Publisher Health

Mitochondria, known as the powerhouses within human cells, generate the energy needed for cell survival. However, as a byproduct of this process, mitochondria also produce reactive oxygen species (ROS). At high enough concentrations, ROS cause oxidative damage and can even kill cells. An overabundance of ROS has been connected to various health issues, including cancers, neurological disorders, and heart disease.
An enzyme called manganese superoxide dismutase, or MnSOD, uses a mechanism involving electron and proton transfers to lower ROS levels in mitochondria, thus preventing oxidative damage and maintaining cell health. More than a quarter of known enzymes also rely on electron and proton transfers to facilitate cellular activities that are essential for human health. However, most of their mechanisms are unclear because of the difficulties in observing how protons move.
Researchers from the University of Nebraska Medical Center (UNMC) and the Department of Energy’s (DOE’s) Oak Ridge National Laboratory (ORNL) have now observed the complete atomic structure of MnSOD, including its proton arrangements, with neutron scattering. The findings, published in Nature Communications, reveal how protons are used as tools to help MnSOD transfer electrons for reducing ROS levels. The work could help experts develop MnSOD-based treatments and design therapeutic drugs that mimic its antioxidant behavior. The neutron study also opens an avenue for studying other enzymes that utilize electron and proton transfers.
“Using neutrons, we were able to see MnSOD features that were completely unexpected, and we believe this will revolutionize how people think this enzyme and other enzymes like it operate,” said Gloria Borgstahl, a UNMC professor and corresponding author of the new study.
MnSOD works by targeting superoxide, a reactive molecule that leaks from the mitochondrial energy production process and is the chemical precursor for other harmful ROS. The enzyme’s active site turns superoxide into less toxic products by using its manganese ion to move electrons to and from the reactive molecule. The manganese ion is capable of stealing an electron from a superoxide molecule, converting it to oxygen. This stolen electron can then be given to another superoxide to make hydrogen peroxide.
For this biochemical reaction to work, a series of proton movements need to take place between the enzyme’s amino acids and other molecules at its active site. The protons act as instruments that enable the electrons to move. Until now, the enzyme’s sequence of electron and proton transfers, also known as its catalytic mechanism, had not been defined at the atomic level because of challenges in tracking how protons are shuttled between molecules. A fundamental understanding of this catalytic process could inform therapeutic approaches that harness this enzyme’s antioxidant abilities.

Exposure to phthalates, a class of chemicals widely used in packaging and consumer products, is known to interfere with normal hormone function and development in human and animal studies. Now researchers have found evidence linking pregnant women’s exposure to phthalates to altered cognitive outcomes in their infants.
Most of the findings involved slower information processing among infants with higher phthalate exposure levels, with males more likely to be affected depending on the chemical involved and the order of information presented to the infants.
Reported in the journal Neurotoxicology, the study is part of the Illinois Kids Development Study, which tracks the effects of hormone-disrupting chemicals on children’s physical and behavioral development from birth to middle childhood. Now in its seventh year, IKIDS has enrolled hundreds of participants and is tracking chemical exposures in pregnant women and developmental outcomes in their children. Susan Schantz, a neurotoxicologist and professor emerita of comparative biosciences at the University of Illinois Urbana-Champaign, is the principal investigator of the study. She is a faculty member in the Beckman Institute for Advanced Science and Technology, which houses the IKIDS program at Illinois.
“IKIDS is part of a larger initiative funded by the National Institutes of Health, the Environmental Influences on Child Health Outcomes program. It is tracking the impact of prenatal chemical exposures and maternal psychosocial stress on children’s growth and development over time,” Schantz said. “We measure numerous birth outcomes, including birth weight and gestational age. We also assess infants’ cognition by studying their looking behavior. This allows us to get measures of working memory, attention and information-processing speed.”
The researchers analyzed metabolites of three commonly occurring phthalates in urine samples regularly collected from the pregnant women in the study. The chemical exposure data were used in combination with assessments of the women’s infants when the children were 7.5 months old.
The researchers used a well-established method that gives insight into the reasoning of children too young to express themselves verbally: Infants typically look longer at unfamiliar or unexpected images or events.
The team used an infrared eye-tracker to follow each infant’s gaze during several laboratory trials. With the infant sitting on a caregiver’s lap, researchers first familiarized the child with two identical images of a face. After the infant learned to recognize the face, the researchers showed that same face paired with an unfamiliar one.
“In repeated trials, half of the 244 infants tested saw one set of faces as familiar, and half learned to recognize a different set of faces as familiar,” Schantz said. “By analyzing the time spent looking at the faces, we could determine both the speed with which the infants processed new information and assess their ability to pay attention.”
The assessment linked pregnant women’s exposure to most of the phthalates that were assessed with slower information processing in their infants, but the outcome depended on the specific chemical, the sex of the infant and which set of faces the infant viewed as familiar. Male infants, in particular, tended to process information more slowly if their mothers had been exposed to higher concentrations of phthalates known to interfere with androgenic hormones.
The specific characteristics of faces presented to the infants in the familiarization trials also appeared to play a role in the outcome, the researchers reported. Phthalate-exposed children who were first familiarized with faces from Set 2 were more likely to experience slower processing speed than those familiarized with faces from Set 1. The finding is perplexing, Schantz said, but is likely related to differences in the infants’ preferences for the faces in the two sets. It also may be an indication that familiarization with the Set 2 faces is a more sensitive detector of changes in processing speed related to phthalate exposure.
