Why Neglected Tropical Diseases Should Matter to Americans
Daisy Hernández was five years old when one of her favorite aunts was struck with a mysterious illness. Tía Dora had stayed behind in Colombia when Daisy's mother immigrated to Union City, New Jersey. A schoolteacher in her late 20s, she began suffering from fevers and abdominal pain, and her belly grew so big that people thought she was pregnant. Exploratory surgery revealed that her large intestine had swollen to ten times its normal size, and she was fitted with a colostomy bag. Doctors couldn't identify the underlying problem—but whatever it was, they said, it would likely kill her within a year or two.
Tía Dora's sisters in New Jersey—Hernández's mother and two other aunts—weren't about to let that happen. They pooled their savings and flew her to New York City, where a doctor at Columbia-Presbyterian Medical Center with a penchant for obscure ailments provided a diagnosis: Chagas disease. Transmitted by the bite of triatomine insects, commonly known as kissing bugs, Chagas is endemic in many parts of Latin America. It's caused by the parasite Trypanoma cruzi, which usually settles in the heart, where it feeds on muscle tissue. In some cases, however, it attacks the intestines or esophagus. Tía Dora belonged to that minority.
In 1980, U.S. immigration laws were more forgiving than they are today. Tía Dora was able to have surgery to remove a part of her colon, despite not being a citizen or having a green card. She eventually married a legal resident and began teaching Spanish at an elementary school. Over the next three decades, she earned a graduate degree, built a career, and was widowed. Meanwhile, Chagas continued its slow devastation. "Every couple of years, we were back in the hospital with her," Hernández recalls. "When I was in high school, she started feeling like she couldn't swallow anything. It was the parasite, destroying the muscles of her esophagus."
When Tía Dora died in 2010, at 59, her niece was among the family members at her bedside. By then, Hernández had become a journalist and fiction writer. Researching a short story about Chagas disease, she discovered that it affected an estimated 6 million people in South America, Central America, and Mexico—as well as 300,000 in the United States, most of whom were immigrants from those places. "I was shocked to learn it wasn't rare," she says. "That made me hungry to know more about this disease, and about the families grappling with it."
Hernández's curiosity led her to write The Kissing Bug, a lyrical hybrid of memoir and science reporting that was published in June. It also led her to another revelation: Chagas is not unique. It's among the many maladies that global health experts refer to as neglected tropical diseases—often-disabling illnesses that afflict 1.7 billion people worldwide, while getting notably less attention than the "big three" of HIV/AIDs, malaria, and tuberculosis. NTDs cause fewer deaths than those plagues, but they wreak untold suffering and economic loss.
Shortly before Hernández's book hit the shelves, the World Health Organization released its 2021-2030 roadmap for fighting NTDs. The plan sets targets for controlling, eliminating, or eradicating all the diseases on the WHO's list, through measures ranging from developing vaccines to improving healthcare infrastructure, sanitation, and access to clean water. Experts agree that for the campaign to succeed, leadership from wealthy nations—particularly the United States—is essential. But given the inward turn of many such countries in recent years (evidenced in movements ranging from America First to Brexit), and the continuing urgency of the COVID-19 crisis, public support is far from guaranteed.
As Hernández writes: "It is easier to forget a disease that cannot be seen." NTDs primarily affect residents of distant lands. They kill only 80,000 people a year, down from 204,000 in 1990. So why should Americans to bother to look?
Breaking the circle of poverty and disease
The World Health Organization counts 20 diseases as NTDs. Along with Chagas, they include dengue and chikungunya, which cause high fevers and agonizing pain; elephantiasis, which deforms victims' limbs and genitals; onchocerciasis, which causes blindness; schistosomiasis, which can damage the heart, lungs, brain, and genitourinary system; helminths such as roundworm and whipworm, which cause anemia, stunted growth, and cognitive disabilities; and a dozen more. Such ailments often co-occur in the same patient, exacerbating each other's effects and those of illnesses such as malaria.
