We know the old saw: necessity is the mother of invention. Well, 2020 has shown us that a global pandemic is one serious mother. Typically, our Top 10 Innovations competition focuses on laboratory technologies, tools designed to plumb the mysteries of basic biology. But as biologists turned their sights to understanding SARS-CoV-2, the innovation landscape changed accordingly, with new tools developed and existing technologies bent to address the pandemic. So this year at The Scientist, our annual contest incorporates inventions aimed at understanding and ultimately solving the COVID-19 problem.
Among our independent judges’ picks for 2020’s Top 10 Innovations were core laboratory technologies—such as a single-cell proteome analyzer and a desktop gene synthesizer—alongside pandemic-focused products, including a rapid COVID-19 test, a tool that can capture antibody profiles from the blood plasma of convalescing coronavirus patients, and a platform for characterizing glycans in the spike protein that studs the surface of SARS-CoV-2. The competition among stellar submissions was so steep that this year’s Top 10 actually contains 12 products, thanks to a couple of ties.
As challenging as 2020 has been for all of us, this tumultuous year has given birth to promising products and approaches for elucidating the complex world of biology. And even more than that, 2020 has shown that the scientific community, when faced with a shared problem, can rise to the challenge and come together to refocus, research, and innovate. Here, The Scientist presents the tools and technologies that make up this year’s Top 10 Innovations.
In late March, biotech firm AbCellera hosted a call with 40 researchers to review the data they’d collected on potential antibodies against SARS-CoV-2. Using AbCellera’s high-throughput microfluidics and single-cell analysis tools to probe samples of COVID-19 patients, the company’s team had deciphered the genetic sequences encoding hundreds of antibodies that might treat the disease. Sifting through all of that data by hand was tedious, though, so the team fed it into Celium, a data visualization tool that intersects more than a million high-quality data points for those antibodies to reveal which ones might work best in patients as a potential therapy. In real time, on the call, the researchers used Celium to probe those relationships and home in on the LY-CoV555 antibody that, months later, entered clinical trials as a possible COVID-19 treatment, says Maia Smith, lead of data visualization at AbCellera and creator of Celium. “I think that kind of says it all.”
Before Celium came on the market in 2017, scientists working with AbCellera to find antibodies would get back complex spreadsheets of data that were difficult to navigate, and it was hard to know where to start, Smith says. Using Celium, data are presented in a visual format and the tool “helps you identify the right molecule for your needs,” Fernando Corrêa, a protein engineer at Kodiak Sciences in Palo Alto, California tells The Scientist. He’s partnered with AbCellera to identify antibodies to treat retinal diseases, and says the company’s package of microfluidics, single-cell analysis, and data visualization tool “streamlines the process of antibody discovery in a user-friendly manner.”
KAMDAR: "AbCellera’s response to the pandemic underscores the real power of the Celium platform at the intersection of biology and AI to make new antibody discoveries at a blazing speed."
Abbott ID NOW COVID-19 Test
Since 2014, Abbott’s ID NOW system has helped physicians detect influenzas A and B, strep A, respiratory syncytial virus (RSV), and most recently SARS-CoV-2, in less than 15 minutes. The toaster-size device works by heating nasal samples in an acidic solution that cracks open the envelope of the viruses, exposing their RNA, which ID NOW amplifies at a constant temperature instead of the heating and cooling cycles that PCR machines use. Gaining emergency authorization from the US Food and Drug Administration in late March, the COVID-19 ID NOW test was one of the first tests accessible to the US public.
Norman Moore, Abbott’s director of scientific affairs for infectious diseases, says the test’s short turnaround time is critical to stopping viral spread. “You’re the most infectious early on—and if we don’t have that result in that timely fashion, what does it help if a molecular test comes back two weeks later?” he tells The Scientist.
With more than 23,000 ID NOW devices in use in the US, mainly in urgent care clinics and pharmacies, Moore says his team is developing tests compatible with the platform for other infectious diseases, such as sexually transmitted infections.
