How a Nobel-Prize Winner Fought Her Family, Nazis, and Bombs to Change our Understanding of Cells Forever
Sarah Watts is a health and science writer based in Chicago. Follow her on Twitter at @swattswrites.
When Rita Levi-Montalcini decided to become a scientist, she was determined that nothing would stand in her way. And from the beginning, that determination was put to the test. Before Levi-Montalcini became a Nobel Prize-winning neurobiologist, the first to discover and isolate a crucial chemical called Neural Growth Factor (NGF), she would have to battle both the sexism within her own family as well as the racism and fascism that was slowly engulfing her country
Levi-Montalcini was born to two loving parents in Turin, Italy at the turn of the 20th century. She and her twin sister, Paola, were the youngest of the family's four children, and Levi-Montalcini described her childhood as "filled with love and reciprocal devotion." But while her parents were loving, supportive and "highly cultured," her father refused to let his three daughters engage in any schooling beyond the basics. "He loved us and had a great respect for women," she later explained, "but he believed that a professional career would interfere with the duties of a wife and mother."
At age 20, Levi-Montalcini had finally had enough. "I realized that I could not possibly adjust to a feminine role as conceived by my father," she is quoted as saying, and asked his permission to finish high school and pursue a career in medicine. When her father reluctantly agreed, Levi-Montalcini was ecstatic: In just under a year, she managed to catch up on her mathematics, graduate high school, and enroll in medical school in Turin.
By 1936, Levi-Montalcini had graduated medical school at the top of her class and decided to stay on at the University of Turin as a research assistant for histologist and human anatomy professor Guiseppe Levi. Levi-Montalcini started studying nerve cells and nerve fibers – the tiny, slender tendrils that are threaded throughout our nerves and that determine what information each nerve can transmit. But it wasn't long before another enormous obstacle to her scientific career reared its head.
Science Under a Fascist Regime
Two years into her research assistant position, Levi-Montalcini was fired, along with every other "non-Aryan Italian" who held an academic or professional career, thanks to a series of antisemitic laws passed by Italy's then-leader Benito Mussolini. Forced out of her academic position, Levi-Montalcini went to Belgium for a fellowship at a neurological institute in Brussels – but then was forced back to Turin when the German army invaded.
Levi-Montalcini decided to keep researching. She and Guiseppe Levi built a makeshift lab in Levi-Montalcini's apartment, borrowing chicken eggs from local farmers and using sewing needles to dissect them. By dissecting the chicken embryos from her bedroom laboratory, she was able to see how nerve fibers formed and died. The two continued this research until they were interrupted again – this time, by British air raids. Levi-Montalcini fled to a country cottage to continue her research, and then two years later was forced into hiding when the German army invaded Italy. Levi-Montalcini and her family assumed different identities and lived with non-Jewish friends in Florence to survive the Holocaust. Despite all of this, Levi-Montalcini continued her work, dissecting chicken embryos from her hiding place until the end of the war.
"The discovery of NGF really changed the world in which we live, because now we knew that cells talk to other cells, and that they use soluble factors. It was hugely important."
A Post-War Discovery
Several years after the war, when Levi-Montalcini was once again working at the University of Turin, a German embryologist named Viktor Hamburger invited her to Washington University in St. Louis. Hamburger was impressed by Levi-Montalcini's research with her chicken embryos, and secured an opportunity for her to continue her work in America. The invitation would "change the course of my life," Levi-Montalcini would later recall.
During her fellowship, Montalcini grew tumors in mice and then transferred them to chick embryos in order to see how it would affect the chickens. To her surprise, she noticed that introducing the tumor samples would cause nerve fibers to grow rapidly. From this, Levi-Montalcini discovered and was able to isolate a protein that she determined was able to cause this rapid growth. She later named this Nerve Growth Factor, or NGF.
From there, Levi-Montalcini and her team launched new experiments to test NGF, injecting it and repressing it to see the effect it had in a test subject's body. When the team injected NGF into embryonic mice, they observed nerve growth, as well as the mouse pups developing faster – their eyes opening earlier and their teeth coming in sooner – than the untreated group. When the team purified the NGF extract, however, it had no effect, leading the team to believe that something else in the crude extract of NGF was influencing the growth of the newborn mice. Stanley Cohen, Levi-Montalcini's colleague, identified another growth factor called EGF – epidermal growth factor – that caused the mouse pups' eyes and teeth to grow so quickly.
