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Fighting fish synchronize their moves—and their genes
Male Siamese fighting fish must be kept separate or they get into long fights.
VALLORIE FRANCIS/ALAMY STOCK PHOTO
I HAVE BEEN RAISING (SAVING) BETA'S FROM STUPID SMALL JARS AND GLASSES FOR DECADES NOW, ONE AT A TIME. THEY GET A TEN GALLON TANK TO THEMSELVES, WELL WITH HALF DOZEN NEON TETRA'S AND A COUPLE OF ALBINO CATFISH. ALL VERY SOCIAL FISH. THEY LIVE TWO YEARS ON AVERAGE, OUR LAST ONE LIVED THREE ALMOST FOUR, THE LAST YEAR WAS SLOW DEATH.
By Elizabeth Pennisi Jun. 17, 2020
When Muhammad Ali duked it out with Joe Frazier in the boxing ring, it’s unlikely anyone thought about what was happening to the genes inside their heads. But a new study in fighting fish has demonstrated that as the fish spar, genes in their brains begin to turn on and off in a coordinated way. It’s still unclear what those genes are doing or how they influence the skirmish, but similar changes may be happening in humans.
The work is “a really cool example of the way that social interactions can get under the skin,” says Alison Bell, a behavioral ecologist at the University of Illinois, Urbana-Champaign, who was not involved with the study.
The molecular basis of how animals, humans included, coordinate behaviors is a mystery. Whether it be mating or fighting, “animals need to be really good at this, but we don’t particularly know how they do it,” says Hans Hofmann, an evolutionary social neuroscientist at the University of Texas, Austin.
When molecular biologist Norihiro Okada at Kitasato University in Japan first saw Siamese fighting fish (Betta splendens) on TV, he realized the animals could help solve this mystery. Native to Thailand, these goldfish-size swimmers have been bred to have very large, vibrantly colored fins and tails. Aquarium owners tend to keep their pets, or “bettas” as they are often called, separate. The fish are territorial and can get into fights that last more than 1 hour, with strikes, bites, and chases (as seen in the video below). They will even lock jaws in a fish version of an arm wrestle.
Okada and colleagues videotaped more than a dozen hours of fights between 17 pairs of fish and then analyzed what happened—and when—in each fight. The longer the fight, the more the fish synchronize their behavior, timing their circling, striking, and biting more than anyone had ever realized, the researchers report today in PLOS Genetics.
The team also determined that fights are highly choreographed. Battles last about 80 minutes, for example, with seemingly “agreed on” breaks between each move. Bouts escalate every 5 to 10 minutes, when fish lock onto each other’s jaws and hold on, a tactic that prevents breathing—and is thus a test of who can hold on the longest. The bettas then break apart to breathe, and the cycle begins anew.
This coordinated behavior happens at a molecular level, too, the researchers found.
After 20 minutes of battle, five pairs of fish were sacrificed, and the researchers compared which genes were turned on in fish brains pre- and postbattle. They did the same for another five pairs after 60 minutes.
At 20 minutes, some of the same genes—“intermediate early genes” that turn on other genes—were active in each fish, the team found. At 60 minutes, hundreds more genes had coordinated expression. The timing of when particular genes turn on is specific to each pair of fish, suggesting the pair’s interactions are coordinating the cascade of changes. “They see a remarkable degree of synchronization,” Hofmann says.
Okada doesn’t know exactly what these genes are doing or how they affect the course of the fight. The weaker fighter needs to be able to assess his opponent’s strength and quit before getting hurt, and the genes may play a role in that, he suggests. But Hofmann and Bell suspect these genes have more influence on how the fish will respond to future fights with other fish.
Last year, two teams reported in Cell that interacting mammals synchronize brain activity. One studied bats flying around a dark room and avoiding collisions, and the other tested dominance in mice in a small arena. In both studies, the longer the animals interacted, the more synchronized their brain activity became.
This latest research “adds a new dimension,” to that work, as it now seems that genes as well as nerve activity get synchronized, says one of the Cell paper’s authors, neuroscientist Weizhe Hong of the University of California, Los Angeles. “Their findings definitely raise many exciting questions for future studies.”
And what we see in fish may apply to humans as well, Bell says. A study from the 1980s, for example, showed the facial features of married couples who had lived together a long time tended to look more and more alike. That, too, Okada says, may also signal a convergence of gene activity.
Posted in:
Plants & Animals
Elizabeth Pennisi
Liz is a senior correspondent covering many aspects of biology for Science.
AMERIKA
A new study suggests stricter gun access and use laws could reduce firearm-related deaths up to 11% annually. 
KRISTOFFER TRIPPLAAR/ALAMY STOCK PHOTO
Three types of laws could reduce gun deaths by more than 10%
By Michael PriceJun. 15, 2020 , 3:05 PM
Nearly 40,000 people were killed by firearms in the United States in 2018, but curbing these numbers has been a statistically tricky—and politically fraught—problem. Now, a study that tracked individual gun laws over time suggests states can reduce gun deaths significantly by doing three things: limiting children’s access to guns, restricting concealed-carry permits, and restricting “stand your ground” policies.
The study isn’t without its flaws, but the basic findings make sense to Elinore Kaufman, a surgeon and public health policy analyst at the University of Pennsylvania. “Stand your ground laws encourage individuals to try to solve problems with bullets,” she says, as do right-to-carry laws. But laws that limit access to guns for children, she says, could help prevent firearm suicides by making it harder for everyone—not just children—to access guns in the first place.
U.S. gun laws vary considerably by state. Some, like Kansas, allow citizens to carry firearms in public and make it legal for gun owners to shoot an assailant in self-defense in some situations (known as the stand your ground doctrine). Others, like California, are more restrictive, limiting not only who is allowed to carry guns in public, but also access to firearms in the home by requiring safety devices such as trigger locks or gun safes.
This patchwork—combined with limited funding for research—has made it hard for scientists to predict the effects of gun laws on gun deaths, says Terry Schell, a senior behavioral scientist at the nonprofit RAND Corporation, which aims to improve public policy through research and analysis.
To limit these problems, Schell and colleagues focused on just three kinds of laws and one outcome: gun deaths per capita. To understand how laws affect death rates, they screened hundreds of existing and novel statistical approaches, finally zeroing in on a model that reduces statistical noise by paying special attention to how different variables affect deaths year by year, rather than averaged over long periods of time.
The researchers counted the number of gun deaths from all 50 states for each year from 1980 to 2016. They then examined each instance of a new law limiting or allowing right to carry, stand your ground, or child access, state by state, through 2013. Finally, they compared that with mortality data from the Centers for Disease Control and Prevention (CDC) for the next 6 years.
On average, establishing right-to-carry and stand your ground laws resulted in a slight uptick in annual gun deaths—about 3% for each law, the team reports today in the Proceedings of the National Academy of Sciences. Conversely, creating laws aimed at making it harder to for children to get their hands on guns—say, by requiring parents to keep guns in safes—reduced gun deaths by an average of 6%. States that enacted strict child access laws, make it illegal to carry a gun in public without a permit, and don’t have a stand your ground law could expect to see an 11% reduction in annual gun deaths, according to the new model.
Eight states presently have that constellation of laws—California, Connecticut, Delaware, Hawaii, Maryland, Massachusetts, New Jersey, and Rhode Island—and six of those states are in the bottom 10 for per capita gun deaths, according to CDC’s state-by-state firearm mortality data.
However, because the study looked at a relatively small subset of gun laws, more research is needed to adequately understand how different laws such as background checks and waiting periods impact gun deaths, Kaufman says. And she suggests future studies could examine how these laws and their enforcement in different communities might also affect the impact that such laws have in different places.
Ali Rowhani-Rahbar, an epidemiologist at the University of Washington, Seattle, who studies gun policy, adds that it will also be important for such models to look at nonfatal gunshot injuries to better understand the impact of guns on communities and public health.
For now, Schell hopes providing more statistically valid data about the effects of different types of gun laws will help policymakers take action on this issue. Kaufman agrees. “Scientific evidence alone is not going to be enough to convince lawmakers who are opposed to any restriction on firearms,” she says, “but I still believe that building the evidence base can slowly change the minds [that are open to change]
Michael Price is a science journalist in San Diego, California.
DNA from ancient Irish tomb reveals incest and an elite class that ruled early farmers
Early Irish royalty may have been buried in Newgrange tomb,
Early Irish royalty may have been buried in Newgrange tomb,
shown at dawn on the winter solstice.
KEN WILLIAMS/SHADOWSANDSTONE.COM
By Andrew Curry Jun. 17, 2020
Twenty-five kilometers north of Dublin, a masterpiece of Stone Age engineering rises from the hills: a circular structure 12 meters high, almost the area of a U.S. football field, and made up of more than 200,000 tons of earth and stone. Some of the first farmers to arrive in Ireland erected this monument, called Newgrange, nearly 1000 years before Stonehenge or Egypt’s first pyramids were built. Archaeologists have assumed it was a ceremonial site and communal tomb—an expression of an egalitarian society.
Now, DNA from a middle-aged man buried in 3200 B.C.E. at the center of this mighty mound suggests otherwise. His genes indicate he had parents so closely related they must have been brother and sister or parent and child.
Across cultures, incest is almost always taboo—except in inbred royal families. Its genetic traces at Newgrange suggest social hierarchy took hold in Ireland earlier than thought, according to a new study. “Maybe we’ve been arguing too far that [these people were] egalitarian,” says Jessica Smyth, an archaeologist at University College Dublin who was not part of the team.
The newly sequenced genomes from Newgrange and other Irish tombs are part of a wider re-evaluation of the Neolithic era, which is marked by the advent of agriculture. Over the past decade, researchers have used ancient DNA to track a slow-motion, 5000-year expansion of ancient farmers from Anatolia across Europe. The Neolithic settlers who arrived in Ireland around 3700 B.C.E. were the westernmost limit of that expansion.
Most Irish Neolithic settlements are small scale, with houses of roughly equal size. As seen in Neolithic graves across Europe, their burials show little sign of hierarchy. Even in major monuments like Newgrange, human remains were jumbled together, as if in a communal tomb. “Archaeologists [have] argued for a long time for a more egalitarian Neolithic,” says co-author Thomas Kador, an archaeologist at University College London.
Newgrange is pierced by a passage that leads to a central chamber; its entrance is oriented so a ray of sunlight illuminates the chamber at dawn on the shortest day of the year. “It’s clearly a place of public ritual and must have taken a lot of manpower to construct,” says geneticist Lara Cassidy of Trinity College Dublin. Hundreds of such passage tomb monuments are found across Ireland.
Most of the bodies in those tombs were cremated. But at the heart of Newgrange, excavators in the 1970s found the unburnt bones of one man, labeled NG10, in a niche decorated with elaborately carved stones. Cassidy and her co-authors were able to extract DNA from NG10’s petrous bone, a dense part of the inner ear.
Comparing NG10’s DNA and that of other Neolithic burials with DNA from people living on the island centuries earlier shows Neolithic farmers arrived in Ireland as part of a mass migration, and soon swamped or eliminated the genetic legacy of earlier hunter-gatherers, says geneticist Daniel Bradley, a co-author also at Trinity College Dublin.
NG10’s DNA also reveals his unusual parentage. In a paper published today in Nature, Cassidy and her co-authors draw on parallels in the historical record to argue that the son of an incestuous union buried in such a prominent tomb points to a hereditary ruling class. “Matings like that are taboo pretty much universally, with very few exceptions,” she says.
Those exceptions include Egyptian pharaohs, who were considered deities who needed to marry each other. Royal siblings in Hawaii and the Incan empire were also known to marry, concentrating power in one family. “I believe we’re seeing a similar social dynamic at play among colonists of Neolithic Ireland,” Cassidy says.
Additional DNA from more than 40 people buried at other Neolithic sites, including three passage tombs, supports the existence of a close-knit elite. People buried in passage tomb sites were more closely related to each other than to people buried in other types of tombs, even though the passage tombs were separated by hundreds of kilometers and spanned more than 500 years. Some individuals in the far-flung passage tombs could have been second or third cousins or great-great-great-great-grandparent and child.
Chemical isotopes in their bones show the people in the passage tomb burials ate more meat and animal products than their contemporaries. The burials also include women and children, suggesting social status was inherited rather than won in a single lifetime, for example in battle. “We’re not talking about strong men, we’re talking about something that could be inherited and maintained over several generations,” Kador says. “A small [related] elite called the shots, like in Egypt.”
But other archaeologists are cautious. “To go from [NG10] to saying these are proto-state societies where you have a godlike elite is pushing it a bit far,” says University of Manchester archaeologist Julian Thomas. “It’s one guy.” He notes Newgrange was a burial place for almost 1000 years, too long to make generalizations from a single burial.
Monuments like Newgrange may have been used communally at certain times and co-opted as personal tombs for brief periods, says Alasdair Whittle, an archaeologist at Cardiff University. “It’s a really stunning discovery,” he says of NG10 parentage. But “social difference in the Neolithic, when it occurs, was often relatively short lived.”
He suggests that in the years before NG10 was born, an elite may have emerged temporarily in response to crisis. A climate downturn in the middle of the fourth millennium B.C.E., around the time the passage tombs reach their peak, could have led to famine, prompting dramatic but temporary change in the way society was organized.
