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.
Avalanche rescue dogs train to find and dig out people buried in snow slides
By the time he is three, Lume, like Huckleberry, will be a fully trained avy pup and will join seven other avy dogs on Breckenridge ski patrol team. Some of the team members, both human and canine, are also certified to work with Colorado Rapid Avalanche Deployment, a coordinated response team that works with the Summit County Sheriff’s office for avalanche emergencies outside of the ski slopes’ boundaries.
There have been 19 avalanche deaths in the U.S. this season, according to avalanche.org, which tracks slides; eight in Colorado. During the entirety of last season there were 17. Avalanche season runs from November through June, but avalanches can occur year-round.
High tech and high stakes
Complementing avy dogs’ ability to smell people buried in a slide, avalanche detection, rescue and recovery is becoming increasingly high tech. There are transceivers, signal locators, ground scanners and drones, which are considered “games changers” by many in avalanche rescue and recovery
For a person buried in an avalanche, the chance of survival plummets after 20 minutes, so every moment counts.
A drone can provide thermal imaging of objects caught in a slide; what looks like a rock from far away might be a human with a heat signature. Transceivers, also known as beacons, send a signal from an avalanche victim to a companion. Signal locators, like RECCO reflectors which are often sewn directly into gear, can echo back a radar signal sent by a detector; most ski resorts have RECCO detector units.
Research suggests that Ground Penetrating Radar (GPR), an electromagnetic tool used by geophysicists to pull images from inside the ground, could be used to locate an avalanche victim. A new study from the Department of Energy’s Sandia National Laboratories suggests that a computer program developed to pinpoint the source of a chemical or biological terrorist attack could also be used to find someone submerged in an avalanche. The search algorithm allows for small robots (described as cockroach-sized) to “swarm” a search area. Researchers say that this distributed optimization algorithm can help find avalanche victims four times faster than current search mechanisms. For a person buried in an avalanche, the chance of survival plummets after 20 minutes, so every moment counts.
An avy dog in training is picking up scent
Sarah McLear
While rescue gear has been evolving, predicting when a slab will fall remains an emerging science — kind of where weather forecasting science was in the 1980s. Avalanche forecasting still relies on documenting avalanches by going out and looking,” says Ethan Greene, director of the Colorado Avalanche Information Center (CAIC). “So if there's a big snowstorm, and as you might remember, most avalanches happened during snowstorms, we could have 10,000 avalanches that release and we document 50,” says Greene. “Avalanche forecasting is essentially pattern recognition,” he adds--and understanding the layering structure of snow.
However, determining where the hazards lie can be tricky. While a dense layer of snow over a softer, weaker layer may be a recipe for an avalanche, there’s so much variability in snowpack that no one formula can predict the trigger. Further, observing and measuring snow at a single point may not be representative of all nearby slopes. Finally, there’s not enough historical data to help avalanche scientists create better prediction models.
That, however, may be changing.
Last year, an international group of researchers created computer simulations of snow cover using 16 years of meteorological data to forecast avalanche hazards, publishing their research in Cold Regions Science and Technology. They believe their models, which categorize different kinds of avalanches, can support forecasting and determine whether the avalanche is natural (caused by temperature changes, wind, additional snowfall) or artificial (triggered by a human or animal).
With smell receptors ranging from 800 million for an average dog, to 4 billion for scent hounds, canines remain key to finding people caught in slides.
With data from two sites in British Columbia and one in Switzerland, researchers built computer simulations of five different avalanche types. “In terms of real time avalanche forecasting, this has potential to fill in a lot of data gaps, where we don't have field observations of what the snow looks like,” says Simon Horton, a postdoctoral fellow with the Simon Fraser University Centre for Natural Hazards Research and a forecaster with Avalanche Canada, who participated in the study. While complex models that simulate snowpack layers have been around for a few decades, they weren’t easy to apply until recently. “It's been difficult to find out how to apply that to actual decision-making and improving safety,” says Horton. If you can derive avalanche problem types from simulated snowpack properties, he says, you’ll learn “a lot about how you want to manage that risk.”
The five categories include “new snow,” which is unstable and slides down the slope, “wet snow,” when rain or heat makes it liquidly, as well as “wind-drifted snow,” “persistent weak layers” and “old snow.” “That's when there's some type of deeply buried weak layer in the snow that releases without any real change in the weather,” Horton explains. “These ones tend to cause the most accidents.” One step by a person on that structurally weak layer of snow will cause a slide. Horton is hopeful that computer simulations of avalanche types can be used by scientists in different snow climates to help predict hazard levels.
Greene is doubtful. “If you have six slopes that are lined up next to each other, and you're going to try to predict which one avalanches and the exact dimensions and what time, that's going to be really hard to do. And I think it's going to be a long time before we're able to do that,” says Greene.
What both researchers do agree on, though, is that what avalanche prediction really needs is better imagery through satellite detection. “Just being able to count the number of avalanches that are out there will have a huge impact on what we do,” Greene says. “[Satellites] will change what we do, dramatically.” In a 2022 paper, scientists at the University of Aberdeen in England used satellites to study two deadly Himalayan avalanches. The imaging helped them determine that sediment from a 2016 ice avalanche plus subsequent snow avalanches contributed to the 2021 avalanche that caused a flash flood, killing over 200 people. The researchers say that understanding the avalanches characteristics through satellite imagery can inform them how one such event increases the magnitude of another in the same area.
Avy dogs trainers hide in dug-out holes in the snow, teaching the dogs to find buried victims
Sarah McLear
Lifesaving combo: human tech and Mother Nature’s gear
Even as avalanche forecasting evolves, dogs with their built-in rescue mechanisms will remain invaluable. With smell receptors ranging from 800 million for an average dog, to 4 billion for scent hounds, canines remain key to finding people caught in slides. (Humans in comparison, have a meager 12 million.) A new study published in the Journal of Neuroscience revealed that in dogs smell and vision are connected in the brain, which has not been found in other animals. “They can detect the smell of their owner's fingerprints on a glass slide six weeks after they touched it,” says Nicholas Dodman, professor emeritus at Cummings School of Veterinary Medicine at Tufts University. “And they can track from a boat where a box filled with meat was buried in the water, 100 feet below,” says Dodman, who is also co-founder and president of the Center for Canine Behavior Studies.
Another recent study from Queens College in Belfast, United Kingdom, further confirms that dogs can smell when humans are stressed. They can also detect the smell of a person’s breath and the smell of the skin cells of a deceased person.
The emerging avalanche-predicting human-made tech and the incredible nature-made tech of dogs’ olfactory talents is the lifesaving “equipment” that Leffler believes in. Even when human-made technology develops further, it will be most efficient when used together with the millions of dogs’ smell receptors, Leffler believes. “It is a combination of technology and the avalanche dog that will always be effective in finding an avalanche victim.”