Levi-Montalcini continued to experiment with NGF for the next several decades at Washington University, illuminating how NGF works in our body. When Levi-Montalcini injected newborn mice with an antiserum for NGF, for example, her team found that it "almost completely deprived the animals of a sympathetic nervous system." Other experiments done by Levi-Montalcini and her colleagues helped show the role that NGF plays in other important biological processes, such as the regulation of our immune system and ovulation.
"The discovery of NGF really changed the world in which we live, because now we knew that cells talk to other cells, and that they use soluble factors. It was hugely important," said Bill Mobley, Chair of the Department of Neurosciences at the University of California, San Diego School of Medicine.
Her Lasting Legacy
After years of setbacks, Levi-Montalcini's groundbreaking work was recognized in 1986, when she was awarded the Nobel Prize in Medicine for her discovery of NGF (Cohen, her colleague who discovered EGF, shared the prize). Researchers continue to study NGF even to this day, and the continued research has been able to increase our understanding of diseases like HIV and Alzheimer's.
Levi-Montalcini never stopped researching either: In January 2012, at the age of 102, Levi-Montalcini published her last research paper in the journal PNAS, making her the oldest member of the National Academy of Science to do so. Before she died in December 2012, she encouraged other scientists who would suffer setbacks in their careers to keep pursuing their passions. "Don't fear the difficult moments," Levi-Montalcini is quoted as saying. "The best comes from them."
Sarah Watts is a health and science writer based in Chicago. Follow her on Twitter at @swattswrites.
In December 1958, on a vacation with his wife in Kenya, a 28-year-old British tea broker named Robin Cavendish became suddenly ill. Neither he nor his wife Diana knew it at the time, but Robin's illness would change the course of medical history forever.
Robin was rushed to a nearby hospital in Kenya where the medical staff delivered the crushing news: Robin had contracted polio, and the paralysis creeping up his body was almost certainly permanent. The doctors placed Robin on a ventilator through a tracheotomy in his neck, as the paralysis from his polio infection had rendered him unable to breathe on his own – and going off the average life expectancy at the time, they gave him only three months to live. Robin and Diana (who was pregnant at the time with their first child, Jonathan) flew back to England so he could be admitted to a hospital. They mentally prepared to wait out Robin's final days.
But Robin did something unexpected when he returned to the UK – just one of many things that would astonish doctors over the next several years: He survived. Diana gave birth to Jonathan in February 1959 and continued to visit Robin regularly in the hospital with the baby. Despite doctors warning that he would soon succumb to his illness, Robin kept living.
After a year in the hospital, Diana suggested something radical: She wanted Robin to leave the hospital and live at home in South Oxfordshire for as long as he possibly could, with her as his nurse. At the time, this suggestion was unheard of. People like Robin who depended on machinery to keep them breathing had only ever lived inside hospital walls, as the prevailing belief was that the machinery needed to keep them alive was too complicated for laypeople to operate. But Diana and Robin were up for the challenges – and the risks. Because his ventilator ran on electricity, if the house were to unexpectedly lose power, Diana would either need to restore power quickly or hand-pump air into his lungs to keep him alive.
Robin's wheelchair was not only the first of its kind; it became the model for the respiratory wheelchairs that people still use today.
In an interview as an adult, Jonathan Cavendish reflected on his parents' decision to live outside the hospital on a ventilator: "My father's mantra was quality of life," he explained. "He could have stayed in the hospital, but he didn't think that was as good of a life as he could manage. He would rather be two minutes away from death and living a full life."
After a few years of living at home, however, Robin became tired of being confined to his bed. He longed to sit outside, to visit friends, to travel – but had no way of doing so without his ventilator. So together with his friend Teddy Hall, a professor and engineer at Oxford University, the two collaborated in 1962 to create an entirely new invention: a battery-operated wheelchair prototype with a ventilator built in. With this, Robin could now venture outside the house – and soon the Cavendish family became famous for taking vacations. It was something that, by all accounts, had never been done before by someone who was ventilator-dependent. Robin and Hall also designed a van so that the wheelchair could be plugged in and powered during travel. Jonathan Cavendish later recalled a particular family vacation that nearly ended in disaster when the van broke down outside of Barcelona, Spain:
"My poor old uncle [plugged] my father's chair into the wrong socket," Cavendish later recalled, causing the electricity to short. "There was fire and smoke, and both the van and the chair ground to a halt." Johnathan, who was eight or nine at the time, his mother, and his uncle took turns hand-pumping Robin's ventilator by the roadside for the next thirty-six hours, waiting for Professor Hall to arrive in town and repair the van. Rather than being panicked, the Cavendishes managed to turn the vigil into a party. Townspeople came to greet them, bringing food and music, and a local priest even stopped by to give his blessing.
