Cows on a pasture, who, among other mammals, could experience immense suffering from the New World screwworm.
Combining CRISPR genome editing with the natural phenomenon of gene drive allows us to rewrite the genomes of wild organisms. The benefits of saving children from malaria by editing mosquitoes are obvious and much discussed, but humans aren't the only creatures who suffer. If we gain the power to intervene in a natural world "red in tooth and claw," yet decline to use it, are we morally responsible for the animal suffering that we could have prevented?
Given the power to alter the workings of the natural world, are we morally obligated to use it?
The scenario that may redefine our relationship with the natural world begins with fine clothing. You're dressed to the nines for a formal event, but you arrived early, and it's such a beautiful day that you decided to take a stroll by the nearby lake. Suddenly, you hear the sound of splashing and screams. A child is drowning! Will you dive in to save them? Or let them die, and preserve your expensive outfit?
The philosopher Peter Singer posited this scenario to show that we are all terrible human beings. Just about everyone would save the child and ruin the outfit... leading Singer to question why so few of us give equivalent amounts of money to save children on the other side of the world. The Against Malaria Foundation averages one life saved for every $7000.
But despite having a local bias, our moral compasses aren't completely broken. You never even considered letting the child drown because the situation wasn't your fault. That's because the cause of the problem simply isn't relevant: as the one who could intervene, the consequences are on your head. We are morally responsible for intervening in situations we did not create.
There is a critical difference between Singer's original scenario and the one above: in his version, it was a muddy pond. Any adult can rescue a child from a muddy pond, but a lake is different; you can only save the child if you know how to swim. We only become morally responsible when we acquire the power to intervene.
Few would disagree with either of these moral statements, but when they are combined with increasingly powerful technologies, the implications are deeply unsettling. Given the power to alter the workings of the natural world, are we morally obligated to use it? Recent developments suggest we had best determine the answer soon because, technologically, we are learning to swim. What choices will we make?
Gene drive is a natural phenomenon that occurs when a genetic element reliably spreads through a population even though it reduces the reproductive fitness of individual organisms. Nature has evolved many different mechanisms that result in gene drive, so many that it's nearly impossible to find an organism that doesn't have at least one driving element somewhere in its genome. More than half of our own DNA comprises the broken remnants of gene drives, plus a few active copies.
Scientists have long dreamed of harnessing gene drive to block mosquito-borne disease, with little success. Then came CRISPR genome editing, which works by cutting target genes and replacing them with a new sequence. What happens if you replace the original sequence with the edited version and an encoded copy of the CRISPR system? Gene drive.
CRISPR is a molecular scalpel that we can use to cut, and therefore replace, just about any DNA sequence in any cell. Encode the instructions for the CRISPR system adjacent to the new sequence, and genome editing will occur in the reproductive cells of subsequent generations of heterozygotes, always converting the original wild-type version to the new edited version. By ensuring that offspring will all be born of one sex, or by arranging for organisms that inherit two copies of the gene drive to be sterile, it's theoretically possible to cause a population crash.
(Credit: Esvelt)
When my colleagues and I first described this technology in 2014, we initially focused on the imperative for early transparency. Gene drive research is more like civic governance than traditional technology development: you can decline a treatment recommended by your doctor, but you can’t opt out when people change the shared environment. Applying the traditional closeted model of science to gene drive actively denies people a voice in decisions intended to affect them - and reforming scientific incentives for gene drive could be the first step to making all of science faster and safer.
But open gene drive research is clearly aligned with virtually all of our values. It's when technology places our deepest moral beliefs in conflict that we struggle, and learn who we truly are.
Two of our strongest moral beliefs include our reverence for the natural world and our abhorrence of suffering. Yet some natural species inherently cause tremendous suffering. Are we morally obligated to alter or even eradicate them?
To anyone who doubts that the natural world can inflict unimaginable suffering, consider the New World screwworm.
Judging by history, the answer depends on who is doing the suffering. We view the eradication of smallpox as one of our greatest triumphs, clearly demonstrating that we value human lives over the existence of disease-causing microorganisms. The same principle holds today for malaria: few would argue against using gene drive to crash populations of malarial mosquitoes to help eradicate the disease. There are more than 3500 species of mosquitoes, only three of which would be affected, and once malaria is gone, the mosquitoes could be allowed to recover. It would be extremely surprising if African nations decided not to eradicate malaria.
