New tech aims to make the ocean healthier for marine life
A defunct drydock basin arched by a rusting 19th century steel bridge seems an incongruous place to conduct state-of-the-art climate science. But this placid and protected sliver of water connecting Brooklyn’s Navy Yard to the East River was just right for Garrett Boudinot to float a small dock topped with water carbon-sensing gear. And while his system right now looks like a trio of plastic boxes wired up together, it aims to mediate the growing ocean acidification problem, caused by overabundance of dissolved carbon dioxide.
Boudinot, a biogeochemist and founder of a carbon-management startup called Vycarb, is honing his method for measuring CO2 levels in water, as well as (at least temporarily) correcting their negative effects. It’s a challenge that’s been occupying numerous climate scientists as the ocean heats up, and as states like New York recognize that reducing emissions won’t be enough to reach their climate goals; they’ll have to figure out how to remove carbon, too.
To date, though, methods for measuring CO2 in water at scale have been either intensely expensive, requiring fancy sensors that pump CO2 through membranes; or prohibitively complicated, involving a series of lab-based analyses. And that’s led to a bottleneck in efforts to remove carbon as well.
But recently, Boudinot cracked part of the code for measurement and mitigation, at least on a small scale. While the rest of the industry sorts out larger intricacies like getting ocean carbon markets up and running and driving carbon removal at billion-ton scale in centralized infrastructure, his decentralized method could have important, more immediate implications.
Specifically, for shellfish hatcheries, which grow seafood for human consumption and for coastal restoration projects. Some of these incubators for oysters and clams and scallops are already feeling the negative effects of excess carbon in water, and Vycarb’s tech could improve outcomes for the larval- and juvenile-stage mollusks they’re raising. “We’re learning from these folks about what their needs are, so that we’re developing our system as a solution that’s relevant,” Boudinot says.
Ocean acidification can wreak havoc on developing shellfish, inhibiting their shells from growing and leading to mass die-offs.
Ocean waters naturally absorb CO2 gas from the atmosphere. When CO2 accumulates faster than nature can dissipate it, it reacts with H2O molecules, forming carbonic acid, H2CO3, which makes the water column more acidic. On the West Coast, acidification occurs when deep, carbon dioxide-rich waters upwell onto the coast. This can wreak havoc on developing shellfish, inhibiting their shells from growing and leading to mass die-offs; this happened, disastrously, at Pacific Northwest oyster hatcheries in 2007.
This type of acidification will eventually come for the East Coast, too, says Ryan Wallace, assistant professor and graduate director of environmental studies and sciences at Long Island’s Adelphi University, who studies acidification. But at the moment, East Coast acidification has other sources: agricultural runoff, usually in the form of nitrogen, and human and animal waste entering coastal areas. These excess nutrient loads cause algae to grow, which isn’t a problem in and of itself, Wallace says; but when algae die, they’re consumed by bacteria, whose respiration in turn bumps up CO2 levels in water.
“Unfortunately, this is occurring at the bottom [of the water column], where shellfish organisms live and grow,” Wallace says. Acidification on the East Coast is minutely localized, occurring closest to where nutrients are being released, as well as seasonally; at least one local shellfish farm, on Fishers Island in the Long Island Sound, has contended with its effects.
The second Vycarb pilot, ready to be installed at the East Hampton shellfish hatchery.
Courtesy of Vycarb
Besides CO2, ocean water contains two other forms of dissolved carbon — carbonate (CO3-) and bicarbonate (HCO3) — at all times, at differing levels. At low pH (acidic), CO2 prevails; at medium pH, HCO3 is the dominant form; at higher pH, CO3 dominates. Boudinot’s invention is the first real-time measurement for all three, he says. From the dock at the Navy Yard, his pilot system uses carefully calibrated but low-cost sensors to gauge the water’s pH and its corresponding levels of CO2. When it detects elevated levels of the greenhouse gas, the system mitigates it on the spot. It does this by adding a bicarbonate powder that’s a byproduct of agricultural limestone mining in nearby Pennsylvania. Because the bicarbonate powder is alkaline, it increases the water pH and reduces the acidity. “We drive a chemical reaction to increase the pH to convert greenhouse gas- and acid-causing CO2 into bicarbonate, which is HCO3,” Boudinot says. “And HCO3 is what shellfish and fish and lots of marine life prefers over CO2.”
