How a Nobel-Prize Winner Fought Her Family, Nazis, and Bombs to Change our Understanding of Cells Forever
Rita Levi-Montalcini survived the Nazis and eventually won a Nobel Prize for her work to understand why certain cells grow so quickly.
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."
Researchers at Stanford have found that the virus that causes Covid-19 can infect fat cells, which could help explain why obesity is linked to worse outcomes for those who catch Covid-19.
Obesity is a risk factor for worse outcomes for a variety of medical conditions ranging from cancer to Covid-19. Most experts attribute it simply to underlying low-grade inflammation and added weight that make breathing more difficult.
Now researchers have found a more direct reason: SARS-CoV-2, the virus that causes Covid-19, can infect adipocytes, more commonly known as fat cells, and macrophages, immune cells that are part of the broader matrix of cells that support fat tissue. Stanford University researchers Catherine Blish and Tracey McLaughlin are senior authors of the study.
Most of us think of fat as the spare tire that can accumulate around the middle as we age, but fat also is present closer to most internal organs. McLaughlin's research has focused on epicardial fat, “which sits right on top of the heart with no physical barrier at all,” she says. So if that fat got infected and inflamed, it might directly affect the heart.” That could help explain cardiovascular problems associated with Covid-19 infections.
Looking at tissue taken from autopsy, there was evidence of SARS-CoV-2 virus inside the fat cells as well as surrounding inflammation. In fat cells and immune cells harvested from health humans, infection in the laboratory drove "an inflammatory response, particularly in the macrophages…They secreted proteins that are typically seen in a cytokine storm” where the immune response runs amok with potential life-threatening consequences. This suggests to McLaughlin “that there could be a regional and even a systemic inflammatory response following infection in fat.”
It is easy to see how the airborne SARS-CoV-2 virus infects the nose and lungs, but how does it get into fat tissue? That is a mystery and the source of ample speculation.
The macrophages studied by McLaughlin and Blish were spewing out inflammatory proteins, While the the virus within them was replicating, the new viral particles were not able to replicate within those cells. It was a different story in the fat cells. “When [the virus] gets into the fat cells, it not only replicates, it's a productive infection, which means the resulting viral particles can infect another cell,” including microphages, McLaughlin explains. It seems to be a symbiotic tango of the virus between the two cell types that keeps the cycle going.
It is easy to see how the airborne SARS-CoV-2 virus infects the nose and lungs, but how does it get into fat tissue? That is a mystery and the source of ample speculation.
Macrophages are mobile; they engulf and carry invading pathogens to lymphoid tissue in the lymph nodes, tonsils and elsewhere in the body to alert T cells of the immune system to the pathogen. Perhaps some of them also carry the virus through the bloodstream to more distant tissue.
ACE2 receptors are the means by which SARS-CoV-2 latches on to and enters most cells. They are not thought to be common on fat cells, so initially most researchers thought it unlikely they would become infected.
However, while some cell receptors always sit on the surface of the cell, other receptors are expressed on the surface only under certain conditions. Philipp Scherer, a professor of internal medicine and director of the Touchstone Diabetes Center at the University of Texas Southwestern Medical Center, suggests that, in people who have obesity, “There might be higher levels of dysfunctional [fat cells] that facilitate entry of the virus,” either through transiently expressed ACE2 or other receptors. Inflammatory proteins generated by macrophages might contribute to this process.
Another hypothesis is that viral RNA might be smuggled into fat cells as cargo in small bits of material called extracellular vesicles, or EVs, that can travel between cells. Other researchers have shown that when EVs express ACE2 receptors, they can act as decoys for SARS-CoV-2, where the virus binds to them rather than a cell. These scientists are working to create drugs that mimic this decoy effect as an approach to therapy.
Do fat cells play a role in Long Covid? “Fat cells are a great place to hide. You have all the energy you need and fat cells turn over very slowly; they have a half-life of ten years,” says Scherer. Observational studies suggest that acute Covid-19 can trigger the onset of diabetes especially in people who are overweight, and that patients taking medicines to regulate their diabetes “were actually quite protective” against acute Covid-19. Scherer has funding to study the risks and benefits of those drugs in animal models of Long Covid.
McLaughlin says there are two areas of potential concern with fat tissue and Long Covid. One is that this tissue might serve as a “big reservoir where the virus continues to replicate and is sent out” to other parts of the body. The second is that inflammation due to infected fat cells and macrophages can result in fibrosis or scar tissue forming around organs, inhibiting their function. Once scar tissue forms, the tissue damage becomes more difficult to repair.
Current Covid-19 treatments work by stopping the virus from entering cells through the ACE2 receptor, so they likely would have no effect on virus that uses a different mechanism. That means another approach will have to be developed to complement the treatments we already have. So the best advice McLaughlin can offer today is to keep current on vaccinations and boosters and lose weight to reduce the risk associated with obesity.
Air pollution can lead to lung cancer. The connection suggests new ways to stop cancer in its tracks.
Researchers at Francis Crick Institute found that air pollution can "wake up" existing mutations, triggering them to turn into lung cancer. The scientists used their new understanding about this connection to prevent cancer in mice.
