The Voice Behind Some of Your Favorite Cartoon Characters Helped Create the Artificial Heart
In June, a team of surgeons at Duke University Hospital implanted the latest model of an artificial heart in a 39-year-old man with severe heart failure, a condition in which the heart doesn't pump properly. The man's mechanical heart, made by French company Carmat, is a new generation artificial heart and the first of its kind to be transplanted in the United States. It connects to a portable external power supply and is designed to keep the patient alive until a replacement organ becomes available.
Many patients die while waiting for a heart transplant, but artificial hearts can bridge the gap. Though not a permanent solution for heart failure, artificial hearts have saved countless lives since their first implantation in 1982.
What might surprise you is that the origin of the artificial heart dates back decades before, when an inventive television actor teamed up with a famous doctor to design and patent the first such device.
A man of many talents
Paul Winchell was an entertainer in the 1950s and 60s, rising to fame as a ventriloquist and guest-starring as an actor on programs like "The Ed Sullivan Show" and "Perry Mason." When children's animation boomed in the 1960s, Winchell made a name for himself as a voice actor on shows like "The Smurfs," "Winnie the Pooh," and "The Jetsons." He eventually became famous for originating the voices of Tigger from "Winnie the Pooh" and Gargamel from "The Smurfs," among many others.
But Winchell wasn't just an entertainer: He also had a quiet passion for science and medicine. Between television gigs, Winchell busied himself working as a medical hypnotist and acupuncturist, treating the same Hollywood stars he performed alongside. When he wasn't doing that, Winchell threw himself into engineering and design, building not only the ventriloquism dummies he used on his television appearances but a host of products he'd dreamed up himself. Winchell spent hours tinkering with his own inventions, such as a set of battery-powered gloves and something called a "flameless lighter." Over the course of his life, Winchell designed and patented more than 30 of these products – mostly novelties, but also serious medical devices, such as a portable blood plasma defroster.
Ventriloquist Paul Winchell with Jerry Mahoney, his dummy, in 1951 |
A meeting of the minds
In the early 1950s, Winchell appeared on a variety show called the "Arthur Murray Dance Party" and faced off in a dance competition with the legendary Ricardo Montalban (Winchell won). At a cast party for the show later that same night, Winchell met Dr. Henry Heimlich – the same doctor who would later become famous for inventing the Heimlich maneuver, who was married to Murray's daughter. The two hit it off immediately, bonding over their shared interest in medicine. Before long, Heimlich invited Winchell to come observe him in the operating room at the hospital where he worked. Winchell jumped at the opportunity, and not long after he became a frequent guest in Heimlich's surgical theatre, fascinated by the mechanics of the human body.
One day while Winchell was observing at the hospital, he witnessed a patient die on the operating table after undergoing open-heart surgery. He was suddenly struck with an idea: If there was some way doctors could keep blood pumping temporarily throughout the body during surgery, patients who underwent risky operations like open-heart surgery might have a better chance of survival. Winchell rushed to Heimlich with the idea – and Heimlich agreed to advise Winchell and look over any design drafts he came up with. So Winchell went to work.
Winchell's heart
As it turned out, building ventriloquism dummies wasn't that different from building an artificial heart, Winchell noted later in his autobiography – the shifting valves and chambers of the mechanical heart were similar to the moving eyes and opening mouths of his puppets. After each design, Winchell would go back to Heimlich and the two would confer, making adjustments along the way to.
By 1956, Winchell had perfected his design: The "heart" consisted of a bag that could be placed inside the human body, connected to a battery-powered motor outside of the body. The motor enabled the bag to pump blood throughout the body, similar to a real human heart. Winchell received a patent for the design in 1963.
At the time, Winchell never quite got the credit he deserved. Years later, researchers at the University of Utah, working on their own artificial heart, came across Winchell's patent and got in touch with Winchell to compare notes. Winchell ended up donating his patent to the team, which included Dr. Richard Jarvik. Jarvik expanded on Winchell's design and created the Jarvik-7 – the world's first artificial heart to be successfully implanted in a human being in 1982.
The Jarvik-7 has since been replaced with newer, more efficient models made up of different synthetic materials, allowing patients to live for longer stretches without the heart clogging or breaking down. With each new generation of hearts, heart failure patients have been able to live relatively normal lives for longer periods of time and with fewer complications than before – and it never would have been possible without the unsung genius of a puppeteer and his love of science.