NTDs may be spread by insects, animals, soil, or tainted water; they may be parasitic, bacterial, viral, or—in the case of snakebite envenoming—non-infectious. What they have in common is their longtime neglect by public health agencies and philanthropies. In part, this reflects their typically low mortality rates. But the biggest factor is undoubtedly their disempowered patient populations.
"These diseases occur in the setting of poverty, and they cause poverty, because of their chronic and debilitating effects," observes Peter Hotez, dean of the National School of Tropical Medicine at Baylor University and co-director of the Texas Children's Hospital for Vaccine Development. And historically, the everyday miseries of impoverished people have seldom been a priority for those who set the global health agenda.
That began to change about 20 years ago, when Hotez and others developed the conceptual framework for NTDs and early proposals for combating them. The WHO released its first roadmap in 2012, targeting 17 NTDs for control, elimination, or eradication by 2020. (Rabies, snakebite, and dengue were added later.) Since then, the number of people at risk for NTDs has fallen by 600 million, and 42 countries have eliminated at least one such disease. Cases of dracunculiasis—known as Guinea worm disease, for the parasite that creates painful blisters in a patient's skin—have dropped from the millions to just 27 in 2020.
Yet the battle is not over, and the COVID-19 pandemic has disrupted prevention and treatment programs around the globe.
A new direction — and longstanding obstacles
The WHO's new roadmap sets even more ambitious goals for 2030. Among them: reducing by 90 percent the number of people requiring treatment for NTDs; eliminating at least one NTD in another 100 countries; and fully eradicating dracunculiasis and yaws, a disfiguring skin infection.
The plan also places an increased focus on "country ownership," relying on nations with high incidence of NTDs to design their own plans based on local expertise. "I was so excited to see that," says Kristina Talbert-Slagle, director of the Yale College Global Health Studies program. "No one is a better expert on how to address these situations than the people who deal with it day by day."
Another fresh approach is what the roadmap calls "cross-cutting" targets. "One of the really cool things about the plan is how much it emphasizes coordination among different sectors of the health system," says Claire Standley, a faculty member at Georgetown University's Center for Global Health Science and Security. "For example, it explicitly takes into account the zoonotic nature of many neglected tropical diseases—the fact that we have to think about animal health as well as human health when we tackle NTDs."
Whether this grand vision can be realized, however, will depend largely on funding—and that, in turn, is a question of political will in the countries most able to provide it. On the upside, the U.S. has ended its Trump-era feud with the WHO. "One thing that's been really encouraging," says Standley, "has been the strong commitment toward global cooperation from the current administration." Even under the previous president, the U.S. remained the single largest contributor to the global health kitty, spending over $100 million annually on NTDs—six times the figure in 2006, when such financing started.
On the downside, America's outlay has remained flat for several years, and the Biden administration has so far not moved to increase it. A "back-of-the-envelope calculation," says Hotez, suggests that the current level of aid could buy medications for the most common NTDs for about 200 million people a year. But the number of people who need treatment, he notes, is at least 750 million.
Up to now, the United Kingdom—long the world's second-most generous health aid donor—has taken up a large portion of the slack. But the UK last month announced deep cuts in its portfolio, eliminating 102 previously supported countries and leaving only 34. "That really concerns me," Hotez says.
The struggle for funds, he notes, is always harder for projects involving NTDs than for those aimed at higher-profile diseases. His lab, which he co-directs with microbiologist Maria Elena Bottazzi, started developing a COVID-19 vaccine soon after the pandemic struck, for example, and is now in Phase 3 trials. The team has been working on vaccines for Chagas, hookworm, and schistosomiasis for much longer, but trials for those potential game-changers lag behind. "We struggle to get the level of resources needed to move quickly," Hotez explains.
Two million reasons to care
One way to prompt a government to open its pocketbook is for voters to clamor for action. A longtime challenge with NTDs, however, has been getting people outside the hardest-hit countries to pay attention.
The reasons to care, global health experts argue, go beyond compassion. "When we have high NTD burden," says Talbert-Slagle, "it can prevent economic growth, prevent innovation, lead to more political instability." That, in turn, can lead to wars and mass migration, affecting economic and political events far beyond an affected country's borders.
