Asthma, a disease of the lungs that causes inflammation, swelling, wheezing and shortness of breath, affects both sexes, but with one notable difference: Boys tend to grow out of asthma after puberty, and men are far less likely to develop it in adulthood than women are. Australian researchers explored the idea that testosterone may have a protective effect against asthma—and they believe it does, pinpointing some of the mechanisms by which it occurs. Their study results are published in the Journal of Experimental Medicine.
To understand testosterone’s effects, says co-lead author Gabrielle Belz, a professor of molecular immunology at the University of Melbourne, you must first understand a family of immune cells known as innate lymphoid cells, or ILC2s. These cells are found on various surfaces in the body: the lungs, gastrointestinal tract, and the skin, to name a few. “Their job is to sense what’s happening in the external environment and make adjustments based on that,” Belz tells Mental Floss. In asthma, these cells proliferate in high numbers and accumulate in the airways where they trigger chemicals, such as cytokines and leukocytes, “that promote that inflammatory response that results in the airways swelling [and] narrowing, and shortness of breath occurs,” she says.
Males have fewer of these cells than females, Belz says, “because the testosterone receptor regulates the generation of these cells.” Plus, the androgen receptors, whose job it is to sense testosterone, become activated in the presence of testosterone. This suppresses the generation of these ILC2 cells, though Belz and her team are still exploring the mechanism by which it does so. With fewer cells present, there are fewer pro-inflammatory signals—which explains why men are less likely to develop asthma.
To test these effects in mouse models, the researchers ran a number of different experiments, beginning with a baseline analysis of the tissues of healthy male and female mice. They found a significantly increased presence of ILC2s in female mice compared to males, specifically in the lungs of the female mice, where the frequencies and total numbers of ILC2s were “twofold higher” than in males.
In another experiment, the researchers tested the tissue of mice that had been genetically modified not to have the testosterone-sensing androgen receptors—essentially, these mice lacked the ability to suppress the ILC2 cells, making them more likely to have asthma symptoms. These mice showed ILC2 numbers comparable to female mice, as did castrated male mice. The castrated male mice “responded as intact females, indicating that endogenous male sex hormones act as critical regulators [of ILC2s],” the authors write in their paper.
They also took tissue from male and female mice that had been given ovalbumin-induced asthma, and found that there were higher numbers of inflammatory leukocytes in the female mice than in the males.
The mouse models suggest that testosterone is protective against asthma, so the next steps are to study human immune cells from blood samples in a dish. Scientists could expose the human cells to different mediators to stimulate the testosterone pathway. They can also implant the human cells into mouse models to get a more accurate understanding of how the human cells might function. “Our preclinical animal modes are surrogates for the situations that might occur in humans,” Belz says.
This is all well and good if you’re male, but if you’re female, or a prepubescent child, further research is needed to come up with a treatment for asthma. Hormones are crucial for the development and growth of the body, so they can’t simply give testosterone to women and children with asthma “because that could disrupt a whole heap of things in the body,” Belz says. What they hope to do next is to discover receptors in women and children that they can target, and to create synthetic molecules that function in the same way as testosterone—without the impact of a hormone.
If they can achieve a synthetic testosterone, they would ideally be able to formulate an inhaled drug that can be taken through an inhaler, similar to other drugs for lung-related diseases.
Delving into these kinds of differences in how the sexes respond to disease is part of a "big push in the field to have a personalized approach to medicine," says Belz. "So you’d have a slightly different approach to males or females to get on top of these diseases."
Irène’s birth in Paris in 1897 launched what would become a world-changing scientific dynasty. A restless Marie rejoined her loving husband in the laboratory shortly after the baby’s arrival. Over the next 10 years, the Curies discovered radium and polonium, founded the science of radioactivity, welcomed a second daughter, Eve, and won a Nobel Prize in Physics. The Curies expected their daughters to excel in their education and their work. And excel they did; by 1925, Irène had a doctorate in chemistry and was working in her mother’s laboratory.
2. HER PARENTS' MARRIAGE WAS A MODEL FOR HER OWN.
Like her mother, Irène fell in love in the lab—both with her work and with another scientist. Frédéric Joliot joined the Curie team as an assistant. He and Irène quickly bonded over shared interests in sports, the arts, and human rights. The two began collaborating on research and soon married, equitably combining their names and signing their work Irène and Frédéric Joliot-Curie.
Their passion for exploration drove them ever onward into exciting new territory. A decade of experimentation yielded advances in several disciplines. They learned how the thyroid gland absorbs radioiodine and how the body metabolizes radioactive phosphates. They found ways to coax radioactive isotopes from ordinarily non-radioactive materials—a discovery that would eventually enable both nuclear power and atomic weaponry, and one that earned them the Nobel Prize in Chemistry in 1935.