“Most previous studies of the relationship between prenatal exposure to phthalates and cognition have focused on early and middle childhood,” Schantz said. “This new work suggests that some of these associations can be detected much earlier in a child’s life.”
The U.S. Environmental Protection Agency, the National Institute of Environmental Health Sciences, the National Institutes of Health ECHO Program supported this research.

A panel recommends biennial screenings, starting at 50, but a new study took issue with the way hundreds of centers are telling women 40 and up to come in yearly. Some experts contend that frequent mammograms can “do more harm than good.”My last breast cancer screening was “b.c.” — before Covid — just a few weeks before the mysterious new disease was detected in China. The timing was perfect: Everything was normal, and by the time we went into lockdown, my to-do list no longer included a mammogram.But by November 2020, exactly one year after that scan, I started getting barraged by phone calls and text messages telling me I was due for another one.“MAMMO MATTERS,” screamed one in all capital letters. “Breast cancer does not take a break during pandemics, and neither should you.” I was well aware that national health guidelines recommend a mammogram only every other year for women at average risk for breast cancer. But there has been a cacophony of advice in recent years as different groups recast their recommendations, often contradicting one another. So the messages were unnerving.It turns out my imaging center is not alone in badgering women to have mammograms more frequently than the U.S. Preventive Services Task Force deems optimal. A recent study found that hundreds of breast centers tell women who are not at elevated risk of cancer to have a routine scan every year, and to start at 40.The task force, however, recommends regular mammograms every two years starting at 50. Its guidelines do recommend that women in their 40s discuss mammography with their doctors, evaluate the risks and benefits and come to an individual decision. (The panel’s recommendations extend to age 74; it has said there is not enough evidence to make recommendations past that age.)The new study, published in JAMA Internal Medicine on March 15, was accompanied by a rather scathing editorial that said extra screening can do “more harm than good.”“I don’t think breast cancer centers that have clear financial benefits from increasing mammography should be the ones that are giving out patient advice, particularly when it conflicts with the patient’s primary care provider’s advice and the task force’s advice,” said Dr. Rita F. Redberg, editor in chief of JAMA Internal Medicine, who co-wrote the editorial along with Dr. Anand R. Habib and Dr. Deborah Grady.The American College of Radiology took umbrage, shooting back that it was “outrageous” to assert that breast cancer centers were promoting mammograms for financial reasons, and that the radiologists’ had a different set of guidelines.When the pandemic started, both routine screenings and appointments triggered by troubling symptoms like the discovery of a lump were delayed as facilities shut down. Even when they reopened, many patients were reluctant to go in.But Dr. Dana Smetherman, who chairs the American College of Radiology’s breast imaging commission, said the breast centers’ recommendations for more frequent screening predate the pandemic.“What this study is telling us is that the experts in breast cancer in the U.S. do not support these recommendations,” Dr. Smetherman said in an interview, referring to the U.S. task force’s guidelines.Indeed: Both the college of radiology and the American Society of Breast Surgeons recommend annual mammograms starting at age 40 (Dr. Redberg’s institution, the University of California, San Francisco, also recommends that schedule).The American Cancer Society scaled back its recommendations recently, however, endorsing yearly scans starting at age 45, with the option of switching to every other year at age 54. The American College of Obstetricians and Gynecologists recommends women at average risk start mammography at 40, but “every one or two years.”The debate over screening frequency for breast cancer — the second leading cause of cancer death for women after lung cancer — dates back to 2009. That is when the U.S. Preventive Services Task Force, an independent expert panel that reviews the evidence and provides guidance to doctors and insurers, rolled back its mammography recommendations for women who were deemed at average risk for breast cancer.Screening can actually be harmful, especially for younger women, the panel found. False positive findings can trigger unnecessary procedures like biopsies, or lead to what experts call over-diagnosis — the aggressive treatment of slow-growing tumors that might never become life-threatening, but cannot be distinguished from fast-growing tumors.When women had mammograms every other year, the harms of false positives and unnecessary treatment were reduced, the panel determined, while it found the life-saving benefits remained relatively unchanged.But some experts believe the panel overstated the harms of more frequent screenings. The appropriate schedule for screenings can vary from doctor to doctor, and patient to patient, and has become quite confusing.“Many women may not even be aware of the guidelines, or that there may be any downside to mammography, and that they have the option to begin screening at age 45 or 50,” Dr. Jennifer L. Marti, an assistant professor of surgery at Weill Cornell Medicine who led the new study, said in an interview. “In almost every other country, women start at 50.”While many women might assume that “the pros of breast cancer screening outweigh the harms,” Dr. Marti said, that is not always the case for women who aren’t at elevated risk.Dr. Marti and her co-authors, Mark Lee and Neal Patel, two Weill Cornell researchers, decided to examine the recommendations posted on the websites of some 606 breast cancer centers in the United States. They found that 376 centers — over half — made recommendations that differed from those of the U.S. task force, saying women at average risk for breast cancer should start imaging at age 40.And 347 centers said women should not only start at 40, but continue annually.More rigorous screening may be appropriate for some high risk groups, like Ashkenazi Jewish women, who are more likely to carry mutations that put them at risk for breast and ovarian cancer, and Black women, who were likely underrepresented in mammography screening trials, Dr. Marti said.Women who want help assessing their individual risk to make screening decisions can use an online tool developed by Dr. Margaret Polaneczky, a gynecologist from Weill Cornell Medicine, and Elena Elkin, a research scientist at Memorial Sloan Kettering Cancer Center, Dr. Marti suggested.As for myself, I’ve been on a two-year plan for a while. I do regular breast self-examinations, and have clinical breast exams too. So even though I felt a smidgen of irrational guilt after receiving the text messages, I politely asked a receptionist to please stop calling. I promised I’d be in touch.

