In nature, few species remain dominant for long. Any sizable population of similar individuals offers immense resources to whichever parasite can evade its defenses, spreading rapidly from one member to the next.
Which will prove greater: our defenses or our vulnerabilities?
Humans are one such dominant species. That wasn't always the case: our hunter-gatherer ancestors lived in groups too small and poorly connected to spread pathogens like wildfire. Our collective vulnerability to pandemics began with the dawn of cities and trade networks thousands of years ago. Roman cities were always demographic sinks, but never more so than when a pandemic agent swept through. The plague of Cyprian, the Antonine plague, the plague of Justinian – each is thought to have killed over ten million people, an appallingly high fraction of the total population of the empire.
With the advent of sanitation, hygiene, and quarantines, we developed our first non-immunological defenses to curtail the spread of plagues. With antibiotics, we began to turn the weapons of microbes against our microbial foes. Most potent of all, we use vaccines to train our immune systems to fight pathogens before we are even exposed. Edward Jenner's original vaccine alone is estimated to have saved half a billion lives.
It's been over a century since we suffered from a swift and deadly pandemic. Even the last deadly influenza of 1918 killed only a few percent of humanity – nothing so bad as any of the Roman plagues, let alone the Black Death of medieval times.
How much of our recent winning streak has been due to luck?
Much rides on that question, because the same factors that first made our ancestors vulnerable are now ubiquitous. Our cities are far larger than those of ancient times. They're inhabited by an ever-growing fraction of humanity, and are increasingly closely connected: we now routinely travel around the world in the course of a day. Despite urbanization, global population growth has increased contact with wild animals, creating more opportunities for zoonotic pathogens to jump species. Which will prove greater: our defenses or our vulnerabilities?
The tragic emergence of coronavirus 2019-nCoV in Wuhan may provide a test case. How devastating this virus will become is highly uncertain at the time of writing, but its rapid spread to many countries is deeply worrisome. That it seems to kill only the already infirm and spare the healthy is small comfort, and may counterintuitively assist its spread: it's easy to implement a quarantine when everyone infected becomes extremely ill, but if carriers may not exhibit symptoms as has been reported, it becomes exceedingly difficult to limit transmission. The virus, a distant relative of the more lethal SARS virus that killed 800 people in 2002 to 2003, has evolved to be transmitted between humans and spread to 18 countries in just six weeks.
Humanity's response has been faster than ever, if not fast enough. To its immense credit, China swiftly shared information, organized and built new treatment centers, closed schools, and established quarantines. The Coalition for Epidemic Preparedness Innovations, which was founded in 2017, quickly funded three different companies to develop three different varieties of vaccine: a standard protein vaccine, a DNA vaccine, and an RNA vaccine, with more planned. One of the agreements was signed after just four days of discussion, far faster than has ever been done before.
The new vaccine candidates will likely be ready for clinical trials by early summer, but even if successful, it will be additional months before the vaccine will be widely available. The delay may well be shorter than ever before thanks to advances in manufacturing and logistics, but a delay it will be.
The 1918 influenza virus killed more than half of its victims in the United Kingdom over just three months.
If we faced a truly nasty virus, something that spreads like pandemic influenza – let alone measles – yet with the higher fatality rate of, say, H7N9 avian influenza, the situation would be grim. We are profoundly unprepared, on many different levels.
So what would it take to provide us with a robust defense against pandemics?
Minimize the attack surface: 2019-nCoV jumped from an animal, most probably a bat, to humans. China has now banned the wildlife trade in response to the epidemic. Keeping it banned would be prudent, but won't be possible in all nations. Still, there are other methods of protection. Influenza viruses commonly jump from birds to pigs to humans; the new coronavirus may have similarly passed through a livestock animal. Thanks to CRISPR, we can now edit the genomes of most livestock. If we made them immune to known viruses, and introduced those engineered traits to domesticated animals everywhere, we would create a firewall in those intermediate hosts. We might even consider heritably immunizing the wild organisms most likely to serve as reservoirs of disease.
None of these defenses will be cheap, but they'll be worth every penny.
Rapid diagnostics: We need a reliable method of detection costing just pennies to be available worldwide inside of a week of discovering a new virus. This may eventually be possible thanks to a technology called SHERLOCK, which is based on a CRISPR system more commonly used for precision genome editing. Instead of using CRISPR to find and edit a particular genome sequence in a cell, SHERLOCK programs it to search for a desired target and initiate an easily detected chain reaction upon discovery. The technology is capable of fantastic sensitivity: with an attomolar (10-18) detection limit, it senses single molecules of a unique DNA or RNA fingerprint, and the components can be freeze-dried onto paper strips.
Better preparations: China acted swiftly to curtail the spread of the Wuhan virus with traditional public health measures, but not everything went as smoothly as it might have. Most cities and nations have never conducted a pandemic preparedness drill. Best give people a chance to practice keeping the city barely functional while minimizing potential exposure events before facing the real thing.
