Dr. Andrew Brooks of RUCDR Infinite Biologics holds up a saliva sample.
The patient tilts back her head and winces as the long swab stick pushes six inches up her nose. The tip twirls around uncomfortably before it's withdrawn.
"Our saliva test can detect the virus in asymptomatic and pre-symptomatic cases."
A gloved and gowned healthcare worker wearing a face shield and mask tells the patient that she will learn whether she is positive for COVID-19 as soon as the lab can process her test.
This is the typical unpleasant scenario for getting a coronavirus test. But times are rapidly changing: Today, for the first time, the U.S. Food and Drug Administration cleared one company to sell saliva collection kits for individuals to use at home.
Scientists at the startup venture, RUCDR Infinite Biologics at Rutgers University in New Jersey, say that saliva testing offers an easier, more useful alternative to the standard nasal swab.
"Our saliva test can detect the virus in asymptomatic and pre-symptomatic cases," said Dr. Andrew Brooks, chief operating officer at RUCDR.
Another venture, Darwin BioSciences in Colorado, has separately developed an innovative method of testing saliva for the coronavirus that causes COVID-19.
Saliva testing can allow earlier detection to identify people who may not know they are contagious, say scientists at both companies. In addition, because patients spit into a tube or cup, saliva testing is safer for healthcare workers than taking swabs. This frees up scarce personal protective equipment (PPE) for use elsewhere. Nasal swabs themselves have been in scarce supply.
Saliva testing, if it becomes widespread, potentially could mean opening society sooner. The more ubiquitous testing becomes across the population, experts say, the more feasible it becomes for public health officials to trace and isolate contacts, especially of asymptomatic cases. Testing early and often will be essential to containing emerging hot spots before a vast outbreak can take root.
Darwin Biosceiences is preparing to seek an FDA Emergency Use Authorization (EUA) this month for its patented "CoVScreen" testing system, which potentially could be available to labs nationally by mid-summer.
Meanwhile, Infinite Biologics will now begin selling kits to consumers for home collection, upon order by a physician. The FDA said that the company's saliva test was as accurate as the nasal swab method used by health care professionals. An FDA summary documenting the company's data reported: "There was 100% positive and negative agreement between the results obtained from testing of saliva and those obtained from nasopharyngeal and oropharyngeal swabs."
The greatest scientific advantage, said Dr. Brooks, is that nasal and oral swabs only collect the surface area where the swab goes, which may not be the place with most viral load. In contrast, the virus occurs throughout a saliva sample, so the test is more trustworthy.
The lab at Rutgers can process 20,000 tests a day, with a 48-hour turnaround. They have 75,000 tests ready to ship now.
The Leap: Detecting Sickness Before You Feel It
"We wanted to create a device that could detect infections before symptoms appeared," explained Nicholas Meyerson, co-founder and CEO of Darwin.
For more than 300 years, he said, "the thermometer was the gold standard for detecting disease because we thought the first sign of illness was a fever. This COVID-19 pandemic has proven that not all pathogens cause a fever. You can be highly contagious without knowing it."
"The question is whether we can scale up fast enough to meet the need. I believe saliva testing can help."
Therefore, Meyerson and co-founder Sara Sawyer from the University of Colorado began to identify RNA biomarkers that can sense when a pathogen first enters a molecule and "sets off alarms." They focused on the nucleic acids concentrated in saliva as the best and easiest place to collect samples for testing.
"The isothermal reaction in saliva takes place at body or room temperature," he said, "so there's no need for complicated testing machinery. The chemical reaction can be read out on a paper strip, like a pregnancy test -- two stripes if you're sick, and one stripe if you're okay."
Before the pandemic, limited but successful human trials were already underway at CU in Boulder and at the CU Anschutz Medical Campus east of Denver. "This was our proof of concept," he said.
Darwin was founded in March and has secured enough venture capital to concentrate protype development on detecting the virus causing COVID-19. So far, said Meyerson, "Everything works."
A small double-blind test of 30 samples at CU produced 100 percent accuracy. "I'm not sure if that will hold true as we go into clinical trials," he said, "but I'm confident we will satisfy all the requirements for at least 95 percent clinical validation."
The specific "CoVStick" test strips will roll out soon, he said: "We hope before the second wave of the pandemic hits."
The broader saliva test-strip product from Darwin, "SickStick," is still one to two years away from deployment by the military and introduction into the consumer drugstore market for home use, said Meyerson. It will affordably and quickly detect a range of viral and bacterial infections.
An illustration of the "CoVStick."
(Darwin Biosciences)
A Potential Game Changer
Society needs widespread testing daily, said George Church, founding core faculty of the Wyss Institute for Biologically Inspired Engineering at Harvard University. Speaking at an online SynBioBeta webinar in April, he urged developing stockpiles of testing kits for home use.
As for any potential of false positives, Church said a much bigger risk is not having enough tests.
"Saliva testing is going to speed up the timeline for opening society a lot," said Meyerson. "People need to self-collect samples at home. A lot more people are going to be willing to spit into a tube than to push a swab six inches up their own nose."
