thescientist--2020-11-24--For a Hefty Fee, Nature Journals Offer Open-Access Publishing

Today ( November 24 ) , the academic publisher Springer Nature announced that , starting in January , authors whose articles are accepted into a Nature-branded journal will have an open-access option for €9,500 ( approximately $ 11,300 US ) .
The publisher also revealed a pilot project in which authors pay a nonrefundable assessment fee of €2,190 ( approximately $ 2,600 US ) to determine whether a manuscript is suitable for a selection of Nature-branded journals , but acceptance is not guaranteed .
If a match is found , the authors then pay the remainder of the publication charge @ @ @ @ @ @ @ .
Most Nature titles are subscription journals , meaning that their content sits behind a paywall .
Springer Nature has inked contracts with institutions to expand open-access ( OA ) offerings of its titles , but the Nature suite has typically been excluded .
This latest move marks a shift toward making the content in those journals freely accessible to the public .
In April , Springer Nature stated that it would be offering ways to publish open access in its Nature-branded journals in order to be compliant with Plan S , an @ @ @ @ @ @ @ freely accessible immediately upon publication , led by a group of funding organizations dubbed cOAlition S. The announcement came shortly after the coalition softened its stance on transformative journals ( those that commit to eventually becoming fully open access ) —introducing various changes , such as dropping the obligation to flip to 100 percent open access by 2024 and reducing the required annual increase in open-access content .
See “ Plan S : The Ambitious Initiative to End the Reign of Paywalls ” “ Springer Nature continues to attempt to position itself as @ @ @ @ @ @ @ , ” says Lisa Hinchliffe , a professor and the coordinator of information literacy services at the University of Illinois at Urbana-Champaign .
“ They are clearly open to trying a large number of models .
Which of these models will succeed .
.
.
remains to be seen.
” Last month , Springer Nature unveiled its first open-access deal for its Nature-branded journals with the Max Planck Society , an association of German research institutes .
The agreement , which comes into effect in January , will enable academics from those participating @ @ @ @ @ @ @ access articles in Nature journals for a lump sum .
The fee is based on a per-article fee of €9,500 to make articles freely accessible upon publication .
The €9,500 price tag has drawn criticism from those who say the amount is too steep to widely benefit the scholarly community .
“ Agreements that arrange for paying exorbitant amounts for publishing OA in prestigious journals do nothing to improve the accessibility and equitability of the scholarly publishing system , and merely show everything can be had if you just throw enough money at @ @ @ @ @ @ @ Kramer , two librarians and scholarly communication researchers at Utrecht University in the Netherlands , wrote in an email to Nature last month .
Today ’ s announcement has also drawn disapproval from academics on social media .
Michael Marks , a professor at the London School of Hygiene and Tropical Medicine called the €9,500 fee “ insane and indefensible ” on Twitter .
“ Paying 2190€ just for the possibility of peer review , or 9500€ for publishing is not an option for researchers in lower income countries , ” tweeted Atay @ @ @ @ @ @ @ in Turkey .
“ This is not the solution for open science .
This makes the situation even worse.
” There is currently no waiver for those who can not afford the €9,500 fee for submissions to Nature journals , with the exception of the already open-access journal Nature Communications .
But according to James Butcher , the vice president of journals at Nature Research and BMC , another journal collection belonging to Springer Nature , a waiver will be introduced once those journals become fully open access .
“ During [ the @ @ @ @ @ @ @ be offering waivers because authors could choose to publish subscription if they want , in the standard way , ” Butcher says .
“ Once the journal becomes fully open access , which would probably be quite a few years down the line , then there will be a waiver policy.
” Starting in the new year , Springer Nature also plans to pilot a system that will give authors the option of publishing open-access articles in Nature titles for half the fee .
Under the new scheme , dubbed “ Guided Open @ @ @ @ @ @ @ paper to a Nature journal ( Nature Physics , for example ) and the manuscript will be simultaneously considered for that journal as well as two other associated , lower-tier journals that are already open access , in this case , Nature Communications and Communications Physics .
Once the article passes through a basic quality check , it will be sent for an “ editorial assessment , ” at which point a nonrefundable charge of €2,190 will be payable by the authors .
At this stage , editors will determine whether the paper @ @ @ @ @ @ @ the three journals and peer reviewers will read the manuscript .
If the article is accepted into one of the journals , authors who choose to publish will pay the remainder of the fee ( which in this scenario would be €2,600 for Nature Physics and Nature Communications , and €800 in Communication Physics ) .
“ It ’ s an efficient peer-review service , ” says Butcher .
“ Effectively what we ’ re doing is assessing the submitted paper across multiple journals at the same time , which should make the @ @ @ @ @ @ @ the inefficiency.
” At the moment , approximately 15–20 percent of papers submitted to Nature journals are sent out for peer review , and around 8 percent are accepted .
Under the new model , all papers that pass the initial quality screen will get peer-reviewed , Butcher adds .
“ I suspect it will be about three-quarters [ of submissions ] , but I don ’ t know for sure.
” According to Butcher , another upside of the system is that it provides a way to spread the cost across publications @ @ @ @ @ @ @ initial editorial assessment report , that means we ’ re able to spread the cost across multiple offers rather than just the ones that are ultimately accepted.
” ( Butcher notes that the current acceptance rates are approximately 16 percent at Nature Communications and 30 percent at the other Communications titles . )
For now , the “ Guided Open Access ” option is only available for submissions to Nature Genetics , Nature Methods , and Nature Physics .
Butcher says that the length of the pilot will depend on how many authors @ @ @ @ @ @ @ .
“ I think this is innovative because it is a step in the direction of charging for services , ” says Bodo Stern , the chief of strategic initiatives at the Howard Hughes Medical Institute , a private biomedical research institution and funder that joined cOAlition S in October .
“ I hope it ’ s successful , but it is not going to be popular with authors.
” ( Journals don ’ t typically ask authors to pay if their manuscripts are not accepted , although there are a handful of @ @ @ @ @ @ @ ) Stern adds that from his perspective , it ’ s fair for publishers to charge for assessments , since it is a service they are providing .
In Stern ’ s view , in the long run , the publishing system should change so that researchers immediately post all their all papers onto preprint servers and journal publishers act primarily as curators rather than a publication service .
Hinchliffe says the big question is whether cOAlition S will accept the Nature journals as transformative journals .
“ This sets their transformative journal @ @ @ @ @ @ @ €9,500 , ” she adds .
“ If Plan S approves their application to be transformative journals , they will be indicating that they have accepted this as a fair and reasonable APC.
” COI statement : Diana Kwon has received payments from Springer Nature as a freelance reporter for Scientific American and Nature , editorially independent publications owned by the publisher .

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Today (November 24), the academic publisher Springer Nature announced that, starting in January, authors whose articles are accepted into a Nature-branded journal will have an open-access option for €9,500 (approximately $11,300 US).
The publisher also revealed a pilot project in which authors pay a nonrefundable assessment fee of €2,190 (approximately $2,600 US) to determine whether a manuscript is suitable for a selection of Nature-branded journals, but acceptance is not guaranteed. If a match is found, the authors then pay the remainder of the publication charge and the paper is made open access.
Most Nature titles are subscription journals, meaning that their content sits behind a paywall. Springer Nature has inked contracts with institutions to expand open-access (OA) offerings of its titles, but the Nature suite has typically been excluded. This latest move marks a shift toward making the content in those journals freely accessible to the public.
In April, Springer Nature stated that it would be offering ways to publish open access in its Nature-branded journals in order to be compliant with Plan S, an initiative to make all the scholarly literature freely accessible immediately upon publication, led by a group of funding organizations dubbed cOAlition S. The announcement came shortly after the coalition softened its stance on transformative journals (those that commit to eventually becoming fully open access)—introducing various changes, such as dropping the obligation to flip to 100 percent open access by 2024 and reducing the required annual increase in open-access content.
“Springer Nature continues to attempt to position itself as a leading [open access] publisher,” says Lisa Hinchliffe, a professor and the coordinator of information literacy services at the University of Illinois at Urbana-Champaign. “They are clearly open to trying a large number of models. Which of these models will succeed . . . remains to be seen.”
Last month, Springer Nature unveiled its first open-access deal for its Nature-branded journals with the Max Planck Society, an association of German research institutes. The agreement, which comes into effect in January, will enable academics from those participating institutions to read content and publish open access articles in Nature journals for a lump sum. The fee is based on a per-article fee of €9,500 to make articles freely accessible upon publication.
The €9,500 price tag has drawn criticism from those who say the amount is too steep to widely benefit the scholarly community. “Agreements that arrange for paying exorbitant amounts for publishing OA in prestigious journals do nothing to improve the accessibility and equitability of the scholarly publishing system, and merely show everything can be had if you just throw enough money at it,” Jeroen Bosman and Bianca Kramer, two librarians and scholarly communication researchers at Utrecht University in the Netherlands, wrote in an email to Nature last month.
Today’s announcement has also drawn disapproval from academics on social media. Michael Marks, a professor at the London School of Hygiene and Tropical Medicine called the €9,500 fee “insane and indefensible” on Twitter. “Paying 2190€ just for the possibility of peer review, or 9500€ for publishing is not an option for researchers in lower income countries,” tweeted Atay Vural, a professor at Koç University in Turkey. “This is not the solution for open science. This makes the situation even worse.”
“Journals will charge authors up to €9,500 to make research papers free to read...” I have paid some crazy submission fees to international journals & can attest that it definitely worsens the entry barrier for scholars from countries like India.https://t.co/jSfMma9i68 — Prof Shamika Ravi (@ShamikaRavi) November 24, 2020
There is currently no waiver for those who cannot afford the €9,500 fee for submissions to Nature journals, with the exception of the already open-access journal Nature Communications. But according to James Butcher, the vice president of journals at Nature Research and BMC, another journal collection belonging to Springer Nature, a waiver will be introduced once those journals become fully open access. “During [the transition period], we will not be offering waivers because authors could choose to publish subscription if they want, in the standard way,” Butcher says. “Once the journal becomes fully open access, which would probably be quite a few years down the line, then there will be a waiver policy.”
Piloting a new model
Starting in the new year, Springer Nature also plans to pilot a system that will give authors the option of publishing open-access articles in Nature titles for half the fee. Under the new scheme, dubbed “Guided Open Access,” authors can submit a paper to a Nature journal (Nature Physics, for example) and the manuscript will be simultaneously considered for that journal as well as two other associated, lower-tier journals that are already open access, in this case, Nature Communications and Communications Physics.
Once the article passes through a basic quality check, it will be sent for an “editorial assessment,” at which point a nonrefundable charge of €2,190 will be payable by the authors. At this stage, editors will determine whether the paper is suitable for publication in one of the three journals and peer reviewers will read the manuscript. If the article is accepted into one of the journals, authors who choose to publish will pay the remainder of the fee (which in this scenario would be €2,600 for Nature Physics and Nature Communications, and €800 in Communication Physics).
I think this is innovative because it is a step in the direction of charging for services. —Bodo Stern, Howard Hughes Medical Institute
“It’s an efficient peer-review service,” says Butcher. “Effectively what we’re doing is assessing the submitted paper across multiple journals at the same time, which should make the process faster and cut out some of the inefficiency.” At the moment, approximately 15–20 percent of papers submitted to Nature journals are sent out for peer review, and around 8 percent are accepted. Under the new model, all papers that pass the initial quality screen will get peer-reviewed, Butcher adds. “I suspect it will be about three-quarters [of submissions], but I don’t know for sure.”
According to Butcher, another upside of the system is that it provides a way to spread the cost across publications. “Because everyone pays for that initial editorial assessment report, that means we’re able to spread the cost across multiple offers rather than just the ones that are ultimately accepted.” (Butcher notes that the current acceptance rates are approximately 16 percent at Nature Communications and 30 percent at the other Communications titles.)
For now, the “Guided Open Access” option is only available for submissions to Nature Genetics, Nature Methods, and Nature Physics. Butcher says that the length of the pilot will depend on how many authors opt to submit via this new method.
“I think this is innovative because it is a step in the direction of charging for services,” says Bodo Stern, the chief of strategic initiatives at the Howard Hughes Medical Institute, a private biomedical research institution and funder that joined cOAlition S in October. “I hope it’s successful, but it is not going to be popular with authors.” (Journals don’t typically ask authors to pay if their manuscripts are not accepted, although there are a handful of publications that collect modest submission fees.) Stern adds that from his perspective, it’s fair for publishers to charge for assessments, since it is a service they are providing. In Stern’s view, in the long run, the publishing system should change so that researchers immediately post all their all papers onto preprint servers and journal publishers act primarily as curators rather than a publication service.
Hinchliffe says the big question is whether cOAlition S will accept the Nature journals as transformative journals. “This sets their transformative journal APC [article processing charge] at €9,500,” she adds. “If Plan S approves their application to be transformative journals, they will be indicating that they have accepted this as a fair and reasonable APC.”
COI statement: Diana Kwon has received payments from Springer Nature as a freelance reporter for Scientific American and Nature, editorially independent publications owned by the publisher.