Faster vaccines: Three months to clinical trials is too long. We need a robust vaccine discovery and production system that can generate six candidates within a week of the pathogen's identification, manufacture a million doses the week after, and scale up to a hundred million inside of a month. That may be possible for novel DNA and RNA-based vaccines, and indeed anything that can be delivered using a standardized gene therapy vector. For example, instead of teaching each person's immune system to evolve protective antibodies by showing it pieces of the virus, we can program cells to directly produce known antibodies via gene therapy. Those antibodies could be discovered by sifting existing diverse libraries of hundreds of millions of candidates, computationally designed from scratch, evolved using synthetic laboratory ecosystems, or even harvested from the first patients to report symptoms. Such a vaccine might be discovered and produced fast enough at scale to halt almost any natural pandemic.
Robust production and delivery: Our defenses must not be vulnerable to the social and economic disruptions caused by a pandemic. Unfortunately, our economy selects for speed and efficiency at the expense of robustness. Just-in-time supply chains that wing their way around the world require every node to be intact. If workers aren't on the job producing a critical component, the whole chain breaks until a substitute can be found. A truly nasty pandemic would disrupt economies all over the world, so we will need to pay extra to preserve the capacity for independent vertically integrated production chains in multiple nations. Similarly, vaccines are only useful if people receive them, so delivery systems should be as robustly automated as possible.
None of these defenses will be cheap, but they'll be worth every penny. Our nations collectively spend trillions on defense against one another, but only billions to protect humanity from pandemic viruses known to have killed more people than any human weapon. That's foolish – especially since natural animal diseases that jump the species barrier aren't the only pandemic threats.
We will eventually make our society immune to naturally occurring pandemics, but that day has not yet come, and future pandemic viruses may not be natural.
The complete genomes of all historical pandemic viruses ever to have been sequenced are freely available to anyone with an internet connection. True, these are all agents we've faced before, so we have a pre-existing armory of pharmaceuticals and vaccines and experience. There's no guarantee that they would become pandemics again; for example, a large fraction of humanity is almost certainly immune to the 1918 influenza virus due to exposure to the related 2009 pandemic, making it highly unlikely that the virus would take off if released.
Still, making the blueprints publicly available means that a large and growing number of people with the relevant technical skills can single-handedly make deadly biological agents that might be able to spread autonomously -- at least if they can get their hands on the relevant DNA. At present, such people most certainly can, so long as they bother to check the publicly available list of which gene synthesis companies do the right thing and screen orders -- and by implication, which ones don't.
One would hope that at least some of the companies that don't advertise that they screen are "honeypots" paid by intelligence agencies to catch would-be bioterrorists, but even if most of them are, it's still foolish to let individuals access that kind of destructive power. We will eventually make our society immune to naturally occurring pandemics, but that day has not yet come, and future pandemic viruses may not be natural. Hence, we should build a secure and adaptive system capable of screening all DNA synthesis for known and potential future pandemic agents... without disclosing what we think is a credible bioweapon.
Whether or not it becomes a global pandemic, the emergence of Wuhan coronavirus has underscored the need for coordinated action to prevent the spread of pandemic disease. Let's ensure that our reactive response minimally prepares us for future threats, for one day, reacting may not be enough.
At age 52, Glen Rouse suffered from arm weakness and a lot of muscle twitches. “I first thought something was wrong when I could not throw a 50-pound bag of dog food over the tailgate of my truck—something I use to do effortlessly,” said the 54-year-old resident of Anderson, California, about three hours north of San Francisco.
In August, Rouse retired as a forester for a private timber company, a job he had held for 31 years. The impetus: amyotrophic lateral sclerosis, or ALS, a progressive neuromuscular disease that is commonly known as Lou Gehrig’s disease, named after the New York Yankees’ first baseman who succumbed to it less than a month shy of his 38th birthday in 1941. ALS eventually robs an individual of the ability to talk, walk, chew, swallow and breathe.
Rouse is now dependent on ventilation through a nasal mask and uses a powerchair to get around. “I can no longer walk or use my arms very well,” he said. “I can still move my wrists and fingers. I can also transfer from my chair to the toilet if I have two of my friends help me.”
It’s “shocking” that modern medicine has very little to offer to people with this devastating condition, Rouse said. But there is hope on the horizon. Yesterday, the U.S. Food and Drug Administration approved Relyvrio, a drug made up of two parts, sodium phenylbutyrate and taurursodiol, to treat patients with ALS.
“This approval provides another important treatment option for ALS, a life-threatening disease that currently has no cure,” said Billy Dunn, director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, in a statement. “The FDA remains committed to facilitating the development of additional ALS treatments.”
Until this point, the FDA had approved only two other medications—Riluzole (rilutek) in 1995 and Radicava (edaravone) in 2017—to extend life in patients with ALS, which typically kills within two to five years after diagnosis. That’s why earlier this week, Rouse was optimistic about the FDA’s likely approval of a controversial new drug for ALS.
When Relyvrio is taken in addition to Riluzole, it appears to slow functional decline by an additional 25 percent and extend life by another 6 to 10 months, said Richard Bedlak, director of the Duke ALS Clinic. “It is not a cure, but it is definitely a step forward.”
“The whole ALS community is extremely excited about it,” he said the day before Relyvrio’s expected approval. “We are very hopeful. We’re on pins and needles.”
