR Systems will further strengthen our contribution as we continue to work with our customers and governments around the world to fight this disease.
About the CFX Opus 96 and CFX Opus 384 Real-Time PCR Systems
Patent-pending block design delivers tight thermal uniformity for improved well-to-well consistency during real-time PCR experiments
Redesigned touchscreen interface and flexible connectivity options provide an intuitive and efficient experience for real-time PCR users
The same proprietary real-time PCR optical design


thescientist--2020-10-15--Climate Change Helped Drive Homo sapiens' Cousins Extinct: Study

The branch on the tree of life that is the genus Homo is a gnarled , twisty one with many offshoots and dead ends .
Of at least six species who have walked the Earth within the past few million years , all but one have gone extinct , for reasons that are largely a mystery .
Now , an extensive modeling study based on paleoclimatic data and nearly 3,000 archaeological records suggests that global cooling episodes were a major driver of the extinction of the Neanderthals as well as the long-gone Homo species H. erectus and H. heidelbergensis .
@ @ @ @ @ @ @ ( October 15 ) in One Earth—the findings are an ominous warning from the past with regard to our own future in a rapidly warming climate .
But some other experts note that the fossil record isn ’ t reliable enough to draw such conclusions about past hominin extinctions with certainty .
“ [ The authors ] did the best job I think they could possibly do with the data there are available , ” remarks anthropologist Jessica Thompson of Yale University who wasn ’ t involved in the new study .
“ @ @ @ @ @ @ @ to the Neanderthal debate [ on how they went extinct ] and a [ valuable ] set of hypotheses that people working earlier in time can look to if they ’ re trying to frame the work that they ’ re doing.
” A few years ago , evolutionary biologist Pasquale Raia of the University of Naples Federico II in Italy discovered a database of paleoclimatic data and decided to team up with archaeologists and paleoclimate modelers to investigate how different Homo species responded to the continuous oscillations of Earth ’ s climate @ @ @ @ @ @ @ of time .
To find out , they used a paleoclimatic emulator that models temperature , rainfall , and net primary productivity for the past 5 million years .
They aligned those climate data with the locations and estimated ages of fossils for six Homo species—habilis , ergaster , erectus , heidelbergensis , neanderthalensis , and sapiens—to characterize the range of climatic conditions each species was able to occupy throughout its existence .
The team compared that to the environmental conditions the species were experiencing at particular timepoints .
Those comparisons suggested that @ @ @ @ @ @ @ heidelbergensis—their climatic niches appeared to suddenly contract just before their last known appearance in the fossil record .
Further analyses using techniques typically employed by conservation biologists to assess how sensitive species are to current global warming suggested that those three Homo species were indeed highly vulnerable to changes in climate .
That affirmed the idea that global cooling episodes played a key role in their demise , although in the case of Neanderthals , that was exacerbated by competition with Homo sapiens .
“ Their resource base was [ likely ] shrinking @ @ @ @ @ @ @ .
other new resources , ” Raia says .
What H. neanderthalensis , erectus , and heidelbergensis have in common , Raia adds , is that their disappearance represents evolutionary dead ends , and therefore a true extinction .
By contrast , H. ergaster and H. habilis probably represent transitional hominins who evolved into other human species .
See “ Infographic : Meet your ancient ancestors and relatives in Africa ” The last known survivors of H. erectus are thought to have existed roughly around 110,000 years ago on the Indonesian island of @ @ @ @ @ @ @ given rise to other hominins such as H. heidelbergensis and migrated out of Africa into Eurasia .
In Java , H. erectus representatives were geographically distant from other known hominins at the time , making it unlikely they left any descendants , the authors write .
The species—which likely thrived under the warm , moist southeast Asian climate—entered its final chapter with the arrival of the last glacial period , which the team ’ s model suggests must have brought on the coldest temperatures the species had ever experienced .
Like H. erectus @ @ @ @ @ @ @ and later ventured into Eurasia .
The species is often thought to be an early ancestor of ourselves and Neanderthals , although skulls and other fossils found in southern China , India , and Germany are younger than the earliest known emergence of Neanderthals and H. sapiens–like hominins .
That suggests some lineages of H. heidelbergensis did not branch off into other species and instead went extinct after those new taxa had evolved .