This de-acidifying “buffering” is something shellfish operations already do to water, usually by adding soda ash (NaHCO3), which is also alkaline. Some hatcheries add soda ash constantly, just in case; some wait till acidification causes significant problems. Generally, for an overly busy shellfish farmer to detect acidification takes time and effort. “We’re out there daily, taking a look at the pH and figuring out how much we need to dose it,” explains John “Barley” Dunne, director of the East Hampton Shellfish Hatchery on Long Island. “If this is an automatic system…that would be much less labor intensive — one less thing to monitor when we have so many other things we need to monitor.”
Across the Sound at the hatchery he runs, Dunne annually produces 30 million hard clams, 6 million oysters, and “if we’re lucky, some years we get a million bay scallops,” he says. These mollusks are destined for restoration projects around the town of East Hampton, where they’ll create habitat, filter water, and protect the coastline from sea level rise and storm surge. So far, Dunne’s hatchery has largely escaped the ill effects of acidification, although his bay scallops are having a finicky year and he’s checking to see if acidification might be part of the problem. But “I think it's important to have these solutions ready-at-hand for when the time comes,” he says. That’s why he’s hosting a second, 70-liter Vycarb pilot starting this summer on a dock adjacent to his East Hampton operation; it will amp up to a 50,000 liter-system in a few months.
If it can buffer water over a large area, absolutely this will benefit natural spawns. -- John “Barley” Dunne.
Boudinot hopes this new pilot will act as a proof of concept for hatcheries up and down the East Coast. The area from Maine to Nova Scotia is experiencing the worst of Atlantic acidification, due in part to increased Arctic meltwater combining with Gulf of St. Lawrence freshwater; that decreases saturation of calcium carbonate, making the water more acidic. Boudinot says his system should work to adjust low pH regardless of the cause or locale. The East Hampton system will eventually test and buffer-as-necessary the water that Dunne pumps from the Sound into 100-gallon land-based tanks where larvae grow for two weeks before being transferred to an in-Sound nursery to plump up.
Dunne says this could have positive effects — not only on his hatchery but on wild shellfish populations, too, reducing at least one stressor their larvae experience (others include increasing water temperatures and decreased oxygen levels). “If it can buffer water over a large area, absolutely this will [benefit] natural spawns,” he says.
No one believes the Vycarb model — even if it proves capable of functioning at much greater scale — is the sole solution to acidification in the ocean. Wallace says new water treatment plants in New York City, which reduce nitrogen released into coastal waters, are an important part of the equation. And “certainly, some green infrastructure would help,” says Boudinot, like restoring coastal and tidal wetlands to help filter nutrient runoff.
In the meantime, Boudinot continues to collect data in advance of amping up his own operations. Still unknown is the effect of releasing huge amounts of alkalinity into the ocean. Boudinot says a pH of 9 or higher can be too harsh for marine life, plus it can also trigger a release of CO2 from the water back into the atmosphere. For a third pilot, on Governor’s Island in New York Harbor, Vycarb will install yet another system from which Boudinot’s team will frequently sample to analyze some of those and other impacts. “Let's really make sure that we know what the results are,” he says. “Let's have data to show, because in this carbon world, things behave very differently out in the real world versus on paper.”
Scientists Are Working to Decipher the Puzzle of ‘Broken Heart Syndrome’
Elaine Kamil had just returned home after a few days of business meetings in 2013 when she started having chest pains. At first Kamil, then 66, wasn't worried—she had had some chest pain before and recently went to a cardiologist to do a stress test, which was normal.
"I can't be having a heart attack because I just got checked," she thought, attributing the discomfort to stress and high demands of her job. A pediatric nephrologist at Cedars-Sinai Hospital in Los Angeles, she takes care of critically ill children who are on dialysis or are kidney transplant patients. Supporting families through difficult times and answering calls at odd hours is part of her daily routine, and often leaves her exhausted.
