The Svalbard Global Seed Vault preserves more than one million of the world's seeds deep inside Platäfjellet Mountain.
"Before, we trusted the permafrost. We do not trust the permafrost anymore."
Art installations on the building's rooftop and front façade glimmer like diamonds in the polar night, but it is what lies buried deep inside the frozen rock, 475 feet from the building's entrance, that is most precious. Here, in the Svalbard Global Seed Vault, are backup copies of more than a million of the world's agricultural seeds.
Inside the vault, seed boxes from many gene banks and many countries. "The seeds don't know national boundaries," says Kent Nnadozie, the UN's Secretary of the International Treaty on Plant Genetic Resources for Food and Agriculture.
(Photo credit: Svalbard Global Seed Vault/Riccardo Gangale)
The Svalbard vault -- which has been called the Doomsday Vault, or a Noah's Ark for seeds -- preserves the genetic materials of more than 6000 crop species and their wild relatives, including many of the varieties within those species. Svalbard's collection represents all the traits that will enable the plants that feed the world to adapt – with the help of farmers and plant breeders – to rapidly changing climactic conditions, including rising temperatures, more intense drought, and increasing soil salinity. "We save these seeds because we want to ensure food security for future generations," says Grethe Helene Evjen, Senior Advisor at the Norwegian Ministry of Agriculture and Food .
A recent study in the journal Nature predicted that global warming could cause catastrophic losses of biodiversity in regions across the globe throughout this century. Yet global warming also threatens the permafrost that surrounds the seed vault, the very thing that was once considered a failsafe means of keeping these seeds frozen and safeguarding the diversity of our crops. In fact, record temperatures in Svalbard a few years ago – and a significant breach of water into the access tunnel to the vault -- prompted the Norwegian government to invest $20 million euros on improvements at the facility to further secure the genetic resources locked inside. The hope: that technology can work in concert with nature's freezer to keep the world's seeds viable.
"Before, we trusted the permafrost," says Hege Njaa Aschim, a spokesperson for Statsbygg, the government agency that recently completed the upgrades at the seed vault. "We do not trust the permafrost anymore."
The Apex of the Global Conservation System
More than 1700 genebanks around the globe preserve the diverse seed varieties from their regions. They range from small community seed banks in developing countries, where small farmers save and trade their seeds with growers in nearby villages, to specialized university collections, to national and international genetic resource repositories. But many of these facilities are vulnerable to war, natural disasters, or even lack of funding.
"If anything should happen to the resources in a regular genebank, Svalbard is the backup – it's essentially the apex of the global conservation system," says Kent Nnadozie, Secretary of the International Treaty on Plant Genetic Resources for Food and Agriculture at the United Nations, who likens the Global Vault to the Central Reserve Bank. "You have regular banks that do active trading, but the Central Bank is the final reserve where the banks store their gold deposits."
Similarly, farmers deposit their seeds in regional genebanks, and also look to these banks for new varieties to help their crops adapt to, say, increasing temperatures, or resist intrusive pests. Regional banks, in turn, store duplicates from their collections at Svalbard. These seeds remain the sovereign property of the country or institution depositing them; only they can "make a withdrawal."
The Global Vault has already proven invaluable: The International Centre for Agricultural Research in the Dry Areas (ICARDA), formerly located outside of Aleppo, Syria, held more than 140,000 seed samples, including plants that were extinct in their natural habitats, before the Syrian Crisis in 2012. Fortunately, they had managed to back up most of their seed samples at Svalbard before they were forced to relocate to Lebanon and Morocco. In 2017, ICARDA became the first – and only – organization to withdraw their stored seeds. They have now regenerated almost all of the samples at their new locations and recently redeposited new seeds for safekeeping at Svalbard.
Rapid Global Warming Threatens Permafrost
The Global Vault, a joint venture between the Norwegian government, the Crop Trust and the Nordic Genetic Resource Centre (NordGen) that started operating in 2008, was sited in Svalbard in part because of its remote yet accessible location: Svalbard is the northernmost inhabited spot on Earth with an airport. But experts also thought it a failsafe choice for long-term seed storage because its permafrost would offer natural freezing – even if cooling systems were to fail. No one imagined that the permafrost could fail.
"We've had record temperatures in the region recently, and there are a lot of signs that global warming is happening faster at the extreme latitudes," says Geoff Hawtin, a world-renowned authority in plant conservation, who is the founding director of -- and now advisor to -- the Crop Trust. "Svalbard is still arguably one of the safest places for the seeds from a temperature point of view, but it's actually not going to be as cold as we thought 20 years ago."