Robin had become a pioneer, showing the world that a person with severe disabilities could still have mobility, access, and a fuller quality of life than anyone had imagined. His mission, along with Hall's, then became gifting this independence to others like himself. Robin and Hall raised money – first from the Ernest Kleinwort Charitable Trust, and then from the British Department of Health – to fund more ventilator chairs, which were then manufactured by Hall's company, Littlemore Scientific Engineering, and given to fellow patients who wanted to live full lives at home. Robin and Hall used themselves as guinea pigs, testing out different models of the chairs and collaborating with scientists to create other devices for those with disabilities. One invention, called the Possum, allowed paraplegics to control things like the telephone and television set with just a nod of the head. Robin's wheelchair was not only the first of its kind; it became the model for the respiratory wheelchairs that people still use today.
Robin went on to enjoy a long and happy life with his family at their house in South Oxfordshire, surrounded by friends who would later attest to his "down-to-earth" personality, his sense of humor, and his "irresistible" charm. When he died peacefully at his home in 1994 at age 64, he was considered the world's oldest-living person who used a ventilator outside the hospital – breaking yet another barrier for what medical science thought was possible.
Sarah Watts is a health and science writer based in Chicago. Follow her on Twitter at @swattswrites.
In June 2012, Kirstie Ennis was six months into her second deployment to Afghanistan and recently promoted to sergeant. The helicopter gunner and seven others were three hours into a routine mission of combat resupplies and troop transport when their CH-53D helicopter went down hard.
Miraculously, all eight people onboard survived, but Ennis' injuries were many and severe. She had a torn rotator cuff, torn labrum, crushed cervical discs, facial fractures, deep lacerations and traumatic brain injury. Despite a severely fractured ankle, doctors managed to save her foot, for a while at least.
In November 2015, after three years of constant pain and too many surgeries to count, Ennis relented. She elected to undergo a lower leg amputation but only after she completed the 1,000-mile, 72-day Walking with the Wounded journey across the UK.
On Veteran's Day of that year, on the other side of the country, orthopedic surgeon Cato Laurencin announced a moonshot challenge he was setting out to achieve on behalf of wounded warriors like Ennis: the Hartford Engineering A Limb (HEAL) Project.
Laurencin, who is a University of Connecticut professor of chemical, materials and biomedical engineering, teamed up with experts in tissue bioengineering and regenerative medicine from Harvard, Columbia, UC Irvine and SASTRA University in India. Laurencin and his colleagues at the Connecticut Convergence Institute for Translation in Regenerative Engineering made a bold commitment to regenerate an entire limb within 15 years – by the year 2030.
Dr. Cato Laurencin pictured in his office at UConn.
Photo Credit: UConn
Regenerative Engineering -- A Whole New Field
Limb regeneration in humans has been a medical and scientific fascination for decades, with little to show for the effort. However, Laurencin believes that if we are to reach the next level of 21st century medical advances, this puzzle must be solved.
An estimated 185,000 people undergo upper or lower limb amputation every year. Despite the significant advances in electromechanical prosthetics, these individuals still lack the ability to perform complex functions such as sensation for tactile input, normal gait and movement feedback. As far as Laurencin is concerned, the only clinical answer that makes sense is to regenerate a whole functional limb.
Laurencin feels other regeneration efforts were hampered by their siloed research methods with chemists, surgeons, engineers all working separately. Success, he argues, requires a paradigm shift to a trans-disciplinary approach that brings together cutting-edge technologies from disparate fields such as biology, material sciences, physical, chemical and engineering sciences.
As the only surgeon ever inducted into the academies of Science, Medicine and Innovation, Laurencin is uniquely suited for the challenge. He is regarded as the founder of Regenerative Engineering, defined as the convergence of advanced materials sciences, stem cell sciences, physics, developmental biology and clinical translation for the regeneration of complex tissues and organ systems.
But none of this is achievable without early clinician participation across scientific fields to develop new technologies and a deeper understanding of how to harness the body's innate regenerative capabilities. "When I perform a surgical procedure or something is torn or needs to be repaired, I count on the body being involved in regenerating tissue," he says. "So, understanding how the body works to regenerate itself and harnessing that ability is an important factor for the regeneration process."
