Under the electronic microscope, the Ebola particles looked like tiny round bubbles floating inside human cells. Except these Ebola particles couldn't get free from their confinement.
They were trapped inside their bubbles, unable to release their RNA into the human cells to start replicating. These cells stopped the Ebola infection. And they did it on their own, without any medications, albeit in a petri dish of immunologist Adam Lacy-Hulbert. He studies how cells fight infections at the Benaroya Research Institute in Seattle, Washington.
These weren't just any ordinary human cells. They had a specific gene turned on—namely CD74, which typically wouldn't be on. Lacy-Hulbert's team was experimenting with turning various genes on and off to see what made cells fight viral infections better. One particular form of the CD74 gene did the trick. Normally, the Ebola particles would use the cells' own proteases—enzymes that are often called "molecular scissors" because they slice proteins—to cut the bubbles open. But CD74 produced a protein that blocked the scissors from cutting the bubbles, leaving Ebola trapped.
"When that gene turns on, it makes the protein that interferes with Ebola replication," Lacy-Hulbert says. "The protein binds to those molecular scissors and stops them from working." Even better, the protein interfered with coronaviruses too, including SARS-CoV-2, as the team published in the journal Science.
This begs the question: If one can turn on cells' viral resistance in a lab, can this be done in a human body so we that we can better fight Ebola, coronaviruses and other viral scourges?
Recent research indeed shows that our ability to fight viral infections is written in our genes. Genetic variability is at least one reason why some coronavirus-infected people don't develop symptoms while others stay on ventilators for weeks—often due to the aberrant response of their immune system, which went on overdrive to kill the pathogen. But if cells activate certain genes early in the infection, they might successfully stop viruses from replicating before the immune system spirals out of control.
"If my father who is 70 years old tests positive, I would recommend he takes interferon as early as possible."
When we talk about fighting infections, we tend to think in terms of highly specialized immune system cells—B-cells that release antibodies and T-cells that stimulate inflammatory responses, says Lacy-Hulbert. But all other cells in the body have the ability to fight infections too via different means. When cells detect the presence of a pathogen, they release interferons—small protein molecules named so because they set off a genetic chain reaction that interferes with viral replication. These molecules work as alarm signals to other cells around them. The neighboring cells transduce these signals inside themselves and turn on genes responsible for cellular defenses.
"There are at least 300 to 400 genes that are stimulated by type I interferons," says professor Jean-Laurent Casanova at Rockefeller University.
Scientists don't yet know exactly what all of these genes do, but they change the molecular behavior of the cells. "The cells go into a dramatic change and start producing hundreds of proteins that interfere with viral replication on the inside," explains Qian Zhang, a researcher at Casanova's lab. "Some block the proteins the virus needs and some physically tether the virus."
Some cells produce only small amount of interferon, enough to alert their neighbors. Others, such microphages and monocytes, whose jobs are to detect foreign invaders, produce a lot, injecting interferons into the blood to sound the alarm throughout the body. "They are professional cells so their jobs [are] to detect a viral or bacterial infection," Zhang explains.
People with impaired interferon responses are more vulnerable to infections, including influenza and coronaviruses. In two recent studies published in the journal Science, Casanova, Zhang and their colleagues found that patients who lacked a certain type of interferon had more severe Covid-19 symptoms and some died from it. The team ran a genetic comparison of blood samples from patients hospitalized with severe coronavirus cases against those with the asymptomatic infections.
They found that people with severe disease had rare variants in the 13 genes responsible for interferon production. More than three percent of them had a genetic mutation resulting in non-functioning genes. And over ten percent had an autoimmune condition, in which misguided antibodies neutralized their interferons, dampening their bodies' defenses—and these patients were predominantly men. These discoveries help explain why some young and seemingly healthy individuals require life support, while others have mild symptoms or none. The findings also offer ways of stimulating cellular resistance.