Ergonomic Pipetting

Pipetting is a simple technique that involves force application and complex muscle movements from the fingers to the back and @ @ @ @ @ their pipettes for hours at a time and rarely think about these muscles .
Yet @ @ @ @ @ utilize their pipettes profoundly impacts their health and their science .
Download this ebook from @ @ @ @ @ power of the right pipette

Pipetting is a simple technique that involves force application and complex muscle movements from the fingers to the back and neck. Researchers often grip their pipettes for hours at a time and rarely think about these muscles. Yet, how researchers hold and utilize their pipettes profoundly impacts their health and their science.
Download this ebook from Biotix to discover


thescientist--2020-11-26--Transcendent Kingdom TS Book Club Discussion

While primarily a respiratory ailment , COVID-19 also influences other major physiological systems .
In particular , growing evidence shows @ @ @ @ @ effects on cardiovascular and neurological health .
In this webinar from The Scientist , John @ @ @ @ @ discuss SARS-CoV-2 's relationship with the cardiovascular and neurological systems and how these effects influence @ @ @ @ @ Assessment of persistent cognitive dysfunction as a first step in treatment decisions for COVID-19 • @ @ @ @ @ from basic mechanisms to clinical perspectives

FREE Webinar
Friday, December 11, 2020
2:30 - 4:00 PM, Eastern Standard Time
Register Now
Transcendent Kingdom is Yaa Gyasi’s sophomore effort. After her critically acclaimed and award-winning debut novel, 2016’s Homegoing, Gyasi’s second book follows the story of Gifty, a fifth-year PhD student in a Stanford University neuroscience lab. As Gifty navigates the pressures of grad school, she also struggles to cope with the memory of her late older brother and with sharing a home with her mentally ill mother. We will convene to discuss the book, raise questions, share observations, and draw parallels between the fictional world of Transcendent Kingdom and the experiences of actual scientists in a December 11th webinar attended by special guest Christina Kim, the Stanford University postdoc who served as the novel’s science advisor, The Scientist's editorial staff, and members of The Scientist Social Club, who have been reading the book for the past several weeks. Before and after the webinar, readers are invited to join the discussion in The Scientist Social Club Facebook Group.
Topics to be covered
The observational research that went into writing Transcendent Kingdom
How closely the book reflects the reality of working in a neuroscience lab
The important take-home messages from the perspective of a graduate student
Register Now
Meet the Speakers:
Christina Kim
Stanford University postdoc


thescientist--2020-11-26--Navigating Research Challenges in Vaccine Development

While vaccines are often an effective way to induce immunity , developing a safe and effective vaccine is an uphill @ @ @ @ @ daunting task for biotech companies fervently working to get life-saving therapeutics into the clinic .
@ @ @ @ @ in recent years alleviate some of the challenges researchers face in target discovery and antigen @ @ @ @ @ this article from Thermo Fisher Scientific to explore ways to improve target discovery and antigen @ @ @ @ @ discovery .

While vaccines are often an effective way to induce immunity, developing a safe and effective vaccine is an uphill battle and can be a daunting task for biotech companies fervently working to get life-saving therapeutics into the clinic. Fortunately, novel technologies developed in recent years alleviate some of the challenges researchers face in target discovery and antigen identification and selection.
Download this article from Thermo Fisher Scientific to explore ways to improve target discovery and antigen identification and selection for vaccine discovery.


thescientist--2020-11-25--CRISPR Technologies for the New Era of Cell and Gene Therapy

Cell and gene therapies revolutionize how scientists treat disease .
To develop these therapies , some researchers use new CRISPR @ @ @ @ @ genome , from fixing mutations associated with disease to modifying immune cells to attack cancer @ @ @ @ @ to you by Synthego , cell and gene therapy experts will discuss how they use @ @ @ @ @ including repairing genetic diseases in induced pluripotent stem cells ( iPSCs ) .
• Decoding @ @ @ @ @ CRISPR and iPSCs • The future of cell and gene therapy using CRISPR Bruce Conklin @ @ @ @ @ Gladstone Institutes Deputy Director , Innovative Genomics Institute Professor , Departments of Medicine , Pharmacology @ @ @ @ @ , San Francisco

FREE Webinar
Thursday, December 10, 2020
2:00 - 3:30 PM, Eastern Standard Time
Register Now
Cell and gene therapies are revolutionizing next-generation therapeutics. Many researchers are now leveraging the power of CRISPR precision genome engineering in their cell and gene therapies research, from fixing mutations associated with disease to modifying immune cells to attack cancer. In this webinar, brought to you by Synthego, cell and gene therapy experts will discuss the applications of CRISPR in studying genetic diseases and beyond.
Topics to be covered
Decoding and repairing genetic disease with CRISPR and iPSCs
The future of cell and gene therapy using CRISPR
Register Now
Meet the Speakers:
Robert Deans, PhD
Chief Scientific Officer
Synthego
Bruce Conklin, MD
Senior Investigator, Gladstone Institutes
Deputy Director, Innovative Genomics Institute
Professor, Departments of Medicine, Pharmacology, and Ophthalmology
University of California, San Francisco


thescientist--2020-11-30--Blood MicroRNA Patterns Linked to Chronic Fatigue Syndrome

