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% of patients die from the attack, and 20% 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% 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.
A recent 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% 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 recently 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."
When Lynne Maquat, who leads the Center for RNA Biology at the University of Rochester, became interested in the ribonucleic acid molecule in the 1970s, she was definitely in the minority. The same was true for Joan Steitz, now professor of molecular biophysics and biochemistry at Yale University, who began to study RNA a decade earlier in the 1960s.
"My first RNA experiment was a failure, because we didn't understand how things worked," Steitz recalls. In her first undergraduate experiment, she unwittingly used a lab preparation that destroyed the RNA. "Unknowingly, our preparation contained enzymes that degraded our RNA."
At the time, scientists pursuing genetic research tended to focus on DNA, or deoxyribonucleic acid — and for good reason. It was clear that the enigmatic double-helix ribbon held the answers to organisms' heredity, genetic traits, development, growth and aging. If scientists could decipher the secrets of DNA and understand how its genetic instructions translate into the body's functions in health and disease, they could develop treatments for all kinds of diseases. On the contrary, the prevailing dogma of the time viewed RNA as merely a helper that passively carried out DNA's genetic instructions for protein-making — so it received much less attention.
But Maquat and Steitz weren't interested in heredity. They studied biochemistry and biophysics, so they wanted to understand how RNA functioned on the molecular level — how it carried instructions, catalyzed reactions, and helped build protein bonds, among other things.
"I'm a mechanistic biochemist, so I like to know how things happen," Maquat says. "Once you understand the mechanism, you can think of how to solve problems." And so the quest to understand how RNA does its job became the focus of both women's careers.
"People can now appreciate why some of us studied RNA for such a long time."
Half a century later, in 2021, their RNA work has earned two prestigious recognitions only months from each other. In February, they received the Wolf Prize in Medicine, followed by the Warren Alpert Foundation Prize in May, awarded to scientists whose achievements led to prevention, cure or treatments of human diseases.
It was the development of the COVID-19 vaccines that made RNA a household name. Made by Moderna and Pfizer, the vaccines use the RNA molecule to deliver genetic instructions for making SARS-CoV-2's characteristic spike protein in our cells. The presence of this foreign-looking protein triggers the immune system to attack and remember the pathogen. As the vaccines reached the finish line, RNA took center stage, and it was Maquat's and Steitz's research that helped reveal how these molecular cogwheels drive many biological functions within cells.
If you think of a cell as a kingdom, the DNA plays the role of a queen. Like a monarch in a palace, DNA nestles inside the cell's nucleus issuing instructions needed for the cell to function. But no queen can successfully govern without her court, her messengers, and her soldiers, as well as other players that make her kingdom work. That's what RNAs do — they act as the DNA's vassals. They carry instructions for protein assembly, catalyze reactions and supervise many other processes to make sure the cellular kingdom performs as it should.
There are a myriad of these RNA vassals in our cells, and each type has its own specific task. There are messenger RNAs that deliver genetic instructions for protein synthesis from DNA to ribosomes, the cells' protein-making factories. There are ribosomal RNAs that help stitch together amino acids to make proteins. There are transfer RNAs that can bring amino acids to this protein synthesis machine, keeping it going. Then there are circular RNAs that act as sponges, absorbing proteins to help regulate the activity of genes. And that's only the tip of the iceberg when it comes to RNA diversity, researchers say.
"We know what the most abundant and important RNAs are doing," says Steitz. "But there are thousands of different ones, and we still don't have a full knowledge of them."
Critical to RNA's proper functioning is a process called splicing, in which a precursor mRNA is transformed into mature, fully-functional mRNA — a phenomenon that Steitz's work helped elucidate. The splicing process, which takes place in cellular assembly lines, involves removing extra RNA sequences and stringing the remaining RNA pieces together. Steitz found that tiny RNA particles called snRNPs are crucial to this process. They act as handy helpers, finding and removing errant genetic material from the mRNA molecules.