The more interesting question concerns our moral obligations to animals in the state of nature.
To anyone who doubts that the natural world can inflict unimaginable suffering, consider the New World screwworm, Cochyliomyia hominivorax. Female screwworm flies lay their eggs in open wounds, generating maggots that devour healthy tissue, gluttonously burrowing into the flesh of their host until they drop, engorged and sated, to metamorphose. Yet before they fall, the maggots in a wound emit a pheromone attracting new females, thereby acting as both conductors and performers in a macabre parade that consumes the host alive. The pain is utterly excruciating, so much so that infested people often require morphine before doctors can even examine the wound. Worst of all, the New World screwworm specializes in devouring complex mammals.
Every second of every day, hundreds of millions of animals suffer the excruciating agony of being eaten alive. It has been so throughout North and South America for millions of years. Until 2001, when humanity eradicated the last screwworm fly north of Panama using the “sterile insect technique�. This was not done to protect wild animals or even people, but for economic reasons: the cost of the program was small relative to the immense damage wrought by the screwworm on North American cattle, sheep, and goats. There were no obvious ecological effects. Despite being almost completely unknown even among animal rights activists, the screwworm elimination campaign may well have been one of the greatest triumphs of animal well-being.
Unfortunately, sterile insect technique isn't powerful enough to eradicate the screwworm from South America, where it is more entrenched and protected by the rougher terrain. But gene drive is.
Contrary to news hype, gene drive alone can't cause extinction, but if combined with conventional measures it might be possible to remove targeted species from the wild. For certain species that cause immense suffering, we may be morally obligated to do just that.
(Credit: Esvelt)
South Americans may well decide to eradicate screwworm for the same economic reasons that it was eradicated from North America: the fly inflicts $4 billion in annual damages on struggling rural communities that can least afford it. It need not go extinct, of course; the existence of the sterile insect facility in Panama proves that we can maintain the screwworm indefinitely in captivity on already dead meat.
Yet if for some reason humanity chooses to leave the screwworm as it is - even for upstanding moral reasons, whatever those may be - the knowledge of our responsibility should haunt us.
Tennyson wrote,
Are God and Nature then at strife,
That Nature lends such evil dreams?
So careful of the type she seems,
So careless of the single life.
Evolution by natural selection cares nothing for the single life, nor suffering, nor euphoria, save for their utility in replication. Theoretically, we do. But how much?
[Editor's Note: This story was originally published in May 2018. We are resurfacing archive hits while our staff is on vacation.]
Today's podcast guest, Dr. Renee Wegrzyn, directs ARPA-H, a new agency formed last year to spearhead health innovations. Time will tell if ARPA-H will produce advances on the level of its fellow agency, DARPA.
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How will the agency figure out which projects to take on, especially with so many patient advocates for different diseases demanding moonshot funding for rapid progress?
I talked with Dr. Wegrzyn about the opportunities and challenges, what lessons ARPA-H is borrowing from Operation Warp Speed, how she decided on the first ARPA-H project that was announced recently, why a separate agency was needed instead of reforming HHS and the National Institutes of Health to be better at innovation, and how ARPA-H will make progress on disease prevention in addition to treatments for cancer, Alzheimer’s and diabetes, among many other health priorities.
Dr. Wegrzyn’s resume leaves no doubt of her suitability for this role. She was a program manager at DARPA where she focused on applying gene editing and synthetic biology to the goal of improving biosecurity. For her work there, she received the Superior Public Service Medal and, in case that wasn’t enough ARPA experience, she also worked at another ARPA that leads advanced projects in intelligence, called I-ARPA. Before that, she ran technical teams in the private sector working on gene therapies and disease diagnostics, among other areas. She has been a vice president of business development at Gingko Bioworks and headed innovation at Concentric by Gingko. Her training and education includes a PhD and undergraduate degree in applied biology from the Georgia Institute of Technology and she did her postdoc as an Alexander von Humboldt Fellow in Heidelberg, Germany.
Dr. Wegrzyn told me that she’s “in the hot seat.” The pressure is on for ARPA-H especially after the need and potential for health innovation was spot lit by the pandemic and the unprecedented speed of vaccine development. We'll soon find out if ARPA-H can produce gamechangers in health that are equivalent to DARPA’s creation of the internet.