Is there a way to chemically manipulate small, confined areas on cellular surfaces? Scientists have developed a microfluidic probe to send a flow of free radicals on live cells and track the outcome using fluorescence imaging. As outlined in the journal Angewandte Chemie, this approach makes it possible for the first time to generate a reaction zone of free radicals with controlled size and concentration for subcellular research.
Free radicals are important stimulants for cells. When live cells are exposed to radicals, they develop intense reactions that can lead to cell injury or even death. Many anticancer drugs are based on the action of free radicals sending cancer cells to death.
However, scientists find it difficult to perform research on the reactions of live cells to radicals in a truly controlled way. Free radicals are unstable and react with their environment before reaching their targets. A team of scientists led by Jin-Ming Lin from Tsinghua University, Beijing, has now developed a microfluidic approach to continuously generate a flow of free radicals for subcellular manipulation.
To make the radicals, the researchers chose a microfluidic two-component system. In this setup, one microchannel harbored a solution of enzymes able to cleave hydrogen peroxide. Another channel contained a solution of hydrogen peroxide and an organic dye. Both channels were immersed with their ends in a nutrient solution where a live cell was placed just below the channel ends. A third channel with an upward flow ensured that the fluids leaving the microchannel ends would meet in the middle position, forming a confined reaction zone.
According to the authors, this setup ensured that the reaction zone had the size of only a few micrometers. In this zone, the enzyme horseradish peroxidase would react with the hydrogen peroxide to form reactive enzyme intermediates, which then reacted with the organic dye to give an organic radical. Immediately after their generation, the dye radicals would then attack the cell placed directly below the reaction zone.
After tens of seconds of component flow and radical attack, the researchers observed that a tiny spot emitting bright red fluorescence had emerged on the cellular membrane. Tracking this spot over time, the researchers found it slowly wandered around on the cellular surface.
The authors say that the tiny fluorescent spot and its movement highlight the ability of the microfluidic method to manipulate small subareas on the cell surface. “By contrast with lipophilic tracers, which stain the whole cell, it is convincing that the free radicals generated only attack the target subcellular region of the single cell,” they argue.
One particular application fascinates the authors: they envision using the microfluidic probe as a “pen” for cells. “This will enable us to directly write text or draw graphics on single cells for personalized cell marking or artwork,” they explain.
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A study led by Edward Wojcik, PhD, Associate Professor of Biochemistry & Molecular Biology at LSU Health New Orleans School of Medicine, identified how microcephaly (abnormally small heads) and blindness may develop in Zika-infected fetuses, as well as a new way to potentially prevent these neurodevelopmental defects. The results are published online in iScience.
The mechanism by which Zika virus disrupts neuronal development and results in congenital Zika syndrome was unknown. Because of similarities between Zika syndrome and a recognized congenital genetic disease (Kinesin-5) known to cause microcephaly and retinopathies in developing infants, the research team studied both, looking for similarities. They discovered a direct link, the first molecular and cellular evidence supporting a direct connection between the two.
“We had a hunch that the microcephaly and blindness that results from Kinesin-5 genetic disease could be linked to Zika infection, and the hunch paid off,” notes Dr. Wojcik. “Our experiments identify a molecular motor as a target for degradation by an encoded Zika virus protein (Zika protease). The molecular motor is Kinesin-5, and it is required for cell division in humans. Our data identify Kinesin-5 as a target for the virus and links the infection to microcephaly.”
The researchers observed that Zika protease cuts Kinesin-5 during cell division, disrupting the process and causing a loss of function. They also suggest a way to prevent it.
The Zika protease can degrade only a target protein it can reach. Since the protease is part of the endoplasmic reticulum (ER) membrane, only target proteins that come in direct contact with the ER can be degraded. In this way, the protease acts in a spatially restricted manner in the cell; target proteins are degraded only in certain regions of the cell volume and not in others. So, the research team proposes a drug that would affect only the Zika protease instead of drugs that would affect all target proteins in a cell.
“We predict and hope that potential drugs that inhibit Zika protease may be effective in preventing microcephaly and blindness from developing within Zika-infected fetuses,” Dr. Wojcik concludes.
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Ambient air pollution is a global public health crisis, causing more than 4.9 million premature deaths per year around the world. In Africa, it has surpassed AIDS as the leading cause of premature death. According to one study, air pollution — specifically, fine particulate matter (PM2.5) — may cause at least as many as 780,000 premature deaths annually in Africa and worsen a significant number of diseases, including asthma, lung cancer, and chronic obstructive pulmonary disease.
