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How climate change fueled Melissa’s record-breaking rampage
New York will fight ruling requiring state to speed up climate regs
Judge rejects lawsuit over ‘certified climate neutral’ snack bars
California starts looking for deeper emissions cuts
EV sales look promising later this decade, analyst says
Tokyo metropolitan government issues climate resilience bond
Ex-Pimco executive plans Europe’s first catastrophe-bond ETF
Vietnam’s tourist sites submerged as record rainfall causes major flooding
Study: Citing climate, some young Americans say they don’t want children
This is your brain without sleep
Nearly everyone has experienced it: After a night of poor sleep, you don’t feel as alert as you should. Your brain might seem foggy, and your mind drifts off when you should be paying attention.
A new study from MIT reveals what happens inside the brain as these momentary failures of attention occur. The scientists found that during these lapses, a wave of cerebrospinal fluid (CSF) flows out of the brain — a process that typically occurs during sleep and helps to wash away waste products that have built up during the day. This flushing is believed to be necessary for maintaining a healthy, normally functioning brain.
When a person is sleep-deprived, it appears that their body attempts to catch up on this cleansing process by initiating pulses of CSF flow. However, this comes at a cost of dramatically impaired attention.
“If you don’t sleep, the CSF waves start to intrude into wakefulness where normally you wouldn’t see them. However, they come with an attentional tradeoff, where attention fails during the moments that you have this wave of fluid flow,” says Laura Lewis, the Athinoula A. Martinos Associate Professor of Electrical Engineering and Computer Science, a member of MIT’s Institute for Medical Engineering and Science and the Research Laboratory of Electronics, and an associate member of the Picower Institute for Learning and Memory.
Lewis is the senior author of the study, which appears today in Nature Neuroscience. MIT visiting graduate student Zinong Yang is the lead author of the paper.
Flushing the brain
Although sleep is a critical biological process, it’s not known exactly why it is so important. It appears to be essential for maintaining alertness, and it has been well-documented that sleep deprivation leads to impairments of attention and other cognitive functions.
During sleep, the cerebrospinal fluid that cushions the brain helps to remove waste that has built up during the day. In a 2019 study, Lewis and colleagues showed that CSF flow during sleep follows a rhythmic pattern in and out of the brain, and that these flows are linked to changes in brain waves during sleep.
That finding led Lewis to wonder what might happen to CSF flow after sleep deprivation. To explore that question, she and her colleagues recruited 26 volunteers who were tested twice — once following a night of sleep deprivation in the lab, and once when they were well-rested.
In the morning, the researchers monitored several different measures of brain and body function as the participants performed a task that is commonly used to evaluate the effects of sleep deprivation.
During the task, each participant wore an electroencephalogram (EEG) cap that could record brain waves while they were also in a functional magnetic resonance imaging (fMRI) scanner. The researchers used a modified version of fMRI that allowed them to measure not only blood oxygenation in the brain, but also the flow of CSF in and out of the brain. They also measured each subject’s heart rate, breathing rate, and pupil diameter.
The participants performed two attentional tasks while in the fMRI scanner, one visual and one auditory. For the visual task, they had to look at a screen that had a fixed cross. At random intervals, the cross would turn into a square, and the participants were told to press a button whenever they saw this happen. For the auditory task, they would hear a beep instead of seeing a visual transformation.
Sleep-deprived participants performed much worse than well-rested participants on these tasks, as expected. Their response times were slower, and for some of the stimuli, the participants never registered the change at all.
During these momentary lapses of attention, the researchers identified several physiological changes that occurred at the same time. Most significantly, they found a flux of CSF out of the brain just as those lapses occurred. After each lapse, CSF flowed back into the brain.
“The results are suggesting that at the moment that attention fails, this fluid is actually being expelled outward away from the brain. And when attention recovers, it’s drawn back in,” Lewis says.
The researchers hypothesize that when the brain is sleep-deprived, it begins to compensate for the loss of the cleansing that normally occurs during sleep, even though these pulses of CSF flow come with the cost of attention loss.