Forget taking a deep breath. Around the world, 99 percent of people breathe air polluted to unsafe levels, according to data from the World Health Organization. Activities such as burning fossil fuels release greenhouse gases that contribute to air pollution, which could lead to heart disease, stroke, asthma, emphysema, and some types of cancer.
“The burden of disease attributable to air pollution is now estimated to be on a par with other major global health risks such as unhealthy diet and tobacco smoking, and air pollution is now recognized as the single biggest environmental threat to human health,” wrote the authors of a 2021 WHO report.
The majority of lung cancer is attributed to smoking. But as pollution levels have increased, and anti-smoking campaigns have discouraged smoking, the proportion of lung cancers diagnosed in non-smokers has grown. The CDC estimates that 10 to 20 percent of lung cancers in the U.S. currently occur in non-smokers.
The mechanism between air pollution and the development of lung cancer has been unclear, but researchers at London’s Francis Crick Institute recently made an important breakthrough in understanding the connection. Lead investigator Charles Swanton presented this research last month at a conference in Paris.
Pollution awakens mutations
The Crick Institute scientists were able to identify a new link between common air pollutants and non-small cell lung cancer (NSCLC). They focused on pollutants called particulate matter, or PM, that are 2.5 microns wide, narrower than human cells.
Most cancer diagnosed in non-smoking people is NSCLC, but this type of cancer hasn’t received the same research attention as more common lung cancers found in smokers, according to Clare Weeden, a cancer researcher at the Crick Institute and a co-author of the study.
“This is a really underserved and under-researched population that we really need to tackle, as well as lung cancers that occur in smokers,” she says. “Lung cancer is the number one cancer killer worldwide.”
In the past, some researchers believed air pollution caused mutations that led to cancer. Others believed these mutations could remain dormant without any detriment to health until pollutants or other stressors triggered them to become cancerous. Reviving the latter hypothesis that carcinogens may activate pre-existing mutations, instead of directly causing them, the Crick researchers analyzed samples from 463,679 people in the UK and parts of Asia, noting mutations and comparing changes in gene expression in mice and human cells.
“The mutation can exist in a nascent clone without causing cancer,” says Emilia Lim, a bioinformatics expert and a co-first author of the Crick study. “It is the carcinogen that promotes a conducive environment for this one little clone to grow and expand into cancer. Through our work, we were able to revive excitement for this hypothesis and bring it to light.”
The study explains a confusing pattern of lung cancer developing, particularly in women, despite a lack of environmental risk factors like smoking, secondhand smoke, or radon exposure. The culprit in these cases may have been too much PM 2.5 exposure.
Other researchers had previously identified a link between mutations in certain genes that control epidermal growth factor receptors, or EGFR mutations, and the development of NSCLC. In a 2019 study of 250 people with this type of cancer, about 32 percent had the mutation. Women are more likely to have EGFR mutations than men.
Not everyone who has the EGFR mutation will develop lung cancer. Respirologist Stephen Lam studies lung cancer at the BC Cancer Research Centre in Vancouver, Canada, but was not involved in the Crick Institute research. He says the study explains a confusing pattern of lung cancer developing, particularly in women, despite a lack of environmental risk factors like smoking, secondhand smoke, or radon exposure. The culprit in these cases may have been too much PM 2.5 exposure.
More exposure leads to inflammation and lesions
The Crick researchers found that an excess of PM 2.5 in the air sparked an inflammatory process in cells within the lung. This inflammation set the stage for NSCLC to develop in people and mice with existing EGFR mutations.
The researchers also exposed mice without EGFR mutations to PM 2.5 pollution—an experiment that couldn’t be ethically conducted in humans—to link pollution exposure to NSCLC. The mice experiments also showed that NSCLC is dose-dependent; higher levels of exposure were associated with higher number of cancerous lesions forming.
Ultimately, the study “fundamentally changed how we view lung cancer in people who have never smoked,” said Swanton in a Crick Institute press release. “Cells with cancer-causing mutations accumulate naturally as we age, but they are normally inactive. We’ve demonstrated that air pollution wakes these cells up in the lungs, encouraging them to grow and potentially form tumors.”
Preventing cancer before it begins
Targeted therapies already exist for people with EGFR mutations who’ve developed NSCLC, but they have many side effects, according to Weeden. Researchers hope that making more definitive links between pollutants and cancer could help prevent people with EGFR or other mutations from developing lung cancer in the first place.
Along those lines, as an additional component of their study presented last month, the Crick researchers were able to prevent cancer in mice that had the EGFR mutations by blocking inflammation. They used an antibody to inhibit a protein called interleukin 1 beta, which plays a key role in inflammation. Scientists could eventually use such antibodies or other therapies to make a drug treatment that people can take to stop cancer in its tracks, even if they live in highly polluted areas.
Such potential could reach beyond lung cancer; in the past, Crick and other researchers have also found associations between exposure to air pollution and mesothelioma, as well as cancers of the small intestine, lip, mouth, and throat. These links could be meaningful to a growing number of people as climate change intensifies, and with increases in air pollution from fossil fuel combustion and natural disasters like forest fires.
Plus, air pollution is just one external condition that can flip the switch of these inflammatory pathways. Identifying a link between pollution and cancer “has wide ramifications for many other environmental factors that may [play] similar roles,” Weedon says. She hopes that the Crick study and future research in this area will offer some hope for non-smokers frustrated by cancer diagnoses.