She figured the pain would go away. But instead, it intensified that night. Kamil's husband drove her to the Cedars-Sinai hospital, where she was admitted to the coronary care unit. It turned out she wasn't having a heart attack after all. Instead, she was diagnosed with a much less common but nonetheless dangerous heart condition called takotsubo syndrome, or broken heart syndrome.
A heart attack happens when blood flow to the heart is obstructed—such as when an artery is blocked—causing heart muscle tissue to die. In takotsubo syndrome, the blood flow isn't blocked, but the heart doesn't pump it properly. The heart changes its shape and starts to resemble a Japanese fishing device called tako-tsubo, a clay pot with a wider body and narrower mouth, used to catch octopus.
"The heart muscle is stunned and doesn't function properly anywhere from three days to three weeks," explains Noel Bairey Merz, the cardiologist at Cedar Sinai who Kamil went to see after she was discharged.
"The heart muscle is stunned and doesn't function properly anywhere from three days to three weeks."
But even though the heart isn't permanently damaged, mortality rates due to takotsubo syndrome are comparable to those of a heart attack, Merz notes—about 4-5 percent of patients die from the attack, and 20 percent within the next five years. "It's as bad as a heart attack," Merz says—only it's much less known, even to doctors. The condition affects only about 1 percent of people, and there are around 15,000 new cases annually. It's diagnosed using a cardiac ventriculogram, an imaging test that allows doctors to see how the heart pumps blood.
Scientists don't fully understand what causes Takotsubo syndrome, but it usually occurs after extreme emotional or physical stress. Doctors think it's triggered by a so-called catecholamine storm, a phenomenon in which the body releases too much catecholamines—hormones involved in the fight-or-flight response. Evolutionarily, when early humans lived in savannas or forests and had to either fight off predators or flee from them, these hormones gave our ancestors the needed strength and stamina to take either action. Released by nerve endings and by the adrenal glands that sit on top of the kidneys, these hormones still flood our bodies in moments of stress, but an overabundance of them could sometimes be damaging.
Elaine Kamil
A study by scientists at Harvard Medical School linked increased risk of takotsubo to higher activity in the amygdala, a brain region responsible for emotions that's involved in responses to stress. The scientists believe that chronic stress makes people more susceptible to the syndrome. Notably, one small study suggested that the number of Takotsubo cases increased during the COVID-19 pandemic.
There are no specific drugs to treat takotsubo, so doctors rely on supportive therapies, which include medications typically used for high blood pressure and heart failure. In most cases, the heart returns to its normal shape within a few weeks. "It's a spontaneous recovery—the catecholamine storm is resolved, the injury trigger is removed and the heart heals itself because our bodies have an amazing healing capacity," Merz says. It also helps that tissues remain intact. 'The heart cells don't die, they just aren't functioning properly for some time."
That's the good news. The bad news is that takotsubo is likely to strike again—in 5-20 percent of patients the condition comes back, sometimes more severe than before.
That's exactly what happened to Kamil. After getting her diagnosis in 2013, she realized that she actually had a previous takotsubo episode. In 2010, she experienced similar symptoms after her son died. "The night after he died, I was having severe chest pain at night, but I was too overwhelmed with grief to do anything about it," she recalls. After a while, the pain subsided and didn't return until three years later.
For weeks after her second attack, she felt exhausted, listless and anxious. "You lose confidence in your body," she says. "You have these little twinges on your chest, or if you start having arrhythmia, and you wonder if this is another episode coming up. It's really unnerving because you don't know how to read these cues." And that's very typical, Merz says. Even when the heart muscle appears to recover, patients don't return to normal right away. They have shortens of breath, they can't exercise, and they stay anxious and worried for a while.
Women over the age of 50 are diagnosed with takotsubo more often than other demographics. However, it happens in men too, although it typically strikes after physical stress, such as a triathlon or an exhausting day of cycling. Young people can also get takotsubo. Older patients are hospitalized more often, but younger people tend to have more severe complications. It could be because an older person may go for a jog while younger one may run a marathon, which would take a stronger toll on the body of a person who's predisposed to the condition.