Brooks, of Rutgers, addressed the big picture. "It's critical that we open society as soon as possible to minimize the economic impact of the pandemic. Testing is the surest and safest path. The question is whether we can scale up fast enough to meet the need. I believe saliva testing can help."
A string of the code that comprises a DNA molecule, pictured at Miraikan, the National Museum of Emerging Science and Innovation in Japan.
New Alzheimer's Therapies
Mary Carrillo, Chief Science Officer at the Alzheimer’s Association
Alzheimer's Association
One of the biggest health stories of 2021 was the FDA’s accelerated approval of aducanumab, the first drug that treats the underlying biology of Alzheimer’s, not just the symptoms. But, Alzheimer’s is a complex disease and will likely need multiple treatment strategies that target various aspects of the disease. It’s been exciting to see many of these types of therapies advance in 2021.
Following the FDA action in June, we saw renewed excitement in this class of disease-modifying drugs that target beta-amyloid, a protein that accumulates in the brain and leads to brain cell death. This class includes drugs from Eli Lilly (donanemab), Eisai (lecanemab) and Roche (gantenerumab), all of which received Breakthrough Designation by the FDA in 2021, advancing the drugs more quickly through the approval process.
We’ve also seen treatments advance that target other hallmarks of Alzheimer’s this year. We heard topline results from a phase 2 trial of semorinemab, a drug that targets tau tangles, a toxic protein that destroys neurons in the Alzheimer’s brain. Plus, strategies targeting neuroinflammation, protecting brain cells, and reducing vascular contributions to dementia – all funded through the Alzheimer's Association Part the Cloud program – advanced into clinical trials.
The future of Alzheimer’s treatment will likely be combination therapy, including drug therapies and healthy lifestyle changes, similar to how we treat heart disease. Washington University announced they will be testing a combination of both anti-amyloid and anti-tau drugs in a first-of-its-kind clinical trial, with funding from the Alzheimer’s Association.
AlphaFold
Olivier Elemento, Director of the Caryl and Israel Englander Institute for Precision Medicine at Cornell University
Cornell University
AlphaFold is an artificial intelligence system designed by Google’s DeepMind that opens the door to understanding the three-dimensional structures and functions of proteins, the building blocks that make up almost half of our bodies' dry weight. In 2021, Google made AlphaFold available for free and since then, researchers have used it to drive greater understanding of how proteins interact. This is a foundational event in the field of biotech.
It’s going to take time for the benefits from AlphaFold to transpire, but once we know the 3-D structures of proteins that cause various diseases, it will be much easier to design new drugs that can bind to these proteins and change their activity. Prior to AlphaFold, scientists had identified the 3-D structure of just 17 percent of about 20,000 proteins in the body, partly because mapping the structures was extremely difficult and expensive. Thanks to AlphaFold, we’ve now jumped to knowing – with at least some degree of certainty – the protein structures of 98.5 percent of the proteome.
For example, kinases are a class of proteins that modify other proteins and are often aberrantly active in cancer due to DNA mutations. Some of the earliest targeted therapies for cancer were ones that block kinases but, before AlphaFold, we had only a premature understanding of a few hundred kinases. We can now determine the structures of all 1,500 kinases. This opens up a universe of drug targets we didn’t have before.
Additional progress has been made this year toward potentially using AlphaFold to develop blockers of certain protein receptors that contribute to psychiatric illnesses and other neurological diseases. And in July, scientists used AlphaFold to map the dimensions of a bacterial protein that may be key to countering antibiotic resistance. Another discovery in May could be essential to finding treatments for COVID-19. Ongoing research is using AlphaFold principles to create entirely new proteins from scratch that could have therapeutic uses. The AlphaFold revolution is just beginning.
Virtual First Care
Jennifer Goldsack, CEO of Digital Medicine Society
Digital Medicine Society
Imagine a new paradigm of healthcare defined by how good we are at keeping people healthy and out of the clinic, not how good we are at offering services to a sick person at the clinic. That is the promise of virtual-first care, or V1C, what I consider to be the greatest, and most underappreciated, advance that occurred in medicine this year.
V1C is defined as medical care accessed through digital interactions where possible, guided by a clinician, and integrated into a person’s everyday life. This type of care includes spit kits mailed for laboratory tests and replacing in-person exams with biometric sensors. It’s built around the patient, not the clinic, and provides us with the opportunity to fundamentally reimagine what good healthcare looks like.
V1C flew under the radar in 2021, eclipsed by the ongoing debate about the value of telehealth more broadly as we emerge from the pandemic. However, the growth in the number of specialty and primary care virtual-first providers has been matched only by the number of national health plans offering virtual-first plans. Our own virtual-first community, IMPACT, has tripled in size, mirroring the rapid growth of the field driven by patient demand for care on their terms.
V1C differs from the ‘bolt on’ approach of video visits as an add-on to traditional visit-based, episodic care. V1C takes a much more holistic approach; it allows individuals to initiate care at any time in any place, recognizing that healthcare needs extend beyond 9-5. It matches the care setting with each individual’s clinical needs and personal preferences, advancing a thorough, evidence-based, safe practice while protecting privacy and recognizing that patients’ expectations have changed following the pandemic. V1C puts the promise of digital health into practice. This is the blueprint for what good healthcare looks like in the digital era.
