thescientist--2020-09-24--Advancements in Exosome Research Tools and Diagnostics

Exosomes and other extracellular vesicles ( EVs ) are a versatile source of biomarkers for molecular diagnostics .
EVs enable @ @ @ @ @ liquid biopsy , from mutation detection to RNA profiling and protein analysis .
Researchers have @ @ @ @ @ biopsy and EV based-diagnostics , resulting in the first commercially available exosome-based test to aid @ @ @ @ @ clinical decision-making process .
In this webinar , brought to you by Bio-Techne , Chris @ @ @ @ @ to Simple Western technology and , Johan Skog , will cover an introduction to exosomes @ @ @ @ @ diagnostic applications in the exosome field , and how automated western blotting systems can help @ @ @ @ @

FREE Webinar
Tuesday, October 27, 2020
11:00 AM - 12:00 PM, Eastern Standard Time
Register Now
Exosomes and other extracellular vesicles (EVs) are a versatile source of biomarkers for molecular diagnostics. EVs enable and enhance the field of liquid biopsy, from mutation detection to RNA profiling and protein analysis. Researchers have made substantial progress in liquid biopsy and EV-based diagnostics, resulting in the first commercially available exosome-based test to aid doctors and patients in the clinical decision-making process. In this webinar, brought to you by Bio-Techne, Chris Heger will cover an introduction to Simple Western technology, and Johan Skog will cover an introduction to exosomes, some of the latest diagnostic applications in the exosome field, and how automated Western blotting systems can help streamline your exosome research.
Register Now
Meet the Speakers:
Chris Heger, PhD
Senior Manager, Applications Science
Analytical Solutions Division
ProteinSimple, a Bio-Techne brand
Johan Skog, PhD
Chief Scientific Officer, Vice President
Exosome Diagnostics, a Bio-Techne brand


thescientist--2020-10-01--Cheese Preservative Slows Oral Cancer Spread in Mice: Study

ABOVE : Oral cancer cells ( left ) are infected with one of three periodontal pathogens ( stained in green ) for two hours before being injected into the mouth of mice .
Treponema denticola ( right ) can be seen invading oral cancer cells , which researchers found leads to a more aggressive cancer .
ALLAN RADAIC AND LEA SEDGHI , UNIVERSITY OF CALIFORNIA , SAN FRANCISCO In the last few decades , scientists have identified more than a dozen pathogens—from human papillomavirus to Helicobacter pylori—that contribute to the progression of cancers .
In a study published today ( @ @ @ @ @ @ @ researchers demonstrate the mechanism by which three oral bacteria found in cells of the gums promote oral squamous cell carcinoma ( OSCC ) tumor development and progression in mice .
And they show that a bacteriocin , an antimicrobial peptide that bacteria produce , counters the effects of the oral bacteria and slows tumor growth .
“ This study fits in nicely in a growing body of evidence that a variety of known pathogens contribute to the initiation and progression of different cancers , ” says Mark Herzberg , a biologist at the @ @ @ @ @ @ @ cancer and was not involved with the report .
“ Oral cancer has been known to be caused by tobacco smoking , alcohol use , and HPV , but now they are presenting mechanistic evidence that the bacteria in the oral cavity exacerbate carcinogenesis.
” Yvonne Kapila , the vice-chair of periodontology at the University of California , San Francisco , says she first conceived of the idea to do this research when she noticed that some of the patients she treats in her clinic developed oral cancer in the same areas of @ @ @ @ @ @ @ or inserted dental implants .
Prior research suggests that there is a link between inflammation and cancer , and Kapila wanted to understand if there was something else , such as oral pathogens , that predisposed those areas of the mouth to cancer .
To find out , Kapila and her colleagues took human OSCC cells that were infected with one of three periodontal bacteria—Porphyromonas gingivalis , Treponema denticola , and Fusobacterium nucleatum—and injected them into the floor of the mouth of six-week-old mice .
F. nucleatum is commonly found in the mouth @ @ @ @ @ @ @ are rarely found in healthy gum tissue .
Two weeks later , the mice were divided into a control group that was given water and a treatment group that received the bacteriocin nisin .
After seven weeks of treatment , the researchers euthanized the mice and harvested the tumors to study them .
The presence of the periodontal bacteria caused cancerous cells to replicate and migrate more efficiently , leading to a more aggressive form of OSCC .
Using immunoblots , researchers discovered that the pathogens activated two signaling pathways within the tumor @ @ @ @ @ @ @ of which are key to cell migration .
Tumors in mice that received nisin showed decreased movement , invasion , and size .
Tumors in the nisin-treated mice also appeared whiter in color , which the researchers say represents a decrease in blood vessels , typically a good sign for recovery , as tumors require a large blood supply .
“ This report shows that cancers can be treated with antimicrobials , which is really new—nobody ’ s ever really thought of treating cancers with antimicrobials or something as simple as bacteriocins , @ @ @ @ @ @ @ This is also confirmation that oral bacteria that are associated with disease really aggravate other diseases like cancers.
” Nam Joo , a former postdoc in Kapila ’ s laboratory , was the first to raise the possibility of nisin ’ s therapeutic role .
Joo began his nisin research while studying kimchi , which is rich in bacteria that produce nisin , for his master ’ s degree in South Korea .
He wondered if the bacteriocin might work as an anticancer agent because of its known properties in promoting cell death @ @ @ @ @ @ @ bacteriocins inhibit only closely related species , nisin acts as a broad-spectrum antibacterial that is effective against many Gram-positive bacteria .
In this study , nisin did not target the oral pathogens , but the cancerous cells themselves .
The bacteriocin inhibited the effects of the bacteria , deactivating the signaling pathways they enabled by latching onto the cancer cell membranes and allowing calcium to flow into the cell .
Kapila says she is currently investigating why nisin binds to tumor cells , rather than healthy cells , but she says it may @ @ @ @ @ @ @ lipid bilayers , which cell membranes are made of , previous research shows .
“ It ’ s particularly noteworthy to modulate a microbial community to prevent a noncommunicable disease , ” says David Moyes , a microbiologist who studies oral pathogens at King ’ s College London and was not involved with the study .
“ Bacteriocins are a fairly new kid on the block for use in clinical therapy.
” The bacteriocin was first isolated in the 1920s from Lactococcus lactis , a bacterium used extensively in the production of cheese @ @ @ @ @ @ @ an additive to protect food against harmful bacteria in the 1960s .
Head and neck squamous cell carcinoma ( HNSCC ) is the seventh most common cancer worldwide , with 600,000 new cases diagnosed each year , according to the National Institutes of Health .
OSCC is a subset of HNSCC that is extremely prevalent in some countries such as India , where OSCC makes up more than 50 percent of all cancers .
Kapila has submitted a grant to test the bacteriocin on patients with oral cancer in a clinical trial .
@ @ @ @ @ @ @ particularly because it has long been deemed safe enough to include in food products , so it may be easier to approve if there is conclusive evidence from human trials that it helps fight cancer .
Indeed , in a 2015 study , Kapila notes that that people in the US consume 0.94 to 2.24 mg of nisin per day , according to an estimate from the US Food and Drug Administration .
There is no indication that this helps prevent or treat oral cancer .
Kapila ’ s team also examined the @ @ @ @ @ @ @ the liver , kidney , and lung to see if nisin led to downstream consequences but found no differences between these animals and those that didn ’ t get the treatment .
Oral pathogens have previously been shown to promote other cancers such as colorectal cancer , so Kapila remains hopeful that her study opens the door for research on antimicrobial peptides to treat other cancers .
“ One of the real negative side effects of the current gold standard treatment , chemoradiation , is the really nasty off-target effects of these medications @ @ @ @ @ @ @ “ It would be fantastic if we can find a treatment that does not have all these side effects.
” P. Kamarajan et al.
, “ Periodontal pathogens promote cancer aggressivity via TLR/MyD88 triggered activation of Integrin/FAK signaling that is therapeutically reversible by a probiotic bacteriocin , ” PLOS Pathog , doi:10.1371/journal.ppat.1008881 , 2020 .