H. heidelbergensis too succumbed to cold temperatures in southern Eurasia some 200,000 years ago , according to Raia ’ @ @ @ @ @ @ @ , which went extinct in southern Europe around 40,000 years ago , competition with modern humans—who by that time had joined them on the European continent—almost certainly played a role in their demise .
But “ they were nonetheless still vulnerable [ to climate change ] , ” Raia says .
There are a number of factors that may explain why our species survived when Neanderthals did not , including cultural and linguistic capabilities , and the fact that H. sapiens had a vast reservoir of individuals in Africa that could colonize Europe @ @ @ @ @ @ @ Neanderthals are physically extinct , some of their DNA continues to live on in people today .
See “ Genetics Steps in to Help Tell the Story of Human Origins ” The study ’ s findings on Neanderthals contribute to a lively debate about the relative importance of cold spells and the arrival of anatomically modern humans in Europe in the extinction of Neanderthals .
That ’ s where the paper draws on the richest and most reliable fossil and dating records , notes Chris Stringer , a paleoanthropologist at the Natural History @ @ @ @ @ @ @ involved in the new research .
Yet looking further back in time towards the other species , the fossil record becomes less reliable .
“ Personally , I think that climate change probably was a significant factor in some of those extinctions , ” but the quality of the fossil record makes such ambitious investigations difficult at this stage , he writes to The Scientist in an email .
It ’ s unclear how much a relatively sparse record for most early Homo species actually tells us about their historic distributions , due @ @ @ @ @ @ @ in different places and where people tend to look for them , Thompson notes .
Nor is it clear whether a hominin ’ s last appearance in the fossil record actually represents when it went extinct .
Making matters harder , many fossils are poorly dated and archaeologists don ’ t have a good handle on the chronology of specimens for some species such as H. erectus .
For instance , Stringer notes that the authors based the last appearance of H. erectus on dates obtained from fossils at a site known as @ @ @ @ @ @ @ can ’ t be sure whether other less well dated sites .
.
.
might be younger still.
” He adds that the authors made particular choices that in his view could influence the strength of their results , such as deciding to include fossils identified as another hominin species , H. rudolfensis , as part of the H. habilis lineage , and their interpretation of certain specimens where there is disagreement about their classification .
Raia points toward several analyses he and his colleagues conducted to test various assumptions they made , @ @ @ @ @ @ @ the end , the results still hold , ” he says .
“ I actually think these authors do a pretty tidy job of arguing for why they chose the particular taxa that they did , ” Thompson says .
“ They really went above and beyond trying to justify ” their decisions , as is evident in the 110-page supplement that accompanies the paper .
The study may not provide definitive answers about the history of our genus , but it ’ s valuable in that it provides a hypothesis that could @ @ @ @ @ @ @ .
“ It might change where you might want to look for sites .
.
.
.
You might find out that maybe the animals represented in the fossils there are reflective of a climate that really supports the model , or you might find otherwise , ” she adds .
In paleontological terms , it ’ s not uncommon for climatic changes to push species to the brink .
But to Raia , the fact that even some of the most technologically advanced and intelligent creatures of their time weren ’ t @ @ @ @ @ @ @ warning to our species today .
Both Raia and Thompson agree that Homo sapiens is well-endowed to survive climate change .
But survival as a species isn ’ t the goal—rather , it ’ s survival and wellbeing of the human population as a whole , as well as the living flora and fauna that support our existence on Earth .
“ When you think of what is happening right now , with all of the change we are causing because of our exploitation of fossil fuels , it makes thinking into the @ @ @ @ @ @ @ know that climate change [ can ] be that bad to species—even to those which were , cognitively speaking , the biggest fish in the tank , ” Raia says .
P. Raia et al.
, “ Past extinctions of Homo species coincided with increased vulnerability to climatic change , ” One Earth , doi:10/1016/j.oneear.2020.09.007 .

ABOVE: © ISTOCK.COM, 1971YES
The branch on the tree of life that is the genus Homo is a gnarled, twisty one with many offshoots and dead ends. Of at least six species who have walked the Earth within the past few million years, all but one have gone extinct, for reasons that are largely a mystery.
