This research is published in PLoS Biology in the paper, “Multi-drug resistant E. coli encoding high genetic diversity in carbohydrate metabolism genes displace commensal E. coli from the intestinal tract.”

“Antibiotic resistance has been hailed as one of the biggest health problems of our time by the World Health Organization, noted Alan McNally, PhD, professor at the Institute of Microbiology and Infection at the University of Birmingham, U.K. “There are further problems looming unless we get a better understanding of what is happening so that further drug resistance can be halted in its tracks.”

“Scientists have long questioned what makes certain types of E. coli successful multi-drug resistant pathogens,” McNally continues. “It seems that extra-intestinal pathogenic E. coli, which cause urinary tract and bloodstream infections, are particularly successful when it comes to developing resistance and are therefore especially tricky to treat. Our study provides evidence that certain types of E. coli are more prone to develop antibiotic resistance than others.”

The researchers first showed that both multi-drug resistant and non-resistant gut-dwelling E. coli were found to easily colonize a mammalian gut. In addition, using mice colonized with non-MDR E. coli strains, a challenge with MDR E. coli (either by oral gavage or co-housing with colonized mice) resulted in displacement and dominant intestinal colonization by MDR E. coli ST131.

The researchers went on to determine, using a functional pangenomic analysis of 19,571 E. coli genomes, that “carriage of AMR genes is associated with increased diversity in carbohydrate metabolism genes.”

Although some strains of E. coli are harmless, others can cause illness, including diarrhea, urinary tract infections, and often-fatal bloodstream infections. More severe infections are usually treated with antibiotics but the rise in multidrug resistance strains of E. coli is concerning. Previous work shows that multi-drug resistance alone is not sufficient to drive strains to complete dominance.

This study suggests that “independent of antibiotic selective pressures, MDR E. coli display a competitive advantage to colonize the mammalian gut and points to a vital role of metabolism in the evolution and success of MDR lineages of E. coli via carriage and spread.”

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To date, no validated biomarkers have been identified to predict immunotherapy responsiveness across head and neck squamous cell carcinomas (HNSCC) patients. Now, researchers from Akoya Biosciences and the University of Queensland, Brisbane, Australia, have optimized and applied an ultra-high plex, single-cell spatial protein analysis in HNSCCs. Tissues were analyzed with a panel of 101 antibodies that targeted biomarkers related to tumor immune, metabolic, and stress microenvironments.

“This work brought together the latest advances in spatial biology and paired these with ultra-high plex antibody panels and profiled real-world patient samples,” noted Arutha Kulasinghe, PhD, senior research fellow, Frazer Institute, University of Queensland, Australia, where he also leads the Clinical-oMx Lab.

This work is published in GEN Biotechnology in the paper, “Mapping the Spatial Proteome of Head and Neck Tumors: Key Immune Mediators and Metabolic Determinants in the Tumor Microenvironment.”

HNSCCs are tumors that develop in the lip, oral cavity, larynx, salivary glands, nose, sinuses, or the skin of the face. They are the seventh most common cancer globally causing more than 300,000 deaths annually. Immune checkpoint inhibitors have shown promise in treating recurrent/metastatic cases.

Here, researchers present a framework for single-cell spatial analysis of proteins to analyze HNSCCs. First, they developed an ultra-high plex antibody panel with antibodies for detection of immune cells, cancer cells, and markers that identify cellular metabolism, apoptosis and stress, tumor invasion, and metastasis, as well as cellular proliferation and deregulation.

“It’s a significant step forward,” noted Kulasinghe. “Usually, we profile 10–20 markers on tissue routinely. This study developed and tested 101 markers focused on the hallmarks of cancer pathways. It’s a technological breakthrough and now lends itself for high throughput applications such as clinical studies.”

The data uncovered a “high degree of intra-tumoral heterogeneity intrinsic to HNSCC” and provided unique insights into the biology underlying the disease.

This study showed, explained Kulasinghe, that tumors are highly heterogeneous and have areas akin to “north” and “south” poles for treatment sensitivity. “Understanding this and visualizing this is very powerful for the field of immunotherapy and precision medicine,” he asserted.

Single-cell spatial phenotyping of the human FFPE head and neck squamous cell carcinoma revealed six spatial neighborhoods across 14 distinct cell types. In addition, functional phenotyping based on key metabolic and stress markers identified four distinct tumor regions with high intra-tumoral heterogeneity and differential protein signatures.

More specifically, the authors noted that one region was marked by infiltration of CD8+ cytotoxic T cells and overexpression of a proapoptotic regulator—suggesting strong immune activation and stress. Another adjacent region within the same tumor had high levels of expression of G6PD and MMP9. These proteins are known to drive the processes of tumor resistance and invasion, respectively.