ABOVE: Oral cancer cells (left) are infected with one of three periodontal pathogens (stained in green) for two hours before being injected into the mouth of mice. Treponema denticola (right) can be seen invading oral cancer cells, which researchers found leads to a more aggressive cancer.
ALLAN RADAIC AND LEA SEDGHI, UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
In the last few decades, scientists have identified more than a dozen pathogens—from human papillomavirus to Helicobacter pylori—that contribute to the progression of cancers. In a study published today (October 1) in PLOS Pathogens, researchers demonstrate the mechanism by which three oral bacteria found in cells of the gums promote oral squamous cell carcinoma (OSCC) tumor development and progression in mice. And they show that a bacteriocin, an antimicrobial peptide that bacteria produce, counters the effects of the oral bacteria and slows tumor growth.
“This study fits in nicely in a growing body of evidence that a variety of known pathogens contribute to the initiation and progression of different cancers,” says Mark Herzberg, a biologist at the University of Minnesota who has studied oral cancer and was not involved with the report. “Oral cancer has been known to be caused by tobacco smoking, alcohol use, and HPV, but now they are presenting mechanistic evidence that the bacteria in the oral cavity exacerbate carcinogenesis.”
Yvonne Kapila, the vice-chair of periodontology at the University of California, San Francisco, says she first conceived of the idea to do this research when she noticed that some of the patients she treats in her clinic developed oral cancer in the same areas of the mouth where she performed gum surgery or inserted dental implants. Prior research suggests that there is a link between inflammation and cancer, and Kapila wanted to understand if there was something else, such as oral pathogens, that predisposed those areas of the mouth to cancer.
To find out, Kapila and her colleagues took human OSCC cells that were infected with one of three periodontal bacteria—Porphyromonas gingivalis, Treponema denticola, and Fusobacterium nucleatum—and injected them into the floor of the mouth of six-week-old mice. F. nucleatum is commonly found in the mouth, whereas P. gingivalis and T. denticola are rarely found in healthy gum tissue. Two weeks later, the mice were divided into a control group that was given water and a treatment group that received the bacteriocin nisin.
After seven weeks of treatment, the researchers euthanized the mice and harvested the tumors to study them. The presence of the periodontal bacteria caused cancerous cells to replicate and migrate more efficiently, leading to a more aggressive form of OSCC. Using immunoblots, researchers discovered that the pathogens activated two signaling pathways within the tumor cells: integrin/FAK and TLR/MyDD88, both of which are key to cell migration.
Tumors in mice that received nisin showed decreased movement, invasion, and size. Tumors in the nisin-treated mice also appeared whiter in color, which the researchers say represents a decrease in blood vessels, typically a good sign for recovery, as tumors require a large blood supply.
“This report shows that cancers can be treated with antimicrobials, which is really new—nobody’s ever really thought of treating cancers with antimicrobials or something as simple as bacteriocins,” Kapila tells The Scientist. “This is also confirmation that oral bacteria that are associated with disease really aggravate other diseases like cancers.”
Nam Joo, a former postdoc in Kapila’s laboratory, was the first to raise the possibility of nisin’s therapeutic role. Joo began his nisin research while studying kimchi, which is rich in bacteria that produce nisin, for his master’s degree in South Korea. He wondered if the bacteriocin might work as an anticancer agent because of its known properties in promoting cell death in other cell systems.
While most bacteriocins inhibit only closely related species, nisin acts as a broad-spectrum antibacterial that is effective against many Gram-positive bacteria. In this study, nisin did not target the oral pathogens, but the cancerous cells themselves. The bacteriocin inhibited the effects of the bacteria, deactivating the signaling pathways they enabled by latching onto the cancer cell membranes and allowing calcium to flow into the cell.
Kapila says she is currently investigating why nisin binds to tumor cells, rather than healthy cells, but she says it may be because nisin preferentially binds to phosphocholine lipid bilayers, which cell membranes are made of, previous research shows.
“It’s particularly noteworthy to modulate a microbial community to prevent a noncommunicable disease,” says David Moyes, a microbiologist who studies oral pathogens at King’s College London and was not involved with the study. “Bacteriocins are a fairly new kid on the block for use in clinical therapy.”
The bacteriocin was first isolated in the 1920s from Lactococcus lactis, a bacterium used extensively in the production of cheese and buttermilk, and was approved as an additive to protect food against harmful bacteria in the 1960s.
Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide, with 600,000 new cases diagnosed each year, according to the National Institutes of Health. OSCC is a subset of HNSCC that is extremely prevalent in some countries such as India, where OSCC makes up more than 50 percent of all cancers.
Kapila has submitted a grant to test the bacteriocin on patients with oral cancer in a clinical trial. Herzberg emphasizes nisin’s potential, particularly because it has long been deemed safe enough to include in food products, so it may be easier to approve if there is conclusive evidence from human trials that it helps fight cancer. Indeed, in a 2015 study, Kapila notes that that people in the US consume 0.94 to 2.24 mg of nisin per day, according to an estimate from the US Food and Drug Administration. There is no indication that this helps prevent or treat oral cancer.
Kapila’s team also examined the mice’s internal organs such as the liver, kidney, and lung to see if nisin led to downstream consequences but found no differences between these animals and those that didn’t get the treatment.
Oral pathogens have previously been shown to promote other cancers such as colorectal cancer, so Kapila remains hopeful that her study opens the door for research on antimicrobial peptides to treat other cancers.
“One of the real negative side effects of the current gold standard treatment, chemoradiation, is the really nasty off-target effects of these medications and treatment,” she says. “It would be fantastic if we can find a treatment that does not have all these side effects.”
P. Kamarajan et al., “Periodontal pathogens promote cancer aggressivity via TLR/MyD88 triggered activation of Integrin/FAK signaling that is therapeutically reversible by a probiotic bacteriocin,” PLOS Pathog, doi:10.1371/journal.ppat.1008881, 2020.


thescientist--2020-10-01--Majority of Respondents Support Chimeric Animal Research: Survey

ABOVE : Pigs are thought to be a suitable host for growing human organs using HACE technology .
© ISTOCK.COM , K NEVILLE Human-animal chimeric embryos—organisms created using cells from two or more species—have the potential to change how researchers study disease and generate organs and tissues for human transplants .
One day , scientists have proposed , it may be possible for someone with , say , pancreatic cancer to have their stem cells injected into a modified swine embryo lacking its own pancreas so it can grow the human organ for donation .
Already , human-animal chimeric embryos @ @ @ @ @ @ @ human cells injected into pigs , sheep , mice , rats , and monkeys , although none in the US have been brought to term .
In fact , their very existence is ethically contentious .
What happens , for example , if scientists were to grow a human brain in an animal , blurring the line between species ?
In response to ethical , social , and legal concerns , the National Institutes of Health ( NIH ) issued a moratorium on funding for HACE research in 2015 pending the development of @ @ @ @ @ @ @ While research continues in other countries—and even in the US , through collaborations with foreign researchers and private funding—the NIH has yet to reverse its decision , despite previous announcements that it would do so .
To gauge the American public ’ s support for HACE research , Francis Shen , a professor of law at the University of Minnesota , recreated two recent surveys carried out in Japan , where many of the world ’ s HACE studies are done .
In those surveys , Shen ’ s colleagues found that the @ @ @ @ @ @ @ use of HACEs , although their feelings varied depending on the type of organ or tissue being grown .
“ We thought , ‘ Boy , it ’ d be really interesting to see if the American public thinks about things the same way , ’ ” Shen tells The Scientist .
Shen ’ s team directly translated the Japanese surveys into English , asking 430 participants to rate their support for each of the three steps involved in producing an organ using HACE technology : the insertion of human stem cells into @ @ @ @ @ @ @ the embryo into a surrogate , and the harvesting of the resulting organ for use in a human .
As before , they gauged people ’ s reactions to organ and tissue types , including skin , liver , blood , heart , brain , and gametes .
The Scientist spoke with Shen about the results of the US study , published today ( October 1 ) in Stem Cell Reports .
The Scientist : What can we do with HACEs , or what are we hoping to do with them ?
Francis @ @ @ @ @ @ @ goal , and that would be a major breakthrough .
When I describe [ HACEs ] to .
.
.
colleagues who maybe haven ’ t heard of them before , I talk about organ transplantation .
And they understand that , yes , if you grow an organ from your own cells , it makes intuitive sense that your body might be more receptive .
I think there are also a large number of applications that fall broadly under regenerative medicine .
One is to better understand the mechanisms of disease and @ @ @ @ @ @ @ science advances to be achieved there .
And then there are applied clinical advances and improvements in treatment across a wide range of diseases and disorders .
We can develop better interventions , pharmacological and otherwise .
The techniques are not just about improving organ donation .
There are also a number of ways , through both basic and applied science , this work can really improve our knowledge and therefore response to any number of diseases and disorders .
TS : What did your survey tell you about the American public ’ @ @ @ @ @ @ @ FS : One of the main findings was that there seems to be very broad support , even broader than in the Japanese public , for the different steps of HACE research .
Support was 59 percent , so a strong majority , support all three steps , including the returning of the organ into a human .
Second was that there are some differences across subgroups in the public .
One thing that we thought was interesting is that , although lower , in some instances the support of those who are @ @ @ @ @ @ @ .
.
suggesting that this type of stem cell research—using [ induced pluripotent stem ] cells and not embryonic stem cells harvested from a fetus—perhaps could be more politically palatable .
TS : Why do you think people feel differently about applying this to something like a brain or our gametes versus something like a liver ?
FS : [ People are ] more accepting of using HACEs to grow things like livers and skin than sperm , eggs , or brains , and I think it gets to humanization .
It ’ @ @ @ @ @ @ @ ’ s informed speculation based on other ethical scholarship and work that has been done .
A liver is kind of a liver , it doesn ’ t seem to have too many special properties , but the sperm and the egg and the brain , those are part and parcel of a person .
So it feels much more ethically concerning to grow a person in a pig , as opposed to growing just some constituent part of a person .
Someone has a heart transplant or a liver transplant , and @ @ @ @ @ @ @ more sense .
I think there ’ s a cultural acceptance and understanding that ’ s easier to analogize to .
TS : What are the ethical considerations here when you start considering using HACEs to grow something like a human brain in animals ?
There are a series of ethical concerns , and we tried pretty hard in the paper to emphasize that .
They include animal welfare , human dignity , and then the potential for the neurological humanization of chimeric animals .
I think addressing them is tremendously important .
@ @ @ @ @ @ @ , it doesn ’ t mean this type of research isn ’ t going to happen .
If the NIH doesn ’ t fund it with these ethical guidelines in place , it could be funded and produced elsewhere outside of NIH purview .
So not only is there an opportunity to set the ethics frameworks here , there ’ s almost an imperative to do so .
The bottom line for me is that the ethics and the laws and regulation should go hand in hand with the development of the research @ @ @ @ @ @ @ we need to get together and work through these complicated issues .
What our study suggests is that the American public would like us to do that .
Editor ’ s note : The interview was edited for brevity .