Now, an extensive modeling study based on paleoclimatic data and nearly 3,000 archaeological records suggests that global cooling episodes were a major driver of the extinction of the Neanderthals as well as the long-gone Homo species H. erectus and H. heidelbergensis. To the authors of the research—published today (October 15) in One Earth—the findings are an ominous warning from the past with regard to our own future in a rapidly warming climate. But some other experts note that the fossil record isn’t reliable enough to draw such conclusions about past hominin extinctions with certainty.
“[The authors] did the best job I think they could possibly do with the data there are available,” remarks anthropologist Jessica Thompson of Yale University who wasn’t involved in the new study. “This is an interesting contribution, mostly to the Neanderthal debate [on how they went extinct] and a [valuable] set of hypotheses that people working earlier in time can look to if they’re trying to frame the work that they’re doing.”
A few years ago, evolutionary biologist Pasquale Raia of the University of Naples Federico II in Italy discovered a database of paleoclimatic data and decided to team up with archaeologists and paleoclimate modelers to investigate how different Homo species responded to the continuous oscillations of Earth’s climate between cold glacial periods and warmer stretches of time. To find out, they used a paleoclimatic emulator that models temperature, rainfall, and net primary productivity for the past 5 million years.
We know that climate change [can] be that bad to species—even to those which were, cognitively speaking, the biggest fish in the tank. —Pasquale Raia, University of Naples Federico II
They aligned those climate data with the locations and estimated ages of fossils for six Homo species—habilis, ergaster, erectus, heidelbergensis, neanderthalensis, and sapiens—to characterize the range of climatic conditions each species was able to occupy throughout its existence. The team compared that to the environmental conditions the species were experiencing at particular timepoints. Those comparisons suggested that for three species—neanderthalensis, erectus, and heidelbergensis—their climatic niches appeared to suddenly contract just before their last known appearance in the fossil record.
Further analyses using techniques typically employed by conservation biologists to assess how sensitive species are to current global warming suggested that those three Homo species were indeed highly vulnerable to changes in climate. That affirmed the idea that global cooling episodes played a key role in their demise, although in the case of Neanderthals, that was exacerbated by competition with Homo sapiens. “Their resource base was [likely] shrinking faster than they could find . . . other new resources,” Raia says.
What H. neanderthalensis, erectus, and heidelbergensis have in common, Raia adds, is that their disappearance represents evolutionary dead ends, and therefore a true extinction. By contrast, H. ergaster and H. habilis probably represent transitional hominins who evolved into other human species.
The last known survivors of H. erectus are thought to have existed roughly around 110,000 years ago on the Indonesian island of Java, long after the species had given rise to other hominins such as H. heidelbergensis and migrated out of Africa into Eurasia. In Java, H. erectus representatives were geographically distant from other known hominins at the time, making it unlikely they left any descendants, the authors write. The species—which likely thrived under the warm, moist southeast Asian climate—entered its final chapter with the arrival of the last glacial period, which the team’s model suggests must have brought on the coldest temperatures the species had ever experienced.
Like H. erectus, H. heidelbergensis also evolved in Africa and later ventured into Eurasia. The species is often thought to be an early ancestor of ourselves and Neanderthals, although skulls and other fossils found in southern China, India, and Germany are younger than the earliest known emergence of Neanderthals and H. sapiens–like hominins. That suggests some lineages of H. heidelbergensis did not branch off into other species and instead went extinct after those new taxa had evolved. H. heidelbergensis too succumbed to cold temperatures in southern Eurasia some 200,000 years ago, according to Raia’s research.
As for the Neanderthals, which went extinct in southern Europe around 40,000 years ago, competition with modern humans—who by that time had joined them on the European continent—almost certainly played a role in their demise. But “they were nonetheless still vulnerable [to climate change],” Raia says. There are a number of factors that may explain why our species survived when Neanderthals did not, including cultural and linguistic capabilities, and the fact that H. sapiens had a vast reservoir of individuals in Africa that could colonize Europe anew, Raia adds.
While the Neanderthals are physically extinct, some of their DNA continues to live on in people today.