A recent report by the Norwegian Centre for Climate Services predicted that Svalbard could become 50 degrees Fahrenheit warmer by the year 2100. And data from the Norwegian government's environmental monitoring system in Svalbard shows that the permafrost is already thawing: The "active layer," that is, the layer of surface soil that seasonally thaws, has become 25-30 cm thicker since 1998.
Among the 35 depositors were several bringing their seeds to Svalbard for the first time, including the Cherokee Nation, which deposited nine heirloom seed varieties that predate European colonization.
Though the permafrost surrounding the seed vault chambers, which are situated well below the active layer, is still intact, the permafrost around the access tunnel never re-established as expected after construction of the Global Vault twelve years ago. As a result, when Svalbard saw record high temperatures and unprecedented rainfall in 2016, about 164 feet of rainwater and snowmelt leaked into the tunnel, turning it into a skating rink and spurring authorities to take what they called a "better safe than sorry approach." They invested in major upgrades to the facility. "The seeds in the vault were never threatened," says Aschim, "but technology has become more important at Svalbard."
Technology Gives Nature a Boost
For now, the permafrost deep inside the mountain still keeps the temperature in the vault down to about -25°F. The cooling systems then give nature a mechanical boost to keep the seed vault chilled even further, to about -64°F, the optimal temperature for conserving seeds. In addition to upgrading to a more effective and sustainable cooling system that runs on CO2, the Norwegian government added backup generators, removed heat-generating electrical equipment from inside the facility to an outside building, installed a thick, watertight door to the vault, and replaced the corrugated steel access tunnel with a cement tunnel that uses the same waterproofing technology as the North Sea oil platforms.
To re-establish the permafrost around the tunnel, they layered cooling pipes with frozen soil around the concrete tunnel, covered the frozen soil with a cooling mat, and topped the cooling mat with the original permafrost soil. They also added drainage ditches on the mountainside to divert meltwater away from the tunnel as the climate gets warmer and wetter.
New Deposits to the Global Vault
The day before COVID-19 arrived in Norway, on February 25th, Prime Minister Erna Solberg hosted the biggest seed-depositing event in the vault's history in honor of the new and improved vault. As snow fell on Svalbard, depositors from almost every continent traveled the windy road from Longyearbyen up Platåfjellet Mountain and braved frigid -8°F weather to celebrate the massive technical upgrades to the facility – and to hand over their seeds.
Among the 35 depositors were several bringing their seeds to Svalbard for the first time, including the Cherokee Nation, which deposited nine heirloom seed varieties that predate European colonization, and Israel's University of Haifa, whose deposit included multiple genotypes of wild emmer wheat, an ancient relative of the modern domesticated crop. The storage boxes carried ceremoniously over the threshold that day contained more than 65,000 new seed samples, bringing the total to more than a million, and almost filling the first of three seed chambers in the vault. (The Global Vault can store up to 4.5 million seed samples.)
"Svalbard's samples contain all the possibilities, all the options for the future of our agricultural crops – it's how crops are going to adapt," says Cary Fowler, former executive director of the Crop Trust, who was instrumental in establishing the Global Vault. "If our crops don't adapt to climate change, then neither will we." Dr. Fowler says he is confident that with the recent improvements in the vault, the seeds are going to remain viable for a very long time.
"It's sometimes tempting to get distracted by the romanticism of a seed vault inside a mountain near the North Pole – it's a little bit James Bondish," muses Dr. Fowler. "But the reality is we've essentially put an end to the extinction of more than a million samples of biodiversity forever."
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.
Jamie Rettinger with his now fiance Amie Purnel-Davis, who helped him through the clinical trial.
Melanoma is the deadliest form of skin cancer. About 85,000 people are diagnosed with it each year in the U.S. and more than 8,000 die of the cancer when it spreads to other parts of the body, according to the Centers for Disease Control and Prevention (CDC).
There are two peaks in diagnosis of melanoma; one is in younger women ages 30-40 and often is tied to past use of tanning beds; the second is older men 60+ and is related to outdoor activity from farming to sports. Light-skinned people have a twenty-times greater risk of melanoma than do people with dark skin.
"When I graduated from medical school, in 2005, melanoma was a death sentence" --Diwakar Davar.
Jamie had a follow up PET scan about six months after his surgery. A suspicious spot on his lung led to a biopsy that came back positive for melanoma. The cancer had spread. Treatment with a monoclonal antibody (nivolumab/Opdivo®) didn't prove effective and he was referred to the UPMC Hillman Cancer Center in Pittsburgh, a four-hour drive from his home in western Ohio.
An alternative monoclonal antibody treatment brought on such bad side effects, diarrhea as often as 15 times a day, that it took more than a week of hospitalization to stabilize his condition. The only options left were experimental approaches in clinical trials.