Formerly known as chronic fatigue syndrome , myalgic encephalomyelitis/chronic fatigue syndrome has long been neglected by physicians , researchers , and funding agencies , not least due to its mysterious causes .
It ’ s often hard for patients to find doctors who can diagnose ME/CFS , a widespread condition characterized by debilitating post-exertion fatigue and other symptoms .
A new study appears to make headway toward solving those difficulties .
A recent analysis from more than 40 ME/CFS patients reports that a disease-specific stress test leaves a distinct signature of 11 microRNAs in their blood that change in abundance @ @ @ @ @ @ @ .
Most of these microRNAs are involved in regulating immunity , supporting the idea that immune dysfunction plays a key role in the disease ’ s pathology .
The findings lay the groundwork for developing a molecular diagnostic test for the disease , the authors write in their study , which was published on November 12 in Scientific Reports .
Although the findings need to be replicated in larger cohorts , “ I think there are many strengths here , ” remarks Mady Hornig , an immunologist at the Columbia University Mailman School @ @ @ @ @ @ @ involved in the research .
“ There ’ s a lot here , in terms of the findings , that are really intriguing and important clues.
” MicroRNAs are short nucleotide snippets that act inside cells to regulate gene expression and have garnered much research interest over the past decade as potential diagnostic tools for several conditions in which they ’ re dysregulated .
To Alain Moreau , who specializes in the molecular genetics of musculoskeletal diseases at the University of Montreal and the Sainte-Justine University Hospital , they were an attractive focus @ @ @ @ @ @ @ microRNAs also circulate in the blood , providing an easily accessible source of gene-regulatory information .
Previous studies have flagged distinctive circulating or cellular microRNAs in ME/CFS patients , but some had very small sample sizes or didn ’ t compare patients with appropriate controls , making the data often hard to interpret , Moreau says .
He and his colleagues wanted to overcome these issues , while also looking for microRNAs tied to specific symptoms in the condition , which he says he hoped would yield robust biomarkers .
The hallmark symptom @ @ @ @ @ @ @ ) , a worsening of fatigue and other symptoms following physical or mental exercise that can leave patients bedridden for weeks .
The researchers sought to probe microRNAs associated with this symptom , but to spare patients a full-blown bout of PEM in the clinic , Moreau ’ s team figured out that they could use a therapeutic massager—an inflatable arm cuff that exerts gentle pulsating compressions—to induce a milder form of PEM , as evidenced by headaches , muscle pain , and profound fatigue that patients reported in later questionnaires .
Starting @ @ @ @ @ @ @ patients , the team drew plasma samples before and 90 minutes after this challenge and screened for differences in levels of microRNAs .
Computational analysis revealed 17 microRNAs whose levels had changed significantly after the test ; their response also differed from that of eight age- and sex-matched healthy individuals who had been subjected to the massager but didn ’ t report any PEM symptoms .
Repeating this analysis in a larger cohort of 32 ME/CFS patients and 17 matched controls , the team discovered the same response patterns for 11 microRNAs .
@ @ @ @ @ @ @ the researchers trained could correctly diagnose someone with ME/CFS based solely on the change in concentration of these microRNAs after the massage intervention .
“ We were unable to misdiagnose a [ healthy ] control as ME/CFS , or inversely , ME/CFS as a control , ” Moreau says .
The need for diagnostics and drugs for ME/CFS There ’ s an overwhelming need for definitive diagnostic tests for ME/CFS , says Frances Williams , a genomic epidemiologist at King ’ s College London who wasn ’ t involved in the research .
@ @ @ @ @ @ @ conditions , which is difficult , time-consuming , and a frustration for patients .
The fact that Moreau ’ s team could replicate their results in a larger cohort is encouraging , but she says she doubts that microRNAs will form a standalone test for ME/CFS , simply because of the genetic and epigenetic complexity of the disease .
However , microRNAs “ could be helpful in combination with other things , ” she says .
Hornig says the test has many strengths in terms of translating it for use in a clinical @ @ @ @ @ @ @ on free-floating sequences in the blood makes it technologically simpler than a technique used in a previous study that requires extracting microRNAs from inside blood cells .
She also praises the team ’ s PEM-inducing stressor , which reflects the sensitivity of severely affected ME/CFS patients to their sensory environment , but is less taxing than physical exertion “ and respectful of the patients ’ experience and fears , ” she says .
Moreau encourages other institutions to replicate the results .
The findings will require validation in larger cohorts to ensure the @ @ @ @ @ @ @ of ME/CFS , different stages of the disease , and those from a variety of regions and ethnicities .
Hornig adds it ’ s also important to investigate differences with the results of other studies—for instance , previous work on cellular microRNAs in ME/CFS suggested disparities in how men and women responded to exercise , whereas Moreau ’ s results found no sex-based differences .
She ’ s also curious about where the microRNAs come from , suspecting immune cells or muscle tissue as possible origins .
“ This opens a lot of @ @ @ @ @ @ @ Moreau ’ s team found that they could cluster the patients into four discrete groups based on the precise pattern of their microRNA responses to the PEM challenge .
Interestingly , these groups happened to also share clinical features—one group , for instance , had markedly severe symptoms .
To Moreau , this indicates that different mechanisms operate in different subsets of the disease , which could help explain why drug trials for ME/CFS patients have so far been largely inconclusive .
But he says he hopes to use microRNA data soon to @ @ @ @ @ @ @ more likely to respond to .
His team suspects , for instance , that the immunomodulating drug rintatolimod , which activates Toll-like receptor 3 , might not be effective in patients with high levels of microRNAs that impede the transcription of that receptor .
“ I [ hope ] the test will open the door to more .
.
.
precision medicine in the field of ME/CFS , ” Moreau says .
To Williams , the major value of the study lies in an analysis Moreau ’ s team conducted with the microRNA @ @ @ @ @ @ @ 11 sequences are involved in .
This revealed that 7 out of the 11 microRNAs were involved in regulating immune functions , which “ certainly fits with one arm of the research that suggests that immune activation is very important in leading to chronic fatigue , ” she says .
An additional network analysis flagged the key genes each microRNA is associated with and other diseases they ’ ve been linked to , which included viral infection , sleep disorders , and cognitive impairments .
“ Using a network approach , you can @ @ @ @ @ @ @ processes are important .
And then if that ties in with what we know already about the cellular processes in ME/CFS , then that all begins to paint a bit of a picture.
” The findings are relevant in light of the COVID-19 pandemic and the increasing numbers of “ long-hauler ” patients left with enduring fatigue symptoms , a phenomenon that has many experts concerned that the coronavirus could trigger ME/CFS in a subset of infected people .
The pandemic “ will bring a huge number of new [ ME/CFS ] patients @ @ @ @ @ @ @ young .
That will create some devastating impacts for themselves and their families , ” Moreau says .
“ That ’ s why we need to hurry and hope that we will convince governments and funding agencies to [ put more funding into the field ] .
” E. Nepotchatykh et al.
, “ Profile of circulating microRNAs in myalgic encephalomyelitis and their relation to symptom severity , and disease pathophysiology , ” Sci Rep , doi:10.1038/s41598-020-76438-y , 2020 .

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Formerly known as chronic fatigue syndrome, myalgic encephalomyelitis/chronic fatigue syndrome has long been neglected by physicians, researchers, and funding agencies, not least due to its mysterious causes. It’s often hard for patients to find doctors who can diagnose ME/CFS, a widespread condition characterized by debilitating post-exertion fatigue and other symptoms.
A new study appears to make headway toward solving those difficulties. A recent analysis from more than 40 ME/CFS patients reports that a disease-specific stress test leaves a distinct signature of 11 microRNAs in their blood that change in abundance compared with blood drawn before the test. Most of these microRNAs are involved in regulating immunity, supporting the idea that immune dysfunction plays a key role in the disease’s pathology. The findings lay the groundwork for developing a molecular diagnostic test for the disease, the authors write in their study, which was published on November 12 in Scientific Reports.
Although the findings need to be replicated in larger cohorts, “I think there are many strengths here,” remarks Mady Hornig, an immunologist at the Columbia University Mailman School of Public Health who wasn’t involved in the research. “There’s a lot here, in terms of the findings, that are really intriguing and important clues.”
MicroRNAs are short nucleotide snippets that act inside cells to regulate gene expression and have garnered much research interest over the past decade as potential diagnostic tools for several conditions in which they’re dysregulated. To Alain Moreau, who specializes in the molecular genetics of musculoskeletal diseases at the University of Montreal and the Sainte-Justine University Hospital, they were an attractive focus for exploring ME/CFS, in part because microRNAs also circulate in the blood, providing an easily accessible source of gene-regulatory information.
Previous studies have flagged distinctive circulating or cellular microRNAs in ME/CFS patients, but some had very small sample sizes or didn’t compare patients with appropriate controls, making the data often hard to interpret, Moreau says. He and his colleagues wanted to overcome these issues, while also looking for microRNAs tied to specific symptoms in the condition, which he says he hoped would yield robust biomarkers.
The hallmark symptom of ME/CFS is post-exertional malaise (PEM), a worsening of fatigue and other symptoms following physical or mental exercise that can leave patients bedridden for weeks. The researchers sought to probe microRNAs associated with this symptom, but to spare patients a full-blown bout of PEM in the clinic, Moreau’s team figured out that they could use a therapeutic massager—an inflatable arm cuff that exerts gentle pulsating compressions—to induce a milder form of PEM, as evidenced by headaches, muscle pain, and profound fatigue that patients reported in later questionnaires.
Starting with 11 severely affected, housebound ME/CFS patients, the team drew plasma samples before and 90 minutes after this challenge and screened for differences in levels of microRNAs. Computational analysis revealed 17 microRNAs whose levels had changed significantly after the test; their response also differed from that of eight age- and sex-matched healthy individuals who had been subjected to the massager but didn’t report any PEM symptoms.
Repeating this analysis in a larger cohort of 32 ME/CFS patients and 17 matched controls, the team discovered the same response patterns for 11 microRNAs. In fact, a machine learning algorithm the researchers trained could correctly diagnose someone with ME/CFS based solely on the change in concentration of these microRNAs after the massage intervention. “We were unable to misdiagnose a [healthy] control as ME/CFS, or inversely, ME/CFS as a control,” Moreau says.
The need for diagnostics and drugs for ME/CFS
There’s an overwhelming need for definitive diagnostic tests for ME/CFS, says Frances Williams, a genomic epidemiologist at King’s College London who wasn’t involved in the research. Diagnosis is currently made by excluding other conditions, which is difficult, time-consuming, and a frustration for patients. The fact that Moreau’s team could replicate their results in a larger cohort is encouraging, but she says she doubts that microRNAs will form a standalone test for ME/CFS, simply because of the genetic and epigenetic complexity of the disease. However, microRNAs “could be helpful in combination with other things,” she says.
Hornig says the test has many strengths in terms of translating it for use in a clinical setting. For one, its focus on free-floating sequences in the blood makes it technologically simpler than a technique used in a previous study that requires extracting microRNAs from inside blood cells. She also praises the team’s PEM-inducing stressor, which reflects the sensitivity of severely affected ME/CFS patients to their sensory environment, but is less taxing than physical exertion “and respectful of the patients’ experience and fears,” she says.
We were unable to misdiagnose a [healthy] control as ME/CFS, or inversely, ME/CFS as a control. —Alain Moreau, University of Montreal and Sainte-Justine University Hospital
Moreau encourages other institutions to replicate the results. The findings will require validation in larger cohorts to ensure the test can diagnose patients with all subtypes of ME/CFS, different stages of the disease, and those from a variety of regions and ethnicities. Hornig adds it’s also important to investigate differences with the results of other studies—for instance, previous work on cellular microRNAs in ME/CFS suggested disparities in how men and women responded to exercise, whereas Moreau’s results found no sex-based differences. She’s also curious about where the microRNAs come from, suspecting immune cells or muscle tissue as possible origins. “This opens a lot of questions.”
Using a different algorithm, Moreau’s team found that they could cluster the patients into four discrete groups based on the precise pattern of their microRNA responses to the PEM challenge. Interestingly, these groups happened to also share clinical features—one group, for instance, had markedly severe symptoms. To Moreau, this indicates that different mechanisms operate in different subsets of the disease, which could help explain why drug trials for ME/CFS patients have so far been largely inconclusive. But he says he hopes to use microRNA data soon to match patients with drugs they’re more likely to respond to. His team suspects, for instance, that the immunomodulating drug rintatolimod, which activates Toll-like receptor 3, might not be effective in patients with high levels of microRNAs that impede the transcription of that receptor. “I [hope] the test will open the door to more . . . precision medicine in the field of ME/CFS,” Moreau says.
To Williams, the major value of the study lies in an analysis Moreau’s team conducted with the microRNA data that untangles the molecular pathways the 11 sequences are involved in.
This revealed that 7 out of the 11 microRNAs were involved in regulating immune functions, which “certainly fits with one arm of the research that suggests that immune activation is very important in leading to chronic fatigue,” she says.
An additional network analysis flagged the key genes each microRNA is associated with and other diseases they’ve been linked to, which included viral infection, sleep disorders, and cognitive impairments. “Using a network approach, you can start to shed light on which cellular processes are important. And then if that ties in with what we know already about the cellular processes in ME/CFS, then that all begins to paint a bit of a picture.”
The findings are relevant in light of the COVID-19 pandemic and the increasing numbers of “long-hauler” patients left with enduring fatigue symptoms, a phenomenon that has many experts concerned that the coronavirus could trigger ME/CFS in a subset of infected people. The pandemic “will bring a huge number of new [ME/CFS] patients, and some of them are relatively young. That will create some devastating impacts for themselves and their families,” Moreau says. “That’s why we need to hurry and hope that we will convince governments and funding agencies to [put more funding into the field].”
E. Nepotchatykh et al., “Profile of circulating microRNAs in myalgic encephalomyelitis and their relation to symptom severity, and disease pathophysiology,” Sci Rep, doi:10.1038/s41598-020-76438-y, 2020.


