Sammy Basso is one of around 400 young people in the world with progeria.
Just 400 or so people in the world live with progeria: The mutation that causes it usually arises de novo, or "of new," meaning that it is not inherited but happens spontaneously during gestation. The challenge, as with all rare diseases, is that few cases means few treatments.
"When we first started, there was absolutely nothing out there," says Leslie Gordon, a physician-researcher who co-founded the Progeria Research Foundation in 1999 after her own son, also named Sam, was diagnosed with the disease. "We knew we had to jumpstart the entire field, so we collected money through road races and special events and writing grants and all sorts of donors… I think the first year we raised $75,000, most of it from one donor."
"We have not only the possibility but the responsibility to make the world a better world, and also to make a body a better body."
By 2003, the foundation had collaborated with Francis Collins, a geneticist who is now director of the National Institutes of Health, to work out the genetic basis for progeria—that single mutation Sammy has. The discovery led to interest in lonafarnib, a drug that was already being used in cancer patients but could potentially operate downstream of the mutation, preventing the buildup of the defective progerin in the body. "We funded cellular studies to look at a lonafarnib in cells, mouse studies to look at lonafarnib in mouse models of progeria… and then we initiated the clinical trials," Gordon says.
Sammy Basso's family had gotten involved with the Progeria Research Foundation through their international patient registry, which maintains relationships with families in 49 countries. "We started to hear about lonafarnib in 2006 from Leslie Gordon," says Sammy's father, Amerigo Basso, with his son translating. "She told us about the lonafarnib. And we were very happy because for the first time we understood that there was something that could help our son and our lives." Amerigo used the Italian word speranza, which means hope.
Still, Sammy wasn't sure if lonafarnib was right for him. "Since when I was very young I thought that everything happens for a reason. So, in my mind, if God made me with progeria, there was a reason, and to try to heal from progeria was something wrong," he says. Gradually, his parents and doctors, and Leslie Gordon, convinced him otherwise. Sammy began to believe that God was also the force behind doctors, science, and research. "And so we have not only the possibility but the responsibility to make the world a better world, and also to make a body a better body," he says.
Sammy Basso and his parents.
Courtesy of Basso
Sammy began taking lonafarnib, with the Progeria Research Foundation intermittently flying him, and other international trial participants, to Boston for tests. He was immediately beset by some of the drug's more unpleasant side effects: Stomach problems, nausea, and vomiting. "The first period was absolutely the worst period of my life," he says.
At first, doctors prescribed other medicines for the side effects, but to Sammy it had as much effect as drinking water. He visited doctor after doctor, with some calling him weekly or even daily to ask how he was doing. Eventually the specialists decided that he should lower his dose, balancing his pain with the benefit of the drug. Sammy can't actually feel any positive effect of the lonafarnib, but his health measurements have improved relative to people with progeria who don't take it.
While they never completely disappeared, Sammy's side effects decreased to the point that he could live. Inspired by the research that led to lonafarnib, he went to university to study molecular biology. For his thesis work, he travelled to Spain to perform experiments on cells and on mice with progeria, learning how to use the gene-editing technique CRISPR-Cas9 to cut out the mutated bit of DNA. "I was so excited to participate in this study," Sammy says. He felt like his work could make a difference.
In 2018, the Progeria Research Foundation was hosting one of their biennial workshops when Francis Collins, the researcher who had located the mutation behind progeria 15 years earlier, got in touch with Leslie Gordon. "Francis called me and said, Hey, I just saw a talk by David Liu from the Broad [Institute]. And it was pretty amazing. He has been looking at progeria and has very early, but very exciting data… Do you have any spaces, any slots you could make in your program for late breaking news?"
Gordon found a spot, and David Liu came to talk about what was going on in his lab, which was an even more advanced treatment that led to mice with the progeria mutation living into their senior mouse years—substantially closer to a normal lifespan. Liu's lab had built on the idea of CRISPR-Cas9 to create a more elegant genetic process called base editing: Instead of chopping out mutated DNA, a scientist could chemically convert an incorrect DNA letter to the correct one, like the search and replace function in word processing software. Mice who had their Lamin-A mutations corrected this way lived more than twice as long as untreated animals.