“One way to think about those events is because your brain is so in need of sleep, it tries its best to enter into a sleep-like state to restore some cognitive functions,” Yang says. “Your brain’s fluid system is trying to restore function by pushing the brain to iterate between high-attention and high-flow states.”
A unified circuit
The researchers also found several other physiological events linked to attentional lapses, including decreases in breathing and heart rate, along with constriction of the pupils. They found that pupil constriction began about 12 seconds before CSF flowed out of the brain, and pupils dilated again after the attentional lapse.
“What’s interesting is it seems like this isn’t just a phenomenon in the brain, it’s also a body-wide event. It suggests that there’s a tight coordination of these systems, where when your attention fails, you might feel it perceptually and psychologically, but it’s also reflecting an event that’s happening throughout the brain and body,” Lewis says.
This close linkage between disparate events may indicate that there is a single circuit that controls both attention and bodily functions such as fluid flow, heart rate, and arousal, according to the researchers.
“These results suggest to us that there’s a unified circuit that’s governing both what we think of as very high-level functions of the brain — our attention, our ability to perceive and respond to the world — and then also really basic fundamental physiological processes like fluid dynamics of the brain, brain-wide blood flow, and blood vessel constriction,” Lewis says.
In this study, the researchers did not explore what circuit might be controlling this switching, but one good candidate, they say, is the noradrenergic system. Recent research has shown that this system, which regulates many cognitive and bodily functions through the neurotransmitter norepinephrine, oscillates during normal sleep.
The research was funded by the National Institutes of Health, a National Defense Science and Engineering Graduate Research Fellowship, a NAWA Fellowship, a McKnight Scholar Award, a Sloan Fellowship, a Pew Biomedical Scholar Award, a One Mind Rising Star Award, and the Simons Collaboration on Plasticity in the Aging Brain.
New method could improve manufacturing of gene-therapy drugs
Some of the most expensive drugs currently in use are gene therapies to treat specific diseases, and their high cost limits their availability for those who need them. Part of the reason for the cost is that the manufacturing process yields as much as 90 percent non-active material, and separating out these useless parts is slow, leads to significant losses, and is not well adapted to large-scale production. Separation accounts for almost 70 percent of the total gene therapy manufacturing cost. But now, researchers at MIT’s Department of Chemical Engineering and Center for Biomedical Innovation have found a way to greatly improve that separation process.
The findings are described in the journal ACS Nano, in a paper by MIT Research Scientist Vivekananda Bal, Edward R. Gilliland Professor Richard Braatz, and five others.
“Since 2017, there have been around 10,000 clinical trials of gene therapy drugs,” Bal says. Of those, about 60 percent are based on adeno-associated virus, which is used as a carrier for the modified gene or genes. These viruses consist of a sort of shell structure, known as capsids, that protects the genetic material within, but the production systems used to manufacture these drugs tend to produce large quantities of empty capsids with no genetic material inside.
These empty capsids, which can make up anywhere from half to 90 percent of the yield, are useless therapeutically, and in fact can be counterproductive because they can add to any immune reaction in the patient without providing any benefit. They must be removed prior to the formulation as a part of the manufacturing process. The existing purification processes are not scalable and involve multiple stages, have long processing times, and incur high product losses and high cost.
Separating full from empty capsids is complicated by the fact that in almost every way, they appear nearly identical. “They both have similar structure, the same protein sequences,” Bal says. “They also have similar molecular weight, and similar density.” Given the similarity, it’s extremely challenging to separate them. “How do you come up with a method?”
Most systems presently use a method based on chromatography, in which the mixture passes through a column of absorbent material, and slight differences in the properties can cause them to pass through at different rates, so that they can be separated out. Because the differences are so slight, the process requires multiple rounds of processing, in addition to filtration steps, adding to the time and cost. The method is also inefficient, wasting up to 30 or 40 percent of the product, Bal says. And the resulting product is still only about two-thirds pure, with a third of inactive material remaining.