See “Genetics Steps in to Help Tell the Story of Human Origins”
The study’s findings on Neanderthals contribute to a lively debate about the relative importance of cold spells and the arrival of anatomically modern humans in Europe in the extinction of Neanderthals. That’s where the paper draws on the richest and most reliable fossil and dating records, notes Chris Stringer, a paleoanthropologist at the Natural History Museum in London who wasn’t involved in the new research. Yet looking further back in time towards the other species, the fossil record becomes less reliable. “Personally, I think that climate change probably was a significant factor in some of those extinctions,” but the quality of the fossil record makes such ambitious investigations difficult at this stage, he writes to The Scientist in an email.
It’s unclear how much a relatively sparse record for most early Homo species actually tells us about their historic distributions, due to biases in how well fossils preserve in different places and where people tend to look for them, Thompson notes. Nor is it clear whether a hominin’s last appearance in the fossil record actually represents when it went extinct. Making matters harder, many fossils are poorly dated and archaeologists don’t have a good handle on the chronology of specimens for some species such as H. erectus. For instance, Stringer notes that the authors based the last appearance of H. erectus on dates obtained from fossils at a site known as Ngandong in Java, “but we can’t be sure whether other less well dated sites . . . might be younger still.”
He adds that the authors made particular choices that in his view could influence the strength of their results, such as deciding to include fossils identified as another hominin species, H. rudolfensis, as part of the H. habilis lineage, and their interpretation of certain specimens where there is disagreement about their classification. Raia points toward several analyses he and his colleagues conducted to test various assumptions they made, including different taxonomic attributions. “In the end, the results still hold,” he says.
For three species—H. neanderthalensis, erectus, and heidelbergensis—their climatic niches appeared to suddenly contract just before their last known appearance in the fossil record.
“I actually think these authors do a pretty tidy job of arguing for why they chose the particular taxa that they did,” Thompson says. “They really went above and beyond trying to justify” their decisions, as is evident in the 110-page supplement that accompanies the paper.
The study may not provide definitive answers about the history of our genus, but it’s valuable in that it provides a hypothesis that could inform future archaeological research, she adds. “It might change where you might want to look for sites. . . . You might find out that maybe the animals represented in the fossils there are reflective of a climate that really supports the model, or you might find otherwise,” she adds.
In paleontological terms, it’s not uncommon for climatic changes to push species to the brink. But to Raia, the fact that even some of the most technologically advanced and intelligent creatures of their time weren’t immune to climate change serves as a warning to our species today. Both Raia and Thompson agree that Homo sapiens is well-endowed to survive climate change. But survival as a species isn’t the goal—rather, it’s survival and wellbeing of the human population as a whole, as well as the living flora and fauna that support our existence on Earth.
“When you think of what is happening right now, with all of the change we are causing because of our exploitation of fossil fuels, it makes thinking into the future even more worrisome, because we know that climate change [can] be that bad to species—even to those which were, cognitively speaking, the biggest fish in the tank,” Raia says.
P. Raia et al., “Past extinctions of Homo species coincided with increased vulnerability to climatic change,” One Earth, doi:10/1016/j.oneear.2020.09.007.


thescientist--2020-10-13--Shifting Space and Time: How Harnessing Our Most Powerful Cells Is Changing Immune Medicine

Immune medicines are promising therapies for debilitating disorders such as cancer , infectious disease , and inflammatory disease .
By @ @ @ @ @ researchers gain insights into which patients will respond to various immunotherapies .
To accelerate the @ @ @ @ @ scientists use applications that decrease the space and time needed for assays that target single @ @ @ @ @ event brought to you by IsoPlexis , industry and academic leaders will describe how data @ @ @ @ @ cell subsets shift conceptions about how humans mount effective immune responses , including which cells @ @ @ @ @ They will discuss technological advancements that enable all labs to detect powerful , highly active @ @ @ @ @ functional proteome .
Additionally , the speakers will highlight applications for harnessing these powerful cell @ @ @ @ @ gene therapies .

Shifting Space and Time
How harnessing our most powerful cells is changing immune medicine
Immune medicines hold promise as therapies for debilitating disorders such as cancer, infectious diseases, and inflammatory diseases. By studying immune cell subsets, researchers gain insights into which patients will respond to various immunotherapies. To accelerate the timelines for finding cures, scientists use applications that decrease the space and time needed for assays that target single immune cells.