Kinshasa, capital of the Democratic Republic of the Congo, and Brazzaville, capital of the Republic of Congo, are both large metropolises. However, neither Kinshasa (population 14. 3 million) nor Brazzaville (population 2.4 million) have had comprehensive air quality monitoring programs. There are no national ambient air quality standards in either country, according to an analysis done by the UN Environment Programme.
A new study, led by Lamont-Doherty Earth Observatory atmospheric scientist Daniel Westervelt and Columbia University undergraduate student Celeste McFarlane, has yielded the first-ever multi-year ambient PM2.5 dataset in Kinshasa and Brazzaville. The team deployed a cadre of low-cost sensors and interpreted data in the context of changing weather and changing human activity related to COVID-19 stay-at-home orders. The study was supported by two local universities and their scientists in both cities, and is published online on Aerosol and Air Quality Research.
What it shows is concerning. During the investigation, which began in March 2018, researchers found PM2.5 is highest during the dry season — June, July, and August — when it is up to five times higher than World Health Organization guidelines. It is lower in the remaining months, thanks in part to rainfall, but even then, it is more than four times higher than WHO guidelines.
“Average PM2.5 concentrations suggest unhealthy levels of human exposure, which, over time, can lead to cardiopulmonary problems and premature death,” said Westervelt.
The study also found that last year’s stay-at-home and lockdown directives in response to COVID-19 corresponded to a 40% decrease in PM2.5.
“We were able to demonstrate that it is possible to robustly characterize air quality in African megacities using well-calibrated, relatively simple, cheap devices,” Westervelt said.
He added that given the health risks from air pollution, this data is urgently needed to draw attention to the problem. Researchers hope this study will lead to more concerted efforts to characterize sources of air pollution and develop strategies to mitigate the negative health impacts.
Study collaborators include: Columbia University, Department of Chemical Engineering; Ecole Régionale postuniversitaire d’Aménagement et de Gestion Intégrés des Forêts et Territoire tropicaux (ERAIFT) Kinshasa Democratic Republic of Congo; World Bank Group; Kinshasa, Democratic Republic of Congo; Département de chimie, Université Marien Ngouabi, Brazzaville, Republic of Congo; Washington State Department of Ecology; Department of Chemistry, University of California Berkeley; 9OSU-EFLUVE — Observatoire Sciences de l’Univers-Enveloppes Fluides de la Ville à l’Exobiologie, Université Paris-Est-Créteil, France; NASA Postdoctoral Program Fellow; Goddard Space Flight Center; Center for Atmospheric Particle Studies, Carnegie Mellon University; Kigali Collaborative Research Centre, Kigali, Rwanda; and NASA Goddard Institute for Space Studies.
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The Baltimore plant that recently had to scrap up to 15 million ruined doses had flouted rules and downplayed errors, according to internal audits, ex-employees and clients. Other doses had to be scrapped last year.WASHINGTON — More than eight years ago, the federal government invested in an insurance policy against vaccine shortages during a pandemic. It paid Emergent BioSolutions, a Maryland biotech firm known for producing anthrax vaccines, to have its factory in Baltimore always at the ready.When the coronavirus pandemic arrived, the factory became the main U.S. location for manufacturing Covid-19 vaccines developed by Johnson & Johnson and AstraZeneca, churning out about 150 million doses as of last week.But so far not a single dose has been usable because regulators have not yet certified the factory to allow the vaccines to be distributed to the public. Last week, Emergent said it would destroy up to 15 million doses’ worth of the Johnson & Johnson vaccine after contamination with the AstraZeneca vaccine was discovered.Emergent and government health officials have long touted their partnership as a success, but an examination by The New York Times of manufacturing practices at the Baltimore facility found serious problems, including a corporate culture that often ignored or deflected missteps and a government sponsor, the Biomedical Advanced Research and Development Authority, that acted more as a partner than a policeman. Previously undisclosed internal documents and interviews with current and former federal officials and former company employees depict a factory operation that was ill-equipped to take on such a mammoth manufacturing task, despite Emergent’s having received a $163 million federal contract to improve the facility and prepare it for high-volume production.The loss of the Johnson & Johnson doses was not the first time the company threw out coronavirus vaccine for fear of contamination. Between early October and January, Emergent discarded five lots of AstraZeneca vaccine — each the equivalent of two million to three million doses — because of contamination or suspected contamination, according to internal logs, a government official and a former company supervisor.Audits and investigations — including ones conducted in 2020 by Johnson & Johnson, AstraZeneca, two federal agencies and Emergent’s own quality evaluators — found that Emergent had not followed some basic industry standards at the Baltimore plant, and identified repeated shortcomings in efforts to disinfect and prevent contamination.While audits always find problems, federal officials and outside experts said that the pattern of lapses suggested deeper quality issues.“These are the fundamental steps,” said Dr. Ajaz Hussain, a pharmaceutical quality expert who oversaw efforts by the Food and Drug Administration to ensure quality in drug development and manufacturing from 2000 to 2005. “If you are making mistakes or errors in the fundamentals, what else is wrong with your system? That would be my question.”An audit conducted for AstraZeneca specifically highlighted the risks of viral cross-contamination, which experts believe was responsible for tainting the millions of Johnson & Johnson doses, according to a review of the confidential document by The Times. The audits and investigations also flagged a persistent problem with mold in areas required to be kept clean, poor disinfection of some plant equipment leading to growth of bacteria, the repeated approval of raw materials that had not been fully tested, and inadequate training of some employees. A lab at the Baltimore facility, where both internal and external audits have identified problems. Jerry Jackson/Baltimore Sun MediaIn their own audit last July, Emergent’s auditors said errors “are not investigated to determine root