There is another purification method that is widely used in the small molecule pharmaceutical industry, which uses a preferential crystallization process instead of chromatography, but this method had not been tried for protein purification — specifically, capsid-based drugs — before. Bal decided to try it, since with this method “its operating time is low and the product loss is also very low, and the purity achieved is very, very high because of the high selectivity,” he says. The method separates out empty from full capsids in the solution, as well as separating out cell debris and other useless material, all in one step, without requiring the significant pre-processing and post-processing steps needed by the other methods.
“The time required for purification using the crystallization method is around four hours, compared to that required for the chromatography method, which is about 37 to 40 hours,” he says. “So basically, it is about 10 times more effective in terms of operating time.” This novel method will reduce the cost of gene therapy drugs by five to 10 times, he says.
The method relies on a very slight difference in the electrical potential of the full versus empty capsids. DNA molecules have a slight negative charge, whereas the surface of the capsids has a positive charge. “Because of that, the overall charge density distribution of the full capsids will be different from that of the empty capsids,” he says. That difference leads to a difference in the crystallization rates, which can be used to create conditions that favor the crystallization of the full capsids while leaving the empty ones behind.
Tests proved the effectiveness of the method, which can be easily adapted to large-scale pharmaceutical manufacturing processes, he says. The team has applied for a patent through MIT’s Technology Licensing Office, and is already in discussions with a number of pharmaceutical companies about beginning trials of the system, which could lead to the system becoming commercialized within a couple of years, Bal says.
“They’re basically collaborating,” he says of the companies. “They’re transferring their samples for a trial with our method,” and ultimately the process will either be licensed to a company, or form the basis of a new startup company, he says.
In addition to Bal and Braatz, the research team also included Jacqueline Wolfrum, Paul Barone, Stacy Springs, Anthony Sinskey, and Robert Kotin, all of MIT’s Center for Biomedical Innovation. The work was supported by the Massachusetts Life Sciences Center, Sanofi S.A., Sartorius AG, Artemis Life Sciences, and the U.S. Food and Drug Administration.
The joy of life (sciences)
For almost 30 years, Mary Gallagher has supported award-winning faculty members and their labs in the same way she tends the soil beneath her garden. In both, she pairs diligence and experience with a delight in the way that interconnected ecosystems contribute to the growth of a plant, or an idea, seeded in the right place.
Gallagher, a senior administrative assistant in the Department of Biology, has spent much of her career at MIT. Her mastery in navigating the myriad tasks required by administrators, and her ability to build connections, have supported and elevated everyone she interacts with, at the Institute and beyond.
Oh, the people you’ll know
Gallagher didn’t start her career at MIT. Her first role following graduation from the University of Vermont in the early 1980s was at a nearby community arts center, where she worked alongside a man who would become a household name in American politics.
“This guy had just been elected mayor, shockingly, of Burlington, Vermont, by under 100 votes, unseating the incumbent. He went in and created this arts council and youth office,” Gallagher recalls.
That political newcomer was none other than a young Bernie Sanders, now the longest-serving independent senator in U.S. congressional history.
Gallagher arrived at MIT in 1996, becoming an administrative assistant (aka “lab admin”) in what was then called the MIT Energy Laboratory. Shortly after her arrival, Cecil and Ida Green Professor of Physics and Engineering Systems Ernest Moniz transformed the laboratory into the MIT Energy Initiative (MITEI).
Gallagher quickly learned how versatile the work of an administrator can be. As MITEI rapidly grew, she interacted with people across campus and its vast array of disciplines at the Institute, including mechanical engineering, political science, and economics.
“Admin jobs at MIT are really crazy because of the depth of work that we’re willing to do to support the institution. I was hired to do secretarial work, and next thing I know, I was traveling all the time, and planning a five-day, 5,000-person event down in D.C.,” Gallagher says. “I developed crazy computer and event-planner skills.”
Although such tasks may seem daunting to some, Gallagher has been thrilled with the opportunities she’s had to meet so many people and develop so many new skills. As a lab admin in MITEI for 18 years, she mastered navigating MIT administration, lab finances, and technical support. When Moniz left MITEI to lead the U.S. Department of Energy under President Obama, she moved to the Department of Biology at MIT.