Like Hernández's aunt Dora, many people driven out of NTD-wracked regions wind up living elsewhere. And that points to another reason to care about these diseases: Some of your neighbors might have them. In the U.S., up to 14 million people suffer from neglected parasitic infections—including 70,000 with Chagas in California alone.
When Hernández was researching The Kissing Bug, she worried that such statistics would provide ammunition to racists and xenophobes who claim that immigrants "bring disease" or exploit overburdened healthcare systems. (This may help explain some of the stigma around NTDs, which led Tía Dora to hide her condition from most people outside her family.) But as the book makes clear, these infections know no borders; they flourish wherever large numbers of people lack access to resources that most residents of rich countries take for granted.
Indeed, far from gaming U.S. healthcare systems, millions of low-income immigrants can't access them—or must wait until they're sick enough to go to an emergency room. Since Congress changed the rules in 1996, green card holders have to wait five years before they can enroll in Medicaid. Undocumented immigrants can never qualify.
Closing the great divide
Hernández uses a phrase borrowed from global health crusader Paul Farmer to describe this access gap: "the great epi divide." On one side, she explains, "people will die from cancer, from diabetes, from chronic illnesses later in life. On the other side of the epidemiological divide, people are dying because they can't get to the doctor, or they can't get medication. They don't have a hospital anywhere near them. When I read Dr. Farmer's work, I realized how much that applied to neglected diseases as well."
When it comes to Chagas disease, she says, the epi divide is embodied in the lack of a federal mandate for prenatal or newborn screening. Each year, according to the Centers for Disease Control and Prevention, up to 300 babies in the U.S. are born with Chagas, which can be passed from the mother in utero. The disease can be cured with medication if treated in infancy. (It can also be cured in adults in the acute stage, but is seldom detected in time.) Yet the CDC does not require screening for Chagas—even though newborns are tested for 15 diseases that are less common. According to one study, it would be 10 times cheaper to screen and treat babies and their mothers than to cover the costs related to the illness in later years. Few states make the effort.
The gap that enables NTDs to persist, Hernández argues, is the same one that has led to COVID-19 death rates in Black and Latinx communities that are double those elsewhere in America. To close it, she suggests, caring is not enough.
"When I was working on my book," she says, "I thought about HIV in the '80s, when it had so much stigma that no one wanted to talk about it. Then activists stepped up and changed the conversation. I thought a lot about breast cancer, which was stigmatized for years, until people stepped forward and started speaking out. I thought about Lyme disease. And it wasn't only patients—it was also allies, right? The same thing needs to happen with neglected diseases around the world. Allies need to step up and make demands on policymakers. We need to make some noise."
A Doctor Who Treated His Own Rare Disease Is Tracking COVID-19 Treatments Hiding In Plain Sight
In late March, just as the COVID-19 pandemic was ramping up in the United States, David Fajgenbaum, a physician-scientist at the University of Pennsylvania, devised a 10-day challenge for his lab: they would sift through 1,000 recently published scientific papers documenting cases of the deadly virus from around the world, pluck out the names of any drugs used in an attempt to cure patients, and track the treatments and their outcomes in a database.
Before late 2019, no one had ever had to treat this exact disease before, which meant all treatments would be trial and error. Fajgenbaum, a pioneering researcher in the field of drug repurposing—which prioritizes finding novel uses for existing drugs, rather than arduously and expensively developing new ones for each new disease—knew that physicians around the world would be embarking on an experimental journey, the scale of which would be unprecedented. His intention was to briefly document the early days of this potentially illuminating free-for-all, as a sidebar to his primary field of research on a group of lymph node disorders called Castleman disease. But now, 11 months and 29,000 scientific papers later, he and his team of 22 are still going strong.
They're running a publicly accessible database called the CORONA Project (COvid19 Registry of Off-label & New Agents) that to date tracks 400 different COVID-19 treatments that have been tried somewhere in the world, along with the frequency of their use, and the outcomes.