In this event brought to you by IsoPlexis, industry and academic leaders describe how data from small immune cell subsets shift conceptions about how humans mount effective immune responses, including which cells orchestrate a balanced attack. They discuss technological advancements that enable researchers to use functional proteomes to detect powerful, highly active immune cell subsets. Additionally, the speakers highlight applications for harnessing these powerful cell subsets to advance cell and gene therapies.


thescientist--2020-10-16--Serotonin and Dopamine Linked to Decision-Making: Study

ABOVE : To capture simultaneous and continuous measurements of the neuromodulators dopamine and serotonin , the study authors designed a microelectrode capable of taking 10 measurements per second .
VIRGINIA TECH Long associated with reward and pleasure , dopamine and serotonin may also be involved in general cognition , shaping how people perceive the world and act on those perceptions , a new study finds .
For the first time , researchers have continuously and simultaneously monitored the two neuromodulators in the human brain .
The results , published October 12 in Neuron , offer new opportunities to test hypotheses @ @ @ @ @ @ @ “ This study isn ’ t just measuring dopamine and serotonin ; it ’ s building upon the deep foundation looking at neural mechanisms for perceptual decisions in animals and humans ” and linking the findings of these studies together , Tim Hanks , a neuroscientist at the University of California , Davis , who was not involved in the study , tells The Scientist .
“ There ’ s a growing recognition that [ dopamine and serotonin ] have more refined and nuanced roles than what may have once been believed , @ @ @ @ @ @ @ clear in human decision-making.
” Both neuromodulators have been heavily studied in animals , but animals require training to carry out decision-making tasks—training that often comes with a reward .
As a result , it can be difficult to tease apart the decision-making from the reinforcement they receive in return .
“ Animals are a limited model of the rich thoughts and behaviors that we see in humans , ” says Dan Bang , a neuroscientist at University College London and the lead author of the new study .
To study dopamine and @ @ @ @ @ @ @ recruited five volunteers who were set to undergo brain surgery to treat either Parkinson ’ s or essential tremors and agreed to have their neurochemicals monitored during the procedure .
Surgeons keep patients awake during the operation and use probes to measure brain activity for safety .
Bang ’ s group was able to insert its own microelectrode into the caudate nucleus of four of the volunteers and the putamen of the fifth .
Both structures are regions of the striatum and are involved in movement , learning , and reward .
As @ @ @ @ @ @ @ a modified version of a common visual task called the random dot motion paradigm .
In each round of the task , a person was shown a cloud of flickering dots moving across a screen .
Some dots moved together in the same direction , while the rest moved randomly ; the proportions undergoing each type of movement determined the difficulty of the task .
In the standard test , the dots disappear , and the subject must indicate whether they had , on average , been moving toward the left or the @ @ @ @ @ @ @ participants were instead shown a random angle after the dots had disappeared and had to decide whether the dots had been moving to the left or right of that angle .
In this way , the scientists were able to vary the difficulty and uncertainty of a person ’ s perception by changing both the number of dots moving in synchrony and how close their path of motion came to the randomly selected reference angle .
After making their choice , participants rated how sure they were of their decision .
A microelectrode @ @ @ @ @ @ @ in the caudate nucleus or putamen , taking 10 measurements each second .
Scientists have never before been able to monitor these neurotransmitters at such biologically relevant speeds in humans .
Less-invasive methods such as PET scanning or fMRI typically take only one measurement per minute .
Within the caudate nucleus , serotonin levels were linked to uncertainty around perceptions in three of the four participants .
When the task was more difficult and the outcome uncertain , as estimated by the task variables and the participants ’ self-reported uncertainty about their decisions @ @ @ @ @ @ @ after the dots appeared on the screen .
When the task was easier , serotonin spiked .
In some previous human and animal studies , dopamine has had the opposite relationship with serotonin , and therefore with uncertainty , but in the new study , variations in the caudate nucleus ’ s dopamine levels did not track consistently with task uncertainty .
In the putamen , however , the team did find strong evidence in support of opposing roles for dopamine and serotonin in relation to action , as evidenced by the time @ @ @ @ @ @ @ about the direction of the dots .
Both an increase in dopamine and a corresponding decrease in serotonin were associated with the subject ’ s choice to act , and both the change in neuromodulator levels and the decision itself happened more quickly when the task was easier and less uncertain .