A dysfunctional RNA assembly line leads to diseases, including many cancers. For instance, Steitz found that people with Lupus — an autoimmune disorder — have antibodies that mistakenly attack the little snRNP helpers. She also discovered that when snRNPs don't do their job properly, they can cause what scientists call mis-splicing, producing defective mRNAs.
Fortunately, cells have a built-in quality-control process that can spot and correct these mistakes, which is what Maquat studied in her work. In 1981, she discovered a molecular quality-control system that spots and destroys such incorrectly assembled mRNA. With the cryptic name "nonsense-mediated mRNA decay" or NMD, this process is vital to the health and wellbeing of a cellular kingdom in humans — because splicing mistakes happen far more often than one would imagine.
"We estimate that about a third of our mRNA are mistakes," Maquat says. "And nonsense-mediated mRNA decay cleans up these mistakes." When this quality-control system malfunctions, defective mRNA forge faulty proteins, which mess up the cellular machinery and cause disease, including various forms of cancer.
Scientists' newfound appreciation of RNA opens door to many novel treatments.
Now that the first RNA-based shots were approved, the same principle can be used for create vaccines for other diseases, the two RNA researchers say. Moreover, the molecule has an even greater potential — it can serve as a therapeutic target for other disorders. For example, Spinraza, a groundbreaking drug approved in 2016 for spinal muscular atrophy, uses small snippets of synthetic genetic material that bind to the RNA, helping fix splicing errors. "People can now appreciate why some of us studied RNA for such a long time," says Maquat.
Steitz is thrilled that the entire field of RNA research is enjoying the limelight. "I'm delighted because the prize is more of a recognition of the field than just our work," she says. "This is a more general acknowledgment of how basic research can have a remarkable impact on human health."
Before the onset of the coronavirus pandemic, Dutch doctoral researcher Joep Beumer had used miniature lab-grown organs to study the human intestine as part of his PhD thesis. When lockdown hit, however, he was forced to delay his plans for graduation. Overwhelmed by a sense of boredom after the closure of his lab at the Hubrecht Institute, in the Netherlands, he began reading literature related to COVID-19.
"By February , there were already reports on coronavirus symptoms in the intestinal tract," Beumer says, adding that this piqued his interest. He wondered if he could use his miniature models – called organoids -- to study how the coronavirus infects the intestines.
But he wasn't the only one to follow this train of thought. In the year since the pandemic began, many researchers have been using organoids to study how the coronavirus infects human cells, and find potential treatments. Beumer's pivot represents a remarkable and fast-emerging paradigm shift in how drugs and diseases will be studied in the coming decades. With future pandemics likely to be more frequent and deadlier, such a shift is necessary to reduce the average clinical development time of 5.9 years for antiviral agents.
Part of that shift means developing models that replicate human biology in the lab. Animal models, which are the current standard in biomedical research, fail to do so—96% of drugs that pass animal testing, for example, fail to make it to market. Injecting potentially toxic drugs into living creatures, before eventually slaughtering them, also raises ethical concerns for some. Organoids, on the other hand, respond to infectious diseases, or potential treatments, in a way that is relevant to humans, in addition to being slaughter-free.
Human intestinal organoids infected with SARS-CoV-2 (white).
Credit: Joep Beumer/Clevers group/Hubrecht Institute
Urgency Sparked Momentum
Though brain organoids were previously used to study the Zika virus during the 2015-16 epidemic, it wasn't until COVID-19 that the field really started to change. "The organoid field has advanced a lot in the last year. The speed at which it happened is crazy," says Shuibing Chen, an associate professor at Weill Cornell Medicine in New York. She adds that many federal and private funding agencies have now seen the benefits of organoids, and are starting to appreciate their potential in the biomedical field.