How the Human Brain Project Built a Mind of its Own
In 2009, neuroscientist Henry Markram gave an ambitious TED talk. “Our mission is to build a detailed, realistic computer model of the human brain,” he said, naming three reasons for this unmatched feat of engineering. One was because understanding the human brain was essential to get along in society. Another was because experimenting on animal brains could only get scientists so far in understanding the human ones. Third, medicines for mental disorders weren’t good enough. “There are two billion people on the planet that are affected by mental disorders, and the drugs that are used today are largely empirical,” Markram said. “I think that we can come up with very concrete solutions on how to treat disorders.”
Markram's arguments were very persuasive. In 2013, the European Commission launched the Human Brain Project, or HBP, as part of its Future and Emerging Technologies program. Viewed as Europe’s chance to try to win the “brain race” between the U.S., China, Japan, and other countries, the project received about a billion euros in funding with the goal to simulate the entire human brain on a supercomputer, or in silico, by 2023.
Now, after 10 years of dedicated neuroscience research, the HBP is coming to an end. As its many critics warned, it did not manage to build an entire human brain in silico. Instead, it achieved a multifaceted array of different goals, some of them unexpected.
Scholars have found that the project did help advance neuroscience more than some detractors initially expected, specifically in the area of brain simulations and virtual models. Using an interdisciplinary approach of combining technology, such as AI and digital simulations, with neuroscience, the HBP worked to gain a deeper understanding of the human brain’s complicated structure and functions, which in some cases led to novel treatments for brain disorders. Lastly, through online platforms, the HBP spearheaded a previously unmatched level of global neuroscience collaborations.
Simulating a human brain stirs up controversy
Right from the start, the project was plagued with controversy and condemnation. One of its prominent critics was Yves Fregnac, a professor in cognitive science at the Polytechnic Institute of Paris and research director at the French National Centre for Scientific Research. Fregnac argued in numerous articles that the HBP was overfunded based on proposals with unrealistic goals. “This new way of over-selling scientific targets, deeply aligned with what modern society expects from mega-sciences in the broad sense (big investment, big return), has been observed on several occasions in different scientific sub-fields,” he wrote in one of his articles, “before invading the field of brain sciences and neuromarketing.”
"A human brain model can simulate an experiment a million times for many different conditions, but the actual human experiment can be performed only once or a few times," said Viktor Jirsa, a professor at Aix-Marseille University.
Responding to such critiques, the HBP worked to restructure the effort in its early days with new leadership, organization, and goals that were more flexible and attainable. “The HBP got a more versatile, pluralistic approach,” said Viktor Jirsa, a professor at Aix-Marseille University and one of the HBP lead scientists. He believes that these changes fixed at least some of HBP’s issues. “The project has been on a very productive and scientifically fruitful course since then.”
After restructuring, the HBP became a European hub on brain research, with hundreds of scientists joining its growing network. The HBP created projects focused on various brain topics, from consciousness to neurodegenerative diseases. HBP scientists worked on complex subjects, such as mapping out the brain, combining neuroscience and robotics, and experimenting with neuromorphic computing, a computational technique inspired by the human brain structure and function—to name just a few.
Simulations advance knowledge and treatment options
In 2013, it seemed that bringing neuroscience into a digital age would be farfetched, but research within the HBP has made this achievable. The virtual maps and simulations various HBP teams create through brain imaging data make it easier for neuroscientists to understand brain developments and functions. The teams publish these models on the HBP’s EBRAINS online platform—one of the first to offer access to such data to neuroscientists worldwide via an open-source online site. “This digital infrastructure is backed by high-performance computers, with large datasets and various computational tools,” said Lucy Xiaolu Wang, an assistant professor in the Resource Economics Department at the University of Massachusetts Amherst, who studies the economics of the HBP. That means it can be used in place of many different types of human experimentation.
Jirsa’s team is one of many within the project that works on virtual brain models and brain simulations. Compiling patient data, Jirsa and his team can create digital simulations of different brain activities—and repeat these experiments many times, which isn’t often possible in surgeries on real brains. “A human brain model can simulate an experiment a million times for many different conditions,” Jirsa explained, “but the actual human experiment can be performed only once or a few times.” Using simulations also saves scientists and doctors time and money when looking at ways to diagnose and treat patients with brain disorders.
Compiling patient data, scientists can create digital simulations of different brain activities—and repeat these experiments many times.