A study of 137 ALS patients did not result in “substantial evidence” that Relyvrio was effective, the agency’s Peripheral and Central Nervous System Drugs Advisory Committee concluded in March. However, after some persuasion from FDA officials, patients and their families, the committee met again and decided to recommend approving the drug.
In January 2019, following an ALS diagnosis at age 58 in October the previous year, Jeff Sarnacki, of Chester, Maryland, was accepted into a trial for Relyvrio. “Because of the trial, we did experience hope and a greater sense of help than had we not had that opportunity,” said Juliet Taylor, his wife and caregiver. They both believed the drug “worked for him in giving him more time.”
In June 2019, Sarnacki chose an open-label extension, offered to patients by drug researchers after a study ends, and took the active drug until he died peacefully at home under hospice care in May 2020, five days after his 60th birthday. A retired agent with the federal Bureau of Alcohol, Tobacco, Firearms and Explosives who later worked as a security consultant, Sarnacki lived about 19 months after diagnosis, which is shorter than the typical prognosis.
His symptoms began with leg cramps in fall 2017 and foot drop in early 2018. A feeding tube was placed in 2019, as it became necessary early in his illness, Taylor said. He also took Radicava and Riluzole, the two previously approved drugs, for his ALS. “We were both incredulous that, so many years after Lou Gehrig’s own diagnosis, there were so few treatments available,” she said.
The dearth of successful treatments for ALS is “certainly not for lack of trying,” said Karen Raley Steffens, a registered nurse and ALS support services coordinator at the Les Turner ALS Foundation in Skokie, Ill. “There are thousands of researchers and scientists all over the world working tirelessly to try to develop treatments for ALS.”
Unfortunately, she added, research takes time and exorbitant amounts of funding, while bureaucratic challenges persist. The rare disease also manifests and progresses in many different ways, so many treatments are needed.
As of 2017, the Centers for Disease Control and Prevention estimated that more than 31,000 people in the U.S. live with ALS, and an average of 5,000 people are newly diagnosed every year. It is slightly more common in men than women. Most people are diagnosed between the ages of 55 and 75.
Most cases of ALS are sporadic, meaning that doctors don’t know the cause. There is about a one-year interval between symptom onset and an ALS diagnosis for most patients, so many motor neurons are lost by the time individuals can enroll in a clinical trial, said Richard Bedlack, professor of neurology and director of the Duke ALS Clinic in Durham, North Carolina.
Bedlack found the new drug, Relyvrio, to be “very promising,” which is why he testified to the FDA in favor of approval. (He’s a consultant and disease state speaker for multiple companies including Amylyx, manufacturer of Relyvrio.)
The “drug has different mechanisms of action than the currently approved treatments,” Bedlack said. He added that, when Relyvrio is taken in addition to Riluzole, it appears to slow functional decline by an additional 25 percent and extend life by another 6 to 10 months. “It is not a cure, but it is definitely a step forward.”
T. Scott Diesing, a neurohospitalist and director of general neurology at the University of Nebraska Medical Center in Omaha, said he hopes the drug is “as good as people anticipated it should be, because there are not too many options for these patients.”
"FDA went out on a limb in approving Relyvrio based on limited results from a small trial while a larger study remains in progress," said Florian P. Thomas, co-director of the ALS Center at Hackensack University Medical Center and the Meridian School of Medicine. "While it is definitely promising, clearly, the last word on this drug has not been spoken."
So far, Rouse's voice is holding up, but he knows the day will come when ALS will steal that and much more from him.
ALS is 100 percent fatal, with some patients dying as soon as a year after diagnosis. A few have lasted as long as 15 years, but those are the exceptions, Diesing said.
“If this drug can provide even months of additional life, or would maintain quality of life, that’s a big deal,” he noted, adding that “the patients are saying, ‘I know it’s not proven conclusively, but what do we have to lose?’ So, they would like to try it while additional studies are ongoing.” The drug has already been conditionally approved in Canada.
As his disease progresses, Rouse hopes to get a speech-to-text voice-generating computer that he can control with his eyes. So far, his voice is holding up, but he knows the day will come when ALS will steal that and much more from him. He works at I AM ALS, a patient-led community, and six of his friends have already died of the disease.
“Every time I lose a friend to ALS, I grieve and am sad but I resolve myself to keep working harder for them, myself and others,” Rouse said. “People living with ALS find great purpose in life advocating and trying to make a difference.”
The Friday Five covers important stories in health and science research that you may have missed - usually over the previous week, but today's episode is a lookback on important studies over the month of September.
Most recently, on September 27, pharmaceuticals Biogen and Eisai announced that a clinical trial showed their drug, lecanemab, can slow the rate of Alzheimer's disease. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on scientific creativity and progress to give you a therapeutic dose of inspiration headed into the weekend and the new month.
This Friday Five episode covers the following studies published and announced over the past month:
- A new drug is shown to slow the rate of Alzheimer's disease
- The need for speed if you want to reduce your risk of dementia
- How to refreeze the north and south poles
- Ancient wisdom about Neti pots could pay off for Covid
- Two women, one man and a baby