One way to settle the debate is to look at similar passage tombs built on the Orkney Islands and in Wales and France. “The question is whether this arose in Ireland or whether they were importing existing social structures into the island,” Cassidy says. “It’s going to be very exciting to see if this is a pattern we see in other areas.”
Posted in:
Archaeology
doi:10.1126/science.abd3676Andrew Curry is a journalist in Berlin.
By Andrew Curry Jun. 17, 2020
Twenty-five kilometers north of Dublin, a masterpiece of Stone Age engineering rises from the hills: a circular structure 12 meters high, almost the area of a U.S. football field, and made up of more than 200,000 tons of earth and stone. Some of the first farmers to arrive in Ireland erected this monument, called Newgrange, nearly 1000 years before Stonehenge or Egypt’s first pyramids were built. Archaeologists have assumed it was a ceremonial site and communal tomb—an expression of an egalitarian society.
Now, DNA from a middle-aged man buried in 3200 B.C.E. at the center of this mighty mound suggests otherwise. His genes indicate he had parents so closely related they must have been brother and sister or parent and child.
Across cultures, incest is almost always taboo—except in inbred royal families. Its genetic traces at Newgrange suggest social hierarchy took hold in Ireland earlier than thought, according to a new study. “Maybe we’ve been arguing too far that [these people were] egalitarian,” says Jessica Smyth, an archaeologist at University College Dublin who was not part of the team.
The newly sequenced genomes from Newgrange and other Irish tombs are part of a wider re-evaluation of the Neolithic era, which is marked by the advent of agriculture. Over the past decade, researchers have used ancient DNA to track a slow-motion, 5000-year expansion of ancient farmers from Anatolia across Europe. The Neolithic settlers who arrived in Ireland around 3700 B.C.E. were the westernmost limit of that expansion.
Most Irish Neolithic settlements are small scale, with houses of roughly equal size. As seen in Neolithic graves across Europe, their burials show little sign of hierarchy. Even in major monuments like Newgrange, human remains were jumbled together, as if in a communal tomb. “Archaeologists [have] argued for a long time for a more egalitarian Neolithic,” says co-author Thomas Kador, an archaeologist at University College London.
Newgrange is pierced by a passage that leads to a central chamber; its entrance is oriented so a ray of sunlight illuminates the chamber at dawn on the shortest day of the year. “It’s clearly a place of public ritual and must have taken a lot of manpower to construct,” says geneticist Lara Cassidy of Trinity College Dublin. Hundreds of such passage tomb monuments are found across Ireland.
Most of the bodies in those tombs were cremated. But at the heart of Newgrange, excavators in the 1970s found the unburnt bones of one man, labeled NG10, in a niche decorated with elaborately carved stones. Cassidy and her co-authors were able to extract DNA from NG10’s petrous bone, a dense part of the inner ear.
Comparing NG10’s DNA and that of other Neolithic burials with DNA from people living on the island centuries earlier shows Neolithic farmers arrived in Ireland as part of a mass migration, and soon swamped or eliminated the genetic legacy of earlier hunter-gatherers, says geneticist Daniel Bradley, a co-author also at Trinity College Dublin.
NG10’s DNA also reveals his unusual parentage. In a paper published today in Nature, Cassidy and her co-authors draw on parallels in the historical record to argue that the son of an incestuous union buried in such a prominent tomb points to a hereditary ruling class. “Matings like that are taboo pretty much universally, with very few exceptions,” she says.
Those exceptions include Egyptian pharaohs, who were considered deities who needed to marry each other. Royal siblings in Hawaii and the Incan empire were also known to marry, concentrating power in one family. “I believe we’re seeing a similar social dynamic at play among colonists of Neolithic Ireland,” Cassidy says.
Additional DNA from more than 40 people buried at other Neolithic sites, including three passage tombs, supports the existence of a close-knit elite. People buried in passage tomb sites were more closely related to each other than to people buried in other types of tombs, even though the passage tombs were separated by hundreds of kilometers and spanned more than 500 years. Some individuals in the far-flung passage tombs could have been second or third cousins or great-great-great-great-grandparent and child.
Chemical isotopes in their bones show the people in the passage tomb burials ate more meat and animal products than their contemporaries. The burials also include women and children, suggesting social status was inherited rather than won in a single lifetime, for example in battle. “We’re not talking about strong men, we’re talking about something that could be inherited and maintained over several generations,” Kador says. “A small [related] elite called the shots, like in Egypt.”
But other archaeologists are cautious. “To go from [NG10] to saying these are proto-state societies where you have a godlike elite is pushing it a bit far,” says University of Manchester archaeologist Julian Thomas. “It’s one guy.” He notes Newgrange was a burial place for almost 1000 years, too long to make generalizations from a single burial.
Monuments like Newgrange may have been used communally at certain times and co-opted as personal tombs for brief periods, says Alasdair Whittle, an archaeologist at Cardiff University. “It’s a really stunning discovery,” he says of NG10 parentage. But “social difference in the Neolithic, when it occurs, was often relatively short lived.”
He suggests that in the years before NG10 was born, an elite may have emerged temporarily in response to crisis. A climate downturn in the middle of the fourth millennium B.C.E., around the time the passage tombs reach their peak, could have led to famine, prompting dramatic but temporary change in the way society was organized.
One way to settle the debate is to look at similar passage tombs built on the Orkney Islands and in Wales and France. “The question is whether this arose in Ireland or whether they were importing existing social structures into the island,” Cassidy says. “It’s going to be very exciting to see if this is a pattern we see in other areas.”
Posted in:
Archaeology
doi:10.1126/science.abd3676Andrew Curry is a journalist in Berlin.
A controversial Russian theory claims forests don’t just make rain—they make wind
By Fred Pearce Jun. 18, 2020
Every summer, as the days get long, Anastassia Makarieva leaves her lab in St. Petersburg for a vacation in the vast forests of northern Russia. The nuclear physicist camps on the shores of the White Sea, amid spruce and pine, and kayaks along the region’s wide rivers, taking notes on nature and the weather. “The forests are a big part of my inner life,” she says. In the 25 years she has made her annual pilgrimage north, they have become a big part of her professional life, too.
For more than a decade, Makarieva has championed a theory, developed with Victor Gorshkov, her mentor and colleague at the Petersburg Nuclear Physics Institute (PNPI), on how Russia’s boreal forests, the largest expanse of trees on Earth, regulate the climate of northern Asia. It is simple physics with far-reaching consequences, describing how water vapor exhaled by trees drives winds: winds that cross the continent, taking moist air from Europe, through Siberia, and on into Mongolia and China; winds that deliver rains that keep the giant rivers of eastern Siberia flowing; winds that water China’s northern plain, the breadbasket of the most populous nation on Earth.
With their ability to soak up carbon dioxide and breathe out oxygen, the world’s great forests are often referred to as the planet’s lungs. But Makarieva and Gorshkov, who died last year, say they are its beating heart, too. “Forests are complex self-sustaining rainmaking systems, and the major driver of atmospheric circulation on Earth,” Makarieva says. They recycle vast amounts of moisture into the air and, in the process, also whip up winds that pump that water around the world. The first part of that idea—forests as rainmakers—originated with other scientists and is increasingly appreciated by water resource managers in a world of rampant deforestation. But the second part, a theory Makarieva calls the biotic pump, is far more controversial.
The theoretical foundation of the work has been published, albeit in lesser known journals, and Makarieva has received support from a small coterie of colleagues. But the biotic pump has faced a head wind of criticism, especially from climate modelers, some of whom say its effects are negligible and dismiss the idea completely. The dispute has made Makarieva an outsider: a theoretical physicist in a world of modelers, a Russian in a field led by Western scientists, and a woman in a field dominated by men.
Yet, if correct, the idea could help explain why, despite their distance from the oceans, the remote interiors of forested continents receive as much rain as the coasts—and why the interiors of unforested continents tend to be arid. It also implies that forests from the Russian taiga to the Amazon rainforest don’t just grow where the weather is right. They also make the weather. “All I have learned so far suggests to me that the biotic pump is correct,” says Douglas Sheil, a forest ecologist at the Norwegian University of Life Sciences. With the future of the world’s forests in doubt, “Even if we thought the theory had only a small chance of being true, it would be profoundly important to know one way or the other.”
Many meteorology textbooks still teach a caricature of the water cycle, with ocean evaporation responsible for most of the atmospheric moisture that condenses in clouds and falls as rain. The picture ignores the role of vegetation and, in particular, trees, which act like giant water fountains. Their roots capture water from the soil for photosynthesis, and microscopic pores in leaves release unused water as vapor into the air. The process, the arboreal equivalent of sweating, is known as transpiration. In this way, a single mature tree can release hundreds of liters of water a day. With its foliage offering abundant surface area for the exchange, a forest can often deliver more moisture to the air than evaporation from a water body of the same size.
The importance of this recycled moisture for nourishing rains was largely disregarded until 1979, when Brazilian meteorologist Eneas Salati reported studies of the isotopic composition of rainwater sampled from the Amazon Basin. Water recycled by transpiration contains more molecules with the heavy oxygen-18 isotope than water evaporated from the ocean. Salati used this fact to show that half of the rainfall over the Amazon came from the transpiration of the forest itself.
By this time, meteorologists were tracking an atmospheric jet above the forest, at a height of about 1.5 kilometers. Known as the South American Low-Level Jet, the winds blow east to west across the Amazon, about as fast as a racing bike, before the Andes Mountains divert them south. Salati and others surmised the jet carried much of the transpired moisture, and dubbed it a “flying river.” The Amazon flying river is now reckoned to carry as much water as the giant terrestrial river below it, says Antonio Nobre, a climate researcher at Brazil’s National Institute for Space Research.
For some years, flying rivers were thought to be limited to the Amazon. In the 1990s, Hubert Savenije, a hydrologist at the Delft University of Technology, began to study moisture recycling in West Africa. Using a hydrological model based on weather data, he found that, as one moved inland from the coast, the proportion of the rainfall that came from forests grew, reaching 90% in the interior. The finding helped explain why the interior Sahel region became dryer as coastal forests disappeared over the past half-century.
One of Savenije’s students, Ruud van der Ent, took the idea further, creating a global model of airborne moisture flow. He combined observational data on rainfall, humidity, wind speed, and temperature with theoretical estimates of evaporation and transpiration to create the first model of moisture flow at scales larger than river basins.
In 2010, van der Ent and his colleagues reported the model’s conclusion: Globally, 40% of all precipitation comes from the land rather than the ocean. Often it is more. The Amazon’s flying river provides 70% of the rain falling in the RÃo de la Plata Basin, which stretches across southeastern South America. Van der Ent was most surprised to find that China gets 80% of its water from the west, mostly Atlantic moisture recycled by the boreal forests of Scandinavia and Russia. The journey involves several stages—cycles of transpiration followed by downwind rain and subsequent transpiration—and takes 6 months or more. “It contradicted previous knowledge that you learn in high school,” he says. “China is next to an ocean, the Pacific, yet most of its rainfall is moisture recycled from land far to the west.”
IF MAKARIEVA IS CORRECT, the forests supply not just the moisture, but the winds that carry it.
For a quarter-century, she worked with Gorshkov, initially as his pupil, at PNPI—part of Russia’s foremost civil and military nuclear research agency, the Kurchatov Institute. They were mavericks from the start, studying ecology in a place full of physicists who use neutron beams from nuclear reactors to study materials. As theorists, she says, they had “exceptional freedom of research and thought,” pursuing atmospheric physics wherever it took them. “Victor taught me: Do not be afraid of anything,” she says.
In 2007, in Hydrology and Earth System Sciences, they first outlined their vision for the biotic pump. It was provocative from the outset because it contradicted a longstanding tenet of meteorology: that winds are driven largely by the differential heating of the atmosphere. When warm air rises, it lowers the air pressure below it, in effect creating space at the surface into which air moves. In summer, for example, land surfaces tend to heat faster and draw in moist breezes from the cooler ocean.
Anastassia Makarieva and Victor Gorshkov developed the biotic pump theory at a nuclear physics institute. ANASTASSIA MAKARIEVA
Makarieva and Gorshkov argued that a second process can sometimes dominate. When water vapor from forests condenses into clouds, a gas becomes a liquid that occupies less volume. That reduces air pressure, and draws in air horizontally from areas with less condensation. In practice, it means condensation above coastal forests turbocharges sea breezes, sucking moist air inland where it will eventually condense and fall as rain. If the forests continue inland, the cycle can continue, maintaining moist winds for thousands of kilometers.
The theory inverts traditional thinking: It is not atmospheric circulation that drives the hydrological cycle, but the hydrological cycle that drives the mass circulation of air.
Sheil, who became a supporter of the theory more than a decade ago, thinks of it as an embellishment of the flying river idea. “They are not mutually exclusive,” he says. “The pump offers an explanation of the power of the rivers.” He says the biotic pump could explain the “cold Amazon paradox.” From January to June, when the Amazon Basin is colder than the ocean, strong winds blow from the Atlantic to the Amazon—the opposite of what would be expected if they resulted from differential heating. Nobre, another early acolyte, enthuses: “They don’t start with data, they start with first principles.”