J.D. Zipkin, chief medical officer of GoHealth Urgent Care, which partnered with San Francisco International Airport to administer the ID NOW COVID-19 test to travelers, calls the test a game changer. “[Abbott] took a platform that’s already really good at detecting very specific disease states and applied it to the biggest pandemic need that we have in this country,” he says.
The ID NOW platform costs $4,500 and each COVID-19 test costs $40.
CRUICKSHANK-QUINN: “The ability to receive COVID-19 test results from a throat or nasal swab in under 15 minutes can provide hospitals, schools, or any other institution with the ability to quickly test persons to determine those who would need to self-isolate at home. Since it is light-weight and portable it can be used in the field and at mobile sites like drive-thru testing locations."
BioLegend TotalSeq™-C Human Universal Cocktail v1.0
In 2017, researchers from the New York Genome Center published a new approach called CITE-seq that allows scientists to assess proteins in individual cells at the same time they are doing single-cell transcriptomics. CITE-seq works by linking antibodies with oligonucleotides that can eventually be sequenced to reveal whether target proteins were present and joined to their corresponding antibodies. Life science company BioLegend licensed CITE-seq and developed the TotalSeqTM-C Human Universal Cocktail v1.0, a collection of 130 oligo-linked antibodies for massive screening of the cell-surface proteins of individual cells, for use on a single-cell sequencing platform from 10X Genomics.
In contrast to proteomics approaches based on visual assessment of tagged proteins, “there’s no theoretical limit anymore as to how many proteins you can [screen for],” says BioLegend’s Head of Proteogenomics Kristopher “Kit” Nazor, adding that the company is already working to expand the number of antibodies included in the cocktail. “That increases the opportunity for unbiased discovery massively.”
“It’s groundbreaking in many ways,” says immunologist and genomicist Alexandra-Chloé Villani of Massachusetts General Hospital, Harvard Medical School, and the Broad Institute of MIT and Harvard University. Like many researchers, Villani, who is one of the coordinators of the immune cell segment of the Human Cell Atlas, pivoted this year to studying COVID-19. She has already used BioLegend’s cocktail, launched in early August at a price of $5,350 for five single-use vials, to analyze blood samples from nearly 300 patients who tested positive for SARS-CoV-2.
“When you have surface protein and RNA in the same cell, it really helps us to derive a more granular definition of the immune cells involved” in response to infection, says Villani. “I actually know a lot of colleagues across the United States and Europe that have used this same panel to analyze their COVID cohorts . . . which means we’ll be able to combine all of our data and compare. And that’s incredible.”
MEAGHER: “This is a really nice merging of next-gen sequencing as a digital readout for sequence barcodes and single-cell barcoding technology to enable single-cell quantitative proteomics."
Seven Bridges GRAF™
The release of the human reference genome in 2013 was a tremendous leap forward for biology, but as far as actually representing humanity, it fell quite short. Our genomes are rife with variants not present in the reference genome, which was built from a small sampling of individuals, primarily of European descent. To account for human genetic diversity, bioinformatics firm Seven Bridges has developed a genomic analysis platform called GRAF that attempts to include all possible iterations of genetic sequences at any given locus. The resulting GRAF/Pan Genome Reference is a graph of the known variants at particular points in the genome, rather than a linear reference sequence. When genomes are aligned to the GRAF reference, any deletions, insertions, single nucleotide polymorphisms, or other variations are therefore not missed as they might be when aligned to the linear reference genome.
With the goal of boosting the presence of underrepresented groups in genomic research, Seven Bridges announced in June that access to its GRAF Germline Variant Detection Workflow and GRAF/Pan Genome Reference would be free to academic researchers. “This is the first production-grade workflow that incorporates ancestry information and diversity of the human genome to provide improved variant calls and alignment,” says the company’s chief scientific officer, Brandi Davis-Dusenbery.
