Magnetic resonance imaging of the brain.
This past March, headlines suddenly flooded the Internet about a startup company called Nectome. Founded by two graduates of the Massachusetts Institute of Technology, the new company was charging people $10,000 to join a waiting list to have their brains embalmed, down to the last neuron, using an award-winning chemical compound.
While the lay public presumably burnt their wills and grew ever more excited about the end of humanity's quest for immortality, neurologists let out a collective sigh.
Essentially, participants' brains would turn to a substance like glass and remain in a state of near-perfect preservation indefinitely. "If memories can truly be preserved by a sufficiently good brain banking technique," Nectome's website explains, "we believe that within the century it could become feasible to digitize your preserved brain and use that information to recreate your mind." But as with most Faustian bargains, Nectome's proposition came with a serious caveat -- death.
That's right, in order for Nectome's process to properly preserve your connectome, the comprehensive map of the brain's neural connections, you must be alive (and under anesthesia) while the fluid is injected. This way, the company postulates, when the science advances enough to read and extract your memories someday, your vitrified brain will still contain your perfectly preserved essence--which can then be digitally recreated as a computer simulation.
Almost immediately this story gained buzz with punchy headlines: "Startup wants to upload your brain to the cloud, but has to kill you to do it," "San Junipero is real: Nectome wants to upload your brain," and "New tech firm promises eternal life, but you have to die."
While the lay public presumably burnt their wills and grew ever more excited about the end of humanity's quest for immortality, neurologists let out a collective sigh -- hype had struck the scientific community once again.
The truth about Nectome is that its claims are highly speculative and no hard science exists to suggest that our connectome is the key to our 'being,' nor that it can ever be digitally revived. "We haven't come even close to understanding even the most basic types of functioning in the brain," says neuroscientist Alex Fox, who was educated at the University of Queensland in Australia. "Memory storage in the brain is only a theoretical concept [and] there are some seriously huge gaps in our knowledge base that stand in the way of testing [the connectome] theory."
After the Nectome story broke, Harvard computational neuroscientist Sam Gershman tweeted out:
"Didn't anyone tell them that we've known the C Elegans (a microscopic worm) connectome for over a decade but haven't figured out how to reconstruct all of their memories? And that's only 7000 synapses compared to the trillions of synapses in the human brain!"
Hype can come from researchers themselves, who are under an enormous amount of pressure to publish original work and maintain funding.
How media coverage of Nectome went from an initial fastidiously researched article in the MIT Technology Review by veteran science journalist Antonio Regalado to the click-bait frenzy it became is a prime example of the 'science hype' phenomenon. According to Adam Auch, who holds a doctorate in philosophy from Dalhousie University in Nova Scotia, Canada, "Hype is a feature of all stages of the scientific dissemination process, from the initial circulation of preliminary findings within particular communities of scientists, to the process by which such findings come to be published in peer-reviewed journals, to the subsequent uptake these findings receive from the non-specialist press and the general public."
In the case of Nectome, hype was present from the word go. Riding the high of several major wins, including having raised over one million dollars in funding and partnering with well-known MIT neurologist Edward Boyden, Nectome founders Michael McCanna and Robert McIntyre launched their website on March 1, 2018. Just one month prior, they were able to purchase and preserve a newly deceased corpse in Portland, Oregon, showing that vitrifixation, their method of chemical preservation, could be used on a human specimen. It had previously won an award for preserving every synaptic structure on a rabbit brain.
The Nectome mission statement, found on its website, is laced with saccharine language that skirts the unproven nature of the procedure the company is peddling for big bucks: "Our mission is to preserve your brain well enough to keep all its memories intact: from that great chapter of your favorite book to the feeling of cold winter air, baking an apple pie, or having dinner with your friends and family."
This rhetoric is an example of hype that can come from researchers themselves, who are under an enormous amount of pressure to publish original work and maintain funding. As a result, there is a constant push to present science as "groundbreaking" when really, as is apparently the case with Nectome, it is only a small piece in a much larger effort.
Calling out the audacity of Nectome's posited future, neuroscientist Gershman commented to another publication, "The important question is whether the connectome is sufficient for memory: Can I reconstruct all memories knowing only the connections between neurons? The answer is almost certainly no, given our knowledge about how memories are stored (itself a controversial topic)."
The former home page of Nectome's website, which has now been replaced by a statement titled, "Response to recent press."
Furthermore, universities like MIT, who entered into a subcontract with Nectome, are under pressure to seek funding through partnerships with industry as a result of the Bayh-Dole Act of 1980. Also known as the Patent and Trademark Law Amendments Act, this piece of legislation allows universities to commercialize inventions developed under federally funded research programs, like Nectome's method of preserving brains, formally called Aldehyde-Stabilized Cryopreservation.
"[Universities use] every incentive now to talk about innovation," explains Dr. Ivan Oransky, president of the Association of Health Care Journalists and co-founder of retractionwatch.com, a blog that catalogues errors and fraud in published research. "Innovation to me is often a fancy word for hype. The role of journalists should not be to glorify what universities [say, but to] tell the closest version of the truth they can."
In this case, a combination of the hyperbolic press, combined with some impressively researched expose pieces, led MIT to cut its ties with Nectome on April 2nd, 2018, just two weeks after the news of their company broke.
The solution to the dangers of hype, experts say, is a more scientifically literate public—and less clickbait-driven journalism.
Because of its multi-layered nature, science hype carries several disturbing consequences. For one, exaggerated coverage of a discovery could mislead the public by giving them false hope or unfounded worry. And media hype can contribute to a general mistrust of science. In these instances, people might, as Auch puts it, "fall back on previously held beliefs, evocative narratives, or comforting biases instead of well-justified scientific evidence."
All of this is especially dangerous in today's 'fake news' era, when companies or political parties sow public confusion for their own benefit, such as with global warming. In the case of Nectome, the danger is that people might opt to end their lives based off a lacking scientific theory. In fact, the company is hoping to enlist terminal patients in California, where doctor-assisted suicide is legal. And 25 people have paid the $10,000 to join Nectome's waiting list, including Sam Altman, president of the famed startup accelerator Y Combinator. Nectome now has offered to refund the money.
Founders McCanna and McIntyre did not return repeated requests for comment for this article. A new statement on their website begins: "Vitrifixation today is a powerful research tool, but needs more research and development before anyone considers applying it in a context other than research."
The solution to the dangers of hype, experts say, is a more scientifically literate public—and less clickbait-driven journalism. Until then, it seems that companies like Nectome will continue to enjoy at least 15 minutes of fame.
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.