Mutual thriving
Over the years, Gallagher has fostered the growth of students and colleagues at MIT, and vice versa.
Friend and former colleague Samantha Farrell recalls her first days at MITEI as a rather nervous and very "green" temp, when Gallagher offered an excellent cappuccino from Gallagher’s new Nespresso coffee machine.
“I treasure her friendship and knowledge,” Farrell says. “She taught me everything I needed to know about being an admin and working in research.”
Gallagher’s experience has also set faculty across the Institute up for success.
According to one principal investigator she currently supports, Novartis Professor of Biology Leonard Guarente, Gallagher is “extremely impactful and, in short, an ideal administrative assistant."
Similarly, professor of biology Daniel Lew is grateful that her extensive MIT experience was available as he moved his lab to the Institute in recent years. “Mary was invaluable in setting up and running the lab, teaching at MIT, and organizing meetings and workshops,” Lew says. “She is a font of knowledge about MIT.”
A willingness to share knowledge, resources, and sometimes a cappuccino, is just as critical as a willingness to learn, especially at a teaching institution like MIT. So it goes without saying that the students at MIT have left their mark on Gallagher in turn — including teaching her how to format a digital table of contents on her very first day at MIT.
“Working with undergrads and grad students is my favorite part of MIT. Their generosity leaves me breathless,” says Gallagher. “No matter how busy they are, they’re always willing to help another person.”
Campus community
Gallagher cites the decline in community following the Covid-19 pandemic shutdown as one of her most significant challenges.
Prior to Covid, Gallagher says, “MIT had this great sense of community. Everyone had projects, volunteered, and engaged. The campus was buzzing, it was a hoot!”
She nurtured that community, from active participation in the MIT Women’s League to organizing an award-winning relaunch of Artist Behind the Desk. This subgroup of the MIT Working Group for Support Staff Issues hosted lunchtime recitals and visual art shows to bring together staff artists around campus, for which the group received a 2005 MIT Excellence Award for Creating Connections.
Moreover, Gallagher is an integral part of the smaller communities within the labs she supports.
Professor of biology and American Cancer Society Professor Graham Walker, yet another Department of Biology faculty member Gallagher supports, says, “Mary’s personal warmth and constant smile has lit up my lab for many years, and we are all grateful to have her as such a good colleague and friend.”
She strives to restore the sense of community that the campus used to have, but recognizes that striving for bygone days is futile.
“You can never go back in time and make the future what it was in the past,” she says. “You have to reimagine how we can make ourselves special in a new way.”
Spreading her roots
Gallagher’s life has been inextricably shaped by the Institute, and MIT, in turn, would not be what it is if not for Gallagher’s willingness to share her wisdom on the complexities of administration alongside the “joie de vivre” of her garden’s butterflies.
She recently bought a home in rural New Hampshire, trading the buzzing crowds of campus for the buzzing of local honeybees. Her work ethic is reflected in her ongoing commitment to curiosity, through reading about native plant life and documenting pollinating insects as they wander about her flowers.
Just as she can admire each bug and flower for the role it plays in the larger system, Gallagher has participated in and contributed to a culture of appreciating the role of every individual within the whole.
“At MIT’s core, they believe that everybody brings something to the table,” she says. “I wouldn’t be who I am if I didn’t work at MIT and meet all these people.”
Social Engineering People’s Credit Card Details
Good Wall Street Journal article on criminal gangs that scam people out of their credit card information:
Your highway toll payment is now past due, one text warns. You have U.S. Postal Service fees to pay, another threatens. You owe the New York City Department of Finance for unpaid traffic violations.
The texts are ploys to get unsuspecting victims to fork over their credit-card details. The gangs behind the scams take advantage of this information to buy iPhones, gift cards, clothing and cosmetics.
Criminal organizations operating out of China, which investigators blame for the toll and postage messages, have used them to make more than $1 billion over the last three years, according to the Department of Homeland Security...