thescientist--2020-12-01--Book Excerpt from When Brains Dream

Book Excerpt from When Brains Dream

In the last quarter of the twentieth century , two brain imaging techniques were developed that would dramatically change our understanding of how the brain works .
Positron emission tomography ( PET ) and functional magnetic resonance imaging ( fMRI ) have allowed scientists to look at brain activity while people are performing a whole range of mental tasks and create detailed 3-D maps of that brain activity .
Using these new techniques , we have learned which brain areas are “ turned on ” during all sorts of mental activity—from staring at geometric patterns to viewing emotional pictures , @ @ @ @ @ @ @ having out-of-body experiences .
To produce these maps of brain activity , individuals are rolled into the center of a huge doughnut-shaped machine .
Pictures of their brain activity are then taken , first while they ’ re just lying there resting and again while they ’ re doing some task .
If we subtract the activity patterns seen while individuals are resting from the patterns seen when they ’ re performing the task , we get a picture of which brain regions are activated by the task—a map , if you will @ @ @ @ @ @ @ actually perform the task .
The use of fMRI to map brain activity in real time was an amazing breakthrough , and scientists quickly began mapping out dozens of brain functions .
As more and more brain imaging studies were published , it slowly became clear that something strange was happening .
While turning on its own specific set of brain regions , each mental task also turned off other regions .
At first this seemed quite reasonable .
But as time went on , it also became clear that the regions being @ @ @ @ @ @ @ matter what task the participants were performing .
And this made no sense .
Over time , however , Marcus Raichle , along with his colleagues at Washington University in St. Louis , realized what they were seeing .
Scientists had been assuming that the activity pattern seen during quiet rest reflected the activity of a brain not doing anything .
In retrospect , this was obviously a foolish assumption .
Our brains are always thinking about something .
Because of this , the brain areas that turn off whenever we start to @ @ @ @ @ @ @ regions that do whatever the brain does when we ’ re “ not doing anything.
” Together these regions make up the default mode network ( DMN ) , whose discovery has helped us appreciate just how true it is that the brain never rests .
When we look at the brain regions that make up the DMN , we find a sub-network that monitors the environment for important changes , watching out for any danger .
Keeping us safe is probably one function of the DMN .
But we also find a @ @ @ @ @ @ @ and imagine future ones , another that helps us navigate through space , and yet another that helps us interpret the words and actions of others .
And these are the mental functions associated with mind wandering .
Much of mind wandering involves hashing over the events of the day or anticipating and planning future events .
Indeed , such planning has been proposed as a function of mind wandering .
So it ’ s perhaps not surprising that mind wandering is associated with increased activity in the DMN .
This appears to @ @ @ @ @ @ @ .
The DMN is not a static structure , however .
It changes based on what you ’ ve been doing earlier .
Bob and his colleague Dara Manoach looked at how activity in the DMN changed after doing one of Bob ’ s favorite tasks : his finger- tapping task , which we saw in Chapter 5 involves learning to type the sequence 4–1–3–2–4 as quickly and accurately as possible .
Young participants get a lot better in just a couple of minutes of practice , but then they plateau .
A @ @ @ @ @ @ @ doesn ’ t make them any faster , but if they get a night of sleep and then try again , they become 15 to 20 percent faster .
It ’ s another example of sleep-dependent memory evolution .
When Bob and Dara had participants learn the task while having their brains scanned , with periods of quiet rest before and after the training , they found that brain regions involved in performing the task were talking to each other more during the quiet rest after training than during the quiet rest before @ @ @ @ @ @ @ normally measured during such periods of quiet rest , was altered by performing the task .
And more important , the more the DMN was altered , the more improvement participants showed the next day .
It was as if this new DMN activity was telling the brain what to work on once it fell asleep .
Indeed , much of the DMN is also activated during REM sleep , suggesting that the term daydreaming may be more appropriate than we thought .
William Domhoff and his colleague Kieran Fox have gone so @ @ @ @ @ @ @ or at least REM sleep dreaming , constitutes a brain state of “ enhanced mind wandering.
” More recently , Domhoff has proposed that the neural substrate of dreaming lies within the DMN .
When you put it all together , you get an exciting extension of our NEXTUP model .
Whenever the waking brain doesn ’ t have to focus on some specific task , it activates the default mode network , identifies ongoing , incomplete mental processes—those needing further attention—and tries to imagine ways to complete them .
Sometimes it completes @ @ @ @ @ @ @ , making decisions without our ever realizing it .
But at other times it sets the problem aside after tagging it for later sleep-dependent processing , either within or without dreaming .
Several dream theories have suggested something like this—that dreaming helps us address areas of concern in our lives .
The DRM might provide the mechanism for identifying these concerns , thereby determining what ’ s NEXTUP .
NEXTUP and Dream Function in Different Sleep Stages With this added insight from the DMN , we can return to our question of how @ @ @ @ @ @ @ different sleep stages .
These differences are likely the greatest when looking at sleep onset .
The hypnagogic period is a unique link between pre-sleep mind wandering and early sleep dreaming .
A “ fracture point ” often takes place in sleep-onset mentation , wherein rational waking thoughts—inevitably about waking concerns or incomplete mental processes—shift into hypnagogic dreams .
Perhaps , then , it ’ s not surprising that Silvana Horovitz at the National Institutes of Health outside of Washington , D.C. , has found that the DMN is active throughout the hypnagogic @ @ @ @ @ @ @ increase in brain activity in visual processing regions after sleep onset .
Other features of these dreams give additional support to the idea that these dreams have a unique role in NEXTUP .
Hypnagogic dream reports from the sleep-onset ( N1 ) stage of sleep are dramatically shorter than other nonREM and REM dream reports .
They ’ re often clearly related to the thoughts you were having immediately before falling asleep , frequently evolving smoothly , if unpredictably , from those thoughts .
Hypnagogic dreams are usually less bizarre and much less @ @ @ @ @ @ @ night , and they often lack two features that are almost always present in other dreams ; namely , self- representation and narrative structure .
Much of the time these dreams are just unusual thoughts , or a random geometrical pattern , or a simple picture , like a landscape or a face .
This finding does not feel like fertile ground for the work of NEXTUP .
Instead , these brief hypnagogic dreams appear to extend the DMN ’ s work into the sleep period , identifying and tagging current concerns for @ @ @ @ @ @ @ beginning to identify associated memories for later consideration .
But the very briefness of such dreams suggests that they can do little more than tag these memories , leaving more extensive processing for later in the night .
NEXTUP saves its best work for REM sleep .
Compared to non-REM dreams , REM dreams are longer and more vivid , emotional , and bizarre , and they have more complex narratives .
In addition , when people try to identify the waking sources of the content within these dreams , they report distinctly @ @ @ @ @ @ @ in our lives that we can fully bring back to mind , essentially allowing us to relive the original event .
For example , if you saw flying saucers in a nonREM dream , you might identify its source as a related episodic memory , saying , “ Oh , those flying saucers looked just like the pizza I had for dinner last night.
” In contrast , in a REM dream , you ’ d be more likely to say , “ Oh , they looked just like pizzas ; I love @ @ @ @ @ @ @ semantic memory ( I love pizza ) instead of a specific episodic memory ( I ate pizza last night ) .
This example aligns with how we imagine NEXTUP working in REM sleep as it tries to use the simulated world of the dream to generalize from these memory sources and create a more integrated understanding of their meaning and importance ( Figure 8.5 ) .
By comparison , N2 dreams are shorter and less emotional , bizarre , and vivid .
But perhaps the most telling difference is that the waking sources @ @ @ @ @ @ @ more recent and more episodic—what you had for dinner , what your partner told you at dinner , who washed the dishes , and so on—and do not arise from less-specific “ semantic ” memories such as what you like to eat , what you often talk about with your partner , and which household chores are yours .
Figure 8.5 : The function of NEXTUP by sleep stage Figure 8.5 : The function of NEXTUP by sleep stage The memory sources used in constructing N2 dreams thus lie between the immediate pre-sleep @ @ @ @ @ @ @ loose , associative links to semantic memories seen in REM dreams .
The function of these N2 dreams is probably intermediate as well .
Although REM sleep appears to be seeking weak , often unexpected , remote associations that might be usefully related to memories of unresolved concerns from the day , N2 dreams appear to search for more obviously related episodic memories from the recent past .
Presumably , this logic would hold for all sleep- dependent memory processing , both within and outside of dreaming .
Anna Schapiro , a former @ @ @ @ @ @ @ the University of Pennsylvania , made this argument in a 2017 paper .
She characterized the role of nonREM sleep ( without reference to dreaming ) as “ an opportunity to recap the details of the day ’ s events , providing additional exposure to information that was recently acquired from the world , ” and that of REM sleep as facilitating the “ exploration of cortical networks containing long- term memories , ” a description that matches the definition of NEXTUP as network exploration .
This separation of REM and nonREM functions @ @ @ @ @ @ @ of sleep stages across the night .
Each night begins with N1 , moves to N2 and N3 , and then moves to REM before cycling between N2/N3 and REM for the rest of the night .
As the night progresses , nonREM decreases and REM increases , allowing the brain to seek out weaker and weaker associations and our dreams to become more and more bizarre .
This evolution of dreams across the night can be seen even on a shorter time scale in the hypnagogic period .
In another study from @ @ @ @ @ @ @ arcade game Alpine Racer II , Erin Wamsley found that some dreams had strong , direct relations to the game , featuring unambiguous depictions of the game specifically , or of skiing in general ; other dreams had weaker , more indirect relations to it , containing sensations , locations , or themes related to the game .
When reports were collected at the start of the hypnagogic period , within 15 seconds of sleep onset , dreams were eight times more likely to show direct incorporation of the game than indirect incorporation @ @ @ @ @ @ @ sleep , the rates of occurrence had become the same for both direct and indirect incorporations .
Another group of participants were allowed to sleep for 2 hours before any reports were collected .
After the 2 hours , they were awoken and then allowed to fall back asleep .
They were then awoken again within 2 minutes and their sleep-onset reports collected .
Now the ratio of indirect to direct incorporations was five times higher than for those collected right at the start of the night .
Interestingly , Stuart Fogel at @ @ @ @ @ @ @ participants practice the Nintendo game Grand Slam Tennis before collecting eight sleep-onset dream reports that night .
Overnight improvement seemed to depend on how similar dream incorporations were to the actual game for the first four of these sleep-onset dreams , but not for the last four .
Perhaps only the earlier , more direct incorporations successfully tagged the game memories for NEXTUP .
This all makes sense .
Whether we look at how pre-sleep activities are linked to dreaming in the hypnagogic period or how they ’ re connected to dreaming in @ @ @ @ @ @ @ of the night , dreaming appears to play an important role in how memories are selected and how they subsequently evolve across the night .
Excerpted from When Brains Dream : Exploring the Science and Mystery of Sleep by Antonio Zadra and Robert Stickgold .
Copyright © 2021 by Antonio Zadra and Robert Stickgold .
Available from W.W. Norton & Company .