cause, or are not investigated adequately,” a report stated. “Investigations are terminated without sufficient cause.”In one example, the Emergent auditors said mold had been repeatedly discovered in the room where cell cultures were grown. Mold can be serious if airborne spores contaminate the vaccine substance. Emergent workers conducted “essentially no investigation” beyond checking the wheels of one cart for mold, and wrongly classified the incident as minor, the audit said.While the Baltimore plant remains under scrutiny, another 62 million doses of the Johnson & Johnson vaccine made there are in jeopardy until it can be determined whether they were also contaminated. Over the weekend, Johnson & Johnson assumed responsibility for the manufacturing at the direction of the Biden administration, which also limited future production to only the Johnson & Johnson vaccine.Because other manufacturers are now churning out so many Covid-19 vaccine doses, it does not appear that the disruptions in Baltimore will upend the Biden administration’s expedited timetable for vaccine supplies and availability. But health experts worry the revelations could heighten safety concerns and make some people more wary about getting shots.Emergent is a longtime government contractor that has spent much of the last two decades cornering a lucrative market in federal spending on biodefense. The Times reported last month that sales of its anthrax vaccines to the Strategic National Stockpile accounted for nearly half of the stockpile’s half-billion-dollar annual budget throughout most of the last decade, leaving the federal government with less money to buy supplies needed in a pandemic.In response to questions about the Baltimore plant, an Emergent spokesman, Matt Hartwig, said in a statement that the company had been cooperating with the federal government “to address issues” and “resolve them in support of the federal Covid response.” He said the company had “a proven track record as a world-class provider of both bulk drug substances and sterile injectable drug products” and that it had “rigorous safety, quality and compliance programs, which include programs, policies, and processes that allow early identification of issues and means to address them.”He added, “Any allegation that our safety, quality and compliance systems are not working or that we do not take these responsibilities seriously is false.”But four former company officials, speaking on the condition of anonymity because they had signed nondisclosure agreements or feared retaliation, described an environment where top Emergent leadership tolerated and even encouraged the flouting of federal standards for manufacturing and marketing products.One of the former officials said that as the company scrambled to meet the heavy demands of vaccine production, a senior manufacturing supervisor often responded to reports of quality errors by asking: “Do you want me to make drugs or fix issues? I don’t have time to do both.”Even before the Covid-19 vaccine production began, there were concerns about Emergent’s ability to deliver on its contract with the government, The Times found. As a test of Emergent’s readiness, the original contract required the company to demonstrate that it could rapidly produce 50 million doses of a pandemic influenza vaccine, but Emergent hadn’t done so by the original deadline last June.“This was the way that you demonstrate you’re surge-ready,” said Dr. Nicole Lurie, who until 2017 oversaw the office that awarded Emergent the 2012 contract. Not meeting that requirement after eight years, she said, “would have been of huge concern to me.”In the end, as the coronavirus swept across the country, federal officials said they had little choice but to turn to Emergent because few companies based in the United States were able to make the type of vaccines developed by Johnson & Johnson and AstraZeneca.Dr. Robert Kadlec, who was with the Department of Health and Human Services under the Trump administration, appearing last March with members of the coronavirus task force.Anna Moneymaker/The New York Times“There weren’t a lot of alternatives,” said Dr. Robert Kadlec, who oversaw the agency that awarded the manufacturing contract under the Trump administration. “We even looked at veterinary vaccine facilities around the country. We couldn’t find the capacity.”Most large pharmaceutical companies have spurned this work because of the relatively small payouts and the hassle of government contracting. Emergent, by contrast, has deployed a well-funded lobbying apparatus and a web of Washington connections to build its business around preparations for potential bioweapon attacks and infectious disease outbreaks.Emergent’s stock has suffered in the last week, closing Monday just under $79, down from $94 before news broke that the doses had been ruined. Still, the Covid-19 work has been lucrative for the company.In all, Emergent’s Covid-19 manufacturing deals are worth up to $1.5 billion, according to company presentations and calls with investors. Profitability for 2020 was “off-the-chart successful,” the company’s chief executive, Robert Kramer, boasted to investors in March.The Last One StandingThe government’s investment in Emergent’s Baltimore facility was rooted in a lesson from the last pandemic, the 2009 H1N1 influenza outbreak that claimed an estimated 12,000 lives in the United States.A government report the next year noted that the nation had developed vaccines for the novel pathogen “in record time,” but that “the vaccines were not broadly available before the virus had spread widely among the U.S. population.”To ensure that didn’t happen again, the report determined, the federal government should partner with companies and universities to expand and sustain domestic manufacturing sites.Barda/Department of Health and Human ServicesIn 2012, the Department of Health and Human Services awarded three contracts, including one to Emergent to retrofit and expand its Baltimore site. And between 2015 and 2019, the government placed a handful of relatively small orders for doses of treatments and vaccines being developed for use against viruses including Ebola and Zika.The contract also required Emergent to stand ready to produce up to 50 million doses of vaccine within four months in the event of an influenza pandemic. To show that it was up to the task, Emergent was supposed to work with a company developing a flu vaccine candidate and seek F.D.A. approval to manufacture it by June 2020.As the deadline neared, however, Emergent still had not met the requirement. The vaccine candidate of its chosen partner company had failed in clinical trials, and Emergent had not found a replacement. “Emergent does not have a candidate, strategy or plan for fulfilling the flu requirement,” according to a government document in June 2019. “Emergent needs to make this a priority so they are not in default.”By then, the government had scaled back its partnership with Emergent, shortening its maximum possible duration to 15 years from 25 years.Dr. Kadlec, who ran the office overseeing the contract, said he commissioned a review of the government partnerships, including the one with Emergent, that concluded in 2019 that their ability to deliver in a pandemic remained largely unproven.