The Human Brain Project
Simulations can help scientists get a full picture that otherwise is unattainable. “Another benefit is data completion,” added Jirsa, “in which incomplete data can be complemented by the model. In clinical settings, we can often measure only certain brain areas, but when linked to the brain model, we can enlarge the range of accessible brain regions and make better diagnostic predictions.”
With time, Jirsa’s team was able to move into patient-specific simulations. “We advanced from generic brain models to the ability to use a specific patient’s brain data, from measurements like MRI and others, to create individualized predictive models and simulations,” Jirsa explained. He and his team are working on this personalization technique to treat patients with epilepsy. According to the World Health Organization, about 50 million people worldwide suffer from epilepsy, a disorder that causes recurring seizures. While some epilepsy causes are known others remain an enigma, and many are hard to treat. For some patients whose epilepsy doesn’t respond to medications, removing part of the brain where seizures occur may be the only option. Understanding where in the patients’ brains seizures arise can give scientists a better idea of how to treat them and whether to use surgery versus medications.
“We apply such personalized models…to precisely identify where in a patient’s brain seizures emerge,” Jirsa explained. “This guides individual surgery decisions for patients for which surgery is the only treatment option.” He credits the HBP for the opportunity to develop this novel approach. “The personalization of our epilepsy models was only made possible by the Human Brain Project, in which all the necessary tools have been developed. Without the HBP, the technology would not be in clinical trials today.”
Personalized simulations can significantly advance treatments, predict the outcome of specific medical procedures and optimize them before actually treating patients. Jirsa is watching this happen firsthand in his ongoing research. “Our technology for creating personalized brain models is now used in a large clinical trial for epilepsy, funded by the French state, where we collaborate with clinicians in hospitals,” he explained. “We have also founded a spinoff company called VB Tech (Virtual Brain Technologies) to commercialize our personalized brain model technology and make it available to all patients.”
The Human Brain Project created a level of interconnectedness within the neuroscience research community that never existed before—a network not unlike the brain’s own.
Other experts believe it’s too soon to tell whether brain simulations could change epilepsy treatments. “The life cycle of developing treatments applicable to patients often runs over a decade,” Wang stated. “It is still too early to draw a clear link between HBP’s various project areas with patient care.” However, she admits that some studies built on the HBP-collected knowledge are already showing promise. “Researchers have used neuroscientific atlases and computational tools to develop activity-specific stimulation programs that enabled paraplegic patients to move again in a small-size clinical trial,” Wang said. Another intriguing study looked at simulations of Alzheimer’s in the brain to understand how it evolves over time.
Some challenges remain hard to overcome even with computer simulations. “The major challenge has always been the parameter explosion, which means that many different model parameters can lead to the same result,” Jirsa explained. An example of this parameter explosion could be two different types of neurodegenerative conditions, such as Parkinson’s and Huntington’s diseases. Both afflict the same area of the brain, the basal ganglia, which can affect movement, but are caused by two different underlying mechanisms. “We face the same situation in the living brain, in which a large range of diverse mechanisms can produce the same behavior,” Jirsa said. The simulations still have to overcome the same challenge.
Understanding where in the patients’ brains seizures arise can give scientists a better idea of how to treat them and whether to use surgery versus medications.
The Human Brain Project
A network not unlike the brain’s own
Though the HBP will be closing this year, its legacy continues in various studies, spin-off companies, and its online platform, EBRAINS. “The HBP is one of the earliest brain initiatives in the world, and the 10-year long-term goal has united many researchers to collaborate on brain sciences with advanced computational tools,” Wang said. “Beyond the many research articles and projects collaborated on during the HBP, the online neuroscience research infrastructure EBRAINS will be left as a legacy even after the project ends.”
Those who worked within the HBP see the end of this project as the next step in neuroscience research. “Neuroscience has come closer to very meaningful applications through the systematic link with new digital technologies and collaborative work,” Jirsa stated. “In that way, the project really had a pioneering role.” It also created a level of interconnectedness within the neuroscience research community that never existed before—a network not unlike the brain’s own. “Interconnectedness is an important advance and prerequisite for progress,” Jirsa said. “The neuroscience community has in the past been rather fragmented and this has dramatically changed in recent years thanks to the Human Brain Project.”