“The hope is that, by accounting for that complexity in the analysis, you will see things you were missing,” says Bruce Gelb, the director of the Mindich Child Health and Development Institute at the Icahn School of Medicine at Mt. Sinai. “That’s been an idea floating around for a few years, but nobody prior to what Seven Bridges is doing implemented a graph-based approach that is practical. They’re the first to do that.”
Gelb has been using the GRAF platform to search for variants related to congenital heart defects and comparing those variants to what turns up when he uses traditional sequence analyses. So far, he says, it appears that GRAF is identifying some variants that would otherwise have been overlooked.
CRUICKSHANK-QUINN: “The fact that Seven Bridges GRAF is being made freely available to academic institutions will certainly pave the way towards precision medicine by allowing research advancement in under-represented populations without the struggle of cost to academic researchers."
A central challenge to delivering gene therapies to patients’ cells is the cost of making adeno-associated virus (AAV), a common vector for genes of interest, says Ryan Cawood, CEO of UK-based biotech company OXGENE. “The first AAV gene therapy product that was approved in the EU cost a million pounds per dose,” he says. “If you wanted to treat a disease [with a therapy targeting a large organ] that you could apply to thousands of people, you just simply couldn’t make enough of it at a cost that would make it viable.”
Currently, Cawood says, batches of cultured human cells are transfected with multiple plasmids to induce them to make the AAV vectors containing a selected gene. But the plasmids are expensive to make, and the transfection process isn’t very efficient. By contrast, infection with adenoviruses naturally induces cells to activate replication of AAVs. The problem is, the adenoviruses also replicate themselves and contaminate the resulting AAV product. To get around this issue, OXGENE devised a genetic switch that shuts down an adenovirus’s activity halfway through its life cycle within a cell, so that it programs the cell to churn out AAV particles but not to make adenovirus. “When the virus goes in, you only get AAV coming out; you don’t get any more of the adenovirus coming back out,” Cawood says. The company began selling its research-grade viral vector, which it calls TESSA, in September, and plans to begin offering clinical-grade material next year, he adds. The cost for the research-grade vector starts at £5,000, and depends on the size of the batch of cells to be infected.
BLAINEY: "Supports translation of gene therapies. Demonstrates the biotechnical value of biological engineering."
Codex DNA BioXp™ 3250 System
Biotech firm Codex DNA released the BioXp™ 3250 system in August 2020 as a follow-up to BioXp™ 3200, released in 2014. The automated platform for on-demand DNA assembly and amplification allows researchers to synthesize genes and genomes faster than ever, with the potential to accelerate the development of vaccines, diagnostics, and treatments, says Peter Duncan, director of product management at Codex DNA. The equipment can be used on cancer cells or a variety of infectious agents, including SARS-CoV-2.
Without BioXp™ 3250 or its predecessor, labs that want to synthesize DNA fragments, clones, or whole genomes have to send samples out to be processed by a third party. In addition to having to deal with transit, such processing could take weeks or months. With the BioXp™ 3250, priced at $100,000, DNA sequences up to 7,000 base pairs in length can be assembled in a matter of days, with the push of a button.
Rather than having to code genetic script on a computer for specific experiments, customers can order a module that comes in about two days, ready to go. The module has a barcode containing all the necessary information; when scanned by the device, instructions for synthesizing the desired DNA are uploaded. A lab technician merely needs to insert the module into the device and press start, Duncan says.
“The BioXp has enabled us to perform simple subcloning steps hands-free,” Mark Tornetta, VP of Biologics Discovery at Tavotek Biotherapeutics, tells The Scientist in an email, describing how the lab uses the device to generate NGS libraries. “All of these methods [that are run] on the BioXP save us time and cost to perform.”
BLAINEY: "Democratizing gene synthesis by placing capability in individual labs for faster turnaround and lower costs at high throughput."