“What I perceived is that we did not pressure-test those systems on a regular basis to see what they could do,” said Dr. Kadlec, who had previously worked as a consultant for Emergent. “The military term is ‘live fire.’”When the June 2020 deadline arrived, Emergent hadn’t met the flu requirement, but the government nevertheless awarded it a $628 million contract to manufacture Covid-19 vaccines.By then, only two of the three government-funded centers remained, and Emergent’s was the only one with the ability to make the type of vaccines being developed by Johnson & Johnson and AstraZeneca. Justifying an exception to normal contracting requirements, the government said it needed to act fast.“Discussions with Emergent have revealed that they are in discussions with multiple vaccine developers interested in reserving the capacity” at the Baltimore plant, according to a government contracting document. Should that happen, it added, the government “would not be in a position to manufacture vaccines in a relevant time frame” to meet the Trump administration’s goal of 300 million vaccine doses.Dr. Kadlec said he knew it was a risky decision.“It’s like trying to take the finest champagne in France and recreate it in parts of the United States,” he said. “You could bring the grapes over, but it’s a science and an art.”A majority of the contract — more than a half-billion dollars — was allocated for monthly fees to reserve manufacturing space at Emergent’s facilities. Emergent’s chief financial officer acknowledged during a July call with Wall Street analysts that for the company, there were “minimal costs associated with the reservation piece itself,” and executives have since cited the reservation fees during investor calls as one reason for an increase in Emergent’s gross profit margins.Emergent’s C.E.O., Robert Kramer, told investors that profitability for 2020 was “off-the-chart successful.”AWNewYork/Shutterstock Mr. Hartwig, the Emergent spokesman, said the government funding “reserved manufacturing capacity and allowed Emergent to acquire the equipment and hire the work force necessary to support vaccine production on a scale of one billion doses annually.”The government later extended the flu vaccine deadline under the original contract. A spokeswoman for the agency administering the deal, the Biomedical Advanced Research and Development Authority, or BARDA, said Emergent’s Covid-19 work “is meeting” the original contract’s “intent.”Meanwhile, the company struck separate deals with Johnson & Johnson and AstraZeneca worth roughly another $875 million. In a July conference call with investors, Emergent announced that it was tripling its projected contract manufacturing revenue for the year.“Emergent is uniquely prepared to answer the call for Covid-19 pandemic,” Mr. Kramer told investors.A Pattern of LapsesIn the days that followed, investors flocked to Emergent’s stock, pushing it to a record high. But out of public view, internal monitors and auditors from the company’s new partners, Johnson & Johnson and AstraZeneca, were finding the Baltimore factory’s procedures deficient, especially in disinfecting the plant and preventing contamination.Internal logs show that Emergent had to toss out one batch of AstraZeneca’s vaccine in early October because of suspected contamination, and four more in December. Those four were spoiled by bacterial contamination of equipment, a former company official said.In November, production of a batch of Johnson & Johnson vaccine was discarded after workers “hooked up” the wrong gas line and accidentally “suffocated” the cells where the virus for the vaccine is grown, the logs show. The next month, the records indicate, workers making AstraZeneca’s vaccine deviated from manufacturing standards on average more than three times a day. About one-fifth of the deviations were classified as major.Because of the pandemic, most of the auditors drew their conclusions from documents and video tours, during which Emergent workers controlled the camera angles, one former company official said.Johnson & Johnson’s auditors said monitoring reports for bacteria or other contaminants were filed four to six months late. AstraZeneca’s said that Emergent repeatedly loosened monitoring criteria so it appeared to meet them, resorting to measures like “historical averages.” But even then it failed the tests, the report said.In another audit, BARDA officials documented similar concerns, classifying some of them, including the risks of microbiological contamination, as “critical.” That designation is reserved for the most serious problems that pose an immediate and significant risk.Emergent’s own internal audit in July also said the flow of workers and materials through the plant was not adequately controlled “to prevent mix-ups or contamination.” The reports echoed quality-control shortcomings documented in an April inspection by the F.D.A., reported earlier by The Associated Press, that concluded the facility was “not ready for commercial operations.” Multiple audits underscore how poorly the company was prepared for the huge workload it accepted. The Covid-19 projects required significantly more testing to ensure materials remained stable, but Emergent had just one employee coordinating it all, the BARDA audit found. Emergent acknowledged at the time that its testing system was “not ideal” and pledged to train at least one more Emergent worker and hire a third. BARDA did not respond to requests for comment on its audit or any of the others, beyond saying that it had “worked with Emergent to resolve the issues” raised during the F.D.A. inspection.Another internal investigation in August found that Emergent approved four raw materials used to produce AstraZeneca’s vaccine without first fully testing them. That type of shortcut, called a conditional release of material, occurred on average twice a week in October, internal logs show. The measure that was deemed necessary because the company was working with shortened production times, testing backlogs and the needs of Operation Warp Speed, the Trump administration’s crash vaccine development program. And while a manager “knowingly deviated” from standards, the report said, the batches of vaccine would be not released without quality and safety tests.Mr. Kramer, right, giving a tour at the lab in Baltimore where Emergent makes Covid-19 vaccines.Joe