Even those who doubt the theory agree that forest loss can have far-reaching climatic consequences. Many scientists have argued that deforestation thousands of years ago was to blame for desertification in the Australian Outback and West Africa. The fear is that future deforestation could dry up other regions, for example, tipping parts of the Amazon rainforest to savanna. Agricultural regions of China, the African Sahel, and the Argentine Pampas are also at risk, says Patrick Keys, an atmospheric chemist at Colorado State University, Fort Collins.
In 2018, Keys and his colleagues used a model, similar to van der Ent’s, to track the sources of rainfall for 29 global megacities. He found that 19 were highly dependent on distant forests for much of their water supply, including Karachi, Pakistan; Wuhan and Shanghai, China; and New Delhi and Kolkata, India. “Even small changes in precipitation arising from upwind land-use change could have big impacts on the fragility of urban water supplies,” he says.
Some modeling even suggests that by removing a moisture source, deforestation could alter weather patterns beyond the paths of flying rivers. Just as El Niño, a shift in currents and winds in the tropical Pacific Ocean, is known to influence weather in faraway places through “teleconnections,” so, too, could Amazon deforestation diminish rainfall in the U.S. Midwest and snowpack in the Sierra Nevada, says Roni Avissar, a climatologist at the University of Miami who has modeled such teleconnections. Far-fetched? “Not at all,” he says. “We know El Niño can do this, because unlike deforestation, it recurs and we can see the pattern. Both are caused by small changes in temperature and moisture that project into the atmosphere.”
Lan Wang-Erlandsson, who researches interactions between land, water, and climate at Stockholm University, says it’s time for water resource managers to shift their focus from water and land use within a river basin to land-use changes occurring outside it. “We need new international hydrological agreements to maintain the forests of source regions,” she says.
We need new international hydrological agreements to maintain the forests of source regions.Lan Wang-Erlandsson, Stockholm University
Two years ago, at a meeting of the United Nations Forum on Forests, a high-level policy group on which all governments sit, David Ellison, a land researcher at the University of Bern, presented a case in point: a study showing that as much as 40% of the total rainfall in the Ethiopian highlands, the main source of the Nile, is provided by moisture recycled from the forests of the Congo Basin. Egypt, Sudan, and Ethiopia are negotiating a long-overdue deal on sharing the waters of the Nile. But such an agreement would be worthless if deforestation in the Congo Basin, far from those three nations, dries up the moisture source, Ellison suggested. “Interactions between forests and water have been almost entirely ignored in the management of global freshwater resources.”
The biotic pump would raise the stakes even further, with its suggestion that forest loss alters not just moisture sources, but also wind patterns. The theory, if correct, would have “crucial implications for planetary air circulation patterns,” Ellison warns, especially those that take moist air inland to continental interiors.
THE THEORY’S SUPPORTERS are a minority. In 2010, Makarieva, Gorshkov, Sheil, Nobre, and Bai-Lian Li, an ecologist at the University of California, Riverside, submitted what was meant to be a landmark description of the biotic pump to Atmospheric Chemistry and Physics, a major journal with open peer review. Titled “Where Do Winds Come From?” the paper faced a barrage of criticism online, and it took the journal many months to find two scientists willing to review it. Isaac Held, a meteorologist at Princeton University’s Geophysical Fluid Dynamics Laboratory, finally volunteered—and recommended rejection. “This is not a mysterious effect,” he says. “It is small and included in some atmospheric models.” Critics said the expansion of air from heat released when water vapor condenses counteracts the space-creating effect of condensation. But Makarieva says the two effects are spatially separate, with the warming effect happening aloft, and the pressure drop of condensation occurring closer to the surface, where it generates the biotic wind.
The other reviewer was Judith Curry, then an atmospheric physicist at the Georgia Institute of Technology, who has long had concerns about the atmospheric dynamics at the core of climate models. She felt it was important to publish the paper and says the standoff was “very bad for climate science, which badly needs an infusion from hard-core physicists.” After 3 years of debate, the journal’s editor overruled Held’s recommendation and published the paper, saying it was published “not as an endorsement” but “to promote continuation of the scientific dialogue on the controversial theory [that] may lead to disproof or validation.”
Since then, there has been neither validation nor disproof, but largely a standoff. Gavin Schmidt, a climate modeler at Columbia University, says, “It’s simply nonsense.” The authors’ responses to criticisms were “really just mathematics that gave no one any confidence that there was any point in continuing the dialogue.” Jose Marengo, a meteorologist in Brazil and head of the National Centre for Monitoring and Warning of Natural Disasters, says: “I think the pump exists, but it’s very theoretical right now. The climate model community hasn’t embraced it, but the Russians are the best theoreticians in the world, so we need proper field experiments to test it.” Yet no one, including Makarieva, has yet proposed clearly what such a test might look like.
For her part, Makarieva is building on the theory, arguing in a series of recent papers that the same mechanism can affect tropical cyclones, which are driven by the heat released when moisture condenses over the ocean. In a 2017 paper in Atmospheric Research, she and her colleagues proposed that biotic pumps set up by the forests on land draw moisture-rich air away from the cyclone nurseries. This, she says, might explain why cyclones rarely form in the South Atlantic Ocean: The Amazon and Congo rainforests between them draw so much moisture away that there is too little left to fuel hurricanes.
Kerry Emanuel, a leading hurricane researcher at the Massachusetts Institute of Technology, says the proposed effects “while not negligible are very small.” He prefers other explanations for the lack of South Atlantic hurricanes, such as the region’s cool waters, which send less moisture into the air, and its strong shearing winds, which disrupt cyclone formation. Makarieva is equally dismissive of the traditionalists, saying some of the existing theories for hurricane intensity “conflict with the laws of thermodynamics.” She has another paper on the topic under peer review at the Journal of the Atmospheric Sciences. “We are concerned that, despite the editor’s encouragement, our work will get rejected once again,” she says.
Even if Makarieva’s ideas are fringy in the West, they are taking root in Russia. Last year, the government began a public dialogue to revise its forestry laws. Aside from strictly protected areas, Russian forests are open to commercial exploitation, but the government and the Federal Forestry Agency are considering a new designation of “climate protection forests.” “Some representatives of our forest department got impressed by the biotic pump and want to introduce a new category,” she says. The idea has the backing of the Russian Academy of Sciences. Being part of a consensus rather than the perennial outsider marks a change, Makarieva says.
This summer, the coronavirus lockdown put the kibosh on her annual trip to the northern forests. Back in St. Petersburg, she has settled down to respond to yet another round of objections to her work from anonymous peer reviewers. She insists the pump theory will ultimately prevail. “There is a natural inertia in science,” she says. With a dark Russian humor, she invokes the words of the legendary German physicist Max Planck, who is said to have once remarked that science “advances one funeral at a time.”
doi:10.1126/science.abd3856
Fred Pearce is a journalist in London.
Researchers say they’ve solved the mystery of the missing dinosaur eggs
A Protoceratops nest with embryos curled up inside soft-shelled eggs
A Protoceratops nest with embryos curled up inside soft-shelled eggs
M. ELLISON/© AMNH
By Colin Barras Jun. 17, 2020
Fifteen years ago, Mark Norell came across a clutch of dinosaur eggs in southern Mongolia. Frozen in place were at least a dozen embryos of the Triceratops relative Protoceratops. But “something weird” was going on, says the paleontologist, who works at the American Museum of Natural History. It was as if the tiny dinosaurs were curled up inside invisible eggs. In the rock immediately surrounding each miniskeleton was an enigmatic white halo. Now, more than 10 years later, he and colleagues say they have solved the mystery: The dinosaurs had laid soft-shelled eggs.
Their new study of the Protoceratops clutch helps explain why dinosaur eggs are relatively rare—many laid soft-shelled eggs that were unlikely to fossilize. Their work may also have implications for how dinosaurs grew and tended their young. And a second study in Nature suggests large marine predators called mosasaurs went soft at breeding time, too.
The Protoceratops paper is convincing, says Ricardo Araújo, a paleontologist at the Technical Univesity of Lisbon’s Institute of Plasma and Nuclear Fusion. It emphasizes “how little we know about the incredible diversity of dinosaur reproduction strategies.”
Norell and molecular paleobiologist Jasmina Wiemann at Yale University analyzed two clutches of fossil dinosaur eggs—that of the 75-million-year-old Protoceratops from Mongolia, and a clutch laid about 215 million years ago by Mussaurus, a relative of long-necked giants like Diplodocus.
A crumpled soft-shelled egg that may have been laid by a mosasaur LEGENDRE ET AL. (2020)
They used a new technique that bathes the samples in laser light and records how the light changes as it interacts with the sample’s surface, offering clues to the chemical composition of the eggshells. The molecular fingerprint of modern soft eggshells differs from that of hard eggshells. The halos around the Protoceratops and Mussaurus eggs both showed a fossilized version of this “soft eggshell” fingerprint.
Mussaurus lived early in the age of the dinosaurs, so Norrell and Wiemann say it’s likely that the first dinosaurs laid soft-shelled eggs. But the Protoceratops nest shows some species were still laying soft eggs toward the end of the age of dinosaurs 66 million years ago, even as others evolved to lay hard-shelled eggs.
Dinosaurs laying soft eggs may have buried them, given that a several-ton adult dinosaur that attempted to sit on such a fragile clutch would probably end up with scrambled eggs. Burying soft-shelled eggs also keeps them from drying out, says ecologist Ricky-John Spencer at Western Sydney University.
If dino moms did bury their eggs, the clutches might experience lower temperatures and develop more slowly—leading to “a more advanced hatchling,” that may have required less parental care, suggests Charles Deeming, a biologist at the University of Lincoln. There’s some evidence for that already in pterosaurs, winged reptiles related to dinosaurs that also laid soft-shelled eggs. Last year, Deeming and his colleague, David Unwin at the University of Leicester, argued that baby pterosaurs were so well-developed that they could fly immediately after hatching.
The second Nature study suggests some ancient marine giants laid soft-shelled eggs that may have hatched just minutes after they were laid. In 68-million-year-old rocks in Antarctica that formed on the sea floor, paleontologist Julia Clarke at the University of Texas, Austin, and colleagues discovered a 30-centimeter-long object that has the size and appearance of a deflated football. Under a microscope, the flimsy and crumpled walls of the object have the layered structure of a reptile egg—which is what Clarke thinks the object is.
It is the second largest fossil egg ever found and may have belonged to a mosasaur, a 10-meter-long marine predator. Some snakes and lizards, living mosasaur relatives, lay eggs with thin shells that hatch almost as soon as they are laid. The new find suggests mosasaurs may have, too.
Fifteen years ago, Mark Norell came across a clutch of dinosaur eggs in southern Mongolia. Frozen in place were at least a dozen embryos of the Triceratops relative Protoceratops. But “something weird” was going on, says the paleontologist, who works at the American Museum of Natural History. It was as if the tiny dinosaurs were curled up inside invisible eggs. In the rock immediately surrounding each miniskeleton was an enigmatic white halo. Now, more than 10 years later, he and colleagues say they have solved the mystery: The dinosaurs had laid soft-shelled eggs.
Their new study of the Protoceratops clutch helps explain why dinosaur eggs are relatively rare—many laid soft-shelled eggs that were unlikely to fossilize. Their work may also have implications for how dinosaurs grew and tended their young. And a second study in Nature suggests large marine predators called mosasaurs went soft at breeding time, too.
The Protoceratops paper is convincing, says Ricardo Araújo, a paleontologist at the Technical Univesity of Lisbon’s Institute of Plasma and Nuclear Fusion. It emphasizes “how little we know about the incredible diversity of dinosaur reproduction strategies.”
Norell and molecular paleobiologist Jasmina Wiemann at Yale University analyzed two clutches of fossil dinosaur eggs—that of the 75-million-year-old Protoceratops from Mongolia, and a clutch laid about 215 million years ago by Mussaurus, a relative of long-necked giants like Diplodocus.
A crumpled soft-shelled egg that may have been laid by a mosasaur LEGENDRE ET AL. (2020)
They used a new technique that bathes the samples in laser light and records how the light changes as it interacts with the sample’s surface, offering clues to the chemical composition of the eggshells. The molecular fingerprint of modern soft eggshells differs from that of hard eggshells. The halos around the Protoceratops and Mussaurus eggs both showed a fossilized version of this “soft eggshell” fingerprint.
Mussaurus lived early in the age of the dinosaurs, so Norrell and Wiemann say it’s likely that the first dinosaurs laid soft-shelled eggs. But the Protoceratops nest shows some species were still laying soft eggs toward the end of the age of dinosaurs 66 million years ago, even as others evolved to lay hard-shelled eggs.
Dinosaurs laying soft eggs may have buried them, given that a several-ton adult dinosaur that attempted to sit on such a fragile clutch would probably end up with scrambled eggs. Burying soft-shelled eggs also keeps them from drying out, says ecologist Ricky-John Spencer at Western Sydney University.