IsoPlexis Single-Cell Intracellular Proteome
The Single-Cell Intracellular Proteome solution from IsoPlexis grew out of several labs at Caltech, all seeking better ways to monitor protein-protein interactions
in cancer cells with the goal of developing targeted treatments. With traditional methods such as Western blot, mass spectrometry, and flow cytometry, only a couple of protein types can be tracked at a given time. With Isoplexis’s system, launched in July, researchers can monitor 30 or more protein pathways, with results available on the same day.
With previous technology, phosphorylation was used to identify the function of the individual proteins, with no insight as to how they work together. The Single-Cell Intracellular Proteome reveals the function the same way, but is also able to provide the context of entire protein signaling pathways, uncovering how the network operates as a whole.
Understanding the entire network of cellular pathways allows researchers to better understand the downstream effects of aberrant cells, says Sean Mackay, CEO and cofounder of IsoPlexis. In cancers, he adds, this approach helps evaluate the efficacy of targeted treatments such as antibody therapies or small-molecule drugs.
“Such pathways basically define how cells are activated, [which] is particularly important for cancer, where activated phosphoprotein signaling is not only a hallmark of cancer,” says James Heath, who ran the Caltech lab that created the technology eight years ago, “but is a major focus of targeted inhibitors.”
MEAGHER: "The Single-Cell Intracellular Proteome solution uses innovative microfluidics to scale down what looks like well-established ELISA chemistry down to the level of single cells."
Scientists have used intravenous immunoglobulin (IVIG) to treat immunodeficient or immunosuppressed patients and convalescent plasma to treat infectious diseases for more than a century. And plasma is one of many treatments now being tried for COVID-19. But biological samples drawn from donors are not the most standardized therapeutics. Enter GigaGen’s Surge platform, which uses single-cell sequencing to “capture and recreate” libraries of antibodies from blood donors. To create these libraries, the company runs donors’ blood samples through the Surge platform to isolate individual antibody-producing B cells into microdroplets and extract the RNA that encodes the antibodies. From these genetic sequences they can create a “blueprint of that person’s immune system,” says GigaGen CEO David Johnson.
Company researchers then select some of those antibodies to engineer in mammalian cells to create a recombinant antibody treatment, which they say is much more potent than convalescent plasma or IVIG, based on in vitro experiments and tests in animal models. GigaGen does not currently plan to sell Surge, but rather has been using the platform to develop treatments for cancers, immunodeficiency disorders, and, most recently, COVID-19. GigaGen hopes to start clinical trials on their COVID-19 treatment, which uses more than 12,500 antibodies from 16 donors, in early 2021. The goal of Surge is to “tease apart the complexity of the immune system,” says Johnson, and then tailor antibody treatments that elicit the strongest response.
Fred and Vicki Modell, who founded the Jeffrey Modell Foundation after their son Jeffrey died at 15 due to complications from primary immunodeficiency, say they have been searching for an alternative to IVIG, which is sometimes in short supply and can lead to side effects in many patients. “[GigaGen] is giving the greatest gift of all—they’re giving hope to [immunodeficient] patients,” Fred Modell says.
CRUICKSHANK-QUINN: "By combining single-cell emulsion droplet microfluidics technology, genomics, and protein library engineering, this antibody drug therapy, if successful, could revolutionize COVID-19 treatment as well as treatments for many different diseases."
10X Genomics Chromium Single Cell Multiome ATAC + Gene Expression
A few years ago, 10X Genomics launched an assay, ATAC-seq, to identify regions of open chromatin in single cells; the product won a spot in The Scientist’s 2019 Top 10 Innovations. According to product marketing manager Laura DeMare, it wasn’t long before customers were clamoring for more, with feedback to the effect of, “‘This is great, but we’d really love to get the gene expression information and the ATAC-seq information in the same cell.’” In September, 10X rolled out Chromium Single Cell ATAC + Gene Expression, which harvests both epigenetic and gene expression data from individual nuclei.
The platform tags mRNA and open chromatin fragments from each nucleus with DNA barcodes, DeMare explains, and the nucleic acids are then amplified and analyzed. “You can begin to actually link which regulatory elements in the genome are turning on or off genes,” she says. It costs approximately $2,400 per reaction for the reagents and a microfluidic chip.