The Birth of the Vision
Laurencin's passion for regeneration began when he was a sports medicine fellow at Cornell University Medical Center in the early 1990s. There he saw a significant number of injuries to the anterior cruciate ligament (ACL), the major ligament that stabilizes the knee. He believed he could develop a better way to address those injuries using biomaterials to regenerate the ligament. He sketched out a preliminary drawing on a napkin one night over dinner. He has spent the next 30 years regenerating tissues, including the patented L-C ligament.
As chair of Orthopaedic Surgery at the University of Virginia during the peak of the wars in Iraq and Afghanistan, Laurencin treated military personnel who survived because of improved helmets, body armor and battlefield medicine but were left with more devastating injuries, including traumatic brain injuries and limb loss.
"I was so honored to care for them and I so admired their steadfast courage that I became determined to do something big for them," says Laurencin.
When he tells people about his plans to regrow a limb, he gets a lot of eye rolls, which he finds amusing but not discouraging. Growing bone cells was relatively new when he was first focused on regenerating bone in 1987 at MIT; in 2007 he was well on his way to regenerating ligaments at UVA when many still doubted that ligaments could even be reconstructed. He and his team have already regenerated torn rotator cuff tendons and ACL ligaments using a nano-textured fabric seeded with stem cells.
Even as a finalist for the $4 million NIH Pioneer Award for high-risk/high-reward research, he faced a skeptical scientific audience in 2014. "They said, 'Well what do you plan to do?' I said 'I plan to regenerate a whole limb in people.' There was a lot of incredulousness. They stared at me and asked a lot of questions. About three days later, I received probably the best score I've ever gotten on an NIH grant."
In the Thick of the Science
Humans are born with regenerative abilities--two-year-olds have regrown fingertips--but lose that ability with age. Salamanders are the only vertebrates that can regenerate lost body parts as adults; axolotl, the rare Mexican salamander, can grow extra limbs.
The axolotl is important as a model organism because it is a four-footed vertebrate with a similar body plan to humans. Mapping the axolotl genome in 2018 enhanced scientists' genetic understanding of their evolution, development, and regeneration. Being easy to breed in captivity allowed the HEAL team to closely study these amphibians and discover a new cell type they believe may shed light on how to mimic the process in humans.
"Whenever limb regeneration takes place in the salamander, there is a huge amount of something called heparan sulfate around that area," explains Laurencin. "We thought, 'What if this heparan sulfate is the key ingredient to allowing regeneration to take place?' We found these groups of cells that were interspersed in tissues during the time of regeneration that seemed to have connections to each other that expressed this heparan sulfate."
Called GRID (Groups that are Regenerative, Interspersed and Dendritic), these cells were also recently discovered in mice. While GRID cells don't regenerate as well in mice as in salamanders, finding them in mammals was significant.
"If they're found in mice. we might be able to find these in humans in some form," Laurencin says. "We think maybe it will help us figure out regeneration or we can create cells that mimic what grid cells do and create an artificial grid cell."
What Comes Next?
Laurencin and his team have individually engineered and made every single tissue in the lower limb, including bone, cartilage, ligament, skin, nerve, blood vessels. Regenerating joints and joint tissue is the next big mile marker, which Laurencin sees as essential to regenerating a limb that functions and performs in the way he envisions.
"Using stem cells and amnion tissue, we can regenerate joints that are damaged, and have severe arthritis," he says. "We're making progress on all fronts, and making discoveries we believe are going to be helping people along the way."
That focus and advancement is vital to Ennis. After laboring over the decision to have her leg amputated below the knee, she contracted MRSA two weeks post-surgery. In less than a month, she went from a below-the-knee-amputee to a through-the-knee amputee to an above-the-knee amputee.
"A below-the-knee amputation is night-and-day from above-the-knee," she said. "You have to relearn everything. You're basically a toddler."
Kirstie Ennis pictured in July 2020.
Photo Credit: Ennis' Instagram
The clock is ticking on the timeline Laurencin set for himself. Nine years might seem like forever if you're doing time but it might appear fleeting when you're trying to create something that's never been done before. But Laurencin isn't worried. He's convinced time is on his side.
"Every week, I receive an email or a call from someone, maybe a mother whose child has lost a finger or I'm in communication with a disabled American veteran who wants to know how the progress is going. That energizes me to continue to work hard to try to create these sorts of solutions because we're talking about people and their lives."
He devotes about 60 hours a week to the project and the roughly 100 students, faculty and staff who make up the HEAL team at the Convergence Institute seem acutely aware of what's at stake and appear equally dedicated.
"We're in the thick of the science in terms of making this happen," says Laurencin. "We've moved from making the impossible possible to making the possible a reality. That's what science is all about."