If dino moms did bury their eggs, the clutches might experience lower temperatures and develop more slowly—leading to “a more advanced hatchling,” that may have required less parental care, suggests Charles Deeming, a biologist at the University of Lincoln. There’s some evidence for that already in pterosaurs, winged reptiles related to dinosaurs that also laid soft-shelled eggs. Last year, Deeming and his colleague, David Unwin at the University of Leicester, argued that baby pterosaurs were so well-developed that they could fly immediately after hatching.
The second Nature study suggests some ancient marine giants laid soft-shelled eggs that may have hatched just minutes after they were laid. In 68-million-year-old rocks in Antarctica that formed on the sea floor, paleontologist Julia Clarke at the University of Texas, Austin, and colleagues discovered a 30-centimeter-long object that has the size and appearance of a deflated football. Under a microscope, the flimsy and crumpled walls of the object have the layered structure of a reptile egg—which is what Clarke thinks the object is.
It is the second largest fossil egg ever found and may have belonged to a mosasaur, a 10-meter-long marine predator. Some snakes and lizards, living mosasaur relatives, lay eggs with thin shells that hatch almost as soon as they are laid. The new find suggests mosasaurs may have, too.
Drug recently shown to reduce coronavirus death risk could run out, experts warn
Injectable dexamethasone is more difficult to manufacture than tablets, because production needs to take place under sterile conditions. SOUMYABRATA ROY/NURPHOTO VIA AP
By Eli Cahan Jun. 21, 2020
Science’s COVID-19 reporting is supported by the Pulitzer Center.
This week’s report that dexamethasone, a commonly used corticosteroid, reduces death rates of COVID-19 by up to one-third was greeted with enthusiasm around the globe.#
It also raised a question: Will there be enough of the medication? So far, doctors are not reporting problems getting dexamethasone for their patients. And as many news stories have pointed out, dexamethasone is off-patent, cheap, and relatively abundant.
Related
FDA just gave a thumbs down to Trump’s favorite COVID-19 drugs
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See all of our coverage of the coronavirus outbreak
But that doesn’t mean there won’t be shortages, says Stephen Schondelmeyer, director of the Pharmaceutical Research in Management and Economics Institute at the University of Minnesota, Twin Cities. “Even though this is an old drug that’s been around a long time, I think people saying that it’s commonly available … spoke too soon, without looking at the data,” he says. Since the trial findings came out, there has been “a degree of irrational exuberance,” about dexamethasone, Schondelmeyer says. “We are already seeing hoarding behaviors and lack of availability of the product because of it,” he adds.
“Hoarding and speculative procurement appear to have already started,” confirms Emer Cooke, head of regulation of medicines and other health technologies at the World Health Organization (WHO). But she says it’s “probably too early to say if there will be a global shortage.”
The situation could become especially dire for the injectable version of the drug, which some physicians say is the preferred formulation and is more complicated to produce than oral dexamethasone. One major Indian manufacturer of intravenous dexamethasone, Cadila Healthcare, has repeatedly gotten in trouble with the U.S. Food and Drug Administration (FDA) for serious problems in its production process. According to a letter from the agency, the company said in October 2019 that it would stop producing injectable drugs for the United States.
The trial that identified dexamethasone’s potential benefit, named Recovery, included more than 6400 patients in the United Kingdom, 2104 of whom received the medication. Its outcome “offers miraculous hope that a dose of a commonplace medication might do what we all want it to do: Help people survive,” says Lewis Kaplan, a surgeon at the University of Pennsylvania’s Perelman School of Medicine and president of the Society of Critical Care Medicine (SCCM). WHO Director-General Tedros Adhanom Ghebreyesus praised the findings as a “lifesaving scientific breakthrough.” The U.K. National Health Service has already incorporated the drug into its standard of care for COVID-19 and the country issued restrictions on exports of dexamethasone. Demand appears to be surging worldwide.
How the drug is given makes a difference
But dexamethasone can be administered in several ways. According to the trial’s protocol, patients received the medication either orally or by intravenous injection. In many cases, the distinction may be trivial. But for the sickest patients, administering oral medications is “rolling the dice to some degree,” says Clifford Deutschman, an intensivist at the Feinstein Institutes for Medical Research and former SCCM president. Gastrointestinal problems in these patients can cause “inconsistencies in uptake of the medication,” leading to blood levels that are too low or too high, Deutschman says. And for patients on ventilators, administering the medication orally means grinding the pills up by hand and delivering them through fluids or a feeding tube. Both for safety and effectiveness, “Hands down, if you’ve got the intravenous stuff, you give the intravenous stuff,” he says.
The sickest patients are the ones most likely to benefit from the drug. In the study, dexamethasone reduced the death risk for patients on a ventilator by one-third, and for those requiring oxygen by one-fifth. Patients with milder disease did not benefit.
Intravenous dexamethasone was already in short supply in the United States before the Recovery results came out, according to an independent shortage tracking tool run by the American Society of Health-System Pharmacists. FDA lists the drug as “in shortage” as well. Dexamethasone is not in the U.S. Strategic National Stockpile.
Hoarding and speculative procurement appear to have already started.Emer Cooke, World Health Organization
The question is whether production of the intravenous form of dexamethasone can be ramped up quickly. Whereas oral dexamethasone is “relatively straightforward to make,” the intravenous form is harder to manufacture, says former FDA Commissioner Mark McClellan, because it needs to be done under sterile conditions to prevent microbes from reducing efficacy or sickening patients. (In 2012, a fungal meningitis outbreak linked to contaminated steroid injectables killed more than 100 people.)
Issues with quality control up the supply chain
Most of the drug is produced by two Indian companies, Wockhardt and Cadila Healthcare. Wockhardt has a “very limited” supply presently available for export, but has “enormous capacity” to produce both oral and intravenous dexamethasone and is able to ramp up further, its CEO said in a 17 June news report.
But Schondelmeyer, whose center recently launched a partnership with the U.S. Biomedical Advanced Research and Development Authority and the Department of Homeland Security to enhance the resilience of the United States’s pharmaceutical supply chain, is skeptical. “There aren’t a lot of [unused] plants that can make sterile injectables of anything, let alone dexamethasone, so I’m not sure how much capacity they really have,” he says. Ramping up supply “takes a lot of time, even if the world was normal and sane, let alone during COVID.”
FDA has turned away Cadila’s products at the U.S. border 83 times since 2004 because of quality concerns. Since 2015, the agency has sent the company three warning letters related to its production process. FDA inspectors found myriad inadequacies at Cadila’s facilities, including noncompliance with sterile procedures, evidence of Pseudomonas bacteria in the water system, and “several plastic bags filled with paperwork in the scrapyard“ including “a torn notebook of deficiencies.”
In the most recent of the three letters, dated 29 October 2019, FDA writes that Cadila Healthcare has informed the agency that it will “permanently cease production of injectable drug products for the United States.” This history “makes me very nervous, as to whether they can ramp up in the first place, and if they can, if that’s a product anyone should use,” Schondelmeyer says. (The company did not respond to requests for comment.)
Cooke stresses the importance of buying dexamethasone from quality-assured suppliers. There’s a “high risk that rogue manufacturers will offer substandard or falsified options,” she says. Trusted producers should be able to meet the rising demand, Cooke adds, but if hoarding and speculative procurement continue, “it will create chaotic demand signals and put scale up plans at risk. This is especially true for injectable products,” whose production is harder to scale up.
Potential for shortages at the bedside
McClellan does not see major problems ahead. “If there’s a reasonable response to this news, with clinicians using the drug appropriately and no disruptions related to stockpiling … I think this is a manageable development,” he says. Based on the study, the drug should only be used in severe cases, a small subset of the total number of COVID-19 patients. And physicians could use other corticosteroids—such as methylprednisolone, hydrocortisone, or prednisone—that may work as well.
Kaplan isn’t so sure: Dexamethasone has “unique properties” in the ways it interacts with the cells and proteins that produce the body’s immune response, he says. And demand may increase because doctors will prescribe the drug for less severe cases as well, Deutschman says. He is “worried” this might accelerate shortages.
“When you’re standing at the bedside watching somebody die as the family stands outside, asking yourself, is there anything else I could have done, it’s difficult to be rational,” Deutschman says. “There’s always a temptation to take the results of a trial and overextend them.”
*Correction, 22 June, 3:15 p.m.: An error in the description of FDA’s October 2019 warning letter to Cadila Healthcare has been corrected.
*Correction, 24 June, 8:05 a.m.: An incorrect statement about back orders of injectable dexamethasone at U.S. drug suppliers has been removed from this story.
Posted in:
Health
Coronavirus
doi:10.1126/science.abd4447
Eli Cahan
Eli is an intern on the News staff of Science. He is pursuing a master’s degree in health policy as a Knight-Hennessy Scholar at the Stanford School of Medicine and his MD at the New York University (NYU) School of Medicine. Twitter
A cheap steroid is the first drug shown to reduce death in COVID-19 patients
The steroid dexamethasone may quickly be added to the global standard of care for severe COVID-19 patients. REUTERS/YVES HERMAN
By Kai Kupferschmidt Jun. 16, 2020
Science’s COVID-19 reporting is supported by the Pulitzer Center.
After months of dire news about the spread of the novel coronavirus and a mounting global death toll, a glimmer of hope arrived today: Researchers announced that dexamethasone, a cheap, widely available corticosteroid, significantly reduced deaths of severely sick COVID-19 patients in a major clinical trial. Although full trial data have not yet been released, several outside commentators hailed the result as a “breakthrough.”
“These are really surprising, but really very convincing results,” says Martin Landray of the University of Oxford, one of the principal investigators of the Recovery trial in the United Kingdom that evaluated the steroid. If they hold up, adds Devi Sridhar, an expert on global public health at the University of Edinburgh, they could be a game-changer for critical patients, as the drugs are accessible even in lower-income countries.
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The Recovery trial, one of the biggest efforts to evaluate whether existing drugs can treat COVID-19, included 2104 patients given a relatively low dose of 6 milligrams of dexamethasone for 10 days. When their outcomes were compared with those of 4321 patients receiving standard care, the steroid reduced deaths by one-third in patients already on ventilators and by one-fifth in patients receiving supplemental oxygen in other ways, Recovery researchers announced in a press release. They did not find any benefit in patients not receiving respiratory support.
Dexamethasone’s effect is seemingly much stronger than that of remdesivir, the only other drug so far shown to help COVID-19 patients in a randomized clinical trial. That antiviral reduced the number of days critical patients were hospitalized, but it did not clearly reduce deaths.
Tedros Adhanom Ghebreyesus, director-general of the World Health Organization (WHO), hailed the dexamethasone results as “great news” given it’s the first COVID-19 drug that has clearly proved to reduce mortality. “The results are pretty remarkable for severely ill patients,” adds Nahid Bhadelia, a physician at Boston Medical Center. “I can see ICU [intensive care unit] physicians being more likely to provide steroids in the critically ill who are mechanically ventilated and who are not improving from other interventions based on these results.”
But she and others expressed disappointment that the Recovery team did not release additional information. “More detailed data would help us identify which subset of COVID-19 patients would benefit from steroids,” Bhadelia says.
Landray acknowledges the criticism. “I fully understand why scientists want to see the details. I’m a scientist, I want to see the details.” But with thousands of people dying of COVID-19 every day, it was important to get the basic message out first, he says. “There is this tension between having the final details and the final decimal points nailed down, and having what is actually a clear-cut and practical message in the public domain.”
Recovery is evaluating several experimental COVID-19 therapies, including the HIV drug combination Kaletra, convalescent plasma, and the controversial antimalarial drug hydroxychloroquine. When researchers found 2 weeks ago that hydroxychloroquine did not improve patient outcomes, they stopped that arm of the trial. In the other arms, Landray says, they stuck to their plan to wait until 2000 patients had received a treatment and 4000 patients had enrolled in a control arm, because that would provide a 90% chance of picking up a reduction in deaths of about 18%. Dexamethasone was the first drug to reach the milestone, so the researchers stopped its arm on 8 June and began to look at the data.
“The decimal points might change a bit when we tidy things up, but we’ve got to a point where the message will not change,” Landray says, adding that Recovery hopes to make public the full data within about 10 days. If the findings hold up under scrutiny, it would mean that treating eight ventilated patients with dexamethasone would save one life. “That is a big effect,” says Ashish Jha, a global health expert at Harvard University’s T.H. Chan School of Public Health who is eager to see the data.
The United Kingdom’s National Health Service has already announced its standard care for COVID-19 patients will now include dexamethasone. “It’s very, very rare that you announce results at lunchtime, and it becomes policy and practice by tea time, and probably starts to save lives by the weekend,” Landray says.
Although much of the early hope for COVID-19 treatment focused on drugs that might directly attack the virus (like remdesivir and hydroxychloroquine), there has also been considerable debate about medicines that dampen the immune system, like dexamethasone. In its fight against the virus, the body’s defenses can overreact, eventually breaking down the thin barrier between the insides of the lungs and the surrounding tissue. That causes the lungs to fill up with liquid and triggers acute respiratory distress syndrome (ARDS) in which patients can end up essentially drowning in their own liquid.
But reducing the immune response through steroids could also hobble the body’s fight against the new coronavirus or secondary infections, Bhadelia says. For this reason, the guidelines of WHO and the U.S. National Institutes of Health have so far recommended against using steroids in COVID-19 patients, she points out.