4. THEY FOUGHT FOR JUSTICE AND PEACE.
The humanist principles that initially drew Irène and Frédéric together only deepened as they grew older. Both were proud members of the Socialist Party and the Comité de Vigilance des Intellectuels Antifascistes (Vigilance Committee of Anti-Fascist Intellectuals). They took great pains to keep atomic research out of Nazi hands, sealing and hiding their research as Germany occupied their country, Irène also served as undersecretary of state for scientific research of the Popular Front government.
5. SHE WAS NOT CONTENT WITH THE STATUS QUO.
Irène eventually scaled back her time in the lab to raise her children Hélène and Pierre. But she never slowed down, nor did she stop fighting for equality and freedom for all. Especially active in women’s rights groups, she became a member of the Comité National de l'Union des Femmes Françaises and the World Peace Council.
6. SHE WORKED HERSELF TO DEATH.
Irène’s extraordinary life was a mirror of her mother’s. Tragically, her death was, too. Years of watching radiation poisoning and cancer taking their toll on Marie never dissuaded Irène from her work. In 1956, dying of leukemia, she entered the Curie Hospital, where she followed her mother’s luminous footsteps into the great beyond.
If the heart in the Functional Materials Laboratory at ETH Zurich University were in a patient in an operating room, its vital signs would not be good. In fact, it would be in heart failure. Thankfully, it's not in a patient—and it's not even real. This heart is made of silicone.
Suspended in a metal frame and connected by tubes to trays of water standing in for blood, the silicone heart pumps water at a beat per second—a serious athlete's resting heart rate—in an approximation of the circulatory system. One valve is leaking, dripping onto the grate below, and the water bins are jerry-rigged with duct tape. If left to finish out its life to the final heartbeat, it would last for about 3000 beats before it ruptured. That's about 30 minutes—not long enough to finish an episode of Grey's Anatomy.
Nicolas Cohrs, a bioengineering Ph.D. student from the university, admits that the artificial heart is usually in better shape. The one he holds in his hands—identical to the first—feels like taut but pliable muscle, and is intact and dry. He'd hoped to demonstrate a new and improved version of the heart, but that one is temporarily lost, likely hiding in a box somewhere at the airport in Tallinn, Estonia, where the researchers recently attended a symposium.
Taking place over the past three years, the experimental research is a part of Zurich Heart, a project involving 17 researchers from multiple institutions, including ETH, the University of Zurich, University Hospital of Zurich, and the German Heart Institute in Berlin, which has the largest artificial heart program in Europe.
A BRIDGE TO TRANSPLANT—OR TO DEATH
Heart failure occurs when the heart cannot pump enough blood and oxygen to support the organs; common causes are coronary heart disease, high blood pressure, and diabetes. It's a global pandemic, threatening 26 million people worldwide every year. More than a quarter of them are in the U.S. alone, and the numbers are rising.
It's a life-threatening disease, but depending on the severity of the condition at the time of diagnosis, it's not necessarily an immediate death sentence. About half of the people in the U.S. diagnosed with the disease die within five years. Right now in the U.S., there are nearly 4000 people on the national heart transplant list, but they're a select few; it's estimated that upwards of 100,000 people need a new heart. Worldwide, demand for a new heart greatly outpaces supply, and many people die waiting for one.
That's why Cohrs, co-researcher Anastasios Petrou, and their colleagues are attempting to create an artificial heart modeled after each patient's own heart that would, ideally, last for the rest of a person's life.
Mechanical assistance devices for failing hearts exist, but they have serious limitations. Doctors treating heart failure have two options: a pump placed next to the heart, generally on the left side, that pumps the blood for the heart (what's known as a left ventricular assist device, or LVAD), or a total artificial heart (TAH). There have been a few total artificial hearts over the years, and at least four others are in development right now in Europe and the U.S. But only one currently has FDA approval and CE marking (allowing its use in European Union countries): the SynCardia total artificial heart. It debuted in the early '90s, and since has been implanted in nearly 1600 people worldwide.
While all implants come with side effects, especially when the immune system grows hostile toward a foreign object in the body, a common problem with existing total artificial hearts is that they're composed of hard materials, which can cause blood to clot. Such clots can lead to thrombosis and strokes, so anyone with an artificial heart has to take anticoagulants. In fact, Cohrs tells Mental Floss, patients with some sort of artificial heart implant—either a LVAD or a TAH—die more frequently from a stroke or an infection than they do from the heart condition that led to the implant. Neurological damage and equipment breakdown are risky side effects as well.