Last summer, the Organo-Strat (OS) network—a German network that uses human organoid models to study COVID-19's effects—received 3.2 million euros in funding from the German government. "When the pandemic started, we became aware that we didn't have the right models to immediately investigate the effects of the virus," says Andreas Hocke, professor of infectious diseases at the Charité Universitätsmedizin in Berlin, Germany, and coordinator of the OS network. Hocke explained that while the World Health Organization's animal models showed an "overlap of symptoms'' with humans, there was "no clear reflection" of the same disease.
"The network functions as a way of connecting organoid experts with infectious disease experts across Germany," Hocke continues. "Having organoid models on demand means we can understand how a virus infects human cells from the first moment it's isolated." Overall, OS aims to create infrastructure that could be applied to future pandemics. There are 28 sub-projects involved in the network, covering a wide assortment of individual organoids.
Cost, however, remains an obstacle to scaling up, says Chen. She says there is also a limit to what we can learn from organoids, given that they only represent a single organ. "We can add drugs to organoids to see how the cells respond, but these tests don't tell us anything about drug metabolism, for example," she explains.
A Related "Leaps" in Progress
One way to solve this issue is to use an organ-on-a-chip system. These are miniature chips containing a variety of human cells, as well as small channels along which functions like blood or air flow can be recreated. This allows scientists to perform more complex experiments, like studying drug metabolism, while producing results that are relevant to humans.
An organ-on-a-chip system.
Credit: Fraunhofer IGB
Such systems are also able to elicit an immune response. The FDA has even entered into an agreement with Wyss Institute spinoff Emulate to use their lung-on-a-chip system to test COVID-19 vaccines. Representing multiple organs in one system is also possible. Berlin-based TissUse are aiming to make a so-called 'human on a chip' system commercially available. But TissUse senior scientist Ilka Maschmeyer warns that there is a limit to how far the technology can go. "The system will not think or feel, so it wouldn't be possible to test for illnesses affecting these abilities," she says.
Some challenges also remain in the usability of organs-on-a-chip. "Specialized training is required to use them as they are so complex," says Peter Loskill, assistant professor and head of the organ-on-a-chip group at the University of Tübingen, Germany. Hocke agrees with this. "Cell culture scientists would easily understand how to use organoids in a lab, but when using a chip, you need additional biotechnology knowledge," he says.
One major advantage of both technologies is the possibility of personalized medicine: Cells can be taken from a patient and put onto a chip, for example, to test their individual response to a treatment. Loskill also says there are other uses outside of the biomedical field, such as cosmetic and chemical testing.
"Although these technologies offer a lot of possibilities, they need time to develop," Loskill continues. He stresses, however, that it's not just the technology that needs to change. "There's a lot of conservative thinking in biomedical research that says this is how we've always done things. To really study human biology means approaching research questions in a completely new way."
Even so, he thinks that the pandemic marked a shift in people's thinking—no one cared how the results were found, as long as it was done quickly. But Loskill adds that it's important to balance promise, potential, and expectations when it comes to these new models. "Maybe in 15 years' time we will have a limited number of animal models in comparison to now, but the timescale depends on many factors," he says.
Beumer, now a post-doc, was eventually allowed to return to the lab to develop his coronavirus model, and found working on it to be an eye-opening experience. He saw first-hand how his research could have an impact on something that was affecting the entire human race, as well as the pressure that comes with studying potential treatments. Though he doesn't see a future for himself in infectious diseases, he hopes to stick with organoids. "I've now gotten really excited about the prospect of using organoids for drug discovery," he says.
The coronavirus pandemic has slowed society down in many respects, but it has flung biomedical research into the future—from mRNA vaccines to healthcare models based on human biology. It may be difficult to fully eradicate animal models, but over the coming years, organoids and organs-on-a-chip may become the standard for the sake of efficacy -- and ethics.
Jack McGovan is a freelance science writer based in Berlin. His main interests center around sustainability, food, and the multitude of ways in which the human world intersects with animal life. Find him on Twitter @jack_mcgovan."