ABOVE: Pigs are thought to be a suitable host for growing human organs using HACE technology.
© ISTOCK.COM, K NEVILLE
Human-animal chimeric embryos—organisms created using cells from two or more species—have the potential to change how researchers study disease and generate organs and tissues for human transplants. One day, scientists have proposed, it may be possible for someone with, say, pancreatic cancer to have their stem cells injected into a modified swine embryo lacking its own pancreas so it can grow the human organ for donation.
Already, human-animal chimeric embryos (HACEs) have been created using human cells injected into pigs, sheep, mice, rats, and monkeys, although none in the US have been brought to term. In fact, their very existence is ethically contentious. What happens, for example, if scientists were to grow a human brain in an animal, blurring the line between species?
In response to ethical, social, and legal concerns, the National Institutes of Health (NIH) issued a moratorium on funding for HACE research in 2015 pending the development of a new set of regulatory guidelines. While research continues in other countries—and even in the US, through collaborations with foreign researchers and private funding—the NIH has yet to reverse its decision, despite previous announcements that it would do so.
To gauge the American public’s support for HACE research, Francis Shen, a professor of law at the University of Minnesota, recreated two recent surveys carried out in Japan, where many of the world’s HACE studies are done. In those surveys, Shen’s colleagues found that the majority of the Japanese public supported the use of HACEs, although their feelings varied depending on the type of organ or tissue being grown. “We thought, ‘Boy, it’d be really interesting to see if the American public thinks about things the same way,’” Shen tells The Scientist.
Shen’s team directly translated the Japanese surveys into English, asking 430 participants to rate their support for each of the three steps involved in producing an organ using HACE technology: the insertion of human stem cells into an animal embryo, the transplanting of the embryo into a surrogate, and the harvesting of the resulting organ for use in a human. As before, they gauged people’s reactions to organ and tissue types, including skin, liver, blood, heart, brain, and gametes.
The Scientist spoke with Shen about the results of the US study, published today (October 1) in Stem Cell Reports.
University of Minnesota Law School
The Scientist: What can we do with HACEs, or what are we hoping to do with them?
Francis Shen: Organ transplantation is a major goal, and that would be a major breakthrough. When I describe [HACEs] to . . . colleagues who maybe haven’t heard of them before, I talk about organ transplantation. And they understand that, yes, if you grow an organ from your own cells, it makes intuitive sense that your body might be more receptive.
I think there are also a large number of applications that fall broadly under regenerative medicine. One is to better understand the mechanisms of disease and organ function. There’s basic science advances to be achieved there. And then there are applied clinical advances and improvements in treatment across a wide range of diseases and disorders. We can develop better interventions, pharmacological and otherwise. The techniques are not just about improving organ donation. There are also a number of ways, through both basic and applied science, this work can really improve our knowledge and therefore response to any number of diseases and disorders.
TS: What did your survey tell you about the American public’s thoughts on human-animal chimeric embryos?
FS: One of the main findings was that there seems to be very broad support, even broader than in the Japanese public, for the different steps of HACE research. Support was 59 percent, so a strong majority, support all three steps, including the returning of the organ into a human.
Second was that there are some differences across subgroups in the public. One thing that we thought was interesting is that, although lower, in some instances the support of those who are politically conservative was still quite strong . . . suggesting that this type of stem cell research—using [induced pluripotent stem] cells and not embryonic stem cells harvested from a fetus—perhaps could be more politically palatable.
TS: Why do you think people feel differently about applying this to something like a brain or our gametes versus something like a liver?
FS: [People are] more accepting of using HACEs to grow things like livers and skin than sperm, eggs, or brains, and I think it gets to humanization. It’s speculation, but I think it’s informed speculation based on other ethical scholarship and work that has been done. A liver is kind of a liver, it doesn’t seem to have too many special properties, but the sperm and the egg and the brain, those are part and parcel of a person. So it feels much more ethically concerning to grow a person in a pig, as opposed to growing just some constituent part of a person.
Someone has a heart transplant or a liver transplant, and it just kind of seems to make more sense. I think there’s a cultural acceptance and understanding that’s easier to analogize to.
TS: What are the ethical considerations here when you start considering using HACEs to grow something like a human brain in animals?
There are a series of ethical concerns, and we tried pretty hard in the paper to emphasize that. They include animal welfare, human dignity, and then the potential for the neurological humanization of chimeric animals.
I think addressing them is tremendously important. Although the NIH has a moratorium presently, it doesn’t mean this type of research isn’t going to happen. If the NIH doesn’t fund it with these ethical guidelines in place, it could be funded and produced elsewhere outside of NIH purview. So not only is there an opportunity to set the ethics frameworks here, there’s almost an imperative to do so.
The bottom line for me is that the ethics and the laws and regulation should go hand in hand with the development of the research. And to do that productively means we need to get together and work through these complicated issues. What our study suggests is that the American public would like us to do that.
Editor’s note: The interview was edited for brevity.


thescientist--2020-10-01--Fecal Transfer from Moms to Babies After C-Section: Trial Results

The composition of gut microbes in babies born via Cesarean section tends to differ from those in babies born vaginally , prompting speculation that this may have long-term health consequences .
To enrich for beneficial bugs in babies ’ bellies after C-section , researchers have performed mom-to-infant microbial transplants , described today ( October 1 ) in Cell .
In a clinical trial in which seven Cesarean-delivered babies were fed tiny amounts of their mothers ’ fecal material , it was found that the babies ’ guts became colonized with the sorts of bacteria normally present in infants delivered vaginally @ @ @ @ @ @ @ effects in the infants , there are no data on whether it has any benefits to the baby , and experts warn it may be dangerous for mothers to attempt such a treatment themselves .
“ This is a very well-balanced , important , and clinically relevant contribution to the field , with really nice , clear-cut conclusions , ” says gut microbe researcher Tine Rask Licht of the Technical University of Denmark who was not involved in the research .
“ They have very nice data .
.
.
[ showing that @ @ @ @ @ @ @ pattern of microbial development which is much more similar to that of children born vaginally.
” As a baby leaves the womb and passes through the birth canal it is bathed in its mother ’ s microbes—an experience that Cesarean-born infants do not share .
As a result , there are differences in the bacteria that colonize the guts of newborns depending on their delivery method .
Epidemiological evidence indicates there may also be later life consequences to missing out on this bacterial baptism , as some call it .
A recent study @ @ @ @ @ @ @ likelihood of developing immune disorders such as inflammatory bowel disease , rheumatoid arthritis , and celiac disease .
The growing prevalence of Cesarean deliveries makes these potential repercussions an increasing concern .
Numerous trials are therefore underway to test the safety and long-term benefits of swabbing Cesarean-born infants with microbes from their mothers ’ vaginas .
But , there aren ’ t a lot of published data to suggest that the gut microbiomes of these swabbed infants match those of vaginally born babies , says microbiologist and immunologist Willem de Vos of the @ @ @ @ @ @ @ led the research .
Furthermore , he adds , “ the bacteria that you find in the baby [ gut ] are not found in the vagina , so it ’ s not so likely it ’ s the source , ” he says .
“ It ’ s more likely that there is a fecal-oral transfer ” at the time of birth , he says , because vaginal delivery is “ a messy business.
” See “ The Infant Microbiome and Priobiotics that Work ” Indeed , anecdotal accounts suggest most women @ @ @ @ @ @ @ .
“ Feces is always part of the delivery process , ” agrees obstetrician Bo Jacobsson of the University of Gothenburg who was not part of the research team .
He says he therefore thinks that “ from a scientific point of view , [ the researchers ] have done the right thing , ” even if on first impression the procedure seems “ nasty.
” A mother ’ s fecal microbes , unlike those from the vagina , are “ geared to actually establish and colonize in the [ baby ’ s @ @ @ @ @ @ @ the gut , ” explains Licht .
So what de Vos and colleagues have done , she says , “ makes sense.
” The team recruited 17 mothers who were due to undergo elective C-sections and collected stool and blood samples from them approximately three weeks prior to delivery .
This gave the team time to prepare the samples and to screen them for infectious pathogens , including HIV , hepatitis , Clostridium difficile , Helicobacter pylori , norovirus , drug-resistant bacteria , group B streptococcus , and a long list of others @ @ @ @ @ @ @ , only seven of the mothers were selected to continue with the procedure .
Each newly delivered baby was given a dose of the live fecal bacteria ( a few million cells ) in their first milk feed ( via a bottle ) and their health was monitored for two days in the maternity ward with follow up visits at four weeks and three months .
None of the babies experienced adverse health effects .
Stool samples from the babies were collected after two days , then each week for four weeks and @ @ @ @ @ @ @ of these samples as well as of control samples collected from 29 vaginally born babies and 18 untreated Cesarean-delivered babies showed that the while the gut microbiota of the treated and vaginally born babies differed in the early days , after a week they were significantly more similar to each other , and both were distinct from the microbiotas of untreated Cesarean babies .
Using previously published data on the microbiota of Cesarean infants who received vaginal swabs , the team showed that these were also distinct from those of the vaginally born @ @ @ @ @ @ @ observed between untreated Cesarean babies and those delivered vaginally or fed feces were that the control infants had a lower abundance of commensal Bacteroides and Bifidobacteria species , but a higher abundance of more pathogenic taxa , in line with previous findings .
While the study provided a proof-of-concept for the procedure , larger and longer-term studies would be necessary to confirm safety and to determine whether there are any health benefits , says Jacobsson .
Because of these unknowns , both he and de Vos warn mothers undergoing Cesareans not to try @ @ @ @ @ @ @ s ] a big risk that people will read about this and make the mistake of doing it themselves , ” Jacobsson says , “ But , you can put your baby into danger if you start to do a home-style version .
”