Show links:
ARPA-H - https://arpa-h.gov/
Dr. Wegrzyn profile - https://arpa-h.gov/people/renee-wegrzyn/
Dr. Wegrzyn Twitter - https://twitter.com/rwegrzyn?lang=en
President Biden Announces Dr. Wegrzyn's appointment - https://www.whitehouse.gov/briefing-room/statement...
Leaps.org coverage of ARPA-H - https://leaps.org/arpa/
ARPA-H program for joints to heal themselves - https://arpa-h.gov/news/nitro/ -
ARPA-H virtual talent search - https://arpa-h.gov/news/aco-talent-search/
Dr. Renee Wegrzyn was appointed director of ARPA-H last October.
Tardigrades can completely dehydrate and later rehydrate themselves, a survival trick that scientists are harnessing to preserve medicines in hot temperatures.
Formulating biologics to withstand drying and hot temperatures has been the holy grail for pharmaceutical researchers for decades. It’s a hard feat to manage. “Biologic pharmaceuticals are highly efficacious, but many are inherently unstable,” says Thomas Boothby, assistant professor of molecular biology at University of Wyoming. Therefore, during storage and shipping, they must be refrigerated at 2 to 8 degrees Celsius (35 to 46 degrees Fahrenheit). Some must be frozen, typically at -20 degrees Celsius, but sometimes as low -90 degrees Celsius as was the case with the Pfizer Covid vaccine.
For Covid, fewer than 73 percent of the global population received even one dose. The need for refrigerated or frozen handling was partially to blame.
The costly cold chain
The logistics network that ensures those temperature requirements are met from production to administration is called the cold chain. This cold chain network is often unreliable or entirely lacking in remote, rural areas in developing nations that have malfunctioning electrical grids. “Almost all routine vaccines require a cold chain,” says Christopher Fox, senior vice president of formulations at the Access to Advanced Health Institute. But when the power goes out, so does refrigeration, putting refrigerated or frozen medical products at risk. Consequently, the mRNA vaccines developed for Covid-19 and other conditions, as well as more traditional vaccines for cholera, tetanus and other diseases, often can’t be delivered to the most remote parts of the world.
To understand the scope of the challenge, consider this: In the U.S., more than 984 million doses of Covid-19 vaccine have been distributed so far. Each one needed refrigeration that, even in the U.S., proved challenging. Now extrapolate to all vaccines and the entire world. For Covid, fewer than 73 percent of the global population received even one dose. The need for refrigerated or frozen handling was partially to blame.
Globally, the cold chain packaging market is valued at over $15 billion and is expected to exceed $60 billion by 2033.
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Freeze-drying, also called lyophilization, which is common for many vaccines, isn’t always an option. Many freeze-dried vaccines still need refrigeration, and even medicines approved for storage at ambient temperatures break down in the heat of sub-Saharan Africa. “Even in a freeze-dried state, biologics often will undergo partial rehydration and dehydration, which can be extremely damaging,” Boothby explains.
The cold chain is also very expensive to maintain. The global pharmaceutical cold chain packaging market is valued at more than $15 billion, and is expected to exceed $60 billion by 2033, according to a report by Future Market Insights. This cost is only expected to grow. According to the consulting company Accenture, the number of medicines that require the cold chain are expected to grow by 48 percent, compared to only 21 percent for non-cold-chain therapies.
Tardigrades to the rescue
Tardigrades are only about a millimeter long – with four legs and claws, and they lumber around like bears, thus their nickname – but could provide a big solution. “Tardigrades are unique in the animal kingdom, in that they’re able to survive a vast array of environmental insults,” says Boothby, the Wyoming professor. “They can be dried out, frozen, heated past the boiling point of water and irradiated at levels that are thousands of times more than you or I could survive.” So, his team is gradually unlocking tardigrades’ survival secrets and applying them to biologic pharmaceuticals to make them withstand both extreme heat and desiccation without losing efficacy.
Boothby’s team is focusing on blood clotting factor VIII, which, as the name implies, causes blood to clot. Currently, Boothby is concentrating on the so-called cytoplasmic abundant heat soluble (CAHS) protein family, which is found only in tardigrades, protecting them when they dry out. “We showed we can desiccate a biologic (blood clotting factor VIII, a key clotting component) in the presence of tardigrade proteins,” he says—without losing any of its effectiveness.
