Scientists achieve 3D molecular mapping with breakthrough hybrid microscope
A hybrid microscope developed at the Marine Biological Laboratory (MBL) allows scientists to capture both the 3D orientation and position of molecular ensembles, such as labeled proteins inside cells.
The microscope combines polarized fluorescence, which measures molecular orientation, with a dual-view light sheet microscope (diSPIM) that captures depth details in a sample. This technology can be useful for studying proteins, as they change their 3D orientation in response to their environment to interact with other molecules and perform their functions.
According to Talon Chandler of CZ Biohub San Francisco, the study's first author and a former University of Chicago graduate student who conducted part of this research at MBL, the instrument allows researchers to record changes in 3D protein orientation.
This capability provides insights that may be missed when looking only at a molecule's position. One example is imaging molecules in the spindle of a dividing cell, a challenge that has long been studied at MBL and other research institutions.
The study's co-author, Rudolf Oldenbourg, a senior scientist at MBL, explained that traditional microscopy, including polarized light, can effectively image the spindle when it is perpendicular to the viewing direction. However, when the spindle is tilted, the readout becomes ambiguous. The new instrument overcomes this limitation by adjusting for tilt, allowing researchers to accurately capture both the 3D orientation and position of spindle molecules, such as microtubules.
Now, the team aims to improve the system's speed to capture how the position and orientation of structures change in live samples over time. They also hope that future fluorescent probes will expand its use, allowing researchers to image a wider range of biological structures.
The idea for the microscope originated in 2016 through brainstorming sessions among microscopy innovators at MBL. Hari Shroff of HHMI Janelia, then at the National Institutes of Health (NIH) and an MBL Whitman Fellow, was using his custom-built diSPIM microscope at MBL, developed in collaboration with Abhishek Kumar, now at MBL.
The diSPIM microscope features two imaging paths that intersect at a right angle, allowing researchers to illuminate and capture the sample from both perspectives. This dual-view approach improves depth resolution compared to a single view and provides greater control over polarization during imaging.
Shroff and Oldenbourg recognized that the dual-view microscope could help overcome a limitation of polarized light microscopy - its difficulty in efficiently illuminating a sample with polarized light along the direction of light propagation. By incorporating two orthogonal views, they saw an opportunity to improve the detection of polarized fluorescence and explored using the diSPIM system for such measurements.
https://www.youtube.com/shorts/AZ3OEw3epzU
Shroff collaborated with Patrick La Riviere from the University of Chicago, whose student Talon Chandler joined the project at MBL. Chandler's doctoral thesis focused on integrating the two systems, working in Oldenbourg's lab for a year. The team, including Shalin Mehta, outfitted the diSPIM with liquid crystals to control input polarization direction.
Chandler dedicated a significant amount of time to exploring how to reconstruct the data and maximize what could be recovered from it. Co-author Min Guo, then at Shroff's previous lab at NIH, also worked extensively on this aspect, and together, they achieved their goal of full 3D reconstructions of molecular orientation and position.
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Get Ready to Hear a Lot More About Your Mitochondria
The Atlantic Daily, a newsletter that guides you through the biggest stories of the day, helps you discover new ideas, and recommends the best in culture. Sign up for it here. Robert F. Kennedy Jr.'s warning about mitochondria slipped in between the anti-vaccine junk science and the excoriation of pharmaceutical drugs as 'the No. 3 killer in our country.' He was speaking in 2023 to Joe Rogan, elaborating on the dangers of Wi-Fi—which no high-quality scientific evidence has shown to harm anyone's health—and arguing that it causes disease by somehow opening the blood-brain barrier, and by degrading victims' mitochondria. The mention of mitochondria—the tiny structures that generate energy within our cells—was brief. Two years later, mitochondrial health is poised to become a pillar of the MAHA movement, already showing up in marketing for supplements and on podcasts across the 'manosphere.' Casey Means, President Donald Trump's newest nominee for surgeon general, has singled out the organelle as the main casualty of the modern American health crisis. According to Means (who has an M.D. but no active medical license), most of America's chronic ailments can be traced to mitochondrial dysfunction. Should she be confirmed to the post of surgeon general, the American public can expect to hear a lot more about mitochondria. Among scientists, interest and investment in mitochondria have risen notably in the past five years, Kay Macleod, a University of Chicago researcher who studies mitochondria's role in cancer, told me. Mitochondria, after all, perform a variety of crucial functions in the human body. Beyond powering cells, they can affect gene expression, help certain enzymes function, and modulate cell death, Macleod said. When mitochondria are defective, people do indeed suffer. Vamsi Mootha, a mitochondrial biologist based at Massachusetts General Hospital and the Broad Institute, told me that rare genetic defects (appearing in about one in 4,300 people) can cause the organelles to malfunction, leading to muscle weakness, heart abnormalities, cognitive disability, and liver and kidney problems. Evidence also suggests that defects in mitochondria directly contribute to symptoms of Parkinson's disease, and could be both a cause and an effect of type 2 diabetes. Other conditions' links to mitochondria are blurrier. Researchers see aberrant mitochondria in postmortem biopsies of patients with illnesses such as Alzheimer's, cancer, and fatty-liver disease, Mootha said; whether those damaged mitochondria cause or result from such conditions is not yet clear. 