NEXTUP and the Default Mode Network
In the last quarter of the twentieth century, two brain imaging techniques were developed that would dramatically change our understanding of how the brain works. Positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have allowed scientists to look at brain activity while people are performing a whole range of mental tasks and create detailed 3-D maps of that brain activity. Using these new techniques, we have learned which brain areas are “turned on” during all sorts of mental activity—from staring at geometric patterns to viewing emotional pictures, reading, and memorizing word lists to having out-of-body experiences.
To produce these maps of brain activity, individuals are rolled into the center of a huge doughnut-shaped machine. Pictures of their brain activity are then taken, first while they’re just lying there resting and again while they’re doing some task. If we subtract the activity patterns seen while individuals are resting from the patterns seen when they’re performing the task, we get a picture of which brain regions are activated by the task—a map, if you will, of which parts of the brain actually perform the task. The use of fMRI to map brain activity in real time was an amazing breakthrough, and scientists quickly began mapping out dozens of brain functions.
As more and more brain imaging studies were published, it slowly became clear that something strange was happening. While turning on its own specific set of brain regions, each mental task also turned off other regions. At first this seemed quite reasonable. But as time went on, it also became clear that the regions being turned off were the same, no matter what task the participants were performing. And this made no sense.
Over time, however, Marcus Raichle, along with his colleagues at Washington University in St. Louis, realized what they were seeing. Scientists had been assuming that the activity pattern seen during quiet rest reflected the activity of a brain not doing anything. In retrospect, this was obviously a foolish assumption. Our brains are always thinking about something. Because of this, the brain areas that turn off whenever we start to carry out a mental task are the regions that do whatever the brain does when we’re “not doing anything.” Together these regions make up the default mode network (DMN), whose discovery has helped us appreciate just how true it is that the brain never rests.
When we look at the brain regions that make up the DMN, we find a sub-network that monitors the environment for important changes, watching out for any danger. Keeping us safe is probably one function of the DMN. But we also find a sub-network that helps us recall past events and imagine future ones, another that helps us navigate through space, and yet another that helps us interpret the words and actions of others. And these are the mental functions associated with mind wandering. Much of mind wandering involves hashing over the events of the day or anticipating and planning future events. Indeed, such planning has been proposed as a function of mind wandering. So it’s perhaps not surprising that mind wandering is associated with increased activity in the DMN. This appears to be a second function of the DMN.
The DMN is not a static structure, however. It changes based on what you’ve been doing earlier. Bob and his colleague Dara Manoach looked at how activity in the DMN changed after doing one of Bob’s favorite tasks: his finger- tapping task, which we saw in Chapter 5 involves learning to type the sequence 4–1–3–2–4 as quickly and accurately as possible. Young participants get a lot better in just a couple of minutes of practice, but then they plateau. A period of rest in the same day doesn’t make them any faster, but if they get a night of sleep and then try again, they become 15 to 20 percent faster. It’s another example of sleep-dependent memory evolution.
When Bob and Dara had participants learn the task while having their brains scanned, with periods of quiet rest before and after the training, they found that brain regions involved in performing the task were talking to each other more during the quiet rest after training than during the quiet rest before training. The DMN, which is normally measured during such periods of quiet rest, was altered by performing the task. And more important, the more the DMN was altered, the more improvement participants showed the next day. It was as if this new DMN activity was telling the brain what to work on once it fell asleep.
Indeed, much of the DMN is also activated during REM sleep, suggesting that the term daydreaming may be more appropriate than we thought. William Domhoff and his colleague Kieran Fox have gone so far as to suggest that dreaming, or at least REM sleep dreaming, constitutes a brain state of “enhanced mind wandering.” More recently, Domhoff has proposed that the neural substrate of dreaming lies within the DMN. When you put it all together, you get an exciting extension of our NEXTUP model. Whenever the waking brain doesn’t have to focus on some specific task, it activates the default mode network, identifies ongoing, incomplete mental processes—those needing further attention—and tries to imagine ways to complete them. Sometimes it completes the process shortly after the problem arises, making decisions without our ever realizing it. But at other times it sets the problem aside after tagging it for later sleep-dependent processing, either within or without dreaming. Several dream theories have suggested something like this—that dreaming helps us address areas of concern in our lives. The DRM might provide the mechanism for identifying these concerns, thereby determining what’s NEXTUP.
NEXTUP and Dream Function in Different Sleep Stages
With this added insight from the DMN, we can return to our question of how the function of NEXTUP might vary in different sleep stages. These differences are likely the greatest when looking at sleep onset. The hypnagogic period is a unique link between pre-sleep mind wandering and early sleep dreaming. A “fracture point” often takes place in sleep-onset mentation, wherein rational waking thoughts—inevitably about waking concerns or incomplete mental processes—shift into hypnagogic dreams.
Perhaps, then, it’s not surprising that Silvana Horovitz at the National Institutes of Health outside of Washington, D.C., has found that the DMN is active throughout the hypnagogic period. She also saw a dramatic increase in brain activity in visual processing regions after sleep onset. Other features of these dreams give additional support to the idea that these dreams have a unique role in NEXTUP. Hypnagogic dream reports from the sleep-onset (N1) stage of sleep are dramatically shorter than other nonREM and REM dream reports. They’re often clearly related to the thoughts you were having immediately before falling asleep, frequently evolving smoothly, if unpredictably, from those thoughts. Hypnagogic dreams are usually less bizarre and much less emotional than dreams from later in the night, and they often lack two features that are almost always present in other dreams; namely, self- representation and narrative structure. Much of the time these dreams are just unusual thoughts, or a random geometrical pattern, or a simple picture, like a landscape or a face.
This finding does not feel like fertile ground for the work of NEXTUP. Instead, these brief hypnagogic dreams appear to extend the DMN’s work into the sleep period, identifying and tagging current concerns for further sleep-dependent processing, and perhaps then beginning to identify associated memories for later consideration. But the very briefness of such dreams suggests that they can do little more than tag these memories, leaving more extensive processing for later in the night.
NEXTUP saves its best work for REM sleep. Compared to non-REM dreams, REM dreams are longer and more vivid, emotional, and bizarre, and they have more complex narratives. In addition, when people try to identify the waking sources of the content within these dreams, they report distinctly fewer episodic memory sources—memories of actual events in our lives that we can fully bring back to mind, essentially allowing us to relive the original event. For example, if you saw flying saucers in a nonREM dream, you might identify its source as a related episodic memory, saying, “Oh, those flying saucers looked just like the pizza I had for dinner last night.” In contrast, in a REM dream, you’d be more likely to say, “Oh, they looked just like pizzas; I love pizza,” thereby identifying a general semantic memory (I love pizza) instead of a specific episodic memory (I ate pizza last night). This example aligns with how we imagine NEXTUP working in REM sleep as it tries to use the simulated world of the dream to generalize from these memory sources and create a more integrated understanding of their meaning and importance (Figure 8.5).
By comparison, N2 dreams are shorter and less emotional, bizarre, and vivid. But perhaps the most telling difference is that the waking sources of N2 dream content tend to be more recent and more episodic—what you had for dinner, what your partner told you at dinner, who washed the dishes, and so on—and do not arise from less-specific “semantic” memories such as what you like to eat, what you often talk about with your partner, and which household chores are yours.


thescientist--2020-12-01--Stress-Induced Chromosome Changes Protect Flies’ Aging Brains

