Like most people at the time, those of us who attended the Advances in Genome Biology and Technology (AGBT) meeting in February 2020 had yet to fully appreciate how much devastation would be wreaked by the COVID-19 pandemic. We enjoyed the meeting’s venue, a Marriot hotel in Marco Island, FL. We took advantage of the usual networking activities. And we crowded the presentations and exhibit spaces. Many of us had little idea that after we flew home, we would find ourselves, well, grounded.

With the pandemic still in our midst, the March 2021 AGBT meeting was, as expected, a virtual event. Although a “chat” in the networking lounge was no match for a conversation by the Marriott pool, one element remained the same—the presentations were chock-full of tremendous science. During his welcome, Eric Green, MD, PhD, director of the National Human Genome Research Institute (NHGRI), shared what is no doubt a widely shared sentiment. The AGBT meeting, he said, remains the annual showcase for the “best of genomics research.” The 2021 program ranged from COVID-19 to CRISPR, and from spatial transcriptomics to spider silks.

The biggest buzz of the meeting surrounded the handful of product launches in spatial transcriptomics, a field that has been making rapid progress, as was evident in several presentations. Epigenomics was also on display, with several companies highlighting advances in methylation detection. And COVID-19 took the coveted last spots of the conference, highlighting the importance of emerging variants and the role that genomics is playing in quelling the pandemic.

Increasing diversity for All of Us

Addressing the lack of diversity in genomics databases and studies is a priority in the genomics community. The conference kicked off with an update on the National Institutes of Health’s All of Us Research Program, presented by the program’s CEO, Josh Denny, MD. Launched in May 2018, All of Us currently has more than 366,000 participants with some 272,000 completing the initial steps of the program; more than 80% are underrepresented in biomedical research. The goal is to deliver a rich database that is available to all researchers and that includes data from one million or more participants.

A second initiative focused on diversity is the Human Pangenome Reference Consortium (HPRC), an effort launched by the NHGRI. The HPRC was represented at the AGBT meeting by Karen Miga, PhD, the director of the HPRC’s Data Production Center. Miga, who is also assistant research scientist at the University of California, Santa Cruz, described the HPRC’s efforts to produce a more complete reference of human genome diversity. She explained that the program’s goal is to complete whole genomes of more than 350 diverse diploid humans or 700 phased haplotypes. According to Miga, this comprehensive map of genome variation should foster a new ecosystem of pangenomics tools.

Spatial: The freshmen

In one way, perhaps, the 2021 AGBT meeting felt a lot like the 2020 meeting—spatial transcriptomics was still the star of the show. Last year, a key spatial transcriptomics development was the commercialization of fluorescent in situ sequencing (FISSEQ) technology, which originated in George Church’s laboratory. The FISSEQ technology from Readcoor had a splashy launch, which was followed later in the year by news that the company had been acquired by 10X Genomics. This year, several new spatial technologies were paraded by other companies.

The Boston-area-based Vizgen presented the Merscope platform, which incorporates the multiplexed error-robust fluorescence in situ hybridization (MERFISH) technology developed by Xiaowei Zhuang, PhD, a Howard Hughes Medical Institute Investigator and professor of chemistry and chemical biology at Harvard University. MERFISH, first described in a 2015 Science paper, is based on single-molecule FISH and incorporates combinatorial labeling with error-robust encoding schemes. Vizgen will offer standard and customizable panels and plans to release the first commercial product this summer.

Silicon Valley–based Rebus Biosystems launched its spatial platform. The platform features the synthetic aperture optics (SAO) technology that the company’s co-founder and chief technology officer, Josh Ryu, PhD, developed when he was a graduate student at MIT. The technology reconstructs low-resolution images to create high-resolution images. The company emphasized the platform’s high resolution and ease of use. Currently, it can analyze 30 genes at most, making it best for researchers who approach their spatial experiments with prior knowledge of what they are looking for.

Resolve Biosciences had a lower profile at the meeting. Headquartered in Monheim, Germany, Resolve uses molecular cartography to obtain single-cell information that preserves spatial context. The company said that its technology is currently available through an early-access program. Veranome Biosystems, another spatial technology newcomer, had its latest work featured in a poster and in a short presentation given by the company’s collaborator, the Genome Institute of Singapore.

Spatial: The three-year-old veterans

“Who would have thought, three years ago, when we did the first spatial summit at AGBT, we’d be looking at data and capabilities like this?” asked Joseph Beechem, PhD, chief scientific officer and senior vice president of research and development at NanoString Technologies. “Even I wouldn’t have dreamt three years ago that we would be where we are now.”