These complications mean that total artificial hearts are "bridges"—either to a new heart, or to death. They're designed to extend the life of a critically ill patient long enough to get on (or to the top of) the heart transplant list, or, if they're not a candidate for transplant, to make the last few years of a person's life more functional. A Turkish patient currently holds the record for the longest time living with a SynCardia artificial heart: The implant has been in his chest for five years. Most TAH patients live at least one year, but survival rates drop off after that.
The ETH team set out to make an artificial heart that would be not a bridge, but a true replacement. "When we heard about these problems, we thought about how we can make an artificial heart that doesn't have side effects," he recalls.
USING AN ANCIENT TECHNIQUE TO MAKE A MODERN MARVEL
Using common computer assisted design (CAD) software, they designed an ersatz organ composed of soft material that hews closely to the composition, form, and function of the human heart. "Our working hypothesis is that when you have such a device which mimics the human heart in function and form, you will have less side effects," Cohrs says.
To create a heart, "we take a CT scan of a patient, then put it into a computer file and design the artificial heart around it in close resemblance to the patient's heart, so it always fits inside [the body]," Cohrs says.
But though it's modeled on a patient's heart and looks eerily like one, it's not identical to the real organ. For one thing, it can't move on its own, so the team had to make some modifications. They omitted the upper chambers, called atria, which collect and store blood, but included the lower chambers, called ventricles, which pump blood. In a real heart, the left and right sides are separated by the septum. Here, the team replaced the septum with an expansion chamber that is inflated and deflated with pressurized air. This action mimics heart muscle contractions that push blood from the heart.
The next step was to 3D-print a negative mold of the heart in ABS, a thermoplastic commonly used in 3D printing. It takes about 40 hours on the older-model 3D printers they have in the lab. They then filled this mold with the "heart" material—initially silicone—and let it cure for 36 hours, first at room temperature and then in an oven kept at a low temperature (about 150°F). The next day, they bathed it in a solvent of acetone, which dissolved the mold but left the printed heart alone. This process is essentially lost-wax casting, a technique used virtually unchanged for the past 4000 years to make metal objects, especially bronze. It takes about four days.
The resulting soft heart weighs about 13 ounces—about one-third more than an average adult heart (about 10 ounces). If implanted in a body, it would be sutured to the valves, arteries, and veins that bring blood through the body. Like existing ventricular assist devices and total artificial hearts on the market, it would be powered by a portable pneumatic driver worn externally by the patient.
FROM 3000 TO 1 MILLION HEARTBEATS
In April 2016, they did a feasibility test to see if their silicone organ could pump blood like a real heart. First they incorporated state-of-the-art artificial valves used every day in heart surgeries around the world. These would direct the flow of blood. Then, collaborating with a team of mechanical engineers from ETH, they placed the heart in a hybrid mock circulation machine, which measures and simulates the human cardiovascular system. "You can really measure the relevant data without having to put your heart into an animal," says Cohrs.
Here's what the test looked like.
"Our results were very nice," Cohrs says. "When you look at the pressure waveform in the aorta, it really looked like the pressure waveform from the human heart, so that blood flow is very comparable to the blood flow from a real human heart."
Their results were published earlier this year in the journal Artificial Organs.
But less promising was the number of heartbeats the heart lasted before rupturing under stress. (On repeated tests, the heart always ruptured in the same place: a weak point between the expansion chamber and the left ventricle where the membrane was apparently too thin.) With the average human heart beating 2.5 billion times in a lifetime, 3000 heartbeats wouldn't get a patient far.
But they're making progress. Since then, they've switched the heart material from silicone to a high-tech polymer. The latest version of the heart—one of which was stuck in that box in the Tallinn airport—lasts for 1 million heartbeats. That's an exponential increase from 3000—but it's still only about 10 days' worth of life.
Right now, the heart costs around $400 USD to produce, "but when you want to do it under conditions where you can manufacture a device where it can be implanted into a body, it will be much more expensive," Cohrs says.
The researchers know they're far from having produced an implantable TAH; this soft heart represents a new concept for future artificial heart development that could one day lead to transplant centers using widely available, easy-to-use design software and commercially available 3D-printers to create a personalized heart for each patient. This kind of artificial heart would be not a bridge to transplantation or, in a few short years, death, but one that would take a person through many years of life.
"My personal goal is to have an artificial heart where you don't have side effects and you don't have any heart problems anymore, so it would last pretty much forever," Cohrs says. Well, perhaps not forever: "An artificial heart valve last 15 years at the moment. Maybe something like that."