ABOVE : When exposed to oxidative stress , Drosophila brain cells ( glia shown above ) can develop more than two sets of chromosomes—a state that may protect the brain from damage .
NANDAKUMAR ET AL.
, 2020 The paper S. Nandakumar et al.
, “ Polyploidy in the adult Drosophila brain , ” eLife , 9 : e54385 , 2020 .
Over a lifetime , mature brain cells face a gauntlet of oxidative stress , DNA damage , and other dangers that can lead to neurodegeneration .
In response , Drosophila ’ s brain cells acquire additional sets of @ @ @ @ @ @ @ chromosome-packed cells appear to be more resistant to cell death , suggesting polyploidy plays a protective role in the fly brain , University of Michigan molecular cell biologist Shyama Nandakumar and colleagues found .
Although the researchers knew that cell damage can lead to the accumulation of additional sets of chromosomes in some cases , such as in the human liver and in the brains of patients with Alzheimer ’ s disease , not much was known about the mechanism behind it or what its function could be .
To study polyploidy , @ @ @ @ @ @ @ in Laura Buttitta ’ s lab used a brain dissection technique developed by teammate Olga Grushko , along with highly sensitive flow cytometry .
When aging fly brains were exposed to oxidative stress , cells in certain areas such as the optic lobes were more likely to obtain extra chromosome sets than cells in other spots .
The cells acquired the extra sets after reverting back into the cell cycle .
And notably , as the number of polyploid cells in an area grew , the rate of local cell death declined .
@ @ @ @ @ @ @ Nandakumar notes .
“ It took us a while to convince ourselves that what we were observing was actually true.
” The study “ fits with the emerging theme that polyploidy emerges as a response to tissue stress , ” Donald Fox , a genomicist at Duke University Medical Center who was not involved with the research , writes in an email to The Scientist .
“ And the fact that these polyploid cells are in the brain raises really interesting questions about the role of polyploidy in aged/stressed neural circuits , and @ @ @ @ @ @ @

ABOVE: When exposed to oxidative stress, Drosophila brain cells (glia shown above) can develop more than two sets of chromosomes—a state that may protect the brain from damage.
NANDAKUMAR ET AL., 2020
EDITOR’S CHOICE IN CELL BIOLOGY
The paper
S. Nandakumar et al., “Polyploidy in the adult Drosophila brain,” eLife, 9:e54385, 2020.
Over a lifetime, mature brain cells face a gauntlet of oxidative stress, DNA damage, and other dangers that can lead to neurodegeneration. In response, Drosophila’s brain cells acquire additional sets of chromosomes beyond the normal two. These chromosome-packed cells appear to be more resistant to cell death, suggesting polyploidy plays a protective role in the fly brain, University of Michigan molecular cell biologist Shyama Nandakumar and colleagues found.
Although the researchers knew that cell damage can lead to the accumulation of additional sets of chromosomes in some cases, such as in the human liver and in the brains of patients with Alzheimer’s disease, not much was known about the mechanism behind it or what its function could be.
To study polyploidy, Nandakumar and the rest of the team in Laura Buttitta’s lab used a brain dissection technique developed by teammate Olga Grushko, along with highly sensitive flow cytometry. When aging fly brains were exposed to oxidative stress, cells in certain areas such as the optic lobes were more likely to obtain extra chromosome sets than cells in other spots. The cells acquired the extra sets after reverting back into the cell cycle. And notably, as the number of polyploid cells in an area grew, the rate of local cell death declined.
The findings came as a surprise, Nandakumar notes. “It took us a while to convince ourselves that what we were observing was actually true.”
The study “fits with the emerging theme that polyploidy emerges as a response to tissue stress,” Donald Fox, a genomicist at Duke University Medical Center who was not involved with the research, writes in an email to The Scientist. “And the fact that these polyploid cells are in the brain raises really interesting questions about the role of polyploidy in aged/stressed neural circuits, and how this might impact behavior.”


thescientist--2020-12-01--Infographic: A Cellular Defense Against Ebola Virus

Overexpressing the transcription factor CIITA in cultured human cells turns on a gene called CD74 , producing the protein p41 @ @ @ @ @ proteases in the endosome ( left ) .
When the cells are exposed to an @ @ @ @ @ cathepsins are unable to cleave off the virus ’ s glycoprotein , stopping it from @ @ @ @ @ thus trapping it inside the endosome .
Later , the virus is likely brought to @ @ @ @ @ pictured ) .
In a cell where CD74 is not overexpressed ( right ) , @ @ @ @ @ s glycoproteins , enabling it to fuse with the side of the endosome and release @ @ @ @ @ cytosol .

Overexpressing the transcription factor CIITA in cultured human cells turns on a gene called CD74, producing the protein p41, which binds to cathepsin proteases in the endosome (left). When the cells are exposed to an Ebola-mimicking virus, the p41-bound cathepsins are unable to cleave off the virus’s glycoprotein, stopping it from fusing with the membrane and thus trapping it inside the endosome. Later, the virus is likely brought to lysosomes and destroyed (not pictured). In a cell where CD74 is not overexpressed (right), cathepsins cleave the virus’s glycoproteins, enabling it to fuse with the side of the endosome and release its genetic material into the cytosol.
© KIMBERLY BATTISTA
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thescientist--2020-12-01--Pharma Looks to Outer Space to Boost Drug R&D