Taken together , these findings suggest that beyond their role as reward chemicals , dopamine and serotonin may contribute to cognition more generally , linking “ how we perceive the world and how we then go on to make decisions , @ @ @ @ @ @ @ at the Wake Forest School of Medicine and a coauthor on the study .
“ This is definitely putting the importance of dopamine and serotonin into a new light.
” Even though this is a new finding in humans , it dovetails with what some researchers have begun to find in animals , says Armin Lak , a neuroscientist at the University of Oxford who was not involved in the study .
In his own work , Lak has found links between dopamine and perception in rodents .
“ It ’ s really @ @ @ @ @ @ @ in neuroscience , to see this spectrum of studies all the way from animals to human volunteers.
” The biggest limitation of the new study , Lak adds , is the small sample size .
Some of the team ’ s results , such as their data on the putamen , stem from only a single person .
Kishida also points out that while dopamine levels varied more between people than did serotonin levels , that may be because some of the patients had Parkinson ’ s , a disease caused by dysregulated @ @ @ @ @ @ @ team plans to refine its microelectrode to recognize additional neurochemicals , such as norepinephrine .
Having shown that the responses of neuromodulators can differ by brain region , they would also like to expand to include the cortex , amygdala , and hippocampus .
Better understanding of how dopamine and serotonin interact and their roles in different parts of the brain will also have important implications for treating neuropsychiatric disorders such as Parkinson ’ s and depression , says Hanks .
Many treatments target these two modulators , but they do so across @ @ @ @ @ @ @ scales , so more knowledge could lead to more targeted and effective therapies .
“ Because these neuromodulators have complex roles that depend on brain region , some will see it as a challenge , because it means that we can ’ t just use a medication that ’ s affecting [ the brain ] diffusely , ” Hanks tells The Scientist .
“ But at the same time , I would argue that this represents a tremendous opportunity to make [ therapies ] even more effective.
” D. Bang et al.
, @ @ @ @ @ @ @ human striatum during perceptual decision-making , ” Neuron , 108:1–12 , 2020 .
Clarification ( October 16 ) : The title of this article has been updated to better reflect the study ’ s findings .

ABOVE: To capture simultaneous and continuous measurements of the neuromodulators dopamine and serotonin, the study authors designed a microelectrode capable of taking 10 measurements per second.
VIRGINIA TECH
Long associated with reward and pleasure, dopamine and serotonin may also be involved in general cognition, shaping how people perceive the world and act on those perceptions, a new study finds.
For the first time, researchers have continuously and simultaneously monitored the two neuromodulators in the human brain. The results, published October 12 in Neuron, offer new opportunities to test hypotheses previously studied mostly in animal models.
“This study isn’t just measuring dopamine and serotonin; it’s building upon the deep foundation looking at neural mechanisms for perceptual decisions in animals and humans” and linking the findings of these studies together, Tim Hanks, a neuroscientist at the University of California, Davis, who was not involved in the study, tells The Scientist. “There’s a growing recognition that [dopamine and serotonin] have more refined and nuanced roles than what may have once been believed, and this study really makes that case clear in human decision-making.”
Both neuromodulators have been heavily studied in animals, but animals require training to carry out decision-making tasks—training that often comes with a reward. As a result, it can be difficult to tease apart the decision-making from the reinforcement they receive in return. “Animals are a limited model of the rich thoughts and behaviors that we see in humans,” says Dan Bang, a neuroscientist at University College London and the lead author of the new study.
See "How Dopamine Tunes Working Memory"
To study dopamine and serotonin signaling in humans, the team recruited five volunteers who were set to undergo brain surgery to treat either Parkinson’s or essential tremors and agreed to have their neurochemicals monitored during the procedure. Surgeons keep patients awake during the operation and use probes to measure brain activity for safety. The research team, led by Read Montague, a neuroscientist at Virginia Tech, was able to insert its own microelectrode into the caudate nucleus of four of the volunteers and the putamen of the fifth. Both structures are regions of the striatum and are involved in movement, learning, and reward.