Notably, the emotional stressors don't always have to be negative—the heart muscle can get out of shape from good emotions, too. "There have been case reports of takotsubo at weddings," Merz says. Moreover, one out of three or four takotsubo patients experience no apparent stress, she adds. "So it could be that it's not so much the catecholamine storm itself, but the body's reaction to it—the physiological reaction deeply embedded into out physiology," she explains.
Merz and her team are working to understand what makes people predisposed to takotsubo. They think a person's genetics play a role, but they haven't yet pinpointed genes that seem to be responsible. Genes code for proteins, which affect how the body metabolizes various compounds, which, in turn, affect the body's response to stress. Pinning down the protein involved in takotsubo susceptibility would allow doctors to develop screening tests and identify those prone to severe repeating attacks. It will also help develop medications that can either prevent it or treat it better than just waiting for the body to heal itself.
Researchers at the Imperial College London found that elevated levels of certain types of microRNAs—molecules involved in protein production—increase the chances of developing takotsubo.
In one study, researchers tried treating takotsubo in mice with a drug called suberanilohydroxamic acid, or SAHA, typically used for cancer treatment. The drug improved cardiac health and reversed the broken heart in rodents. It remains to be seen if the drug would have a similar effect on humans. But identifying a drug that shows promise is progress, Merz says. "I'm glad that there's research in this area."
This article was originally published by Leaps.org on July 28, 2021.
Lina Zeldovich has written about science, medicine and technology for Popular Science, Smithsonian, National Geographic, Scientific American, Reader’s Digest, the New York Times and other major national and international publications. A Columbia J-School alumna, she has won several awards for her stories, including the ASJA Crisis Coverage Award for Covid reporting, and has been a contributing editor at Nautilus Magazine. In 2021, Zeldovich released her first book, The Other Dark Matter, published by the University of Chicago Press, about the science and business of turning waste into wealth and health. You can find her on http://linazeldovich.com/ and @linazeldovich.
Did Anton the AI find a new treatment for a deadly cancer?
Bile duct cancer is a rare and aggressive form of cancer that is often difficult to diagnose. Patients with advanced forms of the disease have an average life expectancy of less than two years.
Many patients who get cancer in their bile ducts – the tubes that carry digestive fluid from the liver to the small intestine – have mutations in the protein FGFR2, which leads cells to grow uncontrollably. One treatment option is chemotherapy, but it’s toxic to both cancer cells and healthy cells, failing to distinguish between the two. Increasingly, cancer researchers are focusing on biomarker directed therapy, or making drugs that target a particular molecule that causes the disease – FGFR2, in the case of bile duct cancer.
A problem is that in targeting FGFR2, these drugs inadvertently inhibit the FGFR1 protein, which looks almost identical. This causes elevated phosphate levels, which is a sign of kidney damage, so doses are often limited to prevent complications.
In recent years, though, a company called Relay has taken a unique approach to picking out FGFR2, using a powerful supercomputer to simulate how proteins move and change shape. The team, leveraging this AI capability, discovered that FGFR2 and FGFR1 move differently, which enabled them to create a more precise drug.
Preliminary studies have shown robust activity of this drug, called RLY-4008, in FGFR2 altered tumors, especially in bile duct cancer. The drug did not inhibit FGFR1 or cause significant side effects. “RLY-4008 is a prime example of a precision oncology therapeutic with its highly selective and potent targeting of FGFR2 genetic alterations and resistance mutations,” says Lipika Goyal, assistant professor of medicine at Harvard Medical School. She is a principal investigator of Relay’s phase 1-2 clinical trial.
Boosts from AI and a billionaire
Traditional drug design has been very much a case of trial and error, as scientists investigate many molecules to see which ones bind to the intended target and bind less to other targets.
“It’s being done almost blindly, without really being guided by structure, so it fails very often,” says Olivier Elemento, associate director of the Institute for Computational Biomedicine at Cornell. “The issue is that they are not sampling enough molecules to cover some of the chemical space that would be specific to the target of interest and not specific to others.”