Andrucyk/Office of Governor Larry HoganPlant supervisors often cited pressures from Operation Warp Speed as a justification for glossing over violations of manufacturing guidelines, according to one former company official. But even before Emergent launched into Covid-19 vaccine production, a major client charged that the firm was too complacent about mistakes.A New Jersey-based company called Soligenix had hired Emergent to produce its experimental vaccine against ricin, a toxin, for use in clinical trials. But shortly after the trial began in December 2019, Emergent informed Soligenix that it had failed to properly test the vaccine before releasing it, according to Soligenix’s filing with the Securities and Exchange Commission, which was reported earlier by The Washington Post.By then, two volunteers had already received doses, the filing stated.Forced to suspend the trial, Soligenix is now seeking $19 million in damages from Emergent, which has denied negligence or deliberate wrongdoing.In follow-up audit in February 2020, Soligenix auditors said “the primary driver” of the mistake was that Emergent had fostered “a culture where written instructions are regularly not followed with no consequences.”62 Million Doses in the BalanceShortly before 6:20 p.m. on March 25, an urgent email landed in the inboxes of top officials at the Department of Health and Human Services. “Developing Situation _ Emergent Bayview,” the subject line read.What followed was even more alarming: “Viral cross-contamination confirmed in the control cells for JANSSEN GMP Lot #8.”The message, referring to the Johnson & Johnson vaccine production at Emergent’s Baltimore factory, set off a series of hurried nighttime telephone calls, according to officials familiar with the situation.The Johnson & Johnson and AstraZeneca vaccines use the same technology: A harmless version of a virus — known as a viral vector — is transmitted into cells to make a protein that stimulates the immune system to produce antibodies.Sometime in February, Emergent workers had unknowingly contaminated Johnson & Johnson’s viral vector with AstraZeneca’s. The error was not discovered for weeks, until, in one of the final checks before release, Johnson & Johnson sampled a batch of 13 million to 15 million doses’ worth of vaccine for purity.In short order, top Biden administration health officials directed a hold on shipments from the Baltimore facility and instructed Johnson & Johnson executives to take charge of its operations. Days later, they quietly told AstraZeneca officials their vaccine would no longer be made at the Baltimore plant, to avoid a repeat of that error.At a Monday morning staff meeting at the plant, Emergent officials claimed the mistake was an isolated incident and the media had exaggerated its significance, according to a person briefed on the meeting. They urged workers to be proud of what the plant had accomplished in such a short time.But quality-control managers are now required to test anew every lot of Johnson & Johnson vaccine made at the plant — 62 million doses in all — to make sure they weren’t also contaminated. Another roughly 70 million doses of AstraZeneca’s may also need to be tested.F.D.A. inspectors are expected to intensely scrutinize the plant before certifying it to release doses to the public. It remains uncertain whether that would occur in time for Johnson & Johnson to deliver the 24 million doses it has promised to ship to the federal government this month.In the meantime, the Emergent factory faces a complex and costly makeover to devote itself solely to producing the Johnson & Johnson vaccine. Experts said it could take weeks to phase out production of AstraZeneca’s vaccine at the 112,000-square-foot plant and restart it somewhere else. Emergent announced on Monday that the government had awarded it another $23 million to help expand Johnson & Johnson’s production lines.The plant remains a risky bet for the government. While Johnson & Johnson is expected to roughly double the number of supervisors on-site, to about 12, the work force of hundreds is still Emergent’s. Some federal officials are privately concerned that the government is stuck in an unhappy marriage with Emergent and that Johnson & Johnson, whose manufacturing expertise is largely overseas, may not be able to salvage it.For President Biden, who has vowed to “always level with the American people,” the factory’s error — which was not known publicly until The Times reported it last week — is as much a public-relations problem as a supply problem.Emergent said last week that it would destroy millions of doses’ worth of the Johnson & Johnson vaccine after contamination with the AstraZeneca vaccine was discovered.Bryan Anselm for The New York TimesEven without any doses made by Emergent, administration officials say they will have enough vaccine by the end of May to cover as many as 240 million of the roughly 260 million American adults. That puts them on track to meet Mr. Biden’s goal of having enough for everyone who wants to be vaccinated.But the story of the ruined doses is also unfolding against the backdrop of a highly politicized public health crisis, just as the administration is trying to convince skeptics that Covid-19 vaccines are safe.“I want to emphasize the issue at the Baltimore plant did not impact any J&J doses that had been distributed, as all J&J finished doses to date were produced in a different, F.D.A.-approved facility,” Jeffrey D. Zients, the White House coronavirus response coordinator, told reporters last week.The Biden administration must also figure out how to rein in a company accustomed to getting its way with the government.After the administration announced Saturday that Johnson & Johnson would take control of the Covid-19 manufacturing from Emergent, the company issued its own statement Sunday night noting that it “continues to own and operate” the plant while also suggesting it welcomed “the additional oversight and support.”The Biden team was apparently displeased. Hours later, sometime past midnight, the statement was amended to acknowledge that Johnson & Johnson now has “final signoff of manufacturing” its vaccine at the Baltimore plant.Kitty Bennett

A tsunami of chronic health conditions as a result of the SARS-CoV-2 pandemic, especially cardiometabolic disease, may produce an enormous wave of death and disability that demands immediate, comprehensive strategies. In addition, COVID-19 has disrupted cardiovascular science and medicine, yet it presents opportunities to transform and create novel approaches that can yield new successes. These are the opinions of two esteemed leaders in cardiovascular disease care, research and strategy, detailed in two new Frame of Reference articles published today in the American Heart Association’s flagship journal Circulation.