Doctors have used steroids to treat viral pneumonias in the past, including those caused by the severe acute respiratory syndrome virus or H1N1 influenza, says Wei Shen Lim, a respiratory physician at Nottingham University Hospital. But there were no randomized clinical trials with those viruses and available data were hard to interpret.
A Cochrane review looking at the data from H1N1 patients, co-written by Lim, found that patients treated with corticosteroids had a higher risk of dying. But that might be explained by the fact that sicker patients were more likely to receive steroids, Lim says. “Before the Recovery trial, I was neither an advocate for or an opponent of steroids,” he says. “You couldn’t be sure.” To get a clearer answer, Lim designed a trial to evaluate steroids in viral pneumonias in the case of another pandemic. When COVID-19 emerged, that was integrated into the Recovery trial as one arm, using dexamethasone.
In places like Spain, dexamethasone has already been widely used against COVID-19. Carlos Ferrando, an anesthesiologist at the Hospital Clinic of Barcelona, was one of the authors on a paper published in Lancet Respiratory Medicine on 7 February that showed the steroid reduced mortality in non–COVID-19 patients with ARDS. When COVID-19 patients started to show up in Spanish hospitals, Ferrando started a randomized clinical trial to test dexamethasone, but recruitment into the placebo group was slow because most patients were given the steroid, he says. Ferrando is now analyzing data from thousands of patients in Spanish ICUs, about 80% of whom received steroids, he says. “It seems like we have a signal that those corticoids decrease mortality, but we need to finalize the analysis.”
Sridhar says the positive result of the Recovery trial also holds an important lesson for the debate about how best to initially respond to a pandemic like this: that delaying the spread of a pathogen, through temporary stay at home orders or other measures, can give people infected later in a pandemic a better chance of surviving. “It shows the value of buying time for science to deliver, and indicates that with time, more and more findings will come to light that help doctors manage COVID-19 patients with better clinical outcomes.”
But even if steroids reduce mortality, they do not solve the problem of COVID-19 patients potentially overwhelming a health care system, Sridhar cautions. That’s because the drug can help treat patients who are already sick, but not prevent the illness in the first place. “The real game-changer will be a drug that prevents people going from mild symptoms to a severe state, and a vaccine.”
Posted in:
Health
Coronavirus
doi:10.1126/science.abd3683
Kai Kupferschmidt
Kai is a contributing correspondent for Science magazine based in Berlin, Germany. He is the author of a book about the color blue, published in 2019.Twitter
Injectable dexamethasone is more difficult to manufacture than tablets, because production needs to take place under sterile conditions. SOUMYABRATA ROY/NURPHOTO VIA AP
By Eli Cahan Jun. 21, 2020
Science’s COVID-19 reporting is supported by the Pulitzer Center.
This week’s report that dexamethasone, a commonly used corticosteroid, reduces death rates of COVID-19 by up to one-third was greeted with enthusiasm around the globe.#
It also raised a question: Will there be enough of the medication? So far, doctors are not reporting problems getting dexamethasone for their patients. And as many news stories have pointed out, dexamethasone is off-patent, cheap, and relatively abundant.
Related
FDA just gave a thumbs down to Trump’s favorite COVID-19 drugs
Could a global ‘observatory’ of blood help stop the next pandemic?
See all of our coverage of the coronavirus outbreak
But that doesn’t mean there won’t be shortages, says Stephen Schondelmeyer, director of the Pharmaceutical Research in Management and Economics Institute at the University of Minnesota, Twin Cities. “Even though this is an old drug that’s been around a long time, I think people saying that it’s commonly available … spoke too soon, without looking at the data,” he says. Since the trial findings came out, there has been “a degree of irrational exuberance,” about dexamethasone, Schondelmeyer says. “We are already seeing hoarding behaviors and lack of availability of the product because of it,” he adds.
“Hoarding and speculative procurement appear to have already started,” confirms Emer Cooke, head of regulation of medicines and other health technologies at the World Health Organization (WHO). But she says it’s “probably too early to say if there will be a global shortage.”
The situation could become especially dire for the injectable version of the drug, which some physicians say is the preferred formulation and is more complicated to produce than oral dexamethasone. One major Indian manufacturer of intravenous dexamethasone, Cadila Healthcare, has repeatedly gotten in trouble with the U.S. Food and Drug Administration (FDA) for serious problems in its production process. According to a letter from the agency, the company said in October 2019 that it would stop producing injectable drugs for the United States.
The trial that identified dexamethasone’s potential benefit, named Recovery, included more than 6400 patients in the United Kingdom, 2104 of whom received the medication. Its outcome “offers miraculous hope that a dose of a commonplace medication might do what we all want it to do: Help people survive,” says Lewis Kaplan, a surgeon at the University of Pennsylvania’s Perelman School of Medicine and president of the Society of Critical Care Medicine (SCCM). WHO Director-General Tedros Adhanom Ghebreyesus praised the findings as a “lifesaving scientific breakthrough.” The U.K. National Health Service has already incorporated the drug into its standard of care for COVID-19 and the country issued restrictions on exports of dexamethasone. Demand appears to be surging worldwide.
How the drug is given makes a difference
But dexamethasone can be administered in several ways. According to the trial’s protocol, patients received the medication either orally or by intravenous injection. In many cases, the distinction may be trivial. But for the sickest patients, administering oral medications is “rolling the dice to some degree,” says Clifford Deutschman, an intensivist at the Feinstein Institutes for Medical Research and former SCCM president. Gastrointestinal problems in these patients can cause “inconsistencies in uptake of the medication,” leading to blood levels that are too low or too high, Deutschman says. And for patients on ventilators, administering the medication orally means grinding the pills up by hand and delivering them through fluids or a feeding tube. Both for safety and effectiveness, “Hands down, if you’ve got the intravenous stuff, you give the intravenous stuff,” he says.
The sickest patients are the ones most likely to benefit from the drug. In the study, dexamethasone reduced the death risk for patients on a ventilator by one-third, and for those requiring oxygen by one-fifth. Patients with milder disease did not benefit.
Intravenous dexamethasone was already in short supply in the United States before the Recovery results came out, according to an independent shortage tracking tool run by the American Society of Health-System Pharmacists. FDA lists the drug as “in shortage” as well. Dexamethasone is not in the U.S. Strategic National Stockpile.
Hoarding and speculative procurement appear to have already started.Emer Cooke, World Health Organization
The question is whether production of the intravenous form of dexamethasone can be ramped up quickly. Whereas oral dexamethasone is “relatively straightforward to make,” the intravenous form is harder to manufacture, says former FDA Commissioner Mark McClellan, because it needs to be done under sterile conditions to prevent microbes from reducing efficacy or sickening patients. (In 2012, a fungal meningitis outbreak linked to contaminated steroid injectables killed more than 100 people.)
Issues with quality control up the supply chain
Most of the drug is produced by two Indian companies, Wockhardt and Cadila Healthcare. Wockhardt has a “very limited” supply presently available for export, but has “enormous capacity” to produce both oral and intravenous dexamethasone and is able to ramp up further, its CEO said in a 17 June news report.
But Schondelmeyer, whose center recently launched a partnership with the U.S. Biomedical Advanced Research and Development Authority and the Department of Homeland Security to enhance the resilience of the United States’s pharmaceutical supply chain, is skeptical. “There aren’t a lot of [unused] plants that can make sterile injectables of anything, let alone dexamethasone, so I’m not sure how much capacity they really have,” he says. Ramping up supply “takes a lot of time, even if the world was normal and sane, let alone during COVID.”
FDA has turned away Cadila’s products at the U.S. border 83 times since 2004 because of quality concerns. Since 2015, the agency has sent the company three warning letters related to its production process. FDA inspectors found myriad inadequacies at Cadila’s facilities, including noncompliance with sterile procedures, evidence of Pseudomonas bacteria in the water system, and “several plastic bags filled with paperwork in the scrapyard“ including “a torn notebook of deficiencies.”
In the most recent of the three letters, dated 29 October 2019, FDA writes that Cadila Healthcare has informed the agency that it will “permanently cease production of injectable drug products for the United States.” This history “makes me very nervous, as to whether they can ramp up in the first place, and if they can, if that’s a product anyone should use,” Schondelmeyer says. (The company did not respond to requests for comment.)
Cooke stresses the importance of buying dexamethasone from quality-assured suppliers. There’s a “high risk that rogue manufacturers will offer substandard or falsified options,” she says. Trusted producers should be able to meet the rising demand, Cooke adds, but if hoarding and speculative procurement continue, “it will create chaotic demand signals and put scale up plans at risk. This is especially true for injectable products,” whose production is harder to scale up.
Potential for shortages at the bedside
McClellan does not see major problems ahead. “If there’s a reasonable response to this news, with clinicians using the drug appropriately and no disruptions related to stockpiling … I think this is a manageable development,” he says. Based on the study, the drug should only be used in severe cases, a small subset of the total number of COVID-19 patients. And physicians could use other corticosteroids—such as methylprednisolone, hydrocortisone, or prednisone—that may work as well.
Kaplan isn’t so sure: Dexamethasone has “unique properties” in the ways it interacts with the cells and proteins that produce the body’s immune response, he says. And demand may increase because doctors will prescribe the drug for less severe cases as well, Deutschman says. He is “worried” this might accelerate shortages.
“When you’re standing at the bedside watching somebody die as the family stands outside, asking yourself, is there anything else I could have done, it’s difficult to be rational,” Deutschman says. “There’s always a temptation to take the results of a trial and overextend them.”
*Correction, 22 June, 3:15 p.m.: An error in the description of FDA’s October 2019 warning letter to Cadila Healthcare has been corrected.
*Correction, 24 June, 8:05 a.m.: An incorrect statement about back orders of injectable dexamethasone at U.S. drug suppliers has been removed from this story.
Posted in:
Health
Coronavirus
doi:10.1126/science.abd4447
Eli Cahan
Eli is an intern on the News staff of Science. He is pursuing a master’s degree in health policy as a Knight-Hennessy Scholar at the Stanford School of Medicine and his MD at the New York University (NYU) School of Medicine. Twitter
A cheap steroid is the first drug shown to reduce death in COVID-19 patients
The steroid dexamethasone may quickly be added to the global standard of care for severe COVID-19 patients. REUTERS/YVES HERMAN
By Kai Kupferschmidt Jun. 16, 2020
Science’s COVID-19 reporting is supported by the Pulitzer Center.
After months of dire news about the spread of the novel coronavirus and a mounting global death toll, a glimmer of hope arrived today: Researchers announced that dexamethasone, a cheap, widely available corticosteroid, significantly reduced deaths of severely sick COVID-19 patients in a major clinical trial. Although full trial data have not yet been released, several outside commentators hailed the result as a “breakthrough.”
“These are really surprising, but really very convincing results,” says Martin Landray of the University of Oxford, one of the principal investigators of the Recovery trial in the United Kingdom that evaluated the steroid. If they hold up, adds Devi Sridhar, an expert on global public health at the University of Edinburgh, they could be a game-changer for critical patients, as the drugs are accessible even in lower-income countries.
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The Recovery trial, one of the biggest efforts to evaluate whether existing drugs can treat COVID-19, included 2104 patients given a relatively low dose of 6 milligrams of dexamethasone for 10 days. When their outcomes were compared with those of 4321 patients receiving standard care, the steroid reduced deaths by one-third in patients already on ventilators and by one-fifth in patients receiving supplemental oxygen in other ways, Recovery researchers announced in a press release. They did not find any benefit in patients not receiving respiratory support.
Dexamethasone’s effect is seemingly much stronger than that of remdesivir, the only other drug so far shown to help COVID-19 patients in a randomized clinical trial. That antiviral reduced the number of days critical patients were hospitalized, but it did not clearly reduce deaths.
Tedros Adhanom Ghebreyesus, director-general of the World Health Organization (WHO), hailed the dexamethasone results as “great news” given it’s the first COVID-19 drug that has clearly proved to reduce mortality. “The results are pretty remarkable for severely ill patients,” adds Nahid Bhadelia, a physician at Boston Medical Center. “I can see ICU [intensive care unit] physicians being more likely to provide steroids in the critically ill who are mechanically ventilated and who are not improving from other interventions based on these results.”
But she and others expressed disappointment that the Recovery team did not release additional information. “More detailed data would help us identify which subset of COVID-19 patients would benefit from steroids,” Bhadelia says.
Landray acknowledges the criticism. “I fully understand why scientists want to see the details. I’m a scientist, I want to see the details.” But with thousands of people dying of COVID-19 every day, it was important to get the basic message out first, he says. “There is this tension between having the final details and the final decimal points nailed down, and having what is actually a clear-cut and practical message in the public domain.”
Recovery is evaluating several experimental COVID-19 therapies, including the HIV drug combination Kaletra, convalescent plasma, and the controversial antimalarial drug hydroxychloroquine. When researchers found 2 weeks ago that hydroxychloroquine did not improve patient outcomes, they stopped that arm of the trial. In the other arms, Landray says, they stuck to their plan to wait until 2000 patients had received a treatment and 4000 patients had enrolled in a control arm, because that would provide a 90% chance of picking up a reduction in deaths of about 18%. Dexamethasone was the first drug to reach the milestone, so the researchers stopped its arm on 8 June and began to look at the data.