ABOVE: © ISTOCK.COM, MVALIGURSKY
The composition of gut microbes in babies born via Cesarean section tends to differ from those in babies born vaginally, prompting speculation that this may have long-term health consequences. To enrich for beneficial bugs in babies’ bellies after C-section, researchers have performed mom-to-infant microbial transplants, described today (October 1) in Cell. In a clinical trial in which seven Cesarean-delivered babies were fed tiny amounts of their mothers’ fecal material, it was found that the babies’ guts became colonized with the sorts of bacteria normally present in infants delivered vaginally. While the procedure produced no ill effects in the infants, there are no data on whether it has any benefits to the baby, and experts warn it may be dangerous for mothers to attempt such a treatment themselves.
“This is a very well-balanced, important, and clinically relevant contribution to the field, with really nice, clear-cut conclusions,” says gut microbe researcher Tine Rask Licht of the Technical University of Denmark who was not involved in the research. “They have very nice data . . . [showing that] with fecal transfer they get a pattern of microbial development which is much more similar to that of children born vaginally.”
As a baby leaves the womb and passes through the birth canal it is bathed in its mother’s microbes—an experience that Cesarean-born infants do not share. As a result, there are differences in the bacteria that colonize the guts of newborns depending on their delivery method.
Epidemiological evidence indicates there may also be later life consequences to missing out on this bacterial baptism, as some call it. A recent study showed that Cesarean-born kids have a higher likelihood of developing immune disorders such as inflammatory bowel disease, rheumatoid arthritis, and celiac disease. The growing prevalence of Cesarean deliveries makes these potential repercussions an increasing concern.
Numerous trials are therefore underway to test the safety and long-term benefits of swabbing Cesarean-born infants with microbes from their mothers’ vaginas. But, there aren’t a lot of published data to suggest that the gut microbiomes of these swabbed infants match those of vaginally born babies, says microbiologist and immunologist Willem de Vos of the University of Helsinki and Wageningen University who led the research. Furthermore, he adds, “the bacteria that you find in the baby [gut] are not found in the vagina, so it’s not so likely it’s the source,” he says. “It’s more likely that there is a fecal-oral transfer” at the time of birth, he says, because vaginal delivery is “a messy business.”
See “The Infant Microbiome and Priobiotics that Work”
Indeed, anecdotal accounts suggest most women delivering babies vaginally do defecate during labor. “Feces is always part of the delivery process,” agrees obstetrician Bo Jacobsson of the University of Gothenburg who was not part of the research team. He says he therefore thinks that “from a scientific point of view, [the researchers] have done the right thing,” even if on first impression the procedure seems “nasty.”
A mother’s fecal microbes, unlike those from the vagina, are “geared to actually establish and colonize in the [baby’s] gut, because they come from the gut,” explains Licht. So what de Vos and colleagues have done, she says, “makes sense.”
The team recruited 17 mothers who were due to undergo elective C-sections and collected stool and blood samples from them approximately three weeks prior to delivery. This gave the team time to prepare the samples and to screen them for infectious pathogens, including HIV, hepatitis, Clostridium difficile, Helicobacter pylori, norovirus, drug-resistant bacteria, group B streptococcus, and a long list of others. On the basis of these screens, only seven of the mothers were selected to continue with the procedure.
Each newly delivered baby was given a dose of the live fecal bacteria (a few million cells) in their first milk feed (via a bottle) and their health was monitored for two days in the maternity ward with follow up visits at four weeks and three months. None of the babies experienced adverse health effects.
Stool samples from the babies were collected after two days, then each week for four weeks and then again at 12 weeks. Analysis of these samples as well as of control samples collected from 29 vaginally born babies and 18 untreated Cesarean-delivered babies showed that the while the gut microbiota of the treated and vaginally born babies differed in the early days, after a week they were significantly more similar to each other, and both were distinct from the microbiotas of untreated Cesarean babies. Using previously published data on the microbiota of Cesarean infants who received vaginal swabs, the team showed that these were also distinct from those of the vaginally born or feces-fed infants.
The main differences observed between untreated Cesarean babies and those delivered vaginally or fed feces were that the control infants had a lower abundance of commensal Bacteroides and Bifidobacteria species, but a higher abundance of more pathogenic taxa, in line with previous findings.
While the study provided a proof-of-concept for the procedure, larger and longer-term studies would be necessary to confirm safety and to determine whether there are any health benefits, says Jacobsson. Because of these unknowns, both he and de Vos warn mothers undergoing Cesareans not to try this themselves.
“[There’s] a big risk that people will read about this and make the mistake of doing it themselves,” Jacobsson says, “But, you can put your baby into danger if you start to do a home-style version.”
K. Korpela et al., “Maternal fecal microbiota transplantation in cesarean-born infants rapidly restores normal gut microbial development: a proof-of-concept study,” Cell, doi:10.1016/j.cell.2020.08.047, 2020.