Sammy was in the audience at Dr. Liu's talk. "When I heard about this base editing as a younger scientist, I thought that I was living in the future," he says. "When my parents had my diagnosis of progeria, the science knew very little information about DNA. And now we are talking about healing the DNA… It is incredible."
Lonafarnib (also called Zokinvy) was approved by the US Food and Drug Administration this past November. Sammy, now 25, still takes it, and still manages his side effects. With luck, the gift of a few extra years will act as a bridge until he can try Liu's revolutionary new gene treatment, which has not yet begun testing in humans. While Leslie Gordon warns that she's always wrong about things like this, she hopes to see the new base editing techniques in clinical trials in the next year or two. Sammy won't need to be convinced to try it this time; his thinking on fate has evolved since his first encounter with lonafarnib.
"I would be very happy to try it," he says. "I know that for a non-scientist it can be difficult to understand. Some people think that we are the DNA. We are not. The DNA is a part of us, and to correct it is to do what we are already doing—just better." In short, a gene therapy, while it may seem like science fiction, is no different from a pill. For Sammy, both are a new way to think about fate: No longer something that simply happens to him.
Recent immigration restrictions have left many foreign researchers' projects and careers in limbo—and some in jeopardy.
"I spent about $4,000 on lawyer fees and another $1,200 to pay for the motions I filed," she recalls. "I had to borrow money from my parents and my cousin because without my salary I just didn't have the $7,000 at hand." But the already narrow window of opportunity slammed completely shut when the Trump administration suspended issuing new visas for foreign researchers in June. All Mohan's attempts were denied. In August, she had to leave the country. "Given the recent work visa ban by the administration, all my options in the U.S. are closed," she wrote a bitter note on Twitter. "I have to uproot my entire life in NY for the past 6 years and leave." She eventually found a temporary position in Calcutta, where she can continue research.
Mohan is hardly alone in her visa saga. Many foreign scholars on H- and J-type visas and other permits that let them remain employed in America had been struggling to keep their rights to continue research, which in certain cases is crucial to battling the pandemic. Some had to leave the country, some filed every possible extension to buy time, and others are stuck in their home countries, unable to return. The already cumbersome process of applying for visas and extensions became crippled during the lockdowns. But in June, when President Trump extended and expanded immigration restrictions to cut the number of immigrant workers entering the U.S., the new limits left researchers' projects and careers in limbo—and some in jeopardy.
"We have been a beneficiary of this flow of human capacity and resource investment for many generations—and this is now threatened."
Rakesh Ramachandran, whose computational biology work contributed to one of the first coronavirus studies to map out its protein structures—is stranded in India. In early March, he had travelled there to attend a conference and visit the American consulate to stamp his H1 visa for a renewal, already granted. The pandemic shut down both the conference and the consulates, and Ramachandran hasn't been able to come back since. The consulates finally opened in September, but so far the online portal has no available appointment slots. "I'm told to keep trying," Ramachandran says.
The visa restrictions affected researchers worldwide, regardless of disciplines or countries. A Ph.D. student in neuroscience, Morgane Leroux had to do her experiments with mice at Gladstone Institutes in America and analyze the data back home at Sorbonne University in France. She had finished her first round of experiments when the lockdowns forced her to return to Paris, and she hasn't been able to come back to resume her work since. "I can't continue the experiments, which is really frustrating," she says, especially because she doesn't know what it means for her Ph.D. "I may have to entirely change my subject," she says, which she doesn't want to do—it would be a waste of time and money.
But besides wreaking havoc in scholars' personal lives and careers, the visa restrictions had—and will continue to have—tremendous deleterious effects on America's research and its global scientific competitiveness. "It's incredibly short-sighted and self-destructing to restrict the immigration of scientists into the U.S.," says Benjamin G. Neel, who directs the Laura and Isaac Perlmutter Cancer Center at New York University. "If they can't come here, they will go elsewhere," he says, causing a brain drain.