Ansu Satpathy, an immunologist at Stanford University School of Medicine and a former postdoc of ATAC-seq codeveloper Howard Chang, tells The Scientist that he’s using the new assay to investigate the effects of epigenetic changes associated with T cell exhaustion in tumor samples biopsied from cancer patients. When exhausted, T cells become less effective at battling cancer, and “what we’re doing now with the RNA and ATAC method combined is asking, How do each of those molecular switches regulate genes that lead to this dysfunctional outcome in the cell?” Satpathy says.
KAMDAR: "This approach allows, for the first time, the simultaneous profiling of the epigenome and transcriptome from the same single cell, enabling a better understanding of cell functionality."
10X Genomics Visium Spatial Gene Expression Solution
Over the last several years, single-cell transcriptomics has provided a wealth of gene expression information for individual cells and cell types. Now, 10X Genomics advances the newer technology of spatial transcriptomics, which provides whole transcriptome data for just one or a few cells, and reveals exactly where in a tissue sample that gene expression is taking place. The Visium Spatial Gene Expression Solution, launched in October 2019, exposes 55-micrometer areas at 5,000 locations within a tissue sample to mRNA-binding oligonucleotides, and overlays the resulting gene expression data with histological images.
The technology was developed and originally marketed by Swedish company Spatial Transcriptomics, which 10X Genomics acquired in 2018. Then 10X developed the product further before launching Visium last year. The Visium Spatial Gene Expression Solution, which sells for $1,000 per sample, has smaller and more densely packed spots—and five times more of them—than it did when the company inherited it, says Nikhil Rao, 10X Genomics’s director of strategic marketing for the spatial platform. This increases resolution, he explains. “We also improved the sensitivity of the assay dramatically, being able to pick up tens of thousands of unique molecular identifiers per spot.”
Rao says that many of Visium’s users focus on neuroscience, studying neurodegenerative diseases, for example. But the product is also being used in developmental biology, oncology, and immunology. Johns Hopkins University computational biologist Elana Fertig has used Visium to understand how a cancer can resist treatment. “By virtue of having the spatial information of these cells, you can really figure out the molecular mechanisms where they interact directly, because you can see if the cells are interacting physically,” she explains.
MEAGHER: "This is another frontier in biology: not just single-cell or few-cell gene expression, but now collecting gene expression data with spatial resolution at the level of a few cells."
Inscripta, Inc. Onyx™ Digital Genome Engineering Platform
While CRISPR-based genome editing has become a widely used technique in labs all over the globe, there are research questions that require a scale of nucleotide tinkering that can be cumbersome, if not prohibitive, for some labs. Inscripta Inc.’s Onyx™ Digital Genome Engineering Platform offers a solution—fully automated genome-engineered libraries with hundreds of thousands of single edits in microbial genomes. The benchtop device, which launched in October 2019 and sells for $347,000, allows users to plant desired variants in the DNA of E. coli bacteria and S. cerevisiae yeast, and the instrument takes care of the rest.
The platform combines everything from the algorithms for optimizing the editing process to the microfluidics for handling cells to the reagents themselves. “Biologists don’t have to worry about the technical optimization anymore and can go ahead and focus on any problem in biology now,” says Nandini Krishnamurthy, the vice president of applications development at Inscripta.
Shelley Copley, a molecular biologist at the University of Colorado Boulder, is an early tester of Onyx. She’s using it to examine the effects of synonymous mutations, those that don’t change the resulting protein, on fitness in E. coli. “The high-throughput part of it is critical to be able to address this,” she says. Rather than attempt to engineer each mutation she wants to examine one by one, Onyx enables Copley to generate all 50,000 variants. Her team can then move straight to the fitness assays. “I don’t know of any other technology that can do it.”