thescientist--2020-10-01--T Cells and Neurons Talk to Each Other

T Cells and Neurons Talk to Each Other

Tiroyaone Brombacher sat in her lab at the University of Cape Town watching a video of an albino mouse swimming around a meter-wide tub filled with water .
The animal , which lacked an immune protein called interleukin 13 ( IL-13 ) , was searching for a place to rest but couldn ’ t find the clear plexiglass stand that sat at one end of the pool , just beneath the water ’ s surface .
Instead , it swam and swam , crisscrossing the tub several times before finally finding the platform on which to stand .
Over and @ @ @ @ @ @ @ mouse failed to learn where the platform was located .
Meanwhile , wildtype mice learned fairly quickly and repeatedly swam right to the platform .
“ When you took out IL-13 , [ the mice ] just could not learn , ” says Brombacher , who studies the intersection of psychology , neuroscience , and immunology .
Curious as to what was going on , Brombacher decided to dissect the mice ’ s brains and the spongy membranes , called the meninges , that separate neural tissue from the skull .
She wanted @ @ @ @ @ @ @ the immune system were communicating using proteins such as IL-13 .
While the knockout mice had no IL-13 , she reported in 2017 that the meninges of wildtype mice were chock full of the cytokine .
Sitting just outside the brain , the immune protein did , in fact , seem to be playing a critical role in learning and memory , Brombacher and her colleagues concluded .
As far back as 2004 , studies in rodents suggested that neurons and their support cells release signals that allow the immune system to passively @ @ @ @ @ @ @ , and debris that might form during learning and memory-making , and that , in response , molecules of the immune system could communicate with neurons to influence learning , memory , and social behavior .
Together with research on the brain ’ s resident immune cells , called microglia , the work overturned a dogma , held since the 1940s , that the brain was “ immune privileged , ” cut off from the immune system entirely .
Brombacher and others are now starting to identify how communication between the nervous system @ @ @ @ @ @ @ 2012 , molecular imaging revealed that fluorescently labeled proteins could flow through a layer of projections , or “ feet , ” of neuronal support cells called astrocytes .
Astrocytes are star-shaped cells that sit at the border of neural and meningeal tissues and along the blood vessels of the brain ; their foot layer is the barrier that separates cerebrospinal fluid ( CSF ) , the watery liquid that envelops the brain and spinal cord , from the neurons of the central nervous system .
If those fluorescently labeled molecules could cross @ @ @ @ @ @ @ out of the brain , so could CSF-based immune-system proteins , which are smaller , scientists figured .
Experiments have also shown that cytokines in the blood can cross the blood-brain barrier ( BBB—which , in addition to the wall of astrocyte feet , includes a tight layer of endothelial cells surrounding the brain ’ s vasculature—and may influence neurons .
A third mode of communication , Brombacher notes , is through immune cytokines ’ interactions with astrocytes themselves : it seems that the signaling molecules don ’ t have to penetrate neural @ @ @ @ @ @ @ .
Her work shows , for example , how cytokines such as IL-13 spur astrocytes to release brain-derived neurotrophic factor ( BDNF ) and other proteins that bolster neural development and influence learning and memory .
This line of work has led to rapid developments in neuroimmunology , a growing field of research that focuses on understanding the ways in which the nervous system draws on immune cells during normal function , and how that interaction plays a role in learning , memory , and social behavior , as well as neurological disease @ @ @ @ @ @ @ immune system might be key to treating some forms of impaired cognition .
One of the first teams to make the connection between the immune system and brain function included Jonathan Kipnis , now at the Washington University School of Medicine in St. Louis .
In 2004 , Kipnis and colleagues showed that mice without adaptive immune cells such as T cells had trouble remembering the location of a submerged platform while they were swimming .
A few years later , the group focused in on a T cell cytokine called interleukin-4 ( @ @ @ @ @ @ @ functional immune systems form long-term memories about the platform ’ s location .
IL-4 is secreted by T cells in the body that can migrate to the meninges , and was somehow affecting the brain .
Following up on that work , Kipnis ’ s then-postdoc Anthony Filiano , now an assistant professor of neurosurgery at Duke University , found that mice lacking T cells didn ’ t socialize with others the way normal mice did .
If the immune-deficient mice got an infusion of immune cells at around four weeks of age @ @ @ @ @ @ @ mimicking the behaviors of normal mice just a few weeks after their immune supplementation .
An analysis of gene expression data collected from both sets of mice revealed that interferon gamma , a cytokine essential for the body ’ s defense against viral and bacterial pathogens , was associated with sociality .
To see if interferon gamma had a direct effect on the brain , Filiano and his collaborators knocked out the gene for the cytokine receptor in neurons in the mouse prefrontal cortex , a region important for social behavior .
This @ @ @ @ @ @ @ with other mice , a sign that they were feeling less social ; the result offered evidence to suggest that interferon gamma from T cells in the meninges was acting directly on the cortical neurons .
Inspired by Kipnis and Filiano ’ s work , Brombacher and colleagues decided to set up a similar experiment .
The team first tested IL-4 knockout mice against wildtype mice in a water maze and successfully replicated Kipnis ’ s original results—the immunodeficient mice were learning impaired .
Then , Brombacher tried the experiment with mice lacking @ @ @ @ @ @ @ IL-4 , and got the more dramatic results : “ learning was abrogated , ” she says .
Both cytokines clearly affected learning , but IL-13 appeared to play a more significant role than IL-4 , perhaps because of some underlying biochemistry : IL-13 and IL-4 share a receptor on the surface of cells called IL-4 receptor alpha , but IL-13 can also transmit its signal using another receptor .
Brombacher is now setting up experiments to remove the cell receptors and see what happens to the mice ’ s performance in the @ @ @ @ @ @ @ for interleukin 17 ’ s involvement in learning and sociality .
In 2016 , Gloria Choi of MIT ’ s McGovern Institute for Brain Research and colleagues linked the cytokine to signs in mouse pups similar to symptoms of autism spectrum disorder ( ASD ) in humans .
Specifically , animals that developed infections while pregnant gave birth to babies that exhibited ASD-like behavioral traits .
Interleukin 17 ( IL-17 ) was among the immune signals secreted to help combat the pathogen , the researchers found , and baby mice born to mouse @ @ @ @ @ @ @ of IL-17 receptors on their brain cells than mice born to uninfected moms .
Blocking those IL-17 receptors with drugs during gestation protected pups against the effects of higher maternal IL-17 ; the pups were born without the signature behavioral issues associated with ASD .
Stimulating the release of IL-17 or administering the cytokine directly also appeared to attenuate ASD-like symptoms in young and old adult mice that had been exposed to the high IL-17 levels in utero , suggesting that exposure to elevated maternal IL-17 during development also paradoxically “ primes ” @ @ @ @ @ @ @ cytokine in maturity .
Last year , neuroimmunologist Julie Ribot of the University of Lisbon and her colleagues added to the IL-17 story when they discovered that mice lacking a certain type of T cell or the cytokine had trouble making short-term memories when exploring a Y-shaped maze .
This is in contrast to the effects on long-term memory formation that researchers have uncovered for IL-4 and IL-13 in the water maze .
The different effects of the interleukins , Ribot says , could have something to do with the fact that the @ @ @ @ @ @ @ reside in the meninges , where they could act within seconds during short-term memory formation .
T cells that produce IL-4 and IL-13 , on the other hand , have to be recruited to the meninges from elsewhere in the body , which takes time , suggesting they support the creation of memories that take longer to form , she notes .
The role of gamma delta T cells and IL-17 in cognition doesn ’ t end with links to memory and autism , though .
The cells and their cytokine may play @ @ @ @ @ @ @ Kipnis ’ s latest experiments .
His team recently showed that the release of IL-17 from gamma delta T cells correlates with anxiety-like behavior in mice , and that deleting the IL-17 receptor from glutamatergic neurons in cortical regions involved in threat perception and response reduced anxiety-like behaviors .
The major takeaway from each of these IL-17 papers is the same , Kipnis says .
“ We ’ re showing that you have a population of immune cells sitting outside the brain that impact neurons inside it.
” In parallel with these studies @ @ @ @ @ @ @ learning and memory , anxiety , and social behavior , researchers are beginning to pull back the curtain on the communication channels that T cells use to talk with neurons .
Although it is still unclear exactly how the two systems physically interact , several possibilities have been identified , including direct messages from T cells sent via cytokines interacting with neurons and indirect signals generated through the interaction of cytokines with astrocytes .
Some neuroscientists remain adamant that , with the exception of some drugs , most molecules do not get through @ @ @ @ @ @ @ the rest of the body unless there ’ s a rupture to the boundary layers intended to cordon off the central nervous system .
But research from several groups now challenges this idea .
A key study in disproving the long-held assumption that the brain is immune privileged came from the lab of neuroscientist Maiken Nedergaard of the University of Rochester Medical Center .
In 2012 , she and her colleagues watched fluorescent and radiolabeled tracers flow from the CSF into the brains of anesthetized mice .
Specifically , Nedergaard ’ s team @ @ @ @ @ @ @ and out of the animals ’ cerebral cortex , the brain ’ s outer layer of folded gray matter , which is essential for consciousness , attention , and making memories .
The researchers learned that CSF carrying cytokines and other signaling molecules flows from the meninges into the space surrounding the brain ’ s vasculature .
As the arteries pulse with each beat of an animal ’ s heart , the blood vessels expand , and the CSF is pushed through water channels in the astrocyte feet and then into the brain @ @ @ @ @ @ @ : CSF that has entered the brain and mixed with the extracellular , or interstitial , fluid—and that now carries waste proteins ready for clearance—is pressed back through astrocytes into the space surrounding the blood vessels .
“ Maiken showed this very , very elegantly , ” Kipnis says .
It completely overthrew the dogma that the brain is immune privileged , he says .
Earlier this year , Andrew Yang of Stanford University and colleagues extended this finding to specifically show that cytokines released from T cells in the blood can also @ @ @ @ @ @ @ researchers extracted blood from the animals , separated out plasma proteins , labeled them with a fluorescent tag , then injected them back into the bloodstreams of the mice they came from .
In healthy young adult mice , lots of the fluorescently tagged proteins crossed the BBB to enter the interstitial fluid in the brain .
“ This finding suggests that a wide variety of neural functions .
.
.
could be modulated by systemic protein signals , ” Roeben Munji and Richard Daneman of the University of California , San Diego @ @ @ @ @ @ @ ’ s study .
Cytokines in the meninges or possibly even in the blood might not have to enter the brain at all to affect the central nervous system , according to Brombacher ’ s studies .
IL-13 and other cell signaling molecules in the CSF or blood could interact with astrocytes at the BBB or at the perimeter of the brain .
In cultured astrocytes , treatment with IL-13 spurred the production of BDNF and triggered the production of glial fibrillary acidic protein ( GFAP ) , an indication that neural connections @ @ @ @ @ @ @ study on IL-17 also showed that the cytokine could spur mice ’ s astrocytes to release BDNF into the brain .
Both BDNF and GFAP , which boost synaptic rewiring , are associated with learning and memory .
Communication between the immune and nervous systems can also happen in the reverse direction , with signals from the brain reaching T cells of the spongy , membranous meninges and of the rest of the body .
Until a few years ago , researchers agreed that the brain lacked a drainage , or lymphatic , @ @ @ @ @ @ @ to transport immune cells .
But to Kipnis , it just didn ’ t make sense that one of the most important organs in the body would not have that kind of plumbing .
So he and his colleagues went looking for it , and in 2015 , they found it—mice ’ s brains did , in fact , have lymphatic vessels that shipped waste and T cells from the meninges to deep cervical lymph nodes in the animals ’ necks .
“ These structures are bona fide vessels—they express all the same @ @ @ @ @ @ @ tissue , ” he told The Scientist at the time .
In mice , T cells residing in the meninges scan the CSF for the cellular waste generated as neuronal circuits undergo changes , whether in response to learning and memory formation or in the case of dysfunction .
Then , T cells in the lymph nodes get a chance to check the CSF for potential threats such as pathogens , he says .
Tracking that lymphatic system in people ’ s brains is much harder , but Kipnis says there ’ s @ @ @ @ @ @ @ in rodents does translate to human biology .
In 2017 , he and collaborators at the National Institute of Neurological Disorders and Stroke used MRI to noninvasively confirm the existence of meningeal lymphatic vessels in humans and nonhuman primates .
Understanding immune cell–neuron crosstalk—both the way T cells respond to what ’ s in CSF coming from the central nervous system and how they send signals into the brain—could be important for understanding neurological disorders , such as Alzheimer ’ s disease , autism , schizophrenia , and even the cognitive decline associated @ @ @ @ @ @ @ these neurological disorders , there ’ s been reports that there ’ s some kind of dysregulation of the immune system , ” Filiano says .
Identifying faulty signals from neurons in the fluid leaving the brain could lead to diagnostic tools for neurological disorders , he notes .
And given that CSF can carry cytokines and other proteins to neurons , Kipnis says he suspects that “ putting [ immune-based ] therapies into that fluid will probably be a very , very efficient route for treating patients.
” Developing molecules to infuse @ @ @ @ @ @ @ with the brain requires a better understanding of how cytokines affect neurons , astrocytes , and micro-glia over the course of a lifetime .
Interferon gamma , for example , appears to have two faces when it comes to influencing neuronal circuits .
In Kipnis ’ s studies of young mice , the cytokine was essential for the animals to be social .
But an analysis of the brains of old mice shows that the same cytokine might be detrimental to making new neurons in aged mice .
Giving the old mice an @ @ @ @ @ @ @ neurogenesis in the animals ’ brains , a team of researchers reported in 2019 .
A similar tactic might provide a novel way to treat various neuropsychiatric disorders such as schizophrenia .
Analyses of immune cells in the blood of schizophrenia patients show that these individuals have higher levels of a variety of cytokines , including IL-13 and interferon gamma , than healthy individuals do .
People with schizophrenia treated with anti-inflammatory and antipsychotic drugs also tend to have fewer cognitive problems than individuals treated with only antipsychotics , hinting that reducing cytokine @ @ @ @ @ @ @ While the neuronal changes that cause schizophrenia are far from clear , studies suggest that when certain neurons produce lower-than-expected levels of dopamine , they alert T cells to a problem , and the T cells respond by releasing cytokines that prompt disease-related deficits in memory , learning , social behavior , and resilience to stress .
Filiano and Kipnis have found evidence that a similar approach might work for helping individuals with autism .
In experiments with mice lacking T cells , the researchers found that the animals not only had social @ @ @ @ @ @ @ circuits that often have abnormal activity in the brains of people with autism .
Not only did social behavior improve when the team infused the mice with immune cells , but the animals ’ abnormal neural activity subsided too .
Meticulously tweaking the immune system might reverse the cognitive and social deficits of the disorder , the experiments suggest .
For now , the results leave Filiano wanting to know more .
He explains , “ We ’ re really interested in how these immune cells talk to the brain , how these @ @ @ @ @ @ @ these neural circuits , how that communication happens in health and disease .
”