The researchers mixed the tardigrade protein with the blood clotting factor and then dried and rehydrated that substance six times without damaging the latter. This suggests that biologics protected with tardigrade proteins can withstand real-world fluctuations in humidity.
Furthermore, Boothby’s team found that when the blood clotting factor was dried and stabilized with tardigrade proteins, it retained its efficacy at temperatures as high as 95 degrees Celsius. That’s over 200 degrees Fahrenheit, much hotter than the 58 degrees Celsius that the World Meteorological Organization lists as the hottest recorded air temperature on earth. In contrast, without the protein, the blood clotting factor degraded significantly. The team published their findings in the journal Nature in March.
Although tardigrades rarely live more than 2.5 years, they have survived in a desiccated state for up to two decades, according to Animal Diversity Web. This suggests that tardigrades’ CAHS protein can protect biologic pharmaceuticals nearly indefinitely without refrigeration or freezing, which makes it significantly easier to deliver them in locations where refrigeration is unreliable or doesn’t exist.
The tricks of the tardigrades
Besides the CAHS proteins, tardigrades rely on a type of sugar called trehalose and some other protectants. So, rather than drying up, their cells solidify into rigid, glass-like structures. As that happens, viscosity between cells increases, thereby slowing their biological functions so much that they all but stop.
Now Boothby is combining CAHS D, one of the proteins in the CAHS family, with trehalose. He found that CAHS D and trehalose each protected proteins through repeated drying and rehydrating cycles. They also work synergistically, which means that together they might stabilize biologics under a variety of dry storage conditions.
“We’re finding the protective effect is not just additive but actually is synergistic,” he says. “We’re keen to see if something like that also holds true with different protein combinations.” If so, combinations could possibly protect against a variety of conditions.
Commercialization outlook
Before any stabilization technology for biologics can be commercialized, it first must be approved by the appropriate regulators. In the U.S., that’s the U.S. Food and Drug Administration. Developing a new formulation would require clinical testing and vast numbers of participants. So existing vaccines and biologics likely won’t be re-formulated for dry storage. “Many were developed decades ago,” says Fox. “They‘re not going to be reformulated into thermo-stable vaccines overnight,” if ever, he predicts.
Extending stability outside the cold chain, even for a few days, can have profound health, environmental and economic benefits.
Instead, this technology is most likely to be used for the new products and formulations that are just being created. New and improved vaccines will be the first to benefit. Good candidates include the plethora of mRNA vaccines, as well as biologic pharmaceuticals for neglected diseases that affect parts of the world where reliable cold chain is difficult to maintain, Boothby says. Some examples include new, more effective vaccines for malaria and for pathogenic Escherichia coli, which causes diarrhea.
Tallying up the benefits
Extending stability outside the cold chain, even for a few days, can have profound health, environmental and economic benefits. For instance, MenAfriVac, a meningitis vaccine (without tardigrade proteins) developed for sub-Saharan Africa, can be stored at up to 40 degrees Celsius for four days before administration. “If you have a few days where you don’t need to maintain the cold chain, it’s easier to transport vaccines to remote areas,” Fox says, where refrigeration does not exist or is not reliable.
Better health is an obvious benefit. MenAfriVac reduced suspected meningitis cases by 57 percent in the overall population and more than 99 percent among vaccinated individuals.
Lower healthcare costs are another benefit. One study done in Togo found that the cold chain-related costs increased the per dose vaccine price up to 11-fold. The ability to ship the vaccines using the usual cold chain, but transporting them at ambient temperatures for the final few days cut the cost in half.
There are environmental benefits, too, such as reducing fuel consumption and greenhouse gas emissions. Cold chain transports consume 20 percent more fuel than non-cold chain shipping, due to refrigeration equipment, according to the International Trade Administration.
A study by researchers at Johns Hopkins University compared the greenhouse gas emissions of the new, oral Vaxart COVID-19 vaccine (which doesn’t require refrigeration) with four intramuscular vaccines (which require refrigeration or freezing). While the Vaxart vaccine is still in clinical trials, the study found that “up to 82.25 million kilograms of CO2 could be averted by using oral vaccines in the U.S. alone.” That is akin to taking 17,700 vehicles out of service for one year.
Although tardigrades’ protective proteins won’t be a component of biologic pharmaceutics for several years, scientists are proving that this approach is viable. They are hopeful that a day will come when vaccines and biologics can be delivered anywhere in the world without needing refrigerators or freezers en route.