Early research
"When I graduated from medical school, in 2005, melanoma was a death sentence" with a cure rate in the single digits, says Diwakar Davar, 39, an oncologist at UPMC Hillman Cancer Center who specializes in skin cancer. That began to change in 2010 with introduction of the first immunotherapies, monoclonal antibodies, to treat cancer. The antibodies attach to PD-1, a receptor on the surface of T cells of the immune system and on cancer cells. Antibody treatment boosted the melanoma cure rate to about 30 percent. The search was on to understand why some people responded to these drugs and others did not.
At the same time, there was a growing understanding of the role that bacteria in the gut, the gut microbiome, plays in helping to train and maintain the function of the body's various immune cells. Perhaps the bacteria also plays a role in shaping the immune response to cancer therapy.
One clue came from genetically identical mice. Animals ordered from different suppliers sometimes responded differently to the experiments being performed. That difference was traced to different compositions of their gut microbiome; transferring the microbiome from one animal to another in a process known as fecal transplant (FMT) could change their responses to disease or treatment.
When researchers looked at humans, they found that the patients who responded well to immunotherapies had a gut microbiome that looked like healthy normal folks, but patients who didn't respond had missing or reduced strains of bacteria.
Davar and his team knew that FMT had a very successful cure rate in treating the gut dysbiosis of Clostridioides difficile, a persistant intestinal infection, and they wondered if a fecal transplant from a patient who had responded well to cancer immunotherapy treatment might improve the cure rate of patients who did not originally respond to immunotherapies for melanoma.
The ABCDE of melanoma detection
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Clinical trial
"It was pretty weird, I was totally blasted away. Who had thought of this?" Jamie first thought when the hypothesis was explained to him. But Davar's explanation that the procedure might restore some of the beneficial bacterial his gut was lacking, convinced him to try. He quickly signed on in October 2018 to be the first person in the clinical trial.
Fecal donations go through the same safety procedures of screening for and inactivating diseases that are used in processing blood donations to make them safe for transfusion. The procedure itself uses a standard hollow colonoscope designed to screen for colon cancer and remove polyps. The transplant is inserted through the center of the flexible tube.
Most patients are sedated for procedures that use a colonoscope but Jamie doesn't respond to those drugs: "You can't knock me out. I was watching them on the TV going up my own butt. It was kind of unreal at that point," he says. "There were about twelve people in there watching because no one had seen this done before."
A test two weeks after the procedure showed that the FMT had engrafted and the once-missing bacteria were thriving in his gut. More importantly, his body was responding to another monoclonal antibody (pembrolizumab/Keytruda®) and signs of melanoma began to shrink. Every three months he made the four-hour drive from home to Pittsburgh for six rounds of treatment with the antibody drug.
"We were very, very lucky that the first patient had a great response," says Davar. "It allowed us to believe that even though we failed with the next six, we were on the right track. We just needed to tweak the [fecal] cocktail a little better" and enroll patients in the study who had less aggressive tumor growth and were likely to live long enough to complete the extensive rounds of therapy. Six of 15 patients responded positively in the pilot clinical trial that was published in the journal Science.
Davar believes they are beginning to understand the biological mechanisms of why some patients initially do not respond to immunotherapy but later can with a FMT. It is tied to the background level of inflammation produced by the interaction between the microbiome and the immune system. That paper is not yet published.
Surviving cancer
It has been almost a year since the last in his series of cancer treatments and Jamie has no measurable disease. He is cautiously optimistic that his cancer is not simply in remission but is gone for good. "I'm still scared every time I get my scans, because you don't know whether it is going to come back or not. And to realize that it is something that is totally out of my control."
"It was hard for me to regain trust" after being misdiagnosed and mistreated by several doctors he says. But his experience at Hillman helped to restore that trust "because they were interested in me, not just fixing the problem."
He is grateful for the support provided by family and friends over the last eight years. After a pause and a sigh, the ruggedly built 47-year-old says, "If everyone else was dead in my family, I probably wouldn't have been able to do it."
"I never hesitated to ask a question and I never hesitated to get a second opinion." But Jamie acknowledges the experience has made him more aware of the need for regular preventive medical care and a primary care physician. That person might have caught his melanoma at an earlier stage when it was easier to treat.
Davar continues to work on clinical studies to optimize this treatment approach. Perhaps down the road, screening the microbiome will be standard for melanoma and other cancers prior to using immunotherapies, and the FMT will be as simple as swallowing a handful of freeze-dried capsules off the shelf rather than through a colonoscopy. Earlier this year, the Food and Drug Administration approved the first oral fecal microbiota product for C. difficile, hopefully paving the way for more.
An older version of this hit article was first published on May 18, 2021