This is definitely putting the importance of dopamine and serotonin into a new light. —Ken Kishida, Wake Forest School of Medicine
As they underwent surgery, each participant completed a modified version of a common visual task called the random dot motion paradigm. In each round of the task, a person was shown a cloud of flickering dots moving across a screen. Some dots moved together in the same direction, while the rest moved randomly; the proportions undergoing each type of movement determined the difficulty of the task. In the standard test, the dots disappear, and the subject must indicate whether they had, on average, been moving toward the left or the right. In the amended protocol, participants were instead shown a random angle after the dots had disappeared and had to decide whether the dots had been moving to the left or right of that angle.
In this way, the scientists were able to vary the difficulty and uncertainty of a person’s perception by changing both the number of dots moving in synchrony and how close their path of motion came to the randomly selected reference angle. After making their choice, participants rated how sure they were of their decision.
A microelectrode continuously measured both dopamine and serotonin levels in the caudate nucleus or putamen, taking 10 measurements each second. Scientists have never before been able to monitor these neurotransmitters at such biologically relevant speeds in humans. Less-invasive methods such as PET scanning or fMRI typically take only one measurement per minute.
The probe used in the study (top, shown with a paperclip for size comparison) is made of carbon fiber and uses low voltages to detect dopamine and serotonin activity in real time. virginia tech
Within the caudate nucleus, serotonin levels were linked to uncertainty around perceptions in three of the four participants. When the task was more difficult and the outcome more uncertain, as estimated by the task variables and the participants’ self-reported uncertainty about their decisions, serotonin levels spiked shortly after the dots appeared on the screen. When the task was easier, serotonin dropped. In some previous human and animal studies, dopamine has had the opposite relationship with serotonin, and therefore with uncertainty, but in the new study, variations in the caudate nucleus’s dopamine levels did not track consistently with perceptual uncertainty.
In the putamen, however, the team did find strong evidence in support of opposing roles for dopamine and serotonin in relation to action, as evidenced by the time it took participants to make their choice about the direction of the dots. Both an increase in dopamine and a corresponding decrease in serotonin were associated with the subject’s choice to act, and both the change in neuromodulator levels and the decision itself happened more quickly when the task was easier and less uncertain.
Taken together, these findings suggest that beyond their role as reward chemicals, dopamine and serotonin may contribute to cognition more generally, linking “how we perceive the world and how we then go on to make decisions,” says Ken Kishida, a neuroscientist at the Wake Forest School of Medicine and a coauthor on the study. “This is definitely putting the importance of dopamine and serotonin into a new light.”
Even though this is a new finding in humans, it dovetails with what some researchers have begun to find in animals, says Armin Lak, a neuroscientist at the University of Oxford who was not involved in the study. In his own work, Lak has found links between dopamine and perception in rodents. “It’s really nice, for those of us working in neuroscience, to see this spectrum of studies all the way from animals to human volunteers.”
The biggest limitation of the new study, Lak adds, is the small sample size. Some of the team’s results, such as their data on the putamen, stem from only a single person. Kishida also points out that while dopamine levels varied more between people than did serotonin levels, that may be because some of the patients had Parkinson’s, a disease caused by dysregulated dopamine signaling.
Moving forward, the team plans to refine its microelectrode to recognize additional neurochemicals, such as norepinephrine. Having shown that the responses of neuromodulators can differ by brain region, they would also like to expand to include the cortex, amygdala, and hippocampus.
Better understanding of how dopamine and serotonin interact and their roles in different parts of the brain will also have important implications for treating neuropsychiatric disorders such as Parkinson’s and depression, says Hanks. Many treatments target these two modulators, but they do so across the entire brain and over longer time scales, so more knowledge could lead to more targeted and effective therapies.
“Because these neuromodulators have complex roles that depend on brain region, some will see it as a challenge, because it means that we can’t just use a medication that’s affecting [the brain] diffusely,” Hanks tells The Scientist. “But at the same time, I would argue that this represents a tremendous opportunity to make [therapies] even more effective.”
D. Bang et al., “Sub-second dopamine and serotonin signaling in human striatum during perceptual decision-making,” Neuron, 108:1–12, 2020.
Clarification (October 16): The title of this article has been updated to better reflect the study’s findings, and a correction was made to clarify that serotonin levels increased in the caudate nucleus when participants were more uncertain.