Personalized nutrition apps could provide valuable data to people trying to eat healthier, though more research must be done to show effectiveness.
“We discovered that different foods spike people differently,” he says. “Some people spike to pasta, others to bread, others to bananas, and so on. It’s very personalized and our feeling was that building programs around these devices could be extremely powerful for better managing people’s glucose.”
Unbeknown to Snyder at the time, thousands of miles away, a group of Israeli scientists at the Weizmann Institute of Science were doing exactly the same experiments. In 2015, they published a landmark paper which used CGM to track the blood sugar levels of 800 people over several days, showing that the biological response to identical foods can vary wildly. Like Snyder, they theorized that giving people a greater understanding of their own glucose responses, so they spend more time in the normal range, may reduce the prevalence of type 2 diabetes.
The commercial potential of such apps is clear, but the underlying science continues to generate intriguing findings.
“At the moment 33 percent of the U.S. population is pre-diabetic, and 70 percent of those pre-diabetics will become diabetic,” says Snyder. “Those numbers are going up, so it’s pretty clear we need to do something about it.”
Fast forward to 2022,and both teams have converted their ideas into subscription-based dietary apps which use artificial intelligence to offer data-informed nutritional and lifestyle recommendations. Snyder’s spinoff, January AI, combines CGM information with heart rate, sleep, and activity data to advise on foods to avoid and the best times to exercise. DayTwo–a start-up which utilizes the findings of Weizmann Institute of Science–obtains microbiome information by sequencing stool samples, and combines this with blood glucose data to rate ‘good’ and ‘bad’ foods for a particular person.
“CGMs can be used to devise personalized diets,” says Eran Elinav, an immunology professor and microbiota researcher at the Weizmann Institute of Science in addition to serving as a scientific consultant for DayTwo. “However, this process can be cumbersome. Therefore, in our lab we created an algorithm, based on data acquired from a big cohort of people, which can accurately predict post-meal glucose responses on a personal basis.”
The commercial potential of such apps is clear. DayTwo, who market their product to corporate employers and health insurers rather than individual consumers, recently raised $37 million in funding. But the underlying science continues to generate intriguing findings.
Last year, Elinav and colleagues published a study on 225 individuals with pre-diabetes which found that they achieved better blood sugar control when they followed a personalized diet based on DayTwo’s recommendations, compared to a Mediterranean diet. The journal Cell just released a new paper from Snyder’s group which shows that different types of fibre benefit people in different ways.
“The idea is you hear different fibres are good for you,” says Snyder. “But if you look at fibres they’re all over the map—it’s like saying all animals are the same. The responses are very individual. For a lot of people [a type of fibre called] arabinoxylan clearly reduced cholesterol while the fibre inulin had no effect. But in some people, it was the complete opposite.”
Eight years ago, Stanford's Michael Snyder began studying how continuous glucose monitors could be used by patients to gain real-time updates on their blood sugar levels, transmitted directly to their phone.
The Snyder Lab, Stanford Medicine
Because of studies like these, interest in precision nutrition approaches has exploded in recent years. In January, the National Institutes of Health announced that they are spending $170 million on a five year, multi-center initiative which aims to develop algorithms based on a whole range of data sources from blood sugar to sleep, exercise, stress, microbiome and even genomic information which can help predict which diets are most suitable for a particular individual.
“There's so many different factors which influence what you put into your mouth but also what happens to different types of nutrients and how that ultimately affects your health, which means you can’t have a one-size-fits-all set of nutritional guidelines for everyone,” says Bruce Y. Lee, professor of health policy and management at the City University of New York Graduate School of Public Health.
With the falling costs of genomic sequencing, other precision nutrition clinical trials are choosing to look at whether our genomes alone can yield key information about what our diets should look like, an emerging field of research known as nutrigenomics.
The ASPIRE-DNA clinical trial at Imperial College London is aiming to see whether particular genetic variants can be used to classify individuals into two groups, those who are more glucose sensitive to fat and those who are more sensitive to carbohydrates. By following a tailored diet based on these sensitivities, the trial aims to see whether it can prevent people with pre-diabetes from developing the disease.
But while much hope is riding on these trials, even precision nutrition advocates caution that the field remains in the very earliest of stages. Lars-Oliver Klotz, professor of nutrigenomics at Friedrich-Schiller-University in Jena, Germany, says that while the overall goal is to identify means of avoiding nutrition-related diseases, genomic data alone is unlikely to be sufficient to prevent obesity and type 2 diabetes.
“Genome data is rather simple to acquire these days as sequencing techniques have dramatically advanced in recent years,” he says. “However, the predictive value of just genome sequencing is too low in the case of obesity and prediabetes.”
Others say that while genomic data can yield useful information in terms of how different people metabolize different types of fat and specific nutrients such as B vitamins, there is a need for more research before it can be utilized in an algorithm for making dietary recommendations.
“I think it’s a little early,” says Eileen Gibney, a professor at University College Dublin. “We’ve identified a limited number of gene-nutrient interactions so far, but we need more randomized control trials of people with different genetic profiles on the same diet, to see whether they respond differently, and if that can be explained by their genetic differences.”
Some start-ups have already come unstuck for promising too much, or pushing recommendations which are not based on scientifically rigorous trials. The world of precision nutrition apps was dubbed a ‘Wild West’ by some commentators after the founders of uBiome – a start-up which offered nutritional recommendations based on information obtained from sequencing stool samples –were charged with fraud last year. The weight-loss app Noom, which was valued at $3.7 billion in May 2021, has been criticized on Twitter by a number of users who claimed that its recommendations have led to them developed eating disorders.
With precision nutrition apps marketing their technology at healthy individuals, question marks have also been raised about the value which can be gained through non-diabetics monitoring their blood sugar through CGM. While some small studies have found that wearing a CGM can make overweight or obese individuals more motivated to exercise, there is still a lack of conclusive evidence showing that this translates to improved health.
However, independent researchers remain intrigued by the technology, and say that the wealth of data generated through such apps could be used to help further stratify the different types of people who become at risk of developing type 2 diabetes.
“CGM not only enables a longer sampling time for capturing glucose levels, but will also capture lifestyle factors,” says Robert Wagner, a diabetes researcher at University Hospital Düsseldorf. “It is probable that it can be used to identify many clusters of prediabetic metabolism and predict the risk of diabetes and its complications, but maybe also specific cardiometabolic risk constellations. However, we still don’t know which forms of diabetes can be prevented by such approaches and how feasible and long-lasting such self-feedback dietary modifications are.”
Snyder himself has now been wearing a CGM for eight years, and he credits the insights it provides with helping him to manage his own diabetes. “My CGM still gives me novel insights into what foods and behaviors affect my glucose levels,” he says.
He is now looking to run clinical trials with his group at Stanford to see whether following a precision nutrition approach based on CGM and microbiome data, combined with other health information, can be used to reverse signs of pre-diabetes. If it proves successful, January AI may look to incorporate microbiome data in future.
“Ultimately, what I want to do is be able take people’s poop samples, maybe a blood draw, and say, ‘Alright, based on these parameters, this is what I think is going to spike you,’ and then have a CGM to test that out,” he says. “Getting very predictive about this, so right from the get go, you can have people better manage their health and then use the glucose monitor to help follow that.”
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.
Adobe Stock
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.