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(Casey Means did not respond to requests for comment; reached by email, Calley did not respond to my questions about mitochondria, but noted, 'There is significant scientific evidence that healthy food, exercise and sleep have a significant impact on reversing chronic disease.') Good Energy follows a typical wellness playbook: using a mixture of valid and dubious research to pin a slew of common health problems on one overlooked element of health—and advertising a cure. Among the culprits for our mitochondrial ravaging, according to the Meanses, are poor sleep, medications, ultraprocessed foods, seed oils, too many calories, and too few vitamins, as well as chronically staying in comfortable ambient temperatures. The Means siblings therefore recommend eschewing refined sugar in favor of leafy greens, avoiding nicotine and alcohol, frequenting saunas and cold plunges, getting seven to eight hours of uninterrupted sleep a night, and cleansing your life of environmental toxins. Some studies indeed suggest that mitochondrial function is linked with sleep and temperature, but they've all been conducted on cell cultures, organoids, or mice. According to Macleod, evidence suggests that diet, too, is likely important. But only one lifestyle intervention—exercise—has been definitively shown to improve mitochondrial health in humans. The Meanses are riding a wave of interest in mitochondrial health in the wellness world. Earlier this year, the longevity influencer Bryan Johnson and the ivermectin enthusiast Mel Gibson both endorsed the dye methylene blue for its power to improve mitochondrial respiration; Kennedy was filmed slipping something that looks a lot like methylene blue into his drink. (Kennedy did not respond to a request for comment; the FDA has approved methylene blue, but only as a treatment for the blood disease methemoglobinemia.) AG1, formerly known as Athletic Greens, formulates its drinkable vitamins for mitochondrial health. 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[Read: The MAHA takeover is complete] In Good Energy, as well as on her website and in podcast appearances, Casey Means promotes a number of supplements for mitochondrial health. She also recommends that people wear continuous glucose monitors—available from her company, Levels Health, for $184 a month—to help prevent overwhelming their mitochondria with too much glucose. (According to Macleod, glucose levels are only 'a very indirect measure' of mitochondrial activity.) As with so many problems that wellness influencers harp on, the supposed solution to this one involves buying products from those exact same people. At best, all of this attention to mitochondria could lead Americans to healthier habits. Much of the advice in Good Energy echoes health recommendations we've all heard for decades; getting regular exercise and plenty of fiber is good guidance, regardless of anyone's reasons for doing so. 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That's no reason, though, to avoid any of these medications if a doctor has determined that you need them. [Read: America can't break its wellness habit] And yet, a whole chapter of Good Energy is dedicated to the idea that readers should mistrust the motives of their doctors, who the authors say profit by keeping Americans sick. The book is less critical of the ways the wellness industry preys on people's fears. Zooming in on mitochondria might offer a reassuringly specific and seemingly scientific explanation of the many real ills of the U.S. population, but ultimately, Means and MAHA are only helping obscure the big picture. Article originally published at The Atlantic
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According to Means (who has an M.D. but no active medical license), most of America's chronic ailments can be traced to mitochondrial dysfunction. Should she be confirmed to the post of surgeon general, the American public can expect to hear a lot more about mitochondria. Among scientists, interest and investment in mitochondria have risen notably in the past five years, Kay Macleod, a University of Chicago researcher who studies mitochondria's role in cancer, told me. Mitochondria, after all, perform a variety of crucial functions in the human body. Beyond powering cells, they can affect gene expression, help certain enzymes function, and modulate cell death, Macleod said. When mitochondria are defective, people do indeed suffer. 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Some studies indeed suggest that mitochondrial function is linked with sleep and temperature, but they've all been conducted on cell cultures, organoids, or mice. According to Macleod, evidence suggests that diet, too, is likely important. But only one lifestyle intervention— exercise —has been definitively shown to improve mitochondrial health in humans. The Meanses are riding a wave of interest in mitochondrial health in the wellness world. Earlier this year, the longevity influencer Bryan Johnson and the ivermectin enthusiast Mel Gibson both endorsed the dye methylene blue for its power to improve mitochondrial respiration; Kennedy was filmed slipping something that looks a lot like methylene blue into his drink. (Kennedy did not respond to a request for comment; the FDA has approved methylene blue, but only as a treatment for the blood disease methemoglobinemia.) AG1, formerly known as Athletic Greens, formulates its drinkable vitamins for mitochondrial health. 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After all, 'if you consistently beat your body up with unhealthy habits, everything is going to fall sick,' Ganesh said. But the mitochondrial approach to wellness carries risks, too. For patients with genetically caused mitochondrial disease, lifestyle changes might marginally improve some symptoms, Ganesh said, but attempting to cure such conditions with supplements and a healthy diet alone could be dangerous. Means also calls out medications—including antibiotics, chemotherapy, antiretrovirals, statins, and high-blood-pressure drugs—for interfering with mitochondria. Macleod told me that statins really do affect mitochondria, as do some antibiotics. (The latter makes sense: Mitochondria are thought to have evolved from bacteria more than a billion years ago.) That's no reason, though, to avoid any of these medications if a doctor has determined that you need them. And yet, a whole chapter of Good Energy is dedicated to the idea that readers should mistrust the motives of their doctors, who the authors say profit by keeping Americans sick. The book is less critical of the ways the wellness industry preys on people's fears. Zooming in on mitochondria might offer a reassuringly specific and seemingly scientific explanation of the many real ills of the U.S. population, but ultimately, Means and MAHA are only helping obscure the big picture.
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University Of Chicago Receives $21 Million Gift For Quantum Medicine
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