"There's so many drugs being used all over the place, in different ways, with different outcomes," says Fajgenbaum. "We're trying to add some order to the madness."
20,000 people have accessed the registry—other physicians and researchers, those in the pharmaceutical industry, and even curious lay people—and the data are now being shared with the U.S. Food and Drug Administration in the hopes of launching large-scale trials that would lead to approving a constellation of treatment options for COVID-19 faster than any new drugs could come online.
"What David's group has done with the CORONA Project is on a scale that I don't think has ever been seen before," says Heather Stone, a health science policy analyst at the FDA who specializes in drug repurposing. She was not involved in establishing the project, but is now working with its data. "To collect and collate that information and make it openly accessible is a massive feat, and a huge benefit to the medical community," she says.
On a Personal Mission
In the science and medical world, Fajgenbaum lives a dual existence: he is both researcher and subject, physician and patient. In July 2010, when he was a healthy and physically fit 25-year-old finishing medical school, he began living through what would become a recurring, unprovoked, and overzealous immune response that repeatedly almost killed him.
His lymph nodes were inflamed; his liver, kidneys, and bone marrow were faltering; and he was dead tired all the time. At first his doctors mistook his mysterious illness for lymphoma, but his inflamed lymph nodes were merely a red herring. A month after his initial hospitalization, pathologists at Mayo Clinic finally diagnosed him with idiopathic multicentric Castleman disease—a particularly ruthless form of a class of lymph node disorders that doesn't just attack one part of the body, but many, and has no known cause. It's a rare diagnosis within an already rare set of disorders. Only about 1,500 Americans a year receive the same diagnosis.
Without many options for treatment, Fajgenbaum underwent recurring rounds of chemotherapy. Each time, the treatment would offer temporary respite from Castleman symptoms, but bring the full spate of chemotherapy side effects. And it wasn't a sustainable treatment for the long haul. Regularly dousing a person's cells in unmitigated toxicity was about as elegant a solution to Fajgenbaum's disease as bulldozing a house in response to a toaster fire. The fire might go out (though not necessarily), but the house would be destroyed.
A swirl of exasperation and doggedness finally propelled Fajgenbaum to take on a crucial question himself: Among all of the already FDA-approved drugs on the market, was there something out there, labeled for another use, that could beat back Castleman disease and that he could tolerate long-term? After months of research, he discovered the answer: sirolimus, a drug normally prescribed to patients receiving a kidney transplant, could be used to suppress his overactive immune system with few known side effects to boot.
Fajgenbaum became hellbent on devoting his practice and research to making similar breakthroughs for others. He founded the Castleman Disease Collaborative Network, to coordinate the research of others studying this bewildering disease, and directs a laboratory consumed with studying cytokine storms—out-of-control immune responses characterized by the body's release of cytokines, proteins that the immune system secretes and uses to communicate with and direct other cells.
In the spring of 2020, when cytokine storms emerged as a hallmark of the most severe and deadly cases of COVID-19, Fajgenbaum's ears perked up. Although SARS-CoV-2 itself was novel, Fajgenbaum already had almost a decade of experience battling the most severe biological forces it brought. Only this time, he thought, it might actually be easier to pinpoint a treatment—unlike Castleman disease, which has no known cause, at least here a virus was clearly the instigator.
"Because [a drug] looks promising, we need to do a well-designed, large randomized controlled trial to really investigate whether this drug works or not ... We don't use that to say, 'You should take it.'"
Thinking Beyond COVID
The week of March 13, when the World Health Organization declared COVID-19 a pandemic, Fajgenbaum found himself hoping that someone would make the same connection and apply the research to COVID. "Then like a minute later I was like, 'Why am I hoping that someone, somewhere, either follows our footsteps, or has a similar background to us? Maybe we just need to do it," he says. And the CORONA Project was born—first as a 10-day exercise, and later as the robust, interactive tool it now is.