Digital Clinical Trials
Craig Lipset, Founder of Clinical Innovation Partners and former Head of Clinical Innovation at Pfizer
Craig Lipset
In 2021, a number of digital- and data-enabled approaches have sustained decentralized clinical trials around the world for many different disease types. Pharma companies and clinical researchers are enthusiastic about this development for good reason. Throughout the pandemic, these decentralized trials have allowed patients to continue in studies with a reduced need for site visits, without compromising their safety or data quality.
Risk-based monitoring was deployed using data and thoughtful algorithms to identify quality and safety issues without relying entirely on human monitors visiting research sites. Some trials used digital measures to ensure high quality data on target health outcomes that could be captured in ways that made the participants’ physical location irrelevant. More than three-quarters of research organizations, such as pharma and biotech, have accelerated their decentralized clinical trial strategies. Before COVID-19, 72 percent of trial sites “rarely or never” used telemedicine for trial participants; during COVID, 64 percent “sometimes, often or always” do.
While the research community does appreciate the tremendous hope and promise brought by these innovations, perhaps what has been under-appreciated is the culture shift toward thoughtful risk-taking and a willingness to embrace and adopt clinical trial innovations. These solutions existed before COVID, but the pandemic shifted the perception of risks versus benefits involved in these trials. If there is one breakthrough that is perhaps under-appreciated in life sciences clinical research today, it’s the power of this new culture of willingness and receptivity to outlast the pandemic. Perhaps the greatest loss to the research ecosystem would be if we lose the momentum with recent trial innovations and must wait for another global pandemic in order to see it again.
Designing Biology
Sudip Parikh, CEO of the American Association for the Advancement of Science and Executive Publisher of the Science family of journals
American Association for the Advancement of Science
As our understanding of basic biology has grown, we are fast approaching an era where it will be possible to design and direct biological machinery to create treatments, medicine, and materials. 2021 saw many breakthroughs in this area, three of which are listed below.
The understanding of the human microbiome is growing as is our ability to modify it. One example is the movement toward the notion of the “bug as the drug.” In June, scientists at the Brigham and Women’s Hospital published a paper showing that they had genetically engineered yeast – using CRISPR/Cas9 – to sense and treat inflammation in the body to relieve symptoms of irritable bowel syndrome in mice. This approach could potentially be used to address issues with your microbiome to treat other chronic conditions.
Another way in which we saw the application of basic biology discoveries to real world problems in 2021 is through groundbreaking research on synthetic biology. Several institutions and companies are pursuing this path. Ginkgo Bioworks, valued at $15 billion, already claims to engineer cells with assembly-line efficiency. Imagine the possibilities of programming cells and tissue to perform chemistry for the manufacturing process, inspired by the way your body does chemistry. That could mean cleaner, more controllable, and affordable ways to manufacture food, therapeutics, and other materials in a factory-like setting.
A final example: consider the possibility of leveraging the mechanics of your own body to deliver proteins as treatments, vaccines, and more. In 2021, several scientists accelerated research to apply the mRNA technology underlying COVID-19 vaccines to make and replace proteins that, when they’re missing or don’t work, cause rare conditions such as cystic fibrosis and multiple sclerosis.
These applications of basic biology to solve real world problems are exciting on their own, but their convergence with incredible advances in computing, materials, and drug delivery hold the promise of game-changing progress in health care and beyond.
Brain Biomarkers
David R. Walt, Professor of Biologically Inspired Engineering, Harvard Medical School, Brigham and Women’s Hospital, Wyss Institute at Harvard University
David Walt
2021 brought the first real hope for identifying biomarkers that can predict neurodegenerative disease. Multiple biomarkers (which are measurable indicators of the presence or severity of disease) were identified that can diagnose disease and that correlate with disease progression. Some of these biomarkers were detected in cerebrospinal fluid (CSF) but others were measured directly in blood by examining precursors of protein fibers.
The blood-brain barrier prevents many biomolecules from both exiting and entering the brain, so it has been a longstanding challenge to detect and identify biomarkers that signal changes in brain chemistry due to neurodegenerative disease. With the advent of omics-based approaches (an emerging field that encompasses genomics, epigenomics, transcriptomics, proteomics, and metabolomics), coupled with new ultrasensitive analytical methods, researchers are beginning to identify informative brain biomarkers. Such biomarkers portend our ability to detect earlier stages of disease when therapeutic intervention could be effective at halting progression.
In addition, these biomarkers should enable drug developers to monitor the efficacy of candidate drugs in the blood of participants enrolled in clinical trials aimed at slowing neurodegeneration. These biomarkers begin to move us away from relying on cognitive performance indicators and imaging—methods that do not directly measure the underlying biology of neurodegenerative disease. The identity of these biomarkers may also provide researchers with clues about the causes of neurodegenerative disease, which can serve as new targets for drug intervention.