According to its website, by 2023 HBP’s network counted over 500 scientists from over 123 institutions and 16 different countries, creating one of the largest multi-national research groups in the world. Even though the project hasn’t produced the in-silico brain as Markram envisioned it, the HBP created a communal mind with immense potential. “It has challenged us to think beyond the boundaries of our own laboratories,” Jirsa said, “and enabled us to go much further together than we could have ever conceived going by ourselves.”
Regenerative medicine has come a long way, baby
The field of regenerative medicine had a shaky start. In 2002, when news spread about the first cloned animal, Dolly the sheep, a raucous debate ensued. Scary headlines and organized opposition groups put pressure on government leaders, who responded by tightening restrictions on this type of research.
Fast forward to today, and regenerative medicine, which focuses on making unhealthy tissues and organs healthy again, is rewriting the code to healing many disorders, though it’s still young enough to be considered nascent. What started as one of the most controversial areas in medicine is now promising to transform it.
Progress in the lab has addressed previous concerns. Back in the early 2000s, some of the most fervent controversy centered around somatic cell nuclear transfer (SCNT), the process used by scientists to produce Dolly. There was fear that this technique could be used in humans, with possibly adverse effects, considering the many medical problems of the animals who had been cloned.
But today, scientists have discovered better approaches with fewer risks. Pioneers in the field are embracing new possibilities for cellular reprogramming, 3D organ printing, AI collaboration, and even growing organs in space. It could bring a new era of personalized medicine for longer, healthier lives - while potentially sparking new controversies.
Engineering tissues from amniotic fluids
Work in regenerative medicine seeks to reverse damage to organs and tissues by culling, modifying and replacing cells in the human body. Scientists in this field reach deep into the mechanisms of diseases and the breakdowns of cells, the little workhorses that perform all life-giving processes. If cells can’t do their jobs, they take whole organs and systems down with them. Regenerative medicine seeks to harness the power of healthy cells derived from stem cells to do the work that can literally restore patients to a state of health—by giving them healthy, functioning tissues and organs.
Modern-day regenerative medicine takes its origin from the 1998 isolation of human embryonic stem cells, first achieved by John Gearhart at Johns Hopkins University. Gearhart isolated the pluripotent cells that can differentiate into virtually every kind of cell in the human body. There was a raging controversy about the use of these cells in research because at that time they came exclusively from early-stage embryos or fetal tissue.
Back then, the highly controversial SCNT cells were the only way to produce genetically matched stem cells to treat patients. Since then, the picture has changed radically because other sources of highly versatile stem cells have been developed. Today, scientists can derive stem cells from amniotic fluid or reprogram patients’ skin cells back to an immature state, so they can differentiate into whatever types of cells the patient needs.
In the context of medical history, the field of regenerative medicine is progressing at a dizzying speed. But for those living with aggressive or chronic illnesses, it can seem that the wheels of medical progress grind slowly.
The ethical debate has been dialed back and, in the last few decades, the field has produced important innovations, spurring the development of whole new FDA processes and categories, says Anthony Atala, a bioengineer and director of the Wake Forest Institute for Regenerative Medicine. Atala and a large team of researchers have pioneered many of the first applications of 3D printed tissues and organs using cells developed from patients or those obtained from amniotic fluid or placentas.
His lab, considered to be the largest devoted to translational regenerative medicine, is currently working with 40 different engineered human tissues. Sixteen of them have been transplanted into patients. That includes skin, bladders, urethras, muscles, kidneys and vaginal organs, to name just a few.
These achievements are made possible by converging disciplines and technologies, such as cell therapies, bioengineering, gene editing, nanotechnology and 3D printing, to create living tissues and organs for human transplants. Atala is currently overseeing clinical trials to test the safety of tissues and organs engineered in the Wake Forest lab, a significant step toward FDA approval.
In the context of medical history, the field of regenerative medicine is progressing at a dizzying speed. But for those living with aggressive or chronic illnesses, it can seem that the wheels of medical progress grind slowly.
“It’s never fast enough,” Atala says. “We want to get new treatments into the clinic faster, but the reality is that you have to dot all your i’s and cross all your t’s—and rightly so, for the sake of patient safety. People want predictions, but you can never predict how much work it will take to go from conceptualization to utilization.”
As a surgeon, he also treats patients and is able to follow transplant recipients. “At the end of the day, the goal is to get these technologies into patients, and working with the patients is a very rewarding experience,” he says. Will the 3D printed organs ever outrun the shortage of donated organs? “That’s the hope,” Atala says, “but this technology won’t eliminate the need for them in our lifetime.”