All of the 400 treatments in the CORONA database are examples of repurposed drugs, or off-label uses: physicians are prescribing drugs to treat COVID that have been approved for a different disease. There are no bonafide COVID treatments, only inferences. The goal for people like Fajgenbaum and Stone is to identify potential treatments for further study and eventual official approval, so that physicians can treat the disease with a playbook in hand. When it works, drug repurposing opens up a way to move quickly: A range of treatments could be available to patients within just a few years of a totally new virus entering our reality compared with the 12 - 19 years new drug development takes.
"Companies for many decades have explored the use of their products for not just a single indication but often for many indications," says Stone. "'Supplemental approvals' are all essentially examples of drug repurposing, we just didn't call it that. The challenge, I think, is to explore those opportunities more comprehensively and systematically to really try to understand the full breadth of potential activity of any drug or molecule."
The left column shows the path of a repurposed drug, and on the right is the path of a newly discovered and developed drug.
Cures Within Reach
In Fajgenbaum's primary work, promising drugs stand out easily. For a disease like Castleman, where improvement almost never occurs on its own, any improvement that follows a treatment can pretty clearly be attributed to that treatment. But Fajgenbaum says tracking COVID outcomes is less straightforward since "the vast majority of people will get better, whether they take steroids or they take Skittles." That's why the intent of the database is to identify promising treatments only to generate hypotheses and fruitful clinical trials, not to offer full-throated treatment recommendations. Within the registry, Fajgenbaum considers a drug promising if it's being used in humans, not just in lab animals, and a significant proportion of cases report patient improvement.
"It's that sort of combination of rock-solid randomized controlled trial data, plus anecdotal retrospective data, that we combine to say, 'Wow, this drug looks more promising than another,'" says Fajgenbaum. "Because it looks promising, we need to do a well-designed, large randomized controlled trial to really investigate whether this drug works or not ... We don't use that to say, 'You should take it.'"
Experts say that the search for repurposed drugs to treat COVID could have implications for rare diseases in general. Rare diseases, of which Castleman is one, affect 400 million people around the world. 95% of them don't have a tailor-made, FDA-approved drug treatment. Developing one is a lengthy and often prohibitively expensive process. If only a dozen people will benefit from and buy a drug, it's not often worth it to pharmaceutical companies to spend millions of dollars making them. On occasion when they do, however, that overhead shows up in the price tag: the top 10 most expensive drugs in the world are all for rare diseases, often making them inaccessible to patients. Identifying new clinical uses for drugs that already exist is critical for opening a trap door out of a cycle that prioritizes profits over health outcomes.
"COVID is an interesting case where it's demonstrated that when the scientific and medical community really focuses all of its efforts and talents on a single problem, a solution can be identified and in a much faster time period than has ever historically been the case," says Stone. "I certainly wish it hadn't taken a pandemic to do that, but I think it does have lessons for the future in terms of our ability to accomplish things that we might have previously not thought were possible"—for example, mainstreaming the idea of drug repurposing as a treatment tool, even long after the pandemic subsides.
A Confounding Virus
The FDA declined to comment on what drugs it was fast-tracking for trials, but Fajgenbaum says that based on the CORONA Project's data, which includes data from smaller trials that have already taken place, he feels there are three drugs that seem the most clearly and broadly promising for large-scale studies. Among them are dexamethasone, which is a steroid with anti-inflammatory effects, and baricitinib, a rheumatoid arthritis drug, both of which have enabled the sickest COVID-19 patients to bounce back by suppressing their immune systems. The third most clearly promising drug is heparin, a blood thinner, which a recent trial showed to be most helpful when administered at a full dose, more so than at a small, preventative dose. (On the flipside, Fajgenbaum says "it's a little sad" that in the database you can see hydroxychloroquine is still the most-prescribed drug being tried as a COVID treatment around the world, despite over the summer being debunked widely as an effective treatment, and continuously since then.)