On a cool December afternoon in 2018 , on a viewing platform at the Kennedy Space Center at Cape Canaveral in Florida , Jordan Greco watched his research project leave planet Earth .
As chief scientific officer of the Connecticut-based biotech LambdaVision , he had spent years developing a protein-based artificial retina to treat patients blinded or severely visually impaired by retinal degenerative diseases .
At 1:15 PM that day , a Falcon 9 launch rocket lit up the sky as it blasted the SpaceX Dragon cargo spacecraft toward the International Space Station ( ISS ) , carrying onboard the @ @ @ @ @ @ @ artificial retina .
“ It didn ’ t really hit me until we were sitting on the balcony at the NASA complex and seeing that rocket off in the distance , ” Greco recalls .
“ Our protein , our experiment that we ’ ve been working on for years , is on that thing.
” Once the SpaceX capsule docked at the ISS , an astronaut in the station ’ s near-weightless environment was to initiate an experiment that Greco hoped would help him understand how to improve the artificial retina ’ @ @ @ @ @ @ @ he and his colleagues had been making progress with the retina—essentially a small film covered in hundreds of layers of the microbial light-activated protein bacteriorhodopsin—but were struggling to produce consistently high-quality retinas .
The team suspected that the bacteriorhodopsin proteins should be oriented the same way with respect to one another for the artificial retina to create robust electrical signals and communicate effectively with patients ’ neurons .
But the team ’ s process of dipping the film into protein solutions seemed to generate somewhat disordered protein arrangements .
Greco suspected that gravity @ @ @ @ @ @ @ , by causing the proteins in the solution to undergo sedimentation , he explains .
To test that hypothesis , he and his colleagues sent materials to the ISS to repeat part of the experiment in microgravity .
Scientific research in space has thrived over the past decade , but it ’ s only recently that the pharmaceutical and biotech sector has started getting in on the action , pursuing new ways to study drugs and other medical treatments .
Pharma giants including Merck , AstraZeneca , Eli Lilly , and Sanofi , @ @ @ @ @ @ @ have all sent experiments to the ISS to reap the unique benefits of microgravity .
Of the 150 or so life science research projects supported in the 2019-2020 fiscal year by the Center for the Advancement of Science in Space ( CASIS ) —a nonprofit that collaborates with NASA to manage the US National Laboratory on the ISS—more than a third have been led by pharmaceutical and biotechnology companies , says CASIS ’ s interim chief scientist , Mike Roberts .
Such endeavors could one day help improve astronaut health and equip humanity @ @ @ @ @ @ @ their primary aim is to develop or improve drugs for people on Earth .
That ’ s certainly the hope of Greco and his colleagues , who found out a few months after that December afternoon that , as they ’ d hypothesized , the proteins layered in space appeared to have more-orderly arrangements—an improvement that could benefit the artificial retina ’ s function .
Studies such as these have yet to yield new blockbuster drugs or even significant improvements to existing ones .
Research in space is slow , and the costs @ @ @ @ @ @ @ through NASA , and many rely on additional financial support through federal grants , spurring a new kind of space race—one aiming to prove that such projects are profitable enough for the private sector to fund on their own .
“ Overcoming that 1G gravitational pull to get rockets up to low Earth orbit or beyond is expensive still , ” says Roberts .
But even so , “ we ’ ve seen a significant uptick in interest ” in conducting experiments in space .
While microgravity can be achieved for a few @ @ @ @ @ @ @ of a parabolic flight , or simulated imperfectly in bioreactors on Earth , the best way to conduct experiments under sustained microgravity is to go to the ISS .
The station orbits approximately 400 km from the planet ’ s surface and is close enough to Earth to experience about 90 percent of its gravitational pull , but astronauts aboard the station feel nearly weightless because it ’ s in constant free fall around the planet .
The resulting microgravity conditions in this setting influence scientific experiments in many ways that appeal to @ @ @ @ @ @ @ currents in fluids , for instance , and hardly any sedimentation—conditions advantageous not only for LambdaVision ’ s layering procedure but also for processes such as protein crystallization , whereby proteins form a regular array .
Under near weightlessness , “ you get a [ higher-quality ] crystal than [ what you ’ d get through ] the crystallization process on Earth , ” making certain proteins easier to study and more attractive as drugs , explains Marlise dos Santos , an aerospace pharmacy specialist at InnovaSpace , a UK-based think tank that @ @ @ @ @ @ @ other activities related to extreme environments .
Paul Reichert , a research scientist at Schering-Plough and at Merck after their merger , was one of the first in the pharmaceutical industry to recognize the value of near weightlessness for protein crystallization .
In the 1990s , before the ISS was operational , he collaborated with NASA to send interferon alfa-2b , the active ingredient in the company ’ s antiviral and cancer drug intron A , into low Earth orbit on the Space Shuttle to see if it would crystallize in space .
@ @ @ @ @ @ @ to Earth , Reichert noticed that the protein had turned into small crystals with perfectly uniform size—the kind that would be ideal for drug delivery .
Although the crystallized interferon alfa-2b was never commercialized , Reichert has conducted similar experiments on the ISS with the monoclonal antibody pembrolizumab , the key ingredient in Merck ’ s popular oncology drug Keytruda .
Because antibodies aren ’ t very soluble under standard conditions , treatments such as Keytruda tend to form viscous solutions at high concentrations and need to be delivered in burdensome , lengthy @ @ @ @ @ @ @ pembrolizumab took the form of a compact crystalline suspension , however , it could be deliverable as an injection , Reichert explains .
In his most recent experiment , published in npj Microgravity , he and his colleagues found that cooling pembrolizumab on the ISS yielded “ a uniform population of particles [ that ] actually gave a better injectability profile than the heterogeneous population of crystals that we got on Earth , ” Reichert says .
Eli Lilly has also sent its products to the ISS to be crystallized , in this @ @ @ @ @ @ @ structurally using analytical techniques such as X-ray diffraction .
The company has also flown mice to the ISS to test an experimental drug that boosts muscle growth .
Under microgravity , the loss of physical strain on bone and muscle accelerates the natural onset of common musculo-skeletal diseases in rodents , making them ideal models of such human conditions , explains Jeremy Hinds , a senior research scientist at Lilly .
In addition , Hinds is studying whether near weightlessness affects the process of freeze-drying materials , a common step in drug distribution @ @ @ @ @ @ @ positive outcomes on the physical properties and resulting drug product performance , ” he explains in an email to The Scientist .
CASIS , which selects the research projects that go to the US national lab on the ISS and provides companies with logistical support , is also working with a number of smaller companies studying everything from treatments for rare diseases to medical devices .
One such company is MIT spinout MakerHealth , which has spent nearly a decade creating a device that can produce a number of personalized pharmaceuticals on demand @ @ @ @ @ @ @ to carry the device ’ s mechanical reactors to the ISS , where they ’ ll produce some simple compounds in space .
Engineer Jose Gomez-Marquez of MIT ’ s Little Devices Lab who helped develop the device says the experiment could not only show that it ’ s possible to make drugs in space—a prerequisite for humanity ’ s future ventures into outer space—but also help his team understand the typical gravitational constraints on the device ’ s function and how they can improve it further : “ It ’ s a @ @ @ @ @ @ @ development in space is well underway , progress has been slow , says Reichert .
“ We ’ re still in the infancy of doing this kind of work.
” Many of the challenges are logistical .
Only six astronauts are stationed on the ISS ; their time for experimental work is limited , and basic laboratory tasks such as pipetting and moving reagents around are challenging in microgravity .
That ’ s in part why pharma entities and biotechs typically contract companies that specialize in automating scientific experiments and packing them into @ @ @ @ @ @ @ astronauts simply need to activate to have the experiments conduct themselves .
LambdaVision , for instance , worked with the microgravity research company Space Tango to turn their 2018 layering experiment and a more recent study of how bacteriorhodopsin functions under microgravity into miniature labs .
The downside of such arrangements is that researchers are often limited to one experiment at a time , and results can be a long time coming , Reichert says .
“ The astronaut just activates the experiment that sits there for two to three weeks , and @ @ @ @ @ @ @ SpaceX module a month later , and then we first see what the results are.
” Doing research in space comes with a host of other challenges as well , such as organizing simultaneous control experiments on the ground , and adapting research methods to the nonstandard laboratory equipment on the ISS .
For Paul Jaminet , founder and president of the Massachusetts-based oncology startup Angiex , which undertook an experiment on the ISS in 2018 , the endeavor “ turned out to be significantly more work than we thought it would be.
@ @ @ @ @ @ @ that endothelial cells ’ response to one of the company ’ s cancer drugs changed over the course of their time on the ISS , and that the cells generally grew and behaved differently in space than on Earth .
In particular , the cells displayed unique characteristics that Angiex founder and head of research Shou-Ching Jaminet tells The Scientist could mimic certain features of cardiovascular conditions afflicting humans on Earth .
The husband-and-wife team is interested in continuing that line of research , but due to the amount of labor , time @ @ @ @ @ @ @ s taken a backseat to the company ’ s work on drug candidates and other projects that are further along .
The biggest challenge is indeed the sheer cost of space experiments .
Getting a single experiment to and back from the ISS can cost some $ 7.5 million , according to CASIS .
Currently , flights to and from the ISS and astronaut time are covered by NASA , and the hardware and research costs of such experiments are sometimes partially funded through federal grants .
Some smaller companies , including MakerHealth @ @ @ @ @ @ @ their endeavors with six-figure microgravity research grants awarded by a partnership between CASIS and Boeing through the Boston-based business accelerator program MassChallenge .
These generous subsidies and incentives are part of a long-term effort by NASA to coax private companies to recognize the value of R & D in space .
In addition to bringing benefits to people on Earth , companies ideally would ultimately pay for their own research and help the US National Laboratory on the ISS become self-supporting .
However , a 2018 report by NASA ’ s Office of @ @ @ @ @ @ @ to recruit enough commercial users to the space station , and “ question [ ed ] whether a sufficient business case exists under which private companies will be able to develop a self-sustaining and profit-making business [ on the ISS ] .
” That ’ s broadly in line with an analysis by Nicholas Vonortas , a microeconomist at George Washington University who received a NASA grant in 2015 to conduct a cost-benefit analysis of using protein crystallization on the ISS to get better structural information about peptides .
Through economic models that @ @ @ @ @ @ @ among other factors , Vonortas found that the potential financial benefits of crystallizing proteins on the ISS will likely not be enough to outweigh the costs if they ’ re shouldered by the private sector alone .
“ All of this together , when you do the calculations , brings a result that is not as attractive as the scientists think , ” he tells The Scientist .
Costs may decrease over time as travel to and from the ISS becomes more frequent , Vonortas says .
Entrepreneur Elon Musk , for instance @ @ @ @ @ @ @ a more regular service to the station than there is currently—an idea not without its skeptics .
But a significant source of uncertainty is that the ISS , after more than 110,000 laps around the planet , may be nearing the end of its life .
NASA and other participating space agencies plan to continue operations through 2024 , but what happens after that is unclear .
Instead , pharma research of the future may take advantage of independent initiatives developed by a growing community of companies working to make conducting experiments in @ @ @ @ @ @ @ more accessible for life scientists .
For instance , the Israeli-Swiss company SpacePharma , founded in 2011 , develops autonomous research stations that can be operated from the ground .
“ Until now , unless you were part of NASA or some space agency , it was very difficult to initiate and perform such experiments ” in space , says Guy Samburski , SpacePharma ’ s director of chemical and pharmaceutical applications .
The company recently launched the satellite DIDO 3 , carrying four experiments by Italian and Israeli researchers on board , @ @ @ @ @ @ @ .
The satellite won ’ t return to Earth , but is currently recording and transmitting research data back to scientists on the ground .
SpacePharma ’ s next launch will involve a larger system that will eventually return home so researchers can physically collect materials and results .
British spaceflight company Virgin Galactic and Jeff Bezos ’ s space company Blue Origin have also begun to offer such opportunities to scientists .
The emergence of an entire ecosystem devoted to bringing pharmaceutical research into space has opened up new possibilities to those @ @ @ @ @ @ @ have space labs in the sky that can operate autonomously and discover new lifesaving medications for us ?
” Gomez-Marquez asks .
And while the return on investment currently isn ’ t ideal , many believe such research will become profitable over time .
Eventually , “ [ it ] might be financially beneficial for a company to have things produced or manufactured in space , ” in the same way we outsource drug production to different countries on Earth , suggests Thais Russomano , a space medicine expert and cofounder and CEO @ @ @ @ @ @ @ is already considering launching production of its artificial retina in space , encouraged by the potential superiority of space-made products .
Whether such visions become reality , only time will tell .
“ If you ’ re asking me whether this is possible—absolutely , this is technically possible , ” Vonortas says .
But “ the economics is a problem .
”