“The decimal points might change a bit when we tidy things up, but we’ve got to a point where the message will not change,” Landray says, adding that Recovery hopes to make public the full data within about 10 days. If the findings hold up under scrutiny, it would mean that treating eight ventilated patients with dexamethasone would save one life. “That is a big effect,” says Ashish Jha, a global health expert at Harvard University’s T.H. Chan School of Public Health who is eager to see the data.
The United Kingdom’s National Health Service has already announced its standard care for COVID-19 patients will now include dexamethasone. “It’s very, very rare that you announce results at lunchtime, and it becomes policy and practice by tea time, and probably starts to save lives by the weekend,” Landray says.
Although much of the early hope for COVID-19 treatment focused on drugs that might directly attack the virus (like remdesivir and hydroxychloroquine), there has also been considerable debate about medicines that dampen the immune system, like dexamethasone. In its fight against the virus, the body’s defenses can overreact, eventually breaking down the thin barrier between the insides of the lungs and the surrounding tissue. That causes the lungs to fill up with liquid and triggers acute respiratory distress syndrome (ARDS) in which patients can end up essentially drowning in their own liquid.
But reducing the immune response through steroids could also hobble the body’s fight against the new coronavirus or secondary infections, Bhadelia says. For this reason, the guidelines of WHO and the U.S. National Institutes of Health have so far recommended against using steroids in COVID-19 patients, she points out.
Doctors have used steroids to treat viral pneumonias in the past, including those caused by the severe acute respiratory syndrome virus or H1N1 influenza, says Wei Shen Lim, a respiratory physician at Nottingham University Hospital. But there were no randomized clinical trials with those viruses and available data were hard to interpret.
A Cochrane review looking at the data from H1N1 patients, co-written by Lim, found that patients treated with corticosteroids had a higher risk of dying. But that might be explained by the fact that sicker patients were more likely to receive steroids, Lim says. “Before the Recovery trial, I was neither an advocate for or an opponent of steroids,” he says. “You couldn’t be sure.” To get a clearer answer, Lim designed a trial to evaluate steroids in viral pneumonias in the case of another pandemic. When COVID-19 emerged, that was integrated into the Recovery trial as one arm, using dexamethasone.
In places like Spain, dexamethasone has already been widely used against COVID-19. Carlos Ferrando, an anesthesiologist at the Hospital Clinic of Barcelona, was one of the authors on a paper published in Lancet Respiratory Medicine on 7 February that showed the steroid reduced mortality in non–COVID-19 patients with ARDS. When COVID-19 patients started to show up in Spanish hospitals, Ferrando started a randomized clinical trial to test dexamethasone, but recruitment into the placebo group was slow because most patients were given the steroid, he says. Ferrando is now analyzing data from thousands of patients in Spanish ICUs, about 80% of whom received steroids, he says. “It seems like we have a signal that those corticoids decrease mortality, but we need to finalize the analysis.”
Sridhar says the positive result of the Recovery trial also holds an important lesson for the debate about how best to initially respond to a pandemic like this: that delaying the spread of a pathogen, through temporary stay at home orders or other measures, can give people infected later in a pandemic a better chance of surviving. “It shows the value of buying time for science to deliver, and indicates that with time, more and more findings will come to light that help doctors manage COVID-19 patients with better clinical outcomes.”
But even if steroids reduce mortality, they do not solve the problem of COVID-19 patients potentially overwhelming a health care system, Sridhar cautions. That’s because the drug can help treat patients who are already sick, but not prevent the illness in the first place. “The real game-changer will be a drug that prevents people going from mild symptoms to a severe state, and a vaccine.”
Posted in:
Health
Coronavirus
doi:10.1126/science.abd3683
Kai Kupferschmidt
Kai is a contributing correspondent for Science magazine based in Berlin, Germany. He is the author of a book about the color blue, published in 2019.Twitter
Researchers around the world prepared to #ShutDownSTEM and ‘Strike For Black Lives’
WWW.SHUTDOWNSTEM.COM; WWW.PARTICLESFORJUSTICE.ORG
By Sophia Chen Jun. 9, 2020
Thousands of researchers around the world have pledged to pause their work on Wednesday to support the ongoing Black Lives Matter movement and efforts against racism in the scientific community and society at large.
Responding to calls from an array of organizers operating under banners including the Strike For Black Lives, #ShutDownSTEM, and #ShutDownAcademia, numerous university laboratories, scientific societies, technical journals, and others have pledged to spend 10 June focused on issues of racial equality and inclusiveness.
“In the wake of the most recent murders of Black people in the U.S., it is clear that white and other non-Black people have to step up and do the work to eradicate anti-Black racism. As members of the global academic and STEM [science, technology, engineering, and math] communities, we have an enormous ethical obligation to stop doing ‘business as usual,’” the organizers of #ShutDownSTEM state on its website.
Those who participate should “stop all usual academic work for the day, including teaching, research, and service responsibilities,” the organizers of Strike For Black Lives write on their website. Black strikers should spend the day doing “whatever nourishes their hearts,” it states, whereas non-Black strikers should “take actions that center Black lives and agitate for change in our communities.”
Organizers are urging scientists to participate in local protests and learn about the history of anti-Black violence and racism; various groups have amassed online resources for participants to use.
Astrophysicist Brian Nord of Fermilab, an organizer of both the Strike For Black Lives and #ShutDownStem, who is black, is urging all strikers to emerge from tomorrow’s activities with plans for making real change at institutions involved in science. “I don’t want more diversity and inclusion seminars,” Nord says. “Those activities are used to provide a shield to institutions so that they can do the bare minimum.”
The movement began with two different groups: a network of mostly particle physicists organizing under the hashtag #Strike4BlackLives; and a multidisciplinary group of largely astronomers and biologists operating under #ShutDownSTEM. (One #ShutDownSTEM organizer, Casey Newlin, works in the music industry. Newlin, who is white, contributed what she learned from participating in that industry’s Blackout Tuesday on 2 June.) The groups coordinated with a third entity, #VanguardSTEM, an online platform that promotes women of color working in STEM, to announce their plans in unison on 5 June.
Brittany Kamai, a physicist at the University of California (UC), Santa Cruz, who started #ShutDownSTEM, says the idea originated, in part, from thinking about how scientists who are stuck at home because of the COVID-19 pandemic could make an attention-getting statement like those made by protesters who block a busy road. “This was my way of answering the question: ‘How do we shut down our digital streets of academia?’” says Kamai, who is Native Hawaiian.
The strike has gotten extensive support. Senior scientists have taken to social media to announce they are backing the effort, as have science facilities, organizations, and journals (including AAAS, which publishes Science). At many academic laboratories, “people have committed to stop group meetings,” Kamai says. Her own research group, the Laser Interferometer Gravitational-Wave Observatory, is participating in the strike by canceling a planned leadership meeting and postponing a test of its public alert system.
Elsewhere, researchers are planning an array of actions—or inactions.
At the online preprint repository arXiv—the backbone of physicists’ information highway—staff say they will participate in the strike by not announcing new submissions on Tuesday night. Many journals, such as the American Physical Society’s Physical Review Letters, have also pledged not to release papers tomorrow.
At UC Irvine, physics department chair Timothy Tait, who helped organize #Strike4BlackLives, says his department will hold a virtual educational event with an invited speaker and a town hall–style meeting with hired moderators. One goal of the events is “to inform ourselves what the black experience in academia is like,” says Tait, who is white.
At the University of New Hampshire (UNH), Durham, Karsten Pohl, a white physicist who signed the strike pledge and chairs the physics department, plans to hold a free-form discussion for his department on Zoom. Pohl especially wants feedback from undergraduate students and staff “who we usually don’t hear from,” he says.
At the University of Chicago and the Woods Hole Oceanographic Institution, scientists plan to march on their campuses.
Nord emphasizes that his group is specifically asking nonblack academics to step up tomorrow, to make up for what it sees as years of inaction. By giving black scientists the option to abstain from doing racial justice work for one day, the group says, nonblack strikers can acknowledge the disproportionate effort to improve diversity and mentor students from underrepresented groups that black scientists are often asked to perform without compensation.
For example, UNH physicist Chanda Prescod-Weinstein, an organizer of the Strike For Black Lives who is black, says that because she frequently speaks out about racism in science, many students from underrepresented backgrounds—and sometimes even their parents—contact her for advice about race-related conflicts in their education. Black students have told her of assailants throwing objects at them on campus, or people threatening to call the police on them when they are leaving the lab. Providing such advice “is a lot of work,” she says. “I also believe it has to be done, and I also believe it is unfair that it has to be done.” (Prescod-Weinstein has spent so much time supporting students of color, she says, that she asked for that work to be explicitly put in her job description when she was hired as a tenure-track professor at her university.)
Nord hopes tomorrow will help catalyze change. “I imagine a future where there is representation, retention, and recruitment of black physicists in academia,” he says. “Representation means there are lots of us around. I’m not just talking about black men. I’m talking about genderqueer, trans, women—all of us, we’re there. I imagine a future where we stay there, and we also work in leadership levels.”
WWW.SHUTDOWNSTEM.COM; WWW.PARTICLESFORJUSTICE.ORG
By Sophia Chen Jun. 9, 2020
Thousands of researchers around the world have pledged to pause their work on Wednesday to support the ongoing Black Lives Matter movement and efforts against racism in the scientific community and society at large.
Responding to calls from an array of organizers operating under banners including the Strike For Black Lives, #ShutDownSTEM, and #ShutDownAcademia, numerous university laboratories, scientific societies, technical journals, and others have pledged to spend 10 June focused on issues of racial equality and inclusiveness.
“In the wake of the most recent murders of Black people in the U.S., it is clear that white and other non-Black people have to step up and do the work to eradicate anti-Black racism. As members of the global academic and STEM [science, technology, engineering, and math] communities, we have an enormous ethical obligation to stop doing ‘business as usual,’” the organizers of #ShutDownSTEM state on its website.
Those who participate should “stop all usual academic work for the day, including teaching, research, and service responsibilities,” the organizers of Strike For Black Lives write on their website. Black strikers should spend the day doing “whatever nourishes their hearts,” it states, whereas non-Black strikers should “take actions that center Black lives and agitate for change in our communities.”
Organizers are urging scientists to participate in local protests and learn about the history of anti-Black violence and racism; various groups have amassed online resources for participants to use.
Astrophysicist Brian Nord of Fermilab, an organizer of both the Strike For Black Lives and #ShutDownStem, who is black, is urging all strikers to emerge from tomorrow’s activities with plans for making real change at institutions involved in science. “I don’t want more diversity and inclusion seminars,” Nord says. “Those activities are used to provide a shield to institutions so that they can do the bare minimum.”
The movement began with two different groups: a network of mostly particle physicists organizing under the hashtag #Strike4BlackLives; and a multidisciplinary group of largely astronomers and biologists operating under #ShutDownSTEM. (One #ShutDownSTEM organizer, Casey Newlin, works in the music industry. Newlin, who is white, contributed what she learned from participating in that industry’s Blackout Tuesday on 2 June.) The groups coordinated with a third entity, #VanguardSTEM, an online platform that promotes women of color working in STEM, to announce their plans in unison on 5 June.
Brittany Kamai, a physicist at the University of California (UC), Santa Cruz, who started #ShutDownSTEM, says the idea originated, in part, from thinking about how scientists who are stuck at home because of the COVID-19 pandemic could make an attention-getting statement like those made by protesters who block a busy road. “This was my way of answering the question: ‘How do we shut down our digital streets of academia?’” says Kamai, who is Native Hawaiian.
The strike has gotten extensive support. Senior scientists have taken to social media to announce they are backing the effort, as have science facilities, organizations, and journals (including AAAS, which publishes Science). At many academic laboratories, “people have committed to stop group meetings,” Kamai says. Her own research group, the Laser Interferometer Gravitational-Wave Observatory, is participating in the strike by canceling a planned leadership meeting and postponing a test of its public alert system.
Elsewhere, researchers are planning an array of actions—or inactions.
At the online preprint repository arXiv—the backbone of physicists’ information highway—staff say they will participate in the strike by not announcing new submissions on Tuesday night. Many journals, such as the American Physical Society’s Physical Review Letters, have also pledged not to release papers tomorrow.
At UC Irvine, physics department chair Timothy Tait, who helped organize #Strike4BlackLives, says his department will hold a virtual educational event with an invited speaker and a town hall–style meeting with hired moderators. One goal of the events is “to inform ourselves what the black experience in academia is like,” says Tait, who is white.
At the University of New Hampshire (UNH), Durham, Karsten Pohl, a white physicist who signed the strike pledge and chairs the physics department, plans to hold a free-form discussion for his department on Zoom. Pohl especially wants feedback from undergraduate students and staff “who we usually don’t hear from,” he says.
At the University of Chicago and the Woods Hole Oceanographic Institution, scientists plan to march on their campuses.