One of the confounding attributes of SARS-CoV-2 is its ability to cause such a huge spectrum of outcomes. It's unlikely a silver bullet treatment will emerge under that reality, so the database also helps surface drugs that seem most promising for a specific population. Fluvoxamine, a selective serotonin reuptake inhibitor used to treat obsessive compulsive disorder, showed promise in the recovery of outpatients—those who were sick, but not severely enough to be hospitalized. Tocilizumab, which was actually developed for Castleman disease, the disease Fajgenbaum is managing, was initially written off as a COVID treatment because it failed to benefit large portions of hospitalized patients, but now seems to be effective if used on intensive care unit patients within 24 hours of admission—these are some of the sickest patients with the highest risk of dying.
Other than fluvoxamine, most of the drugs labeled as promising do skew toward targeting hospitalized patients, more than outpatients. One reason, Fajgenbaum says, is that "if you're in a hospital it's very easy to give you a drug and to track you, and there are very objective measurements as to whether you die, you progress to a ventilator, etc." Tracking outpatients is far more difficult, especially when folks have been routinely asked to stay home, quarantine, and free up hospital resources if they're experiencing only mild symptoms.
But the other reason for the skew is because COVID is very unlike most other diseases in terms of the human immune response the virus triggers. For example, if oncology treatments show some benefit to people with the highest risk of dying, then they usually work extremely well if administered in the earlier stages of a cancer diagnosis. Across many diseases, this dialing backward is a standard approach to identifying promising treatments. With COVID, all of that reasoning has proven moot.
As we've seen over the last year, COVID cases often start as asymptomatic, and remain that way for days, indicating the body is mounting an incredibly weak immune response initially. Then, between days five and 14, as if trying to make up for lost time, the immune system overcompensates by launching a major inflammatory response, which in the sickest patient can lead to the type of cytokine storms that helped Fajgenbaum realize his years of Castleman research might be useful during this public health crisis. Because of this phased response, you can't apply the same treatment logic to all cases.
"In COVID, drugs that work late tend to not work if given early, and drugs that work early tend to not work if given late," says Fajgenbaum. "Generally this … is not a commonplace thing for a virus."
"There are drugs that are literally sitting in every single hospital pharmacy in the country that, if a study shows it's effective, can be deployed that evening to patients on a massive scale."
This see-sawing necessitates tracking a constellation of drugs that might work for different stages of the disease as a patient moves from the weak immune response stage into the overzealous immune response.
"COVID is difficult, compared to other diseases, because there are so many different levels of disease severity, and recovery at different rates," says Stone, the FDA researcher. "That makes it hard to see the patterns or signals and it makes it very important to collect very, very large numbers of cases in order to really reliably identify signals."
This particular moment in the pandemic feels like a massive tipping point, or the instant a tiny pinprick of light finally appeared at the end of the tunnel: several vaccines are already here, with more on the way imminently. In the U.S., more than 65 million doses of the vaccine have been administered, and positive COVID cases are finally falling back to levels not seen since October. On the hopeful surface, it might seem a strange moment to be preparing to launch trials that will validate treatments for a virus it seems the U.S. may finally be beating back. But at best, Americans are still months away from reaching herd immunity through vaccination, and new circulating variants may threaten to upend our fragile progress.
"In the meantime, there are drugs that are literally sitting in every single hospital pharmacy in the country that, if a study shows it's effective, can be deployed that evening to patients on a massive scale. It wouldn't have to be newly produced, it wouldn't have to be shipped, it's literally there already," says Fajgenbaum. "The idea that you can save a lot of lives by finding things that are just already there I think is really compelling, given how many people are going to die over these next few months."
Even after that, not everyone can or will be vaccinated, and, as the Wall Street Journal recently reported, "The pathogen will circulate for years, or even decades, leaving society to coexist with Covid-19 much as it does with other endemic diseases like flu, measles, and HIV." Neither vaccines, personal behavior, or treatments alone is a panacea against the virus, but together they might be.
"It's important to explore all avenues in this public health emergency, and drug repurposing can continue to play a role as the pandemic continues and evolves," says Stone. "I think COVID variants in particular are a big concern at the moment, and therefore continuing to investigate new therapeutics, even as the vaccines roll out, will continue to be a priority."
How a Nobel-Prize Winner Fought Her Family, Nazis, and Bombs to Change our Understanding of Cells Forever
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."