Neel in his lab with postdocs
(Courtesy of Neel)
Neel felt the outcomes of the shortsighted policies firsthand. In the past few months, his lab lost two postdoctoral researchers who had made major strides in understanding the biology of several particularly stubborn, treatment-resistant malignancies. One postdoc studied the underlying mechanisms responsible for 90 percent of pancreatic cancers and half of the colon ones. The other one devised a new system of modeling ovarian cancer in mice to test new therapeutic drug combinations for the deadliest tumor types—but had to return home to China.
"By working around the clock, she was able to get her paper accepted, but she hasn't been able to train us to use this new system, which can set us back six months," Neel says.
Her discoveries also helped the lab secure about $900,000 in grants for new research. Losing people like this is "literally killing the goose that lays the golden eggs," Neel adds. "If you want to make America poor again, this is the way to do it."
Cassidy R. Sugimoto at Indiana University Bloomington, who studies how scientific knowledge is produced and disseminated, says that scientists are the most productive when they are free to move, exchange ideas, and work at labs with the best equipment. Restricting that freedom reduces their achievement.
"Several empirical studied demonstrated the benefits to the U.S. by attracting and retaining foreign scientists. The disproportional number of our Nobel Prize winners were not only foreign-born but also foreign-educated," she says. Scientific advancement bolsters the country's economic prowess, too, so turning scholars away is bad for the economy long-term. "We have been a beneficiary of this flow of human capacity and resource investment for many generations—and this is now threatened," Sugimoto adds—because scientists will look elsewhere. "We are seeing them shifting to other countries that are more hospitable, both ideologically and in terms of health security. Many visiting scholars, postdocs, and graduate students who would otherwise come to the United States are now moving to Canada."
It's not only the Ph.D. students and postdocs who are affected. In some cases, even well-established professors who have already made their marks in the field and direct their own labs at prestigious research institutions may have to pack up and leave the country in the next few months. One scientist who directs a prominent neuroscience lab is betting on his visa renewal and a green card application, but if that's denied, the entire lab may be in jeopardy, as many grants hinge on his ability to stay employed in America.
"It's devastating to even think that it can happen," he says—after years of efforts invested. "I can't even comprehend how it would feel. It would be terrifying and really sad." (He asked to withhold his name for fear that it may adversely affect his applications.) Another scientist who originally shared her story for this article, later changed her mind and withdrew, worrying that speaking out may hurt the entire project, a high-profile COVID-19 effort. It's not how things should work in a democratic country, scientists admit, but that's the reality.
Still, some foreign scholars are speaking up. Mehmet Doğan, a physicist at University of California Berkeley who has been fighting a visa extension battle all year, says it's important to push back in an organized fashion with petitions and engage legislators. "This administration was very creative in finding subtle and not so subtle ways to make our lives more difficult," Doğan says. He adds that the newest rules, proposed by the Department of Homeland Security on September 24, could further limit the time scholars can stay, forcing them into continuous extension battles. That's why the upcoming election might be a turning point for foreign academics. "This election will decide if many of us will see the U.S. as the place to stay and work or whether we look at other countries," Doğan says, echoing the worries of Neel, Sugimoto, and others in academia.
Dogan on Zoom talking to his fellow union members of the Academic Researchers United, a union of almost 5,000 Academic Researchers.
(Credit: Ceyda Durmaz Dogan)
If this year has shown us anything, it is that viruses and pandemics know no borders as they sweep across the globe. Likewise, science can't be restrained by borders either. "Science is an international endeavor," says Neel—and right now humankind now needs unified scientific research more than ever, unhindered by immigration hurdles and visa wars. Humanity's wellbeing in America and beyond depends on it.
[Editor's Note: To read other articles in this special magazine issue, visit the beautifully designed e-reader version.]