New methods are out of this world
Jeanne Loring, another pioneer in the field and director of the Center for Regenerative Medicine at Scripps Research Institute in San Diego, says that investment in regenerative medicine is not only paying off, but is leading to truly personalized medicine, one of the holy grails of modern science.
This is because a patient’s own skin cells can be reprogrammed to become replacements for various malfunctioning cells causing incurable diseases, such as diabetes, heart disease, macular degeneration and Parkinson’s. If the cells are obtained from a source other than the patient, they can be rejected by the immune system. This means that patients need lifelong immunosuppression, which isn’t ideal. “With Covid,” says Loring, “I became acutely aware of the dangers of immunosuppression.” Using the patient’s own cells eliminates that problem.
Microgravity conditions make it easier for the cells to form three-dimensional structures, which could more easily lead to the growing of whole organs. In fact, Loring's own cells have been sent to the ISS for study.
Loring has a special interest in neurons, or brain cells that can be developed by manipulating cells found in the skin. She is looking to eventually treat Parkinson’s disease using them. The manipulated cells produce dopamine, the critical hormone or neurotransmitter lacking in the brains of patients. A company she founded plans to start a Phase I clinical trial using cell therapies for Parkinson’s soon, she says.
This is the culmination of many years of basic research on her part, some of it on her own cells. In 2007, Loring had her own cells reprogrammed, so there’s a cell line that carries her DNA. “They’re just like embryonic stem cells, but personal,” she said.
Loring has another special interest—sending immature cells into space to be studied at the International Space Station. There, microgravity conditions make it easier for the cells to form three-dimensional structures, which could more easily lead to the growing of whole organs. In fact, her own cells have been sent to the ISS for study. “My colleagues and I have completed four missions at the space station,” she says. “The last cells came down last August. They were my own cells reprogrammed into pluripotent cells in 2009. No one else can say that,” she adds.
Future controversies and tipping points
Although the original SCNT debate has calmed down, more controversies may arise, Loring thinks.
One of them could concern growing synthetic embryos. The embryos are ultimately derived from embryonic stem cells, and it’s not clear to what stage these embryos can or will be grown in an artificial uterus—another recent invention. The science, so far done only in animals, is still new and has not been widely publicized but, eventually, “People will notice the production of synthetic embryos and growing them in an artificial uterus,” Loring says. It’s likely to incite many of the same reactions as the use of embryonic stem cells.
Bernard Siegel, the founder and director of the Regenerative Medicine Foundation and executive director of the newly formed Healthspan Action Coalition (HSAC), believes that stem cell science is rapidly approaching tipping point and changing all of medical science. (For disclosure, I do consulting work for HSAC). Siegel says that regenerative medicine has become a new pillar of medicine that has recently been fast-tracked by new technology.
Artificial intelligence is speeding up discoveries and the convergence of key disciplines, as demonstrated in Atala’s lab, which is creating complex new medical products that replace the body’s natural parts. Just as importantly, those parts are genetically matched and pose no risk of rejection.
These new technologies must be regulated, which can be a challenge, Siegel notes. “Cell therapies represent a challenge to the existing regulatory structure, including payment, reimbursement and infrastructure issues that 20 years ago, didn’t exist.” Now the FDA and other agencies are faced with this revolution, and they’re just beginning to adapt.
Siegel cited the 2021 FDA Modernization Act as a major step. The Act allows drug developers to use alternatives to animal testing in investigating the safety and efficacy of new compounds, loosening the agency’s requirement for extensive animal testing before a new drug can move into clinical trials. The Act is a recognition of the profound effect that cultured human cells are having on research. Being able to test drugs using actual human cells promises to be far safer and more accurate in predicting how they will act in the human body, and could accelerate drug development.
Siegel, a longtime veteran and founding father of several health advocacy organizations, believes this work helped bring cell therapies to people sooner rather than later. His new focus, through the HSAC, is to leverage regenerative medicine into extending not just the lifespan but the worldwide human healthspan, the period of life lived with health and vigor. “When you look at the HSAC as a tree,” asks Siegel, “what are the roots of that tree? Stem cell science and the huge ecosystem it has created.” The study of human aging is another root to the tree that has potential to lengthen healthspans.
The revolutionary science underlying the extension of the healthspan needs to be available to the whole world, Siegel says. “We need to take all these roots and come up with a way to improve the life of all mankind,” he says. “Everyone should be able to take advantage of this promising new world.”