Nord emphasizes that his group is specifically asking nonblack academics to step up tomorrow, to make up for what it sees as years of inaction. By giving black scientists the option to abstain from doing racial justice work for one day, the group says, nonblack strikers can acknowledge the disproportionate effort to improve diversity and mentor students from underrepresented groups that black scientists are often asked to perform without compensation.
For example, UNH physicist Chanda Prescod-Weinstein, an organizer of the Strike For Black Lives who is black, says that because she frequently speaks out about racism in science, many students from underrepresented backgrounds—and sometimes even their parents—contact her for advice about race-related conflicts in their education. Black students have told her of assailants throwing objects at them on campus, or people threatening to call the police on them when they are leaving the lab. Providing such advice “is a lot of work,” she says. “I also believe it has to be done, and I also believe it is unfair that it has to be done.” (Prescod-Weinstein has spent so much time supporting students of color, she says, that she asked for that work to be explicitly put in her job description when she was hired as a tenure-track professor at her university.)
Nord hopes tomorrow will help catalyze change. “I imagine a future where there is representation, retention, and recruitment of black physicists in academia,” he says. “Representation means there are lots of us around. I’m not just talking about black men. I’m talking about genderqueer, trans, women—all of us, we’re there. I imagine a future where we stay there, and we also work in leadership levels.”
Who’s to blame? These three scientists are at the heart of the Surgisphere COVID-19 scandal
E. PETERSEN/SCIENCE
By Charles Piller Jun. 8, 2020
Science’s COVID-19 reporting is supported by the Pulitzer Center.
Three unlikely collaborators are at the heart of the fast-moving COVID-19 research scandal, which led to retractions last week by The Lancet and The New England Journal of Medicine (NEJM), and the withdrawal of an online preprint, after the trove of patient data they all relied on was challenged. The three physician-scientists never were at the same institution nor had they ever before written together, but they are the only authors in common on the disputed papers, and the other co-authors all have ties to at least one of them. Their partnership, which seized a high-impact role during a global public health crisis, has now ended disastrously.
The first author for both retracted papers was cardiac surgeon Mandeep Mehra, an eminent Harvard University professor who works at Brigham and Women’s Hospital (BWH) and is known internationally for cardiovascular medicine and heart transplants. He provided the kind of gravitas that can fast-track papers to leading journals. In a statement provided by BWH, Mehra said he had met another of the trio, cardiac surgeon Amit Patel, in “academic and medical circles,” and that Patel had introduced him to Sapan Desai, a vascular surgeon and founder of Surgisphere, the tiny company that supplied the data. Journal disclosures, however, also indicate Mehra received compensation from Triple-Gene, a gene therapy company Patel co-founded to develop cardiovascular treatments.
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Desai publicly aspired to combine big data and artificial intelligence (AI) in ways that he said can replace randomized controlled clinical trials. For a brief moment, it seemed that Surgisphere’s enticing data set, said to include nearly 100,000 detailed patient records from about 700 hospitals on six continents, would settle questions about the possible benefits of various drugs—including the controversial antimalarial hydroxychloroquine—for COVID-19 patients.
Patel once apparently headed cardiac surgery at the University of Miami Miller School of Medicine. A university press release announcing his arrival in 2016 is no longer posted on the university website, however, and the school has not confirmed his job duties there. More recently, he has been a volunteer adjunct professor at the University of Utah. But, as STAT first reported yesterday, Patel tweeted on Friday that he had severed his relationship with the university, which a school spokesperson confirmed. In recent years Patel has developed and commercialized experimental stem cell therapies purported to cure heart problems, reverse aging, or treat sexual dysfunction. He is also part of a network of physicians that just launched a trial to use stem cells from umbilical cord blood to treat COVID-19 patients.
Normally co-authors of high-profile papers share subject area expertise or have clear professional ties, says Jerome Kassirer, chief editor of NEJM during the 1990s. He calls the collaboration of the apparently disparate individuals “completely bizarre,” and a red flag that the studies warranted intensive scrutiny that the journals failed to provide.
None of the three co-authors responded to requests for comment. Patel spoke with a Science reporter initially but said he wanted to wait for audits of the Surgisphere data to comment, and Desai’s spokesperson stopped communicating after the retractions. Still, interviews with former colleagues and a long paper trail shed some light on each of them.
Sapan Desai
Desai had a history of convincing respected researchers of his skill and integrity. One of them, Gilbert Upchurch, department of surgery chair at the University of Florida, wrote last year in a journal commentary that he had only brief encounters with Desai but had nonetheless mentored him remotely and developed an online friendship with him. Upchurch placed the scientist in a group of “amazing and talented young vascular surgeons.”
Sapan Desai SOUTHERN ILLINOIS UNIVERSITY SCHOOL OF MEDICINE
Illinois court records show Desai is facing two medical malpractice lawsuits filed last year. He told The Scientist that he “deems any lawsuit naming him to be unfounded.”
Desai has a history of big aspirations and entrepreneurial ventures—some short-lived. His science-fiction blog, corewardfront.com, was meant “to find the most parsimonious route for mankind to establish a meaningful presence in space.” In 2009, he wrote that the site would publish fiction “grounded in facts and reality,” adding, “the scientific method must be followed … religiously.” The blog is no longer published.
As a student, Desai won several small National Institutes of Health (NIH) grants for studies of the vestibular system. He started Surgisphere in 2007, when he was a medical resident at Duke University. Surgisphere’s initial products were medical guides and textbooks, although Desai has said he was working on big data projects for the company from its birth. In 2010, under the firm’s auspices, he founded the Journal of Surgical Radiology—whose editors included researchers with well-established publishing records. It folded in January 2013. Articles from the journal were cited only 29 times in its history, according to Scimago, a journal rating service. Yet an undated Surgisphere web page, no longer accessible online, said the online-only publication had 50,000 subscribers and nearly 1 million page views monthly—which would have placed it in elite company in academic publishing.
Surgisphere appears over time to have shifted its efforts into developing a database of hospital records that could be used for research. When the pandemic erupted, Desai declared that his data set could answer key questions about the efficacy and safety of treatments. Speaking about the finding that hydroxychloroquine increases mortality in COVID-19 patients, the main finding from the now retracted Lancet paper, he told a Turkish TV reporter, “with data like this, do we even need a randomized controlled trial?” Soon after, the World Health Organization temporarily suspended enrolling patients for its COVID-19 trial of the drug.
Immediately after the Lancet and NEJM studies appeared, however, critics identified anomalies in the data. And they doubted that a tiny firm—with a scant public track record in AI, few employees, and no publicly named scientific board—could convince hundreds of unidentified hospitals in dozens of nations to share complex, protected, and legally fraught patient data. Ultimately, despite Desai promising repeatedly to allow an independent audit of Surgisphere, the firm refused to release the raw patient data and agreements with hospitals for an audit, so no one could validate the authenticity of its database.
No hospitals have come forward to acknowledge working with Surgisphere. Indeed, NHS Scotland, which is mentioned as a case study on the company’s website, says none of its hospitals worked with Surgisphere and that it would ask the firm to remove an image of a Glasgow hospital from its website.
Science contacted several of Desai’s current or former employees or colleagues. Most would not comment. But Fred Rahimi, an Illinois podiatrist and co-author of a paper with Desai, praises the surgeon as highly capable for salvaging limbs, and easy to work with. Through his publicist, Desai cited Mark Melin, a University of Minnesota, Twin Cities, vascular surgeon, as a supporter. Before the retractions, Melin called Desai “a gentleman of the highest integrity” who has “nothing to cover up.”
But one physician-scientist who worked closely with Desai several years ago, says, “Just about everyone who knew him would say: ‘I just didn’t have a good feeling about him.’ … After they’d been with him, most people dissociated themselves from him,” the scientist says, declining to be named to avoid personal and institutional embarrassment.
In the decade since completing his medical residency, Desai moved from job to job—at Duke, the University of Texas, Southern Illinois University, and two private Illinois hospitals, according to his LinkedIn profile. “You might say we should have stopped him, which now seems obvious,” Desai’s former colleague says. “We should have found a way to get together and say, ‘What’s going on here?’ rather than allowing him to move from place to place. We should have done better as a medical community. We looked the other way.”
Amit Patel
Before and after his stint at the University of Miami, which appears to have started in late 2016 or early 2017, Patel’s academic home was the University of Utah. He started as a full-time faculty member at Utah in 2008 and kept that position until he left for Miami. The website for Foldax, a heart valve company that he serves as medical adviser, describes him as a “Tenured Professor of Surgery in the Division of Cardiothoracic Surgery at the University of Utah School of Medicine and Director of Clinical Regenerative Medicine and Tissue Engineering at the University of Utah.”
Amit Patel LAURA SEITZ/DESERET NEWS
The university confirmed Patel had tenure there, but says the directorship was an “unofficial title.” And among more than 100 publications listed on his University of Utah profile, nearly two-thirds were actually co-authored by other scientists who share the same surname. The page was removed from the university website after inquiries from Science. A university spokesperson said the timing, late Friday last week, was when Patel and the school agreed to separate.
According to the NIH database, Patel has never received funding from the agency. Before the recent COVID-19 papers, one of his most notable publications was a 2016 paper in The Lancet, which reported that extracting stem cells from the bone marrow of a person with end-stage heart failure and then reinjecting them could reduce the number of cardiac events that produced deaths or hospital admissions by 37%. The 126 patient, 31-site, phase II trial was billed in a press release, now not available on the University of Utah website but stored elsewhere, as “the largest cell therapy trial for heart failure to date.” Despite the apparent positive results, the sponsoring company Vericel no longer is developing stem cells for heart disease and, according to its webpage, is focused on “advanced cell therapies for the sports medicine and severe burn care markets.”
Patel left Miami under unclear circumstances, but has retained ties with Camillo Ricordi, an influential stem cell researcher at the University of Miami School of Medicine who is also the founder of a nonprofit called the Cure Alliance. The alliance previously focused on testing whether stem cells derived from umbilical cord blood could treat diabetes or Alzheimer’s, but has now pivoted to “fighting COVID-19,” according to its website. Ricordi is the principal investigator on a multisite trial to see whether the stem cells can treat lung inflammation in severe COVID-19 patients and Patel is listed in various references to the trial as a “key contributor” or “co–principal investigator.” Ricordi says Patel is an upaid collaborater on the trial and praises Patel's work in regenerative medicine.
Patel recently tweeted that he is “related to Dr. Desai by marriage” but called that “old news” and added, “Despite this I still do not have the information of what happened at Surgisphere.” In addition to apparently connecting Mehra and Desai, Patel had prior connections with other authors of the NEJM paper and the preprint. David Grainger, co-author of the preprint, is a professor of biomedical engineering at the University of Utah and also works with Foldax. Grainger declined to comment.
Timothy Henry, a cardiovascular clinician and scientist at the Christ Hospital in Cincinnati and a co-author on the NEJM article, has written several scholarly articles with Patel, including the 2016 Lancet paper. Henry, who also declined to comment, advises Patel’s Triple-Gene, which develops cardiovascular gene therapy treatments. Henry and Patel advise—and Patel is a board member of—Creative Medical Technology Holdings, a Phoenix company that develops and markets stem cell therapies, including treatments purported to reverse aging and cure sexual disfunction.
Creative Medical’s CaverStem and FemCelz kits are distributed to physicians who use them to extract stem cells from a patient’s bone marrow, then inject the cells into the penis or clitoral area to stimulate blood flow, according to a statement filed with the U.S. Securities and Exchange Commission. (As of the market close Friday, the publicly traded firm’s shares were valued at one-third of 1 cent.) The CaverStem treatments are advertised by the company as successful in more than 80% of patients, based on a 40-person phase I clinical trial that was not randomized or controlled, and on observations of 100 other patients. Phase I trials typically measure safety, not health benefits of a potential treatment.
Science contacted multiple colleagues or co-authors of Patel. None would comment. Before the retractions, two high-profile researchers—Deepak Bhatt, who directs interventional cardiovascular programs at BWH; and Peter Gruber, a pediatric cardiothoracic surgeon at Yale University—endorsed Patel on his LinkedIn page. Bhatt says he doesn’t know Patel and attempted to remove his endorsement after being contacted by Science. Gruber says he overlapped with Patel at the University of Utah about a decade ago, but doesn’t know his work in detail.
Mandeep Mehra
In contrast, Mehra—author of more than 200 scholarly articles, editor of The Journal of Heart and Lung Transplantation, and head of the cardiology division of the University of Maryland before moving to BWH in 2012—enjoys considerable support even after the unraveling of the recent studies. “Obviously, you don’t rise to the position he’s risen to without being ambitious, but I’ve never had any indication whatsoever that he would do anything unethical,” says Keith Aaronson, a cardiologist at the University of Michigan, Ann Arbor, who collaborated with Mehra on several studies, including a clinical trial of a mechanical pump for heart failure patients.
Mandeep Mehra © STU ROSNER
Mehra, the first author on both retracted papers, was the only one to issue a personal statement of apology, for failing “to ensure that the data source was appropriate for this use.” BWH and Harvard declined to say whether further investigation of Mehra’s roles in the papers would occur. (Mehra has written papers recently with another co-author of the Lancet paper, Frank Ruschitzka of University Hospital Zürich.)