ABOVE: MODIFIED FROM: © ISTOCK.COM, VIDOSLAVA; ANASTASIA USENKO
On a cool December afternoon in 2018, on a viewing platform at the Kennedy Space Center at Cape Canaveral in Florida, Jordan Greco watched his research project leave planet Earth. As chief scientific officer of the Connecticut-based biotech LambdaVision, he had spent years developing a protein-based artificial retina to treat patients blinded or severely visually impaired by retinal degenerative diseases. At 1:15 PM that day, a Falcon 9 launch rocket lit up the sky as it blasted the SpaceX Dragon cargo spacecraft toward the International Space Station (ISS), carrying onboard the proteins that make up Greco’s artificial retina.
“It didn’t really hit me until we were sitting on the balcony at the NASA complex and seeing that rocket off in the distance,” Greco recalls. “Our protein, our experiment that we’ve been working on for years, is on that thing.”
Once the SpaceX capsule docked at the ISS, an astronaut in the station’s near-weightless environment was to initiate an experiment that Greco hoped would help him understand how to improve the artificial retina’s function. Back on Earth, he and his colleagues had been making progress with the retina—essentially a small film covered in hundreds of layers of the microbial light-activated protein bacteriorhodopsin—but were struggling to produce consistently high-quality retinas.
The team suspected that the bacteriorhodopsin proteins should be oriented the same way with respect to one another for the artificial retina to create robust electrical signals and communicate effectively with patients’ neurons. But the team’s process of dipping the film into protein solutions seemed to generate somewhat disordered protein arrangements. Greco suspected that gravity was negatively affecting the layering process—for instance, by causing the proteins in the solution to undergo sedimentation, he explains. To test that hypothesis, he and his colleagues sent materials to the ISS to repeat part of the experiment in microgravity.
Microgravity influences scientific experiments in many ways that appeal to drug developers.
Scientific research in space has thrived over the past decade, but it’s only recently that the pharmaceutical and biotech sector has started getting in on the action, pursuing new ways to study drugs and other medical treatments. Pharma giants including Merck, AstraZeneca, Eli Lilly, and Sanofi, along with dozens of smaller companies, have all sent experiments to the ISS to reap the unique benefits of microgravity. Of the 150 or so life science research projects supported in the 2019-2020 fiscal year by the Center for the Advancement of Science in Space (CASIS)—a nonprofit that collaborates with NASA to manage the US National Laboratory on the ISS—more than a third have been led by pharmaceutical and biotechnology companies, says CASIS’s interim chief scientist, Mike Roberts.
Such endeavors could one day help improve astronaut health and equip humanity for longer ventures into space, but their primary aim is to develop or improve drugs for people on Earth. That’s certainly the hope of Greco and his colleagues, who found out a few months after that December afternoon that, as they’d hypothesized, the proteins layered in space appeared to have more-orderly arrangements—an improvement that could benefit the artificial retina’s function.
Studies such as these have yet to yield new blockbuster drugs or even significant improvements to existing ones. Research in space is slow, and the costs are sky-high. All projects are subsidized through NASA, and many rely on additional financial support through federal grants, spurring a new kind of space race—one aiming to prove that such projects are profitable enough for the private sector to fund on their own. “Overcoming that 1G gravitational pull to get rockets up to low Earth orbit or beyond is expensive still,” says Roberts. But even so, “we’ve seen a significant uptick in interest” in conducting experiments in space.
The benefits of microgravity
While microgravity can be achieved for a few moments on an aircraft rounding the top of a parabolic flight, or simulated imperfectly in bioreactors on Earth, the best way to conduct experiments under sustained microgravity is to go to the ISS. The station orbits approximately 400 km from the planet’s surface and is close enough to Earth to experience about 90 percent of its gravitational pull, but astronauts aboard the station feel nearly weightless because it’s in constant free fall around the planet.
The resulting microgravity conditions in this setting influence scientific experiments in many ways that appeal to drug developers. There are minimal convection currents in fluids, for instance, and hardly any sedimentation—conditions advantageous not only for LambdaVision’s layering procedure but also for processes such as protein crystallization, whereby proteins form a regular array. Under near weightlessness, “you get a [higher-quality] crystal than [what you’d get through] the crystallization process on Earth,” making certain proteins easier to study and more attractive as drugs, explains Marlise dos Santos, an aerospace pharmacy specialist at InnovaSpace, a UK-based think tank that promotes life science in space, among other activities related to extreme environments.
Paul Reichert, a research scientist at Schering-Plough and at Merck after their merger, was one of the first in the pharmaceutical industry to recognize the value of near weightlessness for protein crystallization. In the 1990s, before the ISS was operational, he collaborated with NASA to send interferon alfa-2b, the active ingredient in the company’s antiviral and cancer drug intron A, into low Earth orbit on the Space Shuttle to see if it would crystallize in space. Upon studying the product that was returned to Earth, Reichert noticed that the protein had turned into small crystals with perfectly uniform size—the kind that would be ideal for drug delivery.
Although the crystallized interferon alfa-2b was never commercialized, Reichert has conducted similar experiments on the ISS with the monoclonal antibody pembrolizumab, the key ingredient in Merck’s popular oncology drug Keytruda. Because antibodies aren’t very soluble under standard conditions, treatments such as Keytruda tend to form viscous solutions at high concentrations and need to be delivered in burdensome, lengthy, and regular intravenous infusions. If pembrolizumab took the form of a compact crystalline suspension, however, it could be deliverable as an injection, Reichert explains. In his most recent experiment, published in npj Microgravity, he and his colleagues found that cooling pembrolizumab on the ISS yielded “a uniform population of particles [that] actually gave a better injectability profile than the heterogeneous population of crystals that we got on Earth,” Reichert says.
Eli Lilly has also sent its products to the ISS to be crystallized, in this case to make them easier to study structurally using analytical techniques such as X-ray diffraction. The company has also flown mice to the ISS to test an experimental drug that boosts muscle growth. Under microgravity, the loss of physical
strain on bone and muscle accelerates the natural onset of common musculo-skeletal diseases in rodents, making them ideal models of such human conditions, explains Jeremy Hinds, a senior research scientist at Lilly. In addition, Hinds is studying whether near weightlessness affects the process of freeze-drying materials, a common step in drug distribution and storage. Microgravity “could have positive outcomes on the physical properties and resulting drug product performance,” he explains in an email to The Scientist.
CASIS, which selects the research projects that go to the US national lab on the ISS and provides companies with logistical support, is also working with a number of smaller companies studying everything from treatments for rare diseases to medical devices. One such company is MIT spinout MakerHealth, which has spent nearly a decade creating a device that can produce a number of personalized pharmaceuticals on demand. A mission is slated for 2021 to carry the device’s mechanical reactors to the ISS, where they’ll produce some simple compounds in space. Engineer Jose Gomez-Marquez of MIT’s Little Devices Lab who helped develop the device says the experiment could not only show that it’s possible to make drugs in space—a prerequisite for humanity’s future ventures into outer space—but also help his team understand the typical gravitational constraints on the device’s function and how they can improve it further: “It’s a fundamental physics question.”
EXTRATERRESTRIAL LAB: The Destiny Lab on the International Space Station allows researchers to carry out experiments in microgravity. COURTESY OF NASA
Challenges in space research
While research and development in space is well underway, progress has been slow, says Reichert. “We’re still in the infancy of doing this kind of work.”
Many of the challenges are logistical. Only six astronauts are stationed on the ISS; their time for experimental work is limited, and basic laboratory tasks such as pipetting and moving reagents around are challenging in microgravity. That’s in part why pharma entities and biotechs typically contract companies that specialize in automating scientific experiments and packing them into flight-ready “cube labs,” which astronauts simply need to activate to have the experiments conduct themselves. LambdaVision, for instance, worked with the microgravity research company Space Tango to turn their 2018 layering experiment and a more recent study of how bacteriorhodopsin functions under microgravity into miniature labs.
The downside of such arrangements is that researchers are often limited to one experiment at a time, and results can be a long time coming, Reichert says. “The astronaut just activates the experiment that sits there for two to three weeks, and then it comes back on a Dragon SpaceX module a month later, and then we first see what the results are.”
Doing research in space comes with a host of other challenges as well, such as organizing simultaneous control experiments on the ground, and adapting research methods to the nonstandard laboratory equipment on the ISS. For Paul Jaminet, founder and president of the Massachusetts-based oncology startup Angiex, which undertook an experiment on the ISS in 2018, the endeavor “turned out to be significantly more work than we thought it would be.” The company’s experiment showed that endothelial cells’ response to one of the company’s cancer drugs changed over the course of their time on the ISS, and that the cells generally grew and behaved differently in space than on Earth. In particular, the cells displayed unique characteristics that Angiex founder and head of research Shou-Ching Jaminet tells The Scientist could mimic certain features of cardiovascular conditions afflicting humans on Earth. The husband-and-wife team is interested in continuing that line of research, but due to the amount of labor, time, and money involved, it’s taken a backseat to the company’s work on drug candidates and other projects that are further along.
Researchers are often limited to one experiment at a time, and results can be a long time coming.
The biggest challenge is indeed the sheer cost of space experiments. Getting a single experiment to and back from the ISS can cost some $7.5 million, according to CASIS. Currently, flights to and from the ISS and astronaut time are covered by NASA, and the hardware and research costs of such experiments are sometimes partially funded through federal grants. Some smaller companies, including MakerHealth, Lambda-Vision, and Angiex, financed their endeavors with six-figure microgravity research grants awarded by a partnership between CASIS and Boeing through the Boston-based business accelerator program MassChallenge.
These generous subsidies and incentives are part of a long-term effort by NASA to coax private companies to recognize the value of R&D in space. In addition to bringing benefits to people on Earth, companies ideally would ultimately pay for their own research and help the US National Laboratory on the ISS become self-supporting. However, a 2018 report by NASA’s Office of the Inspector General criticized CASIS for failing to recruit enough commercial users to the space station, and “question[ed] whether a sufficient business case exists under which private companies will be able to develop a self-sustaining and profit-making business [on the ISS].”
That’s broadly in line with an analysis by Nicholas Vonortas, a microeconomist at George Washington University who received a NASA grant in 2015 to conduct a cost-benefit analysis of using protein crystallization on the ISS to get better structural information about peptides. Through economic models that considered the risk of experiments failing, among other factors, Vonortas found that the potential financial benefits of crystallizing proteins on the ISS will likely not be enough to outweigh the costs if they’re shouldered by the private sector alone. “All of this together, when you do the calculations, brings a result that is not as attractive as the scientists think,” he tells The Scientist.
Space pharmacy ahead?
Costs may decrease over time as travel to and from the ISS becomes more frequent, Vonortas says. Entrepreneur Elon Musk, for instance, has said he wants to establish a more regular service to the station than there is currently—an idea not without its skeptics. But a significant source of uncertainty is that the ISS, after more than 110,000 laps around the planet, may be nearing the end of its life. NASA and other participating space agencies plan to continue operations through 2024, but what happens after that is unclear.
Instead, pharma research of the future may take advantage of independent initiatives developed by a growing community of companies working to make conducting experiments in sustained microgravity cheaper, faster, and more accessible for life scientists. For instance, the Israeli-Swiss company SpacePharma, founded in 2011, develops autonomous research stations that can be operated from the ground. “Until now, unless you were part of NASA or some space agency, it was very difficult to initiate and perform such experiments” in space, says Guy Samburski, SpacePharma’s director of chemical and pharmaceutical applications.
The company recently launched the satellite DIDO 3, carrying four experiments by Italian and Israeli researchers on board, all packed into a milk carton–size box. The satellite won’t return to Earth, but is currently recording and transmitting research data back to scientists on the ground. SpacePharma’s next launch will involve a larger system that will eventually return home so researchers can physically collect materials and results. British spaceflight company Virgin Galactic and Jeff Bezos’s space company Blue Origin have also begun to offer such opportunities to scientists.
The emergence of an entire ecosystem devoted to bringing pharmaceutical research into space has opened up new possibilities to those in the industry. “Could we have space labs in the sky that can operate autonomously and discover new lifesaving medications for us?” Gomez-Marquez asks. And while the return on investment currently isn’t ideal, many believe such research will become profitable over time. Eventually, “[it] might be financially beneficial for a company to have things produced or manufactured in space,” in the same way we outsource drug production to different countries on Earth, suggests Thais Russomano, a space medicine expert and cofounder and CEO of InnovaSpace. In fact, LambdaVision is already considering launching production of its artificial retina in space, encouraged by the potential superiority of space-made products.
Whether such visions become reality, only time will tell. “If you’re asking me whether this is possible—absolutely, this is technically possible,” Vonortas says. But “the economics is a problem.”