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Tiroyaone Brombacher sat in her lab at the University of Cape Town watching a video of an albino mouse swimming around a meter-wide tub filled with water. The animal, which lacked an immune protein called interleukin 13 (IL-13), was searching for a place to rest but couldn’t find the clear plexiglass stand that sat at one end of the pool, just beneath the water’s surface. Instead, it swam and swam, crisscrossing the tub several times before finally finding the platform on which to stand. Over and over, in repeated trials, the mouse failed to learn where the platform was located. Meanwhile, wildtype mice learned fairly quickly and repeatedly swam right to the platform. “When you took out IL-13, [the mice] just could not learn,” says Brombacher, who studies the intersection of psychology, neuroscience, and immunology.
Curious as to what was going on, Brombacher decided to dissect the mice’s brains and the spongy membranes, called the meninges, that separate neural tissue from the skull. She wanted to know if the nervous system and the immune system were communicating using proteins such as IL-13. While the knockout mice had no IL-13, she reported in 2017 that the meninges of wildtype mice were chock full of the cytokine. Sitting just outside the brain, the immune protein did, in fact, seem to be playing a critical role in learning and memory, Brombacher and her colleagues concluded.
As far back as 2004, studies in rodents suggested that neurons and their support cells release signals that allow the immune system to passively monitor the brain for pathogens, toxins, and debris that might form during learning and memory-making, and that, in response, molecules of the immune system could communicate with neurons to influence learning, memory, and social behavior. Together with research on the brain’s resident immune cells, called microglia, the work overturned a dogma, held since the 1940s, that the brain was “immune privileged,” cut off from the immune system entirely.
INTO THE BRAIN: Astrocytes (green) have long, thin extensions called feet that line the blood vessels in the brain. Those feet contain water channels (purple) that allow cerebrospinal fluid, including the molecules within it, to move into the astrocytes and out into the brain, where it can interact directly with neurons. J. ILIFF AND M. NEDERGAARD
Brombacher and others are now starting to identify how communication between the nervous system and the immune system happens. In 2012, molecular imaging revealed that fluorescently labeled proteins could flow through a layer of projections, or “feet,” of neuronal support cells called astrocytes. Astrocytes are star-shaped cells that sit at the border of neural and meningeal tissues and along the blood vessels of the brain; their foot layer is the barrier that separates cerebrospinal fluid (CSF), the watery liquid that envelops the brain and spinal cord, from the neurons of the central nervous system. If those fluorescently labeled molecules could cross the astrocyte layer and move into and out of the brain, so could CSF-based immune-system proteins, which are smaller, scientists figured.
Experiments have also shown that cytokines in the blood can cross the blood-brain barrier (BBB—which, in addition to the wall of astrocyte feet, includes a tight layer of endothelial cells surrounding the brain’s vasculature—and may influence neurons. A third mode of communication, Brombacher notes, is through immune cytokines’ interactions with astrocytes themselves: it seems that the signaling molecules don’t have to penetrate neural tissue at all to influence the brain. Her work shows, for example, how cytokines such as IL-13 spur astrocytes to release brain-derived neurotrophic factor (BDNF) and other proteins that bolster neural development and influence learning and memory.
This line of work has led to rapid developments in neuroimmunology, a growing field of research that focuses on understanding the ways in which the nervous system draws on immune cells during normal function, and how that interaction plays a role in learning, memory, and social behavior, as well as neurological disease. Some researchers even propose that the immune system might be key to treating some forms of impaired cognition.
Cytokines that influence cognition
One of the first teams to make the connection between the immune system and brain function included Jonathan Kipnis, now at the Washington University School of Medicine in St. Louis. In 2004, Kipnis and colleagues showed that mice without adaptive immune cells such as T cells had trouble remembering the location of a submerged platform while they were swimming. A few years later, the group focused in on a T cell cytokine called interleukin-4 (IL-4), which helped mice with functional immune systems form long-term memories about the platform’s location. IL-4 is secreted by T cells in the body that can migrate to the meninges, and was somehow affecting the brain.
Following up on that work, Kipnis’s then-postdoc Anthony Filiano, now an assistant professor of neurosurgery at Duke University, found that mice lacking T cells didn’t socialize with others the way normal mice did. If the immune-deficient mice got an infusion of immune cells at around four weeks of age, they became much more social, mimicking the behaviors of normal mice just a few weeks after their immune supplementation. An analysis of gene expression data collected from both sets of mice revealed that interferon gamma, a cytokine essential for the body’s defense against viral and bacterial pathogens, was associated with sociality.
To see if interferon gamma had a direct effect on the brain, Filiano and his collaborators knocked out the gene for the cytokine receptor in neurons in the mouse prefrontal cortex, a region important for social behavior. This caused mice to spend less time interacting with other mice, a sign that they were feeling less social; the result offered evidence to suggest that interferon gamma from T cells in the meninges was acting directly on the cortical neurons.
Inspired by Kipnis and Filiano’s work, Brombacher and colleagues decided to set up a similar experiment. The team first tested IL-4 knockout mice against wildtype mice in a water maze and successfully replicated Kipnis’s original results—the immunodeficient mice were learning impaired. Then, Brombacher tried the experiment with mice lacking IL-13, which is closely related to IL-4, and got the more dramatic results: “learning was abrogated,” she says. Both cytokines clearly affected learning, but IL-13 appeared to play a more significant role than IL-4, perhaps because of some underlying biochemistry: IL-13 and IL-4 share a receptor on the surface of cells called IL-4 receptor alpha, but IL-13 can also transmit its signal using another receptor. Brombacher is now setting up experiments to remove the cell receptors and see what happens to the mice’s performance in the water maze.
Turning to the immune system might be key to treating some forms of impaired cognition.
Evidence is also mounting for interleukin 17’s involvement in learning and sociality. In 2016, Gloria Choi of MIT’s McGovern Institute for Brain Research and colleagues linked the cytokine to signs in mouse pups similar to symptoms of autism spectrum disorder (ASD) in humans. Specifically, animals that developed infections while pregnant gave birth to babies that exhibited ASD-like behavioral traits. Interleukin 17 (IL-17) was among the immune signals secreted to help combat the pathogen, the researchers found, and baby mice born to mouse moms with infections had a higher abundance of IL-17 receptors on their brain cells than mice born to uninfected moms. Blocking those IL-17 receptors with drugs during gestation protected pups against the effects of higher maternal IL-17; the pups were born without the signature behavioral issues associated with ASD. Stimulating the release of IL-17 or administering the cytokine directly also appeared to attenuate ASD-like symptoms in young and old adult mice that had been exposed to the high IL-17 levels in utero, suggesting that exposure to elevated maternal IL-17 during development also paradoxically “primes” the immune system for rescue by the cytokine in maturity.
Last year, neuroimmunologist Julie Ribot of the University of Lisbon and her colleagues added to the IL-17 story when they discovered that mice lacking a certain type of T cell or the cytokine had trouble making short-term memories when exploring a Y-shaped maze. This is in contrast to the effects on long-term memory formation that researchers have uncovered for IL-4 and IL-13 in the water maze. The different effects of the interleukins, Ribot says, could have something to do with the fact that the gamma delta T cells that produce IL-17 reside in the meninges, where they could act within seconds during short-term memory formation. T cells that produce IL-4 and IL-13, on the other hand, have to be recruited to the meninges from elsewhere in the body, which takes time, suggesting they support the creation of memories that take longer to form, she notes.
The role of gamma delta T cells and IL-17 in cognition doesn’t end with links to memory and autism, though. The cells and their cytokine may play a role in anxiety, according to Kipnis’s latest experiments. His team recently showed that the release of IL-17 from gamma delta T cells correlates with anxiety-like behavior in mice, and that deleting the IL-17 receptor from glutamatergic neurons in cortical regions involved in threat perception and response reduced anxiety-like behaviors. The major takeaway from each of these IL-17 papers is the same, Kipnis says. “We’re showing that you have a population of immune cells sitting outside the brain that impact neurons inside it.”
In parallel with these studies demonstrating the capacity of cytokines to affect learning and memory, anxiety, and social behavior, researchers are beginning to pull back the curtain on the communication channels that T cells use to talk with neurons. Although it is still unclear exactly how the two systems physically interact, several possibilities have been identified, including direct messages from T cells sent via cytokines interacting with neurons and indirect signals generated through the interaction of cytokines with astrocytes.
Immune-Neural Crosstalk Several routes exist for immune cells and neurons to communicate, though T cells rarely come in direct contact with neural tissue. This communication can happen as cerebrospinal fluid (CSF) flows from the space surrounding blood vessels deep in the brain into neural tissue and back out again. As an animal learns new information, changing neural circuits can release signals to which the immune system responds. The immune system in the meninges, the spongy membranes that separate neural tissue from the skull, also monitors CSF coming from the brain for signs of infection or injury. © CATHERINE DELPHIA © CATHERINE DELPHIA The meninges’ innermost layer, the pia mater, lines the perimeter of the brain, separating neural tissue from the surrounding fluid and tissue. But gaps in the thin, fibrous tissue allow blood vessels to extend deep into the brain. Along blood vessels in the brain, a tightly packed layer of endothelial cells, along with projections, or “feet,” from astrocytes collectively make up the blood-brain barrier, which prevents blood from entering the organ. But CSF that sits in the space between the pia mater and upper layers of the meninges flows down around the endothelium-lined blood vessels. As arteries pulse with each beat from the heart, CSF pushes into the astrocyte feet through AQP4 water channels. This CSF can carry signals from the immune system such as cytokines IL-17, IL-4, and interferon gamma that may also talk directly with neurons. Cytokines can also trigger astrocytes to release molecules such as brain-derived neurotrophic factor (BDNF), influencing learning, memory, and sociality. Once in the brain, the CSF mixes with extracellular fluid from neuronal tissue, sweeping up cellular waste excreted along with any toxins, pathogen-derived antigens, and debris formed as part of normal neural rewiring. This fluid is then pushed out of the brain through astrocyte feet into the perivascular space, where it can interact with gamma delta T cells. Those T cells may then respond by releasing cytokines such as IL-17 that can move right back into the brain, although this has yet to be shown. The CSF is then channeled to the lymphatic vessels in the meninges and flushed to lymph nodes in the neck, where more T cells are waiting to scan the fluid and respond.
PDF See full infographic: WEB
Communication lines between immune cells and neurons
Some neuroscientists remain adamant that, with the exception of some drugs, most molecules do not get through the barriers that separate the brain from the rest of the body unless there’s a rupture to the boundary layers intended to cordon off the central nervous system. But research from several groups now challenges this idea. A key study in disproving the long-held assumption that the brain is immune privileged came from the lab of neuroscientist Maiken Nedergaard of the University of Rochester Medical Center. In 2012, she and her colleagues watched fluorescent and radiolabeled tracers flow from the CSF into the brains of anesthetized mice.
Specifically, Nedergaard’s team recorded the movement of the tracers into and out of the animals’ cerebral cortex, the brain’s outer layer of folded gray matter, which is essential for consciousness, attention, and making memories. The researchers learned that CSF carrying cytokines and other signaling molecules flows from the meninges into the space surrounding the brain’s vasculature. As the arteries pulse with each beat of an animal’s heart, the blood vessels expand, and the CSF is pushed through water channels in the astrocyte feet and then into the brain. The reverse flow also takes place: CSF that has entered the brain and mixed with the extracellular, or interstitial, fluid—and that now carries waste proteins ready for clearance—is pressed back through astrocytes into the space surrounding the blood vessels. “Maiken showed this very, very elegantly,” Kipnis says. It completely overthrew the dogma that the brain is immune privileged, he says.
Earlier this year, Andrew Yang of Stanford University and colleagues extended this finding to specifically show that cytokines released from T cells in the blood can also reach the brains of mice. The researchers extracted blood from the animals, separated out plasma proteins, labeled them with a fluorescent tag, then injected them back into the bloodstreams of the mice they came from. In healthy young adult mice, lots of the fluorescently tagged proteins crossed the BBB to enter the interstitial fluid in the brain. “This finding suggests that a wide variety of neural functions . . . could be modulated by systemic protein signals,” Roeben Munji and Richard Daneman of the University of California, San Diego, wrote in a commentary accompanying Yang’s study.
Cytokines in the meninges or possibly even in the blood might not have to enter the brain at all to affect the central nervous system, according to Brombacher’s studies. IL-13 and other cell signaling molecules in the CSF or blood could interact with astrocytes at the BBB or at the perimeter of the brain. In cultured astrocytes, treatment with IL-13 spurred the production of BDNF and triggered the production of glial fibrillary acidic protein (GFAP), an indication that neural connections are undergoing rewiring. Ribot’s study on IL-17 also showed that the cytokine could spur mice’s astrocytes to release BDNF into the brain. Both BDNF and GFAP, which boost synaptic rewiring, are associated with learning and memory.
Because we know that cerebrospinal fluid does go into the brain, putting therapies into that fluid will probably be a very, very efficient route for treating patients. —Jonathan Kipnis, Washington University School of Medicine
Communication between the immune and nervous systems can also happen in the reverse direction, with signals from the brain reaching T cells of the spongy, membranous meninges and of the rest of the body. Until a few years ago, researchers agreed that the brain lacked a drainage, or lymphatic, system to clear away its waste and to transport immune cells. But to Kipnis, it just didn’t make sense that one of the most important organs in the body would not have that kind of plumbing. So he and his colleagues went looking for it, and in 2015, they found it—mice’s brains did, in fact, have lymphatic vessels that shipped waste and T cells from the meninges to deep cervical lymph nodes in the animals’ necks. “These structures are bona fide vessels—they express all the same markers as lymphatic vessels in every other tissue,” he told The Scientist at the time.
In mice, T cells residing in the meninges scan the CSF for the cellular waste generated as neuronal circuits undergo changes, whether in response to learning and memory formation or in the case of dysfunction. Then, T cells in the lymph nodes get a chance to check the CSF for potential threats such as pathogens, he says. Tracking that lymphatic system in people’s brains is much harder, but Kipnis says there’s some evidence that what scientists are finding in rodents does translate to human biology. In 2017, he and collaborators at the National Institute of Neurological Disorders and Stroke used MRI to noninvasively confirm the existence of meningeal lymphatic vessels in humans and nonhuman primates.
Understanding immune cell–neuron crosstalk—both the way T cells respond to what’s in CSF coming from the central nervous system and how they send signals into the brain—could be important for understanding neurological disorders, such as Alzheimer’s disease, autism, schizophrenia, and even the cognitive decline associated with aging. “With many of these neurological disorders, there’s been reports that there’s some kind of dysregulation of the immune system,” Filiano says. Identifying faulty signals from neurons in the fluid leaving the brain could lead to diagnostic tools for neurological disorders, he notes. And given that CSF can carry cytokines and other proteins to neurons, Kipnis says he suspects that “putting [immune-based] therapies into that fluid will probably be a very, very efficient route for treating patients.”
Treating brain disorders with cytokines
Developing molecules to infuse into the blood or CSF to communicate with the brain requires a better understanding of how cytokines affect neurons, astrocytes, and micro-glia over the course of a lifetime. Interferon gamma, for example, appears to have two faces when it comes to influencing neuronal circuits. In Kipnis’s studies of young mice, the cytokine was essential for the animals to be social. But an analysis of the brains of old mice shows that the same cytokine might be detrimental to making new neurons in aged mice. Giving the old mice an antibody that neutralizes the immune cytokine restored neurogenesis in the animals’ brains, a team of researchers reported in 2019.
A similar tactic might provide a novel way to treat various neuropsychiatric disorders such as schizophrenia. Analyses of immune cells in the blood of schizophrenia patients show that these individuals have higher levels of a variety of cytokines, including IL-13 and interferon gamma, than healthy individuals do. People with schizophrenia treated with anti-inflammatory and antipsychotic drugs also tend to have fewer cognitive problems than individuals treated with only antipsychotics, hinting that reducing cytokine levels could improve patients’ symptoms. While the neuronal changes that cause schizophrenia are far from clear, studies suggest that when certain neurons produce lower-than-expected levels of dopamine, they alert T cells to a problem, and the T cells respond by releasing cytokines that prompt disease-related deficits in memory, learning, social behavior, and resilience to stress.
Filiano and Kipnis have found evidence that a similar approach might work for helping individuals with autism. In experiments with mice lacking T cells, the researchers found that the animals not only had social deficits but also showed hyperactivity in neural circuits that often have abnormal activity in the brains of people with autism. Not only did social behavior improve when the team infused the mice with immune cells, but the animals’ abnormal neural activity subsided too. Meticulously tweaking the immune system might reverse the cognitive and social deficits of the disorder, the experiments suggest.
For now, the results leave Filiano wanting to know more. He explains, “We’re really interested in how these immune cells talk to the brain, how these signals get from the immune cells to these neural circuits, how that communication happens in health and disease.”