Beechem, who has been attending AGBT for 20 years, gave a sense of how quickly this field is moving. In 2019, Beechem presented spatial profiling of 84 genes. In 2020, he spoke about the 1,800-gene cancer transcriptome atlas. This year, it was the whole transcriptome—22,000 genes.

NanoString indicated that it had introduced several upgrades to its GeoMx digital spatial profiler over the past year. For example, the company announced the availability of the Whole Transcriptome Atlas (WTA) for both human and mouse tissue. The transcriptomes follow the spatial axis, or shape, of the tissue under investigation. It’s not an average transcriptome. Rather, it’s associated with those unique, biological compartments. “The information content is just incredible,” declares Beechem.

Not only can GeoMx users read out high-plex RNA, they also can “read out high-plex protein, with the NGS readout, on exactly the same slide,” Beechem asserted.

Beechem also introduced the new spatial molecular imager (SMI), which he called the Hubble Space Telescope of spatial biology. Whereas the GeoMx attends to the whole transcriptome profiling of key tissue macroscopic substructures (roughly 100 µm), the SMI focuses on analyzing RNA and protein expression at single-cell and subcellular resolution (roughly 1 µm). With SMI, tissue samples may be analyzed using ~1000-plex RNA panels and 100-plex protein panels.

The capabilities of the GeoMx and the SMI complement each other in spatial biology research, Beechem asserts. In his view, the SMI is useful in single-cell discovery, where the focus is on single-cell identity and signaling, and the GeoMx is useful in translational discovery and high-throughput clinical applications.

10X Genomics held its inaugural online event, Xperience, the week before AGBT, where the company discussed the new capabilities it expects to bring to its well-established Visium spatial platform later this year or in 2022. The company described the Visium CytAssist, a benchtop instrument that will stain and prescreen tissue sections prior to Visium spatial experiments. 10X Genomics also teased that next year it will introduce the Visium HD, a product that will provide 400 times the resolution of the current Visium.

Optical mapping fills in gaps for pediatric neurological disorders

“Next-generation sequencing is important, but it is only part of the story,” said Catherine Brownstein, MPH, PhD, research associate, Division of Genetics and Genomics, Boston Children’s Hospital. Brownstein also serves as the scientific director of the Manton Center for Orphan Disease Research. She studies rare neurological disorders in children and is interested in finding ways to help patients avoid prolonged diagnostic odysseys. At the AGBT event, Brownstein presented the story of how investigators determined the genetic basis of early-onset psychosis in patients younger than 14.

Using a chromosomal array, investigators established that one patient had a deletion of three genes on chromosome 16—a notoriously difficult chromosome to analyze. When Brownstein used the Saphyr instrument from Bionano Genomics to look for structural variants (SVs), she obtained optical mapping data showing that the patient was missing 10 genes. By studying extra-long fragments of DNA molecules—from 400 kb to 1 megabase—the Saphyr can detect SVs that are missed using traditional DNA analysis techniques. Brownstein said that the Saphyr can do in three days what took her three years while she was working on her doctorate.

Brownstein and colleagues at Boston Children’s Hospital are now part of the COVID-19 host genome SV consortium and will focus on studying multisystem inflammatory syndrome in children (MIS-C). They will use Bionano’s Saphyr to investigate the role of host genetics by performing optical mapping on more than 80 children that have been admitted at the hospital with MIS-C.

Methylation detection

At the AGBT meeting, three of the sponsors delivered presentations about new tools for analyzing epigenomics and methylation. For example, James Hadfield, PhD, director of epigenomics oncology translational medicine at AstraZeneca, focused on the benchmarking of four methylation technologies: Enzymatic Methyl-seq (EM-seq), from New England Biolabs (NEB); Methyl-Seq, from SwiftBio; 5-methylcytosine capture; and EPIC, from Illumina.

When comparing EM-seq, an enzymatic alternative to bisulfite conversion, and Methyl-Seq, in a whole genome methylation sequencing workflow, Hadfield found that EM-seq generates longer libraries with fewer read duplicates and higher complexity but has lower mapping efficiencies than Methyl-Seq. Total efficiency is similar across the two methods, but EM-seq performs better in regions of high GC content and generates higher coverage over CpG islands. Despite the higher quality libraries produced by EM-Seq, both methods captured biologically relevant signal.