A New Frontier in the Making
The idea of making human cells genetically resistant to infections—and possibly other stressors like cancer or aging—has been considered before. It is the concept behind the Genome Project-write or GP-write project, which aims to create "ultra-safe" versions of human cells that resist a variety of pathogens by way of "recoding" or rewriting the cells' genes.
To build proteins, cells use combinations of three DNA bases called codons to represent amino acids—the proteins' building blocks. But biologists find that many of the codons are redundant so if they were removed from all genes, the human cells would still make all their proteins. However, the viruses, whose genes would still include these eliminated redundant codons, would no longer successfully be able to replicate inside human cells.
In 2016, the GP-Write team successfully reduced the number of Escherichia coli's codons from 64 to 57. Recoding genes in all human cells would be harder, but some recoded cells may be transplanted into the body, says Harvard Medical School geneticist George Church, the GP-Write core founding member.
"You can recode a subset of the body, such as all of your blood," he says. "You can also grow an organ inside a recoded pig and transplant it."
Church adds that these methods are still in stages that are too early to help us with this pandemic.
LeapsMag exclusively interviewed Church in 2019 about his latest progress with DNA recoding:
The Push for Clinical Trials
In the meantime, interferons may prove an easier medicine. Lacy-Hulbert thinks that interferon gamma might play a role in activating the CD74 gene, which gums up the molecular scissors. There also may be other ways to activate that gene. "So we are now thinking, can we develop a drug that mimics that actual activity?" he says.
Some interferons are already manufactured and used for treating certain diseases, including multiple sclerosis. Theoretically, nothing prevents doctors from prescribing interferons to Covid patients, but it must be done in the early stages of infection—to stimulate genes that trigger cellular defenses before the virus invades too many cells and before the immune systems mobilizes its big guns.
"If my father who is 70 years old tests positive, I would recommend he takes interferon as early as possible," says Zhang. But to make it a mainstream practice, doctors need clear prescription guidelines. "What would really help doctors make these decisions is clinical trials," says Casanova, so that such guidelines can be established. "We are now starting to push for clinical trials," he adds.
Jessica Ware is obsessed with bugs.
My guest today is a leading researcher on insects, the president of the Entomological Society of America and a curator at the American Museum of Natural History. Learn more about her here.
You may not think that insects and human health go hand-in-hand, but as Jessica makes clear, they’re closely related. A lot of people care about their health, and the health of other creatures on the planet, and the health of the planet itself, but researchers like Jessica are studying another thing we should be focusing on even more: how these seemingly separate areas are deeply entwined. (This is the theme of an upcoming event hosted by Leaps.org and the Aspen Institute.)
Listen to the Episode
Entomologist Jessica Ware
D. Finnin / AMNH
Maybe it feels like a core human instinct to demonize bugs as gross. We seem to try to eradicate them in every way possible, whether that’s with poison, or getting out our blood thirst by stomping them whenever they creep and crawl into sight.
But where did our fear of bugs really come from? Jessica makes a compelling case that a lot of it is cultural, rather than in-born, and we should be following the lead of other cultures that have learned to live with and appreciate bugs.
The truth is that a healthy planet depends on insects. You may feel stung by that news if you hate bugs. Reality bites.
Jessica and I talk about whether learning to live with insects should include eating them and gene editing them so they don’t transmit viruses. She also tells me about her important research into using genomic tools to track bugs in the wild to figure out why and how we’ve lost 50 percent of the insect population since 1970 according to some estimates – bad news because the ecosystems that make up the planet heavily depend on insects. Jessica is leading the way to better understand what’s causing these declines in order to start reversing these trends to save the insects and to save ourselves.
The first thing Jeroen Perk saw after he partially regained his sight nearly a decade ago was the outline of his guide dog Pedro.
“There was a white floor, and the dog was black,” recalls Perk, a 43-year-old investigator for the Dutch customs service. “I was crying. It was a very nice moment.”