thescientist--2020-10-01--Infographic: How Weight Lifting Changes Monkeys' Neural Connections

Over the course of two months , researchers trained macaque monkeys to lift more and more weight , until they @ @ @ @ @ equivalent of a one-armed pull-up .
When the researchers stimulated a bundle of nerves in @ @ @ @ @ the reticulospinal tract ( RST ) , they saw increases in the resulting neuronal electrical @ @ @ @ @ arm muscles as training progressed , while they did not see the same consistent upward @ @ @ @ @ responses to stimulation of the corticospinal tract ( CST ) .
The results suggest that @ @ @ @ @ critical role in muscle strengthening .

Over the course of two months, researchers trained macaque monkeys to lift more and more weight, until they were able to do the equivalent of a one-armed pull-up. When the researchers stimulated a bundle of nerves in the spinal cord known as the reticulospinal tract (RST), they saw increases in the resulting neuronal electrical signals in the monkeys’ arm muscles as training progressed, while they did not see the same consistent upward trend in the muscles’ responses to stimulation of the corticospinal tract (CST). The results suggest that RST connectivity may play a critical role in muscle strengthening.
© Kelly Finan
Read the full story.


Scientist as Subject

ABOVE : Tasked with finding a cure for malaria in the early 1970s , Institute of Chinese Materia Medica researcher Tu Youyou scoured texts spanning thousands of years for traditional remedies .
Tu successfully derived a drug called artemisinin from sweet wormwood and tested it in animals .
She and two colleagues then tested the treatment on themselves to make sure it wasn ’ t toxic before they began clinical trials .
The work earned her a Nobel Prize in 2015 .
© Xinhua News Agency / Contributor Long before there were rumors of COVID parties , there were “ @ @ @ @ @ @ @ lists were exclusive .
Joseph Goldberger , an infectious disease expert in the US Public Health Service , was tasked in 1914 with determining the cause of pellagra , a deadly systemic disease .
Many physicians of the time believed pellagra stemmed from an unknown microbe , but Goldberger felt strongly , and correctly , that it was the result of a nutritional deficiency .
To prove it , he and his wife Mary held small gatherings in multiple cities during which they and a few brave volunteers injected themselves with the blood @ @ @ @ @ @ @ with the scabs , nasal secretions , feces , and urine of living patients .
History is spattered with sometimes-gruesome examples of medical self-experimentation , some of which have netted notoriety and awards .
Self-experimentation “ has certainly been a well-recognized tradition , ” says Susan Lederer , a professor of the history of medicine and bioethics at the University of Wisconsin–Madison .
“ I would argue .
.
.
it was almost required .
The fact that you would risk it on your own body , or on your own children , @ @ @ @ @ @ @ ” In one of the more famous examples , Jonas Salk , a virologist at the University of Pittsburgh , first tested his polio vaccine on himself and his children in 1952 .
Four years earlier , virologist Hilary Koprowski and his assistant had tested their own rudimentary polio vaccine—this one made of liquefied rat brain and spinal cord—by drinking it themselves .
Research into yellow fever inspired greater personal sacrifice .
A research team led by US Army physician Walter Reed arrived in Cuba at the end of the 19th century during @ @ @ @ @ @ @ , which killed 13 soldiers for every one killed in battle .
To establish how the virus was transmitted , three of Reed ’ s colleagues intentionally exposed themselves and a handful of volunteer soldiers to mosquitoes that had previously fed on victims of yellow fever .
Three of the volunteers got sick , and one , Jesse Lazear , subsequently died .
In 1930 , Max Theiler , a virologist with the Rockefeller Foundation , began developing a yellow fever vaccine that he first tested on himself .
For his discovery , @ @ @ @ @ @ @ in Physiology or Medicine .
Nowadays , in the US , self-experimentation isn ’ t explicitly forbidden , and researchers can put themselves forward as candidates for treatments just as anyone else might .
However , Lederer notes that many people now “ look askance ” at scientists who subject themselves and their families to unregulated treatments .
As Allen Weisse , a retired cardiologist and medical historian , explains in a 2012 article , “ The trend in recent years toward collaborative studies , often on a massive scale , makes self-experimentation @ @ @ @ @ @ @ in his laboratory , seem almost quaint , a relic of the past.
” Still , the last Nobel Prize awarded for work involving self-experimentation was only five years ago , when Tu Youyou was honored for developing an anti-malaria drug that she first tested on herself in the 1970s .
Lederer says it ’ s likely that self-experimentation more often goes unreported nowadays , even as it still happens—including in pursuit of a vaccine to prevent COVID-19 .
A longer version of this article appears on The Scientist ’ s website under @ @ @ @ @ @ @ of COVID-19 ”