Much of the interest in DNA methylation stems from the changes to the methylome that occur during cancer, where methylation is lost throughout the genome and is gained in CpG islands that typically lack methylation. The need for flexible tools to confirm epigenetic signatures from comprehensive genome-wide scans was discussed by Jörg Tost, PhD, director of the Laboratory for Epigenetics and Environment, Centre National de Recherche en Génomique Humaine, CEA-Institut de Biologie François Jacob. Tost, together with QIAGEN, has developed an assay that can analyze a “huge number of CpG in a sequencing-based approach.” This customizable approach will hopefully allow for highly multiplexed identification of DNA methylation changes in complex human disorders.

Emily Leproust, PhD, CEO of Twist Bioscience, introduced Kenneth Chahine, PhD, CEO of Helio Health, an artificial intelligence–driven healthcare company, to discuss diagnostic applications. Specifically, Chahine described how his company is commercializing a methylation technology that can be used to evaluate blood samples and expedite the detection of cancer. Twist recently partnered with NEB. The companies incorporated Twist’s custom methylation panels to EM-seq to create an end-to-end methylation sequencing system, the Twist NGS Methylation Detection System, to improve targeted methylation sequencing.

Finding a needle in a haystack

TwinStrand Biosciences presented its duplex sequencing technology last year, focusing on how the technology can detect genetic variants at very low levels. The company has since expanded the technology to allogeneic cell therapy tracking, an application that could be particularly useful during anticancer cellular therapies such as chimeric antigen receptor T-cell therapies.

Genomics and COVID-19

The closing session featured four leading scientists working in COVID-19 and genomics. Jeffrey Barrett, MD, director of the COVID-19 Genomics Initiative at the Wellcome Sanger Institute, described work in the United Kingdom to sequence SARS-CoV-2 variants. The COVID-19 Genomics UK (COG-UK) Consortium, formed in March 2020, is at the center of this herculean effort. Although numbers are changing every week, as of mid-March, the United Kingdom had contributed more than 300,000 samples, sequencing over 20,000 each week. It is, Barrett said, “a globally unique scale.”

The perspective of a public health laboratory was shared by Natalie Prystajecky, PhD, program head for the Environmental Microbiology program at the British Columbia Centre for Disease Control Public Health Laboratory. She detailed how the program has been scaled up to support the assessment of community transmission, school-based transmission, and hospital outbreaks, as well as the tracking of variants of concern since December 2020. Prystajecky also recalled that on Boxing Day, while she was enjoying a rare moment of relaxation, drinking a beer, she learned that the first confirmed B.1.1.7 variant had come off the sequencer.

Since the program implemented routine screening of all positives, it has been decentralizing and intensifying its work—necessary measures if the program is to sustain the aggressive detection of variants of concern. Prystajecky’s team works from 7:00 am to midnight, seven days a week, despite supply chain issues and the need for more robotics (which were bought on eBay.)

Trevor Bedford, PhD, associate professor, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, presented the evolutionary dynamics of SARS-CoV-2—the emergence of variants of concern, the circulation patterns, and the required scale of genomic surveillance. He shared data from nextstrain.org, the online tool that he helped build to analyze viral genomic data.

At this point, his working hypothesis regarding variants of concern is that within-host evolution is occurring during prolonged infection, driven by natural selection for immune escape. Regarding genomic surveillance, and efforts toward the overall goal of informing vaccine development, Bedford asserts that another 1,000 genomes per month would be far more valuable from South America or Africa than 1,000 more genomes from the United States or the United Kingdom.

The final and much-coveted speaker slot was taken by Edward Holmes, PhD, a professor at the University of Sydney Medical School. Holmes, who has visited Wuhan several times, displayed photos that were taken at the notorious Huanan seafood market in 2014. It was, he said, a “fault line”—the kind of place where a zoonotic event could take place.

Researchers, Holmes explained, have known for years that there were a lot of coronaviruses in bats and that some were spilling into humans. In collaboration with Chinese researchers, Holmes found that bats around Wuhan, along with rodents, carry a lot of coronaviruses. And there were antibodies present in humans. At that time, he knew that the fault line was shaking.

Going forward, Holmes recommends active surveillance, both genomic and immunological, of people living and working at the human–animal interface. He also advocated open data sharing, that is, data sharing that is immediate, free, and protected from political interference. “We have to learn lessons from this,” he insisted, “and prepare for next time, now.”

Virtual events do have their benefits—increased accessibility, lower cost, and a decrease in carbon footprints. (In a recent Nature poll, 74% of scientists agreed that conferences should maintain some virtual aspects.) That said, it would be far more enjoyable to be able to write this meeting wrap-up from the beach next year. Perhaps, if Holmes’s recommendations are followed, we will be there in the flesh for AGBT 2022.

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