Perk was diagnosed with retinitis pigmentosa as a child and had been blind since early adulthood. He has been able to use the implant placed into his retina in 2013 to help identify street crossings, and even ski and pursue archery. A video posted by the company that designed and manufactured the device indicates he’s a good shot.
Less black-and-white has been the journey Perk and others have been on after they were implanted with the Argus II, a second-generation device created by a Los Angeles-based company called Second Sight Medical Devices.
The Argus II uses the implant and a video camera embedded in a special pair of glasses to provide limited vision to those with retinitis pigmentosa, a genetic disease that causes cells in the retina to deteriorate. The camera feeds information to the implant, which sends electrical impulses into the retina to recapitulate what the camera sees. The impulses appear in the Argus II as a 60-pixel grid of blacks, grays and whites in the user’s eye that can render rough outlines of objects and their motion.
Smartphone and computer manufacturers typically stop issuing software upgrades to their devices after two or three years, eventually rendering them bricks. But is the smartphone approach acceptable for a device that helps restore the most crucial sense a human being possesses?
Ross Doerr, a retired disability rights attorney in Maine who received an Argus II in 2019, describes the field of vision as the equivalent of an index card held at arm’s length. Perk often brings objects close to his face to decipher them. Moreover, users must swivel their heads to take in visual data; moving their eyeballs does not work.
Despite its limitations, the Argus II beats the alternative. Perk no longer relies on his guide dog. Doerr was uplifted when he was able to see the outlines of Christmas trees at a holiday show.
“The fairy godmother department sort of reaches out and taps you on the shoulder once in a while,” Doerr says of his implant, which came about purely by chance. A surgeon treating his cataracts was partnered with the son of another surgeon who was implanting the devices, and he was referred.
Doerr had no reason to believe the shower of fairy dust wouldn’t continue. Second Sight held out promises that the Argus II recipients’ vision would gradually improve through upgrades to much higher pixel densities. The ability to recognize individual faces was even touted as a possibility. In the winter of 2020, Doerr was preparing to travel across the U.S. to Second Sight’s headquarters to receive an upgrade. But then COVID-19 descended, and the trip was canceled.
The pandemic also hit Second Sight’s bottom line. Doerr found out about its tribulations only from one of the company’s vision therapists, who told him the entire department was being laid off. Second Sight cut nearly 80% of its workforce in March 2020 and announced it would wind down operations.
Ross Doerr has mostly stopped using his Argus II, the result of combination of fear of losing its assistance from wear and tear and disdain for the company that brought it to market.
Second Sight’s implosion left some 350 Argus recipients in the metaphorical dark about what to do if their implants failed. Skeleton staff seem to have rarely responded to queries from their customers, at least based on the experiences of Perk and Doerr. And some recipients have unfortunately returned to the actual dark as well, as reports have surfaced of Argus II failures due to aging or worn-down parts.
Product support for complex products is remarkably uneven. Although the iconic Ford Mustang ceased production in the late 1960s, its parts market is so robust that it’s theoretically possible to assemble a new vehicle from recently crafted components. Conversely, smartphone and computer manufacturers typically stop issuing software upgrades to their devices after two or three years, eventually rendering them bricks. Consumers have accepted both extremes.
But is the smartphone approach acceptable for a device that helps restore the most crucial sense a human being possesses?
Margaret McLean, a senior fellow at the Markkula Center for Applied Ethics at Santa Clara University in California, notes companies like Second Sight have a greater obligation for product support than other consumer product ventures.
“In this particular case, you have a great deal of risk that is involved in using this device, the implant, and the after care of this device,” she says. “You cannot, like with your car, decide that ‘I don’t like my Mustang anymore,’ and go out and buy a Corvette.”