ABOVE: Tasked with finding a cure for malaria in the early 1970s, Institute of Chinese Materia Medica researcher Tu Youyou scoured texts spanning thousands of years for traditional remedies. Tu successfully derived a drug called artemisinin from sweet wormwood and tested it in animals. She and two colleagues then tested the treatment on themselves to make sure it wasn’t toxic before they began clinical trials. The work earned her a Nobel Prize in 2015.
© Xinhua News Agency / Contributor
Long before there were rumors of COVID parties, there were “filth parties,” and the guest lists were exclusive. Joseph Goldberger, an infectious disease expert in the US Public Health Service, was tasked in 1914 with determining the cause of pellagra, a deadly systemic disease. Many physicians of the time believed pellagra stemmed from an unknown microbe, but Goldberger felt strongly, and correctly, that it was the result of a nutritional deficiency. To prove it, he and his wife Mary held small gatherings in multiple cities during which they and a few brave volunteers injected themselves with the blood of pellagra victims and ingested capsules filled with the scabs, nasal secretions, feces, and urine of living patients.
History is spattered with sometimes-gruesome examples of medical self-experimentation, some of which have netted notoriety and awards. Self-experimentation “has certainly been a well-recognized tradition,” says Susan Lederer, a professor of the history of medicine and bioethics at the University of Wisconsin–Madison. “I would argue . . . it was almost required. The fact that you would risk it on your own body, or on your own children, was a sign of your good faith.”
In one of the more famous examples, Jonas Salk, a virologist at the University of Pittsburgh, first tested his polio vaccine on himself and his children in 1952. Four years earlier, virologist Hilary Koprowski and his assistant had tested their own rudimentary polio vaccine—this one made of liquefied rat brain and spinal cord—by drinking it themselves.
Research into yellow fever inspired greater personal sacrifice. A research team led by US Army physician Walter Reed arrived in Cuba at the end of the 19th century during the Spanish-American war to study the disease, which killed 13 soldiers for every one killed in battle. To establish how the virus was transmitted, three of Reed’s colleagues intentionally exposed themselves and a handful of volunteer soldiers to mosquitoes that had previously fed on victims of yellow fever. Three of the volunteers got sick, and one, Jesse Lazear, subsequently died. In 1930, Max Theiler, a virologist with the Rockefeller Foundation, began developing a yellow fever vaccine that he first tested on himself. For his discovery, he was awarded the 1951 Nobel Prize in Physiology or Medicine.
Nowadays, in the US, self-experimentation isn’t explicitly forbidden, and researchers can put themselves forward as candidates for treatments just as anyone else might. However, Lederer notes that many people now “look askance” at scientists who subject themselves and their families to unregulated treatments. As Allen Weisse, a retired cardiologist and medical historian, explains in a 2012 article, “The trend in recent years toward collaborative studies, often on a massive scale, makes self-experimentation by a single individual, tucked away in his laboratory, seem almost quaint, a relic of the past.”
Still, the last Nobel Prize awarded for work involving self-experimentation was only five years ago, when Tu Youyou was honored for developing an anti-malaria drug that she first tested on herself in the 1970s. Lederer says it’s likely that self-experimentation more often goes unreported nowadays, even as it still happens—including in pursuit of a vaccine to prevent COVID-19.
A longer version of this article appears on The Scientist’s website under the title “Self-Experimentation in the Time of COVID-19”


Wielding Fear

Fear is in the air .
People everywhere have been navigating a potentially deadly new reality , living for months under the weight of a seemingly relentless pandemic .
Economies , hobbled by the severe disruption to business as usual , struggle to regain a foothold , and many livelihoods hang in the balance .
In addition , a US presidential election , arguably the most contentious in modern history , looms on the horizon , and some politicians are capitalizing on the fear-filled climate to achieve their personal , policy , and electoral goals .
This month ’ s @ @ @ @ @ @ @ California , Los Angeles , animal behavior researcher Daniel Blumstein , discusses the ecological power and evolutionary history of fear .
The emotion has for millennia helped species avoid being eaten , and a balanced approach to risk-benefit analysis has helped some individuals prosper and multiply while others succumbed to starvation or predation due to an over- or under-abundance of caution , respectively .
“ Fear , ” Blumstein writes , “ is an essential ingredient in healthy ecosystems and helps maintain biodiversity.
” But the emotion can sometimes overtake sound thinking , @ @ @ @ @ @ @ the political realm , Blumstein notes .
“ [ Fear ] makes us vulnerable to politicians with malevolent intentions who make compelling advertisements that efficiently tap into our well-honed neurophysiological fear systems.
” While editing Blumstein ’ s piece for this issue , I started to think of the overabundance of fear that lingers in our collective consciousness and colors our day-to-day existence .
Not even my seven-year-old daughter is immune .
“ Dad , can you turn the news off ?
” she recently said in the car after hearing a radio @ @ @ @ @ @ @ shot in Chicago .
“ It scares me.
” With a pang in my heart , I muted the radio .
In that moment , fear was something to avoid , to run from .
But perhaps we need to rethink our relationship with the emotion .
Blumstein writes that fear can be useful and constructive in many situations and across many species .
The scared marmot that cowers in its burrow as a golden eagle soars above has its fear to thank for saving its skin .
But if the marmot doesn @ @ @ @ @ @ @ courage necessary to seek food and mates , it could starve or otherwise fail to pass on its genetic legacy .
This is what we risk when fear runs amok .
I think it ’ s what Franklin D. Roosevelt was getting at in the opening of his 1933 inaugural address : “ .
.
.
the only thing we have to fear is fear itself .
.
.
” What followed this frequently cited phrase really drives home FDR ’ s point : “ .
.
.
nameless , unreasoning , unjustified @ @ @ @ @ @ @ retreat into advance.
” Far be it from me to disagree with FDR ’ s famous sentiment , which I interpret as a call to trust in the country ’ s leaders in a time of peril and upheaval as the US economy grappled with the Great Depression .
But in our own challenging times , I would suggest that we embrace fear , rather than fearing or avoiding it .
A healthy measure of fear can help us make smarter choices—wearing a mask at the grocery store , driving safely , investing @ @ @ @ @ @ @ to the advice of public health experts , etc .
An overactive sense of fear can indeed be problematic , clouding our vision and leading us astray from our foundational ethics and morals .
But on the other end of that spectrum , if we seek an existence free from fear , we are rejecting an elemental force that has shaped the course of our evolution and the functioning of our living planet .
We must strike the same balance that successful marmots and our forebears achieved : have enough fear to modulate @ @ @ @ @ @ @ not so much that we abandon our values or squander opportunities .
This is where the use of fearmongering by some in the political realm is particularly nefarious .
To accomplish short-term political goals , such as getting votes or donations , some individuals are perfectly OK with sowing the seeds of terror .
And in doing so , they often push logic , science , rationality , and kindness to the periphery .
It is my sincere hope that as we progress through this challenging year , we realize that there are @ @ @ @ @ @ @ our trepidation , appropriately contextualized , will lead us in the right direction .
But we must remain vigilant to avoid forsaking our humanity by engaging in an overactive , imagined , or exploited sense of dread .
Let ’ s stop fearing fear so that we can understand it and use it to make ourselves , one another , and the world better .

ABOVE: © istock.com, AVESUN
Fear is in the air. People everywhere have been navigating a potentially deadly new reality, living for months under the weight of a seemingly relentless pandemic. Economies, hobbled by the severe disruption to business as usual, struggle to regain a foothold, and many livelihoods hang in the balance. In addition, a US presidential election, arguably the most contentious in modern history, looms on the horizon, and some politicians are capitalizing on the fear-filled climate to achieve their personal, policy, and electoral goals.
This month’s Reading Frames essay, from University of California, Los Angeles, animal behavior researcher Daniel Blumstein, discusses the ecological power and evolutionary history of fear. The emotion has for millennia helped species avoid being eaten, and a balanced approach to risk-benefit analysis has helped some individuals prosper and multiply while others succumbed to starvation or predation due to an over- or under-abundance of caution, respectively. “Fear,” Blumstein writes, “is an essential ingredient in healthy ecosystems and helps maintain biodiversity.” But the emotion can sometimes overtake sound thinking, and that potential imbalance has utility in the political realm, Blumstein notes. “[Fear] makes us vulnerable to politicians with malevolent intentions who make compelling advertisements that efficiently tap into our well-honed neurophysiological fear systems.”
While editing Blumstein’s piece for this issue, I started to think of the overabundance of fear that lingers in our collective consciousness and colors our day-to-day existence. Not even my seven-year-old daughter is immune. “Dad, can you turn the news off?” she recently said in the car after hearing a radio report about an eight-year-old child who was shot in Chicago. “It scares me.” With a pang in my heart, I muted the radio. In that moment, fear was something to avoid, to run from. But perhaps we need to rethink our relationship with the emotion.
ANDRZEJ KRAUZE
Blumstein writes that fear can be useful and constructive in many situations and across many species. The scared marmot that cowers in its burrow as a golden eagle soars above has its fear to thank for saving its skin. But if the marmot doesn’t balance that fear with the courage necessary to seek food and mates, it could starve or otherwise fail to pass on its genetic legacy. This is what we risk when fear runs amok. I think it’s what Franklin D. Roosevelt was getting at in the opening of his 1933 inaugural address: “. . . the only thing we have to fear is fear itself . . .” What followed this frequently cited phrase really drives home FDR’s point: “. . . nameless, unreasoning, unjustified terror which paralyzes needed efforts to convert retreat into advance.”
Far be it from me to disagree with FDR’s famous sentiment, which I interpret as a call to trust in the country’s leaders in a time of peril and upheaval as the US economy grappled with the Great Depression. But in our own challenging times, I would suggest that we embrace fear, rather than fearing or avoiding it. A healthy measure of fear can help us make smarter choices—wearing a mask at the grocery store, driving safely, investing wisely in the stock market, deferring to the advice of public health experts, etc. An overactive sense of fear can indeed be problematic, clouding our vision and leading us astray from our foundational ethics and morals. But on the other end of that spectrum, if we seek an existence free from fear, we are rejecting an elemental force that has shaped the course of our evolution and the functioning of our living planet.
We must strike the same balance that successful marmots and our forebears achieved: have enough fear to modulate our behavior in constructive ways, but not so much that we abandon our values or squander opportunities. This is where the use of fearmongering by some in the political realm is particularly nefarious. To accomplish short-term political goals, such as getting votes or donations, some individuals are perfectly OK with sowing the seeds of terror. And in doing so, they often push logic, science, rationality, and kindness to the periphery.
It is my sincere hope that as we progress through this challenging year, we realize that there are things that we should fear and that our trepidation, appropriately contextualized, will lead us in the right direction. But we must remain vigilant to avoid forsaking our humanity by engaging in an overactive, imagined, or exploited sense of dread. Let’s stop fearing fear so that we can understand it and use it to make ourselves, one another, and the world better.
Bob Grant
Editor-in-Chief