A New Web Could be Coming. Will It Improve Human Health?
The Web has provided numerous benefits over the years, but users have also experienced issues related to privacy, cybersecurity, income inequality, and addiction which negatively impact their quality of life. In important ways, the Web has yet to meet its potential to support human health.
Now, engineers are in the process of developing a new version of the Web, called Web3, which would seek to address the Web’s current shortcomings through a mix of new technologies.
It could also create new problems. Industrial revolutions, including new versions of the Web, have trade-offs. While many activists tend to focus on the negative aspects of Web3 technologies, they overlook some of the potential benefits to health and the environment that aren’t as easily quantifiable such as less stressful lives, fewer hours required for work, and a higher standard of living. What emerging technologies are in the mix to define the new era of the digital age, and how will they contribute to our overall health and well-being?
In order to answer these questions, I have identified three major trends that may help define the future landscape of Web3. These include more powerful machine intelligence that could drive improvements in healthcare, decentralized banking systems that allow consumers to bypass middlemen, and self-driving cars with potential to reduce pollution. However, it is the successes of the enabling technologies that support these goals—improvements in AI, blockchain and smart contracts, and fog computing—that will ultimately define Web3.
Machine Intelligence and Diagnosing Diseases
While the internet is the physical network equipment and computers that keep the world connected, the Web is one of the services that run on the internet. In 1989, British scientist Tim Berners-Lee invented the World Wide Web and, when Web1 went live in 1991, it consisted of pages of text connected by hyperlinks. It remained that way until 2004 with the introduction of Web2, which provided social media websites and let users generate content in addition to consuming it passively.
The Semantic Web could expand the impact of new cognitive skills for machines by feeding data to AI in more readily accessible formats. This will make machines better at solving hard problems such as diagnosing and treating complex diseases.
For the most part, Web2 is what we still have today but, from the beginning, Berners-Lee, now an MIT professor, envisaged a much more sophisticated version of the Web. Known as the Semantic Web, it would not only store data, but actually know what it means. The goal is to make all information on the Internet “machine-readable,” so it can be easily processed by computers, like an Excel sheet full of numbers as opposed to human language. We are now in the early stages of the Semantic Web, which incorporates his vision. For example, there is already a cloud of datasets that links thousands of servers without any form of centralized control. However, due to the costs and technological hurdles related to converting human language into something that computers can understand, the Semantic Web remains an ongoing project.
Currently, AI is only able to perform certain tasks, but it can already make healthcare business practices more efficient by leveraging deep learning to analyze data in supply chains. DeepMind, the company that developed AI for defeating chess masters, has also made huge advances in figuring out protein folding and misfolding, which is responsible for some diseases. Currently, AI is not that useful for diagnosing and treating many complex diseases. This is because deep learning is probabilistic, not causal. So, it is able to understand correlation, but not cause and effect.
Like the Web, though, AI is evolving, and the limitations of deep learning could be overcome in the foreseeable future. A number of government programs and private initiatives are dedicated to better understanding human brain complexity and equipping machines with reasoning, common sense, and the ability to understand cause and effect. The Semantic Web could expand the impact of these new cognitive skills by feeding data to AI in more readily accessible formats. This will make machines better at solving hard problems such as diagnosing and treating complex diseases, which involve genetic, lifestyle, and environment factors. These powerful AIs in the realm of healthcare could become an enduring and important feature of Web3.
Blockchain, Smart Contracts and Income Inequality
The Web2 version of the digital age was certainly impactful in altering our lifestyle both positively and negatively. This is predominately because of the business model used by companies such as Meta (formerly Facebook) and Google. By providing useful products like search engines, these companies have lured consumers into giving away their personal data for free, and the companies use this information to detect buying patterns in order to sell advertising. The digital economy made high tech companies billions of dollars while many users became underemployed or jobless.
In recent years, a similar model has been emerging in the realm of genetics. Personalized genomic companies charge a relatively small fee to analyze a fraction of our genes and provide probabilities of having specific medical conditions. While individual data is not valuable, cumulative data is helpful for deep learning. So, these companies can sell the anonymous DNA data to pharmaceutical companies for millions of dollars.
As these companies improve their ability to collect even more data about our genetic vulnerabilities, the technologies of Web3 could protect consumers from giving it away for free. An emerging technology called blockchain is able to provide a Web-based ledger of financial transactions with checks and balances to ensure that its records cannot be faked or altered. It has yet to reach mass adoption by the public, but the computer scientist Jaron Lanier has proposed storing our genomes and electronic health records in blockchain, utilizing electronic smart contracts between individuals and pharma healthcare industry. Micropayments could then be made to individuals for their data, using cryptocurrency.
These individual payments could become more lucrative in the coming years especially as researchers learn how to fully interpret and apply a person’s genetic data. In this way, blockchain could lead to improvements in income inequality, which currently drives health problems and other challenges for many. A number of start-ups are using this business model which has secure data and eliminates middlemen who don’t create any value, while compensating and protecting the privacy of individuals who contribute their health data.