KAMDAR: "CRISPR is a powerful tool for editing genomes and allowing functional assessments that can elucidate causality and improve our understanding of genome biology. But those outcomes will not be achieved without overcoming a number of the technical and scalability challenges. This is what the Onyx Digital Genome Engineering Platform enables."
John McLean, a bioanalytical chemist at Vanderbilt University, wants to know exactly what’s in a puff of gas, down to a vaporized blood or tissue sample’s very last lipid molecule. For years, he has used mass spectrometry to catalog compounds in a sample by weight. Sometimes different molecules can have the same mass and the same atomic composition, making it hard to distinguish them. Ion mobility separation runs gas samples down meter-long tubes to differentiate molecules by shape and structure, getting around the mass issue. But because the technique was designed decades ago, it hasn’t achieved the same resolution as mass spectrometry. To achieve a similar resolution, the ion separation instrument would need a 13-meter tube.
Making a linear tube that length is impractical due to constraints on lab space. So a few years ago, Richard Smith of Pacific Northwest National Laboratory and colleagues began brainstorming ways to get ions to turn corners. That discussion led to the development of MOBILion’s SLIM, or Structures for Lossless Ion Manipulation, an instrument with a 13-meter track cut as switchbacks in two circuit boards that fit in a 3-meter-long box; the device provides data on the size and shape of compounds in samples in minutes. SLIM “reveals the unseen,” says Laura Maxon, MOBILion’s head of business development and corporate strategy, “without the sacrifice of time.” This first iteration of SLIM, which MOBILion began deploying as a Beta version to early adopter collaborators the second quarter of 2020, is built for scientists in a pharmaceutical or clinical research academic environment. The price is competitive with existing technologies, she notes, and the company plans to design the instrument for use in the clinic to identify biomarkers of disease.
“What we’re seeing today, from MOBILion on SLIM, is just the tip of the iceberg,” McLean says. “There’s a lot of untapped potential . . . from an analytical standpoint,” so “people should really expect huge advances for these technologies.”
BLAINEY: "Ion-selective chromatography is central to biochemistry. Nice integration of microelectronic technology with biotechnology. "
Associate professor of biological engineering at MIT and a core member of the Broad Institute of MIT and Harvard University. The Blainey lab integrates new microfluidic, optical, molecular, and computational tools for application in biology and medicine. The group emphasizes quantitative single-cell and single-molecule approaches, aiming to enable studies that generate data with the power to reveal the workings of natural and engineered biological systems across a range of scales. Blainey did not consider products submitted by 10X Genomics in his rankings due to his financial ties to the company.
Application scientist at Agilent Technologies.Previously, she was a postdoctoral fellow at the University of Colorado Denver - Anschutz Medical Campus, a research fellow at National Jewish Health in Denver, and a graduate student at the State University of New York at Buffalo, where she worked in the instrument center.
Managing partner at Domain Associates, a healthcare-focused venture fund creating and investing in biopharma, device, and diagnostic companies. She began her career as a scientist and pursued drug-discovery research at Novartis/Syngenta for nine years.
Principal member of Technical Staff at Sandia National Laboratories. His main research interest is the development of novel techniques and devices for nucleic acid analysis, particularly applied to problems in infectious disease, biodefense, and microbial communities. Most recently this has led to approaches for simplified molecular diagnostics for emerging viral pathogens which are suitable for use at the point-of-need or in the developing world. Meagher’s comments represent his professional opinion but do not necessarily represent the views of the US Department of Energy or the United States government.
Editor’s Note: The judges considered dozens of entries submitted for a variety of life science products by companies and users. The judging panel evaluated submissions with only basic instructions from The Scientist, and its members were invited to participate based on their familiarity with life science tools and technologies. With the exception of Paul Blainey, who has financial ties to 10X Genomics and therefore did not consider that firm's products in his rankings, they have no financial ties to the products or companies involved in the competition. In this issue of The Scientist, any advertisements placed by winners named in this article were purchased after our independent judges selected the winning products and had no bearing on the outcome of the competition.