While COVID-19 has severely impacted everyone’s daily lives, its societal and economic impact will be present for generations. It has prompted urgent responses in many sectors that could be models for rapidly developing real-world solutions that can improve efforts focused on prevention of chronic health conditions. Dramatic transformation in health care research is needed to align with the disruption of cardiovascular care and heart health caused by the COVID-19 pandemic.
The first article, “Avoiding the Coming Tsunami of Common, Chronic Disease: What the Lessons of the COVID-19 Pandemic Can Teach Us,” is authored by Robert M. Califf, M.D. He is the head of clinical policy and strategy at Verily Life Sciences and Google Health, a former commissioner of the U.S. Food and Drug Administration, former vice chancellor for health data science at Duke University School of Medicine and the founding director of the Duke Clinical Research Institute.
In his article, Califf urges swift and comprehensive action to avoid the dramatic rise in chronic health conditions, particularly cardiometabolic disease, that are to be expected as a result of COVID-19. Three of the top 10 leading causes of death in the U.S., cardiovascular disease, stroke and type 2 diabetes, are linked to cardiometabolic disease.
He calls for critical shifts in the U.S. health care system to include universal health care, public health and research strategies that incorporate “big data,” and improved health data sharing that can inform more effective and efficient prevention and treatment protocols and programs across society.”
Califf also notes the impacts of structural racism and that social determinants of health must be incorporated at all levels of research, clinical care and within communities and society at large for equitable, systemic improvement in health outcomes to be realized. He advocates for universal access to broadband internet that could increase access to medical information, digital support programs and telehealth appointments with health care professionals.

Home brewing enthusiasts and major manufacturers alike experience the same result of the beer-making process: mounds of leftover grain. Once all the flavor has been extracted from barley and other grains, what’s left is a protein- and fiber-rich powder that is typically used in cattle feed or put in landfills. Today, scientists report a new way to extract the protein and fiber from brewer’s spent grain and use it to create new types of protein sources, biofuels and more.
The researchers will present their results today at the spring meeting of the American Chemical Society (ACS). 
“There is a critical need in the brewing industry to reduce waste,” says Haibo Huang, Ph.D., the project’s principal investigator. His team partnered with local breweries to find a way to transform leftover grain into value-added products.
“Spent grain has a very high percentage of protein compared to other agricultural waste, so our goal was to find a novel way to extract and use it,” says Yanhong He, a graduate student who is presenting the work at the meeting. Both Huang and He are at Virginia Polytechnic and State University (Virginia Tech).
Craft brewing has become more popular than ever in the U.S. This increased demand has led to an increase in production, generating a major uptick in waste material from breweries, 85% of which is spent grain. This byproduct comprises up to 30% protein and up to 70% fiber, and while cows and other animals may be able to digest spent grain, it is difficult for humans to digest it because of its high fiber content.
In order to transform this waste into something more functional, Huang and He developed a novel wet milling fractionation process to separate the protein from the fiber. Compared to other techniques, the new process is more efficient because the researchers do not have to dry the grain first. They tested three commercially available enzymes — alcalase, neutrase and pepsin — in this process and found that alcalase treatment provided the best separation without losing large amounts of either component. After a sieving step, the result was a protein concentrate and a fiber-rich product.
Up to 83% of the protein in the spent grain was recaptured in the protein concentrate. Initially the researchers proposed using the extracted protein as a cheaper, more sustainable replacement for fishmeal to feed farmed shrimp. But more recently, Huang and He have started to explore using the protein as an ingredient in food products, catering to the consumer demand for alternate protein sources.
However, that still left the remaining fiber-rich product without a specific use. Last year, Huang’s postdoctoral researcher Joshua O’Hair, Ph.D., reported finding a new species of Bacillus lichenformis in a spring at Yellowstone National Park. In the paper, they noted that the bacteria could convert various sugars to 2,3-butanediol, a compound that is used to make many products, such as synthetic rubber, plasticizers and 2-butanol, a fuel. So, He pretreated the extracted fiber with sulfuric acid, then broke it down into sugars from cellulose and hemicellulose. She then fed the sugars to the microbe, producing 2,3-butanediol.
Next, the team plans to work on scaling up the process of separating the protein and fiber components in order to keep up with the volume of spent grain generated at breweries. They are also working with colleagues to determine the economic feasibility of the separation process, as the enzymes currently used to separate the protein and fiber components are expensive. Huang and He hope to find suitable enzymes and green chemicals to make this process even more sustainable, scalable and affordable.
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