Autonomous Vehicles, Fog Computing and Pollution
A number of trends indicate that modernizing the transportation industry would address a myriad of problems with public health, productivity and the environment. Autonomous vehicles (AVs) could help usher in this new era of transportation, and these AVs would need to be supported by Web3 technologies.
Automobile accidents are the second leading cause of death worldwide, with roughly 1.3 million fatalities annually, according to the World Health Organization. Some estimates suggest that replacing human drivers with AVs could eliminate as many as a million global fatalities annually. Shared AVs would help to reduce traffic congestion that wastes time and fuel, and electric vehicles would help minimize greenhouse gases.
To reap the benefits from replacing gas vehicles with electric, societies will need an infrastructure that enables self-driving cars to communicate with each other. Most data processing in computers is performed using von Neumann architecture, where the data memory and the processor are in two different places. Today, that typically means cloud computing. With self-driving cars, when cameras and sensors generate data to detect objects on the roads, processors will need to rapidly analyze the data and make real-time decisions regarding acceleration, braking, and steering. However, cloud computing is susceptible to latency issues.
One solution to latency is moving processing and data storage closer to where it is needed to improve response times. Edge computing, for example, places the processor at the site where the data is generated. Most new human-driven vehicles contain anywhere from 30 to 100 electronic control units (ECUs) that process data and control electrical systems in vehicles. These embedded systems, typically in the dashboard, control different applications such as airbags, steering, brakes, etc. ECUs process data generated by cameras and sensors in AVs and make crucial decisions on how they operate.
Self-driving cars can benefit by communicating with each other for navigation in the same way that bacteria and animals use swarm intelligence for tasks involving groups. Researchers are currently investigating fog computing which utilizes servers along highways for faster and more reliable navigation and for communicating data analytics among driverless cars.
The Future Landscape of Web3 is Uncertain
The future of Web3 has many possibilities. However, there is no guarantee that blockchain, smart contracts, and fog computing will achieve public acceptance and market saturation or prevail over other technologies or the status quo of Web2. It is also uncertain if or when the breakthroughs in AI will occur that could eradicate complex diseases through Web3.
An example of this uncertainty is the metaverse, which combines blockchain with virtual reality. Currently, the metaverse is primarily used for gaming and recreational use until its infrastructure is further developed. Researchers are interested in the long-term mental health effects of virtual reality, both positive and negative. Using avatars, or virtual representations of humans, in the metaverse, users have greater control of their environment and chosen identities. But, it is unclear what negative mental health effects will occur. As far as regulations, the metaverse is still in the Wild West stage, and bullying or even murder will likely take place. Also, there will be a point where virtual worlds like the metaverse will become so immersive that we won't want to leave them, according to Meta’s Zuckerberg.
The metaverse would rely on virtual reality technology that was developed many years ago, and adoption has been slower than some experts predicted. But most emerging technologies, including other examples related to Web3, follow a similar, nonlinear pattern of development that Gartner has represented in graphical form using the S-curve. To develop a technology forecast for Web3, you can follow the progress along the curve from proof of concept to a particular goal. After a series of successes and failures, entrepreneurs will continue to improve their products until each emerging technology fails or achieves mainstream adoption by the public.
What mix of emerging technologies ultimately defines Web3 will likely be determined by the benefits they provide to society—including whether and how they improve health—how they stimulate the digital economy, and how they address the significant shortcomings of Web2.
Tiny, tough “water bears” may help bring new vaccines and medicines to sub-Saharan Africa
Microscopic tardigrades, widely considered to be some of the toughest animals on earth, can survive for decades without oxygen or water and are thought to have lived through a crash-landing on the moon. Also known as water bears, they survive by fully dehydrating and later rehydrating themselves – a feat only a few animals can accomplish. Now scientists are harnessing tardigrades’ talents to make medicines that can be dried and stored at ambient temperatures and later rehydrated for use—instead of being kept refrigerated or frozen.
Many biologics—pharmaceutical products made by using living cells or synthesized from biological sources—require refrigeration, which isn’t always available in many remote locales or places with unreliable electricity. These products include mRNA and other vaccines, monoclonal antibodies and immuno-therapies for cancer, rheumatoid arthritis and other conditions. Cooling is also needed for medicines for blood clotting disorders like hemophilia and for trauma patients.
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.
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.
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.
Man Who Got the First Fecal Transplant to Cure Melanoma Shares His Experience
Jamie Rettinger was still in his thirties when he first noticed a tiny streak of brown running through the thumbnail of his right hand. It slowly grew wider and the skin underneath began to deteriorate before he went to a local dermatologist in 2013. The doctor thought it was a wart and tried scooping it out, treating the affected area for three years before finally removing the nail bed and sending it off to a pathology lab for analysis.
"I have some bad news for you; what we removed was a five-millimeter melanoma, a cancerous tumor that often spreads," Jamie recalls being told on his return visit. "I'd never heard of cancer coming through a thumbnail," he says. None of his doctors had ever mentioned it either. "I just thought I was being treated for a wart." But nothing was healing and it continued to bleed.
A few months later a surgeon amputated the top half of his thumb. Lymph node biopsy tested negative for spread of the cancer and when the bandages finally came off, Jamie thought his medical issues were resolved.
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.
"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
"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.
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