“I think he just fell into this—perhaps a little naïvely,” says another former collaborator, cardiothoracic surgeon Daniel Goldstein of the Albert Einstein College of Medicine. “Given the amount of data that was in the [Surgisphere] database, it’s just hard to believe someone would [fabricate] something like this.”
Kassirer offers a harsher view: “If you’re a scientist and you’re going to sign on to a project, by God you should know what the data are.”
With reporting by Kelly Servick and John Travis.
This story was supported by the Science Fund for Investigative Reporting.
Posted in:
Health
Scientific Community
Coronavirus
Science Fund for Investigative Reporting
Charles Piller
Charles is a contributing correspondent based in Oakland, California.
E. PETERSEN/SCIENCE
By Charles Piller Jun. 8, 2020
Science’s COVID-19 reporting is supported by the Pulitzer Center.
Three unlikely collaborators are at the heart of the fast-moving COVID-19 research scandal, which led to retractions last week by The Lancet and The New England Journal of Medicine (NEJM), and the withdrawal of an online preprint, after the trove of patient data they all relied on was challenged. The three physician-scientists never were at the same institution nor had they ever before written together, but they are the only authors in common on the disputed papers, and the other co-authors all have ties to at least one of them. Their partnership, which seized a high-impact role during a global public health crisis, has now ended disastrously.
The first author for both retracted papers was cardiac surgeon Mandeep Mehra, an eminent Harvard University professor who works at Brigham and Women’s Hospital (BWH) and is known internationally for cardiovascular medicine and heart transplants. He provided the kind of gravitas that can fast-track papers to leading journals. In a statement provided by BWH, Mehra said he had met another of the trio, cardiac surgeon Amit Patel, in “academic and medical circles,” and that Patel had introduced him to Sapan Desai, a vascular surgeon and founder of Surgisphere, the tiny company that supplied the data. Journal disclosures, however, also indicate Mehra received compensation from Triple-Gene, a gene therapy company Patel co-founded to develop cardiovascular treatments.
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Desai publicly aspired to combine big data and artificial intelligence (AI) in ways that he said can replace randomized controlled clinical trials. For a brief moment, it seemed that Surgisphere’s enticing data set, said to include nearly 100,000 detailed patient records from about 700 hospitals on six continents, would settle questions about the possible benefits of various drugs—including the controversial antimalarial hydroxychloroquine—for COVID-19 patients.
Patel once apparently headed cardiac surgery at the University of Miami Miller School of Medicine. A university press release announcing his arrival in 2016 is no longer posted on the university website, however, and the school has not confirmed his job duties there. More recently, he has been a volunteer adjunct professor at the University of Utah. But, as STAT first reported yesterday, Patel tweeted on Friday that he had severed his relationship with the university, which a school spokesperson confirmed. In recent years Patel has developed and commercialized experimental stem cell therapies purported to cure heart problems, reverse aging, or treat sexual dysfunction. He is also part of a network of physicians that just launched a trial to use stem cells from umbilical cord blood to treat COVID-19 patients.
Normally co-authors of high-profile papers share subject area expertise or have clear professional ties, says Jerome Kassirer, chief editor of NEJM during the 1990s. He calls the collaboration of the apparently disparate individuals “completely bizarre,” and a red flag that the studies warranted intensive scrutiny that the journals failed to provide.
None of the three co-authors responded to requests for comment. Patel spoke with a Science reporter initially but said he wanted to wait for audits of the Surgisphere data to comment, and Desai’s spokesperson stopped communicating after the retractions. Still, interviews with former colleagues and a long paper trail shed some light on each of them.
Sapan Desai
Desai had a history of convincing respected researchers of his skill and integrity. One of them, Gilbert Upchurch, department of surgery chair at the University of Florida, wrote last year in a journal commentary that he had only brief encounters with Desai but had nonetheless mentored him remotely and developed an online friendship with him. Upchurch placed the scientist in a group of “amazing and talented young vascular surgeons.”
Sapan Desai SOUTHERN ILLINOIS UNIVERSITY SCHOOL OF MEDICINE
Illinois court records show Desai is facing two medical malpractice lawsuits filed last year. He told The Scientist that he “deems any lawsuit naming him to be unfounded.”
Desai has a history of big aspirations and entrepreneurial ventures—some short-lived. His science-fiction blog, corewardfront.com, was meant “to find the most parsimonious route for mankind to establish a meaningful presence in space.” In 2009, he wrote that the site would publish fiction “grounded in facts and reality,” adding, “the scientific method must be followed … religiously.” The blog is no longer published.
As a student, Desai won several small National Institutes of Health (NIH) grants for studies of the vestibular system. He started Surgisphere in 2007, when he was a medical resident at Duke University. Surgisphere’s initial products were medical guides and textbooks, although Desai has said he was working on big data projects for the company from its birth. In 2010, under the firm’s auspices, he founded the Journal of Surgical Radiology—whose editors included researchers with well-established publishing records. It folded in January 2013. Articles from the journal were cited only 29 times in its history, according to Scimago, a journal rating service. Yet an undated Surgisphere web page, no longer accessible online, said the online-only publication had 50,000 subscribers and nearly 1 million page views monthly—which would have placed it in elite company in academic publishing.
Surgisphere appears over time to have shifted its efforts into developing a database of hospital records that could be used for research. When the pandemic erupted, Desai declared that his data set could answer key questions about the efficacy and safety of treatments. Speaking about the finding that hydroxychloroquine increases mortality in COVID-19 patients, the main finding from the now retracted Lancet paper, he told a Turkish TV reporter, “with data like this, do we even need a randomized controlled trial?” Soon after, the World Health Organization temporarily suspended enrolling patients for its COVID-19 trial of the drug.
Immediately after the Lancet and NEJM studies appeared, however, critics identified anomalies in the data. And they doubted that a tiny firm—with a scant public track record in AI, few employees, and no publicly named scientific board—could convince hundreds of unidentified hospitals in dozens of nations to share complex, protected, and legally fraught patient data. Ultimately, despite Desai promising repeatedly to allow an independent audit of Surgisphere, the firm refused to release the raw patient data and agreements with hospitals for an audit, so no one could validate the authenticity of its database.
No hospitals have come forward to acknowledge working with Surgisphere. Indeed, NHS Scotland, which is mentioned as a case study on the company’s website, says none of its hospitals worked with Surgisphere and that it would ask the firm to remove an image of a Glasgow hospital from its website.
Science contacted several of Desai’s current or former employees or colleagues. Most would not comment. But Fred Rahimi, an Illinois podiatrist and co-author of a paper with Desai, praises the surgeon as highly capable for salvaging limbs, and easy to work with. Through his publicist, Desai cited Mark Melin, a University of Minnesota, Twin Cities, vascular surgeon, as a supporter. Before the retractions, Melin called Desai “a gentleman of the highest integrity” who has “nothing to cover up.”
But one physician-scientist who worked closely with Desai several years ago, says, “Just about everyone who knew him would say: ‘I just didn’t have a good feeling about him.’ … After they’d been with him, most people dissociated themselves from him,” the scientist says, declining to be named to avoid personal and institutional embarrassment.
In the decade since completing his medical residency, Desai moved from job to job—at Duke, the University of Texas, Southern Illinois University, and two private Illinois hospitals, according to his LinkedIn profile. “You might say we should have stopped him, which now seems obvious,” Desai’s former colleague says. “We should have found a way to get together and say, ‘What’s going on here?’ rather than allowing him to move from place to place. We should have done better as a medical community. We looked the other way.”
Amit Patel
Before and after his stint at the University of Miami, which appears to have started in late 2016 or early 2017, Patel’s academic home was the University of Utah. He started as a full-time faculty member at Utah in 2008 and kept that position until he left for Miami. The website for Foldax, a heart valve company that he serves as medical adviser, describes him as a “Tenured Professor of Surgery in the Division of Cardiothoracic Surgery at the University of Utah School of Medicine and Director of Clinical Regenerative Medicine and Tissue Engineering at the University of Utah.”
Amit Patel LAURA SEITZ/DESERET NEWS
The university confirmed Patel had tenure there, but says the directorship was an “unofficial title.” And among more than 100 publications listed on his University of Utah profile, nearly two-thirds were actually co-authored by other scientists who share the same surname. The page was removed from the university website after inquiries from Science. A university spokesperson said the timing, late Friday last week, was when Patel and the school agreed to separate.
According to the NIH database, Patel has never received funding from the agency. Before the recent COVID-19 papers, one of his most notable publications was a 2016 paper in The Lancet, which reported that extracting stem cells from the bone marrow of a person with end-stage heart failure and then reinjecting them could reduce the number of cardiac events that produced deaths or hospital admissions by 37%. The 126 patient, 31-site, phase II trial was billed in a press release, now not available on the University of Utah website but stored elsewhere, as “the largest cell therapy trial for heart failure to date.” Despite the apparent positive results, the sponsoring company Vericel no longer is developing stem cells for heart disease and, according to its webpage, is focused on “advanced cell therapies for the sports medicine and severe burn care markets.”
Patel left Miami under unclear circumstances, but has retained ties with Camillo Ricordi, an influential stem cell researcher at the University of Miami School of Medicine who is also the founder of a nonprofit called the Cure Alliance. The alliance previously focused on testing whether stem cells derived from umbilical cord blood could treat diabetes or Alzheimer’s, but has now pivoted to “fighting COVID-19,” according to its website. Ricordi is the principal investigator on a multisite trial to see whether the stem cells can treat lung inflammation in severe COVID-19 patients and Patel is listed in various references to the trial as a “key contributor” or “co–principal investigator.” Ricordi says Patel is an upaid collaborater on the trial and praises Patel's work in regenerative medicine.
Patel recently tweeted that he is “related to Dr. Desai by marriage” but called that “old news” and added, “Despite this I still do not have the information of what happened at Surgisphere.” In addition to apparently connecting Mehra and Desai, Patel had prior connections with other authors of the NEJM paper and the preprint. David Grainger, co-author of the preprint, is a professor of biomedical engineering at the University of Utah and also works with Foldax. Grainger declined to comment.
Timothy Henry, a cardiovascular clinician and scientist at the Christ Hospital in Cincinnati and a co-author on the NEJM article, has written several scholarly articles with Patel, including the 2016 Lancet paper. Henry, who also declined to comment, advises Patel’s Triple-Gene, which develops cardiovascular gene therapy treatments. Henry and Patel advise—and Patel is a board member of—Creative Medical Technology Holdings, a Phoenix company that develops and markets stem cell therapies, including treatments purported to reverse aging and cure sexual disfunction.
Creative Medical’s CaverStem and FemCelz kits are distributed to physicians who use them to extract stem cells from a patient’s bone marrow, then inject the cells into the penis or clitoral area to stimulate blood flow, according to a statement filed with the U.S. Securities and Exchange Commission. (As of the market close Friday, the publicly traded firm’s shares were valued at one-third of 1 cent.) The CaverStem treatments are advertised by the company as successful in more than 80% of patients, based on a 40-person phase I clinical trial that was not randomized or controlled, and on observations of 100 other patients. Phase I trials typically measure safety, not health benefits of a potential treatment.
Science contacted multiple colleagues or co-authors of Patel. None would comment. Before the retractions, two high-profile researchers—Deepak Bhatt, who directs interventional cardiovascular programs at BWH; and Peter Gruber, a pediatric cardiothoracic surgeon at Yale University—endorsed Patel on his LinkedIn page. Bhatt says he doesn’t know Patel and attempted to remove his endorsement after being contacted by Science. Gruber says he overlapped with Patel at the University of Utah about a decade ago, but doesn’t know his work in detail.
Mandeep Mehra
In contrast, Mehra—author of more than 200 scholarly articles, editor of The Journal of Heart and Lung Transplantation, and head of the cardiology division of the University of Maryland before moving to BWH in 2012—enjoys considerable support even after the unraveling of the recent studies. “Obviously, you don’t rise to the position he’s risen to without being ambitious, but I’ve never had any indication whatsoever that he would do anything unethical,” says Keith Aaronson, a cardiologist at the University of Michigan, Ann Arbor, who collaborated with Mehra on several studies, including a clinical trial of a mechanical pump for heart failure patients.
Mandeep Mehra © STU ROSNER
Mehra, the first author on both retracted papers, was the only one to issue a personal statement of apology, for failing “to ensure that the data source was appropriate for this use.” BWH and Harvard declined to say whether further investigation of Mehra’s roles in the papers would occur. (Mehra has written papers recently with another co-author of the Lancet paper, Frank Ruschitzka of University Hospital Zürich.)
“I think he just fell into this—perhaps a little naïvely,” says another former collaborator, cardiothoracic surgeon Daniel Goldstein of the Albert Einstein College of Medicine. “Given the amount of data that was in the [Surgisphere] database, it’s just hard to believe someone would [fabricate] something like this.”
Kassirer offers a harsher view: “If you’re a scientist and you’re going to sign on to a project, by God you should know what the data are.”
With reporting by Kelly Servick and John Travis.
This story was supported by the Science Fund for Investigative Reporting.
Posted in:
Health
Scientific Community
Coronavirus
Science Fund for Investigative Reporting
Charles Piller
Charles is a contributing correspondent based in Oakland, California.
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