Relay’s unique hardware and software allow simulations that could never be achieved through traditional experiments, Elemento says.
Some scientists have tried to use X-rays of crystallized proteins to look at the structure of proteins and design better drugs. But they have failed to account for an important factor: proteins are moving and constantly folding into different shapes.
David Shaw, a hedge fund billionaire, wanted to help improve drug discovery and understood that a key obstacle was that computer models of molecular dynamics were limited; they simulated motion for less than 10 millionths of a second.
In 2001, Shaw set up his own research facility, D.E. Shaw Research, to create a supercomputer that would be specifically designed to simulate protein motion. Seven years later, he succeeded in firing up a supercomputer that can now conduct high speed simulations roughly 100 times faster than others. Called Anton, it has special computer chips to enable this speed, and its software is powered by AI to conduct many simulations.
After creating the supercomputer, Shaw teamed up with leading scientists who were interested in molecular motion, and they founded Relay Therapeutics.
Elemento believes that Relay’s approach is highly beneficial in designing a better drug for bile duct cancer. “Relay Therapeutics has a cutting-edge approach for molecular dynamics that I don’t believe any other companies have, at least not as advanced.” Relay’s unique hardware and software allow simulations that could never be achieved through traditional experiments, Elemento says.
How it works
Relay used both experimental and computational approaches to design RLY-4008. The team started out by taking X-rays of crystallized versions of both their intended target, FGFR2, and the almost identical FGFR1. This enabled them to get a 3D snapshot of each of their structures. They then fed the X-rays into the Anton supercomputer to simulate how the proteins were likely to move.
Anton’s simulations showed that the FGFR1 protein had a flap that moved more frequently than FGFR2. Based on this distinct motion, the team tried to design a compound that would recognize this flap shifting around and bind to FGFR2 while steering away from its more active lookalike.
For that, they went back Anton, using the supercomputer to simulate the behavior of thousands of potential molecules for over a year, looking at what made a particular molecule selective to the target versus another molecule that wasn’t. These insights led them to determine the best compounds to make and test in the lab and, ultimately, they found that RLY-4008 was the most effective.
Promising results so far
Relay began phase 1-2 trials in 2020 and will continue until 2024. Preliminary results showed that, in the 17 patients taking a 70 mg dose of RLY-4008, the drug worked to shrink tumors in 88 percent of patients. This was a significant increase compared to other FGFR inhibitors. For instance, Futibatinib, which recently got FDA approval, had a response rate of only 42 percent.
Across all dose levels, RLY-4008 shrank tumors by 63 percent in 38 patients. In more good news, the drug didn’t elevate their phosphate levels, which suggests that it could be taken without increasing patients’ risk for kidney disease.
“Objectively, this is pretty remarkable,” says Elemento. “In a small patient study, you have a molecule that is able to shrink tumors in such a high fraction of patients. It is unusual to see such good results in a phase 1-2 trial.”
A simulated future
The research team is continuing to use molecular dynamic simulations to develop other new drug, such as one that is being studied in patients with solid tumors and breast cancer.
As for their bile duct cancer drug, RLY-4008, Relay plans by 2024 to have tested it in around 440 patients. “The mature results of the phase 1-2 trial are highly anticipated,” says Goyal, the principal investigator of the trial.
Sameek Roychowdhury, an oncologist and associate professor of internal medicine at Ohio State University, highlights the need for caution. “This has early signs of benefit, but we will look forward to seeing longer term results for benefit and side effect profiles. We need to think a few more steps ahead - these treatments are like the ’Whack-a-Mole game’ where cancer finds a way to become resistant to each subsequent drug.”
“I think the issue is going to be how durable are the responses to the drug and what are the mechanisms of resistance,” says Raymond Wadlow, an oncologist at the Inova Medical Group who specializes in gastrointestinal and haematological cancer. “But the results look promising. It is a much more selective inhibitor of the FGFR protein and less toxic. It’s been an exciting development.”