And, whether the Argus II implant works or not, its physical presence can impact critical medical decisions. Doerr’s doctor wanted him to undergo an MRI to assist in diagnosing attacks of vertigo. But the physician was concerned his implant might interfere. With the latest available manufacturer advisories on his implant nearly a decade old, the procedure was held up. Doerr spent months importuning Second Sight through phone calls, emails and Facebook postings to learn if his implant was contraindicated with MRIs, which he never received. Although the cause of his vertigo was found without an MRI, Doerr was hardly assured.
“Put that into context for a minute. I get into a serious car accident. I end up in the emergency room, and I have a tag saying I have an implanted medical device,” he says. “You can’t do an MRI until you get the proper information from the company. Who’s going to answer the phone?”
Second Sight’s management did answer the call to revamp its business. It netted nearly $78 million through a private stock placement and an initial public offering last year. At the end of 2021, Second Sight had nearly $70 million in cash on hand, according to a recent filing with the Securities and Exchange Commission.
And while the Argus II is still touted at length on Second Sight’s home page, it appears little of its corporate coffers are earmarked toward its support. These days, the company is focused on obtaining federal approvals for Orion, a new implant that would go directly into the recipient’s brain and could be used to remedy blindness from a variety of causes. It obtained a $6.4 million grant from the National Institutes of Health in May 2021 to help develop Orion.
Presented with a list of written questions by email, Second Sight’s spokesperson, Dave Gentry of the investor relations firm Red Chip Companies, copied a subordinate with an abrupt message to “please handle.” That was the only response from a company representative. A call to Second Sight acting chief executive officer Scott Dunbar went unreturned.
Whether or not the Orion succeeds remains to be seen. The company’s SEC filings suggest a viable and FDA-approved device is years away, and that operational losses are expected for the “foreseeable future.” Second Sight reported zero revenue in 2020 or 2021.
Moreover, the experiences of the Argus II recipients could color the reception of future Second Sight products. Doerr notes that his insurer paid nearly $500,000 to implant his device and for training on how to use it.
“What’s the insurance industry going to say the next time this crops up?” Doerr asks, noting that the company’s reputation is “completely shot” with the recipients of its implants.
Perk, who made speeches to praise the Argus II and is still featured in a video on the Second Sight website, says he also no longer supports the company.
Jeroen Perk, an investigator for the Dutch customs service, cried for joy after partially regaining his sight, but he no longer trusts Second Sight, the company that provided his implant.
Nevertheless, Perk remains highly reliant on the technology. When he dropped an external component of his device in late 2020 and it broke, Perk briefly debated whether to remain blind or find a way to get his Argus II working again. Three months later, he was able to revive it by crowdsourcing parts, primarily from surgeons with spare components or other Argus II recipients who no longer use their devices. Perk now has several spare parts in reserve in case of future breakdowns.
Despite the frantic efforts to retain what little sight he has, Perk has no regrets about having the device implanted. And while he no longer trusts Second Sight, he is looking forward to possibly obtaining more advanced implants from companies in the Netherlands and Australia working on their own products.
Doerr suggests that biotech firms whose implants are distributed globally be bound to some sort of international treaty requiring them to service their products in perpetuity. Such treaties are still applied to the salvage rights for ships that sunk centuries ago, he notes.
“I think that in a global tech economy, that would be a good thing,” says McLean, the fellow at Santa Clara, “but I am not optimistic about it in the near term. Business incentives push toward return on share to stockholders, not to patients and other stakeholders. We likely need to rely on some combination of corporately responsibility…and [international] government regulation. It’s tough—the Paris Climate Accord implementation at a slow walk comes to mind.”
Unlike Perk, Doerr has mostly stopped using his Argus II, the result of combination of fear of losing its assistance from wear and tear and disdain for the company that brought it to market. At 70, Doerr says he does not have the time or energy to hold the company more accountable. And with Second Sight having gone through a considerable corporate reorganization, Doerr believes a lawsuit to compel it to better serve its Argus recipients would be nothing but an extremely costly longshot.
“It’s corporate America at its best,” he observes.