The research provides a more complete understanding of the tumor immune microenvironment. It also provides insights into the metabolic state and biology of different regions within the tumor. The data describe an interplay between immune infiltration and the metabolic and stress responses of tumor cells in certain areas. In addition, the findings demonstrate that heterogenous niches and competing microenvironments may underpin variable clinical responses.

Lastly, noted Kulasinghe, “The study sets the framework and workflow for true highplex discovery studies for clinical applications.”

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Now researchers have uncovered how the fungus Candida albicans enters the brain, activates two separate mechanisms in brain cells that promote its clearance, and generates amyloid beta (Ab)-like peptides—toxic protein fragments from the amyloid precursor protein that are considered to be at the center of the development of Alzheimer’s disease. More specifically, they show that C. albicans “activates microglia through two mechanisms involving the production of amyloid b-like peptides that signal through TLR4 and candidalysin that activates CD11b, together promoting clearance of C. albicans from the brain.”

This work is published in Cell Reports in the paper, “Toll-like receptor 4 and CD11b. expressed on microglia coordinate eradication of Candida albicans cerebral mycosis.”

“Our lab has years of experience studying fungi, so we embarked on the study of the connection between C. albicans and Alzheimer’s disease in animal models,” said David Corry, MD, professor of pathology and immunology and medicine at Baylor College School of Medicine. “In 2019, we reported that C. albicans does get into the brain where it produces changes that are very similar to what is seen in Alzheimer’s disease. The current study extends that work to understand the molecular mechanisms.”

First, they show that C. albicans enters the mouse brain from the blood and induces two neuroimmune sensing mechanisms involving secreted aspartic proteinases (Saps) and candidalysin.

“Our first question was, how does C. albicans enter the brain? We found that C. albicans produces enzymes (called secreted aspartic proteases or Saps) that breakdown the blood-brain barrier, giving the fungus access to the brain where it causes damage,” said Yifan Wu, MD, PhD, postdoctoral scientist in pediatrics working in the Corry lab.

Corry and his colleagues had previously shown that a C. albicans brain infection is fully resolved in otherwise healthy mice after 10 days. In this study, they reported that this occurred thanks to two mechanisms triggered by the fungus in microglia.

“The same Saps that the fungus uses to break the blood-brain barrier also break down the amyloid precursor protein into Ab-like peptides,” Wu said. “These peptides activate microglial brain cells via a cell surface receptor called Toll-like receptor 4 (TLR4), which keeps the fungi load low in the brain, but does not clear the infection.”

C. albicans also produces the candidalysin protein that binds to microglia via the CD11b receptor. “Candidalysin-mediated activation of microglia is essential for clearance of Candida in the brain,” Wu said. “If we take away this pathway, fungi are no longer effectively cleared in the brain.”

The authors summarized, “The Saps hydrolyze amyloid precursor protein (APP) into amyloid b (Ab)-like peptides that bind to Toll-like receptor 4 (TLR4) and promote fungal killing in vitro while candidalysin engages the integrin CD11b (Mac-1) on microglia.”

“This work potentially contributes an important new piece of the puzzle regarding the development of Alzheimer’s disease,” Corry said. “The current explanation for this condition is that it is mostly the result of the accumulation of toxic Ab-like peptides in the brain that leads to neurodegeneration. The dominant thinking is that these peptides are produced endogenously, our own brain proteases break down the amyloid precursor proteins generating the toxic Ab peptides.”

Here, the researchers showed that the Ab-like peptides also can be generated from a different source—C. albicans. This common fungus, which has been detected in the brains of people with Alzheimer’s disease and other chronic neurodegenerative disorders, has its own set of proteases that can generate the same Ab-like peptides the brain can generate endogenously.

“We propose that the brain Ab-peptide aggregates that characterize multiple Candida-associated neurodegenerative conditions including Alzheimer’s disease, Parkinson’s disease, and others, may be generated both intrinsically by the brain and by C. albicans,” Corry said. “These findings in animal models support conducting further studies to evaluate the role of C. albicans in the development of Alzheimer’s disease in people, which can potentially lead to innovative therapeutic strategies.”

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The papers detail the exceptionally complex diversity of cells in the human brain and the nonhuman primate brain. The studies identify similarities and differences in how cells are organized and how genes are regulated in the human brain and the nonhuman primate brain.

The new work is part of the National Institute of Health’s Brain Research Through Advancing Innovative Neurotechnologies Initiative (The BRAIN Initiative)—an effort launched in 2014. The studies in this package are part of the National Institutes of Health’s BRAIN Initiative Cell Census Network (BICCN), a program launched in 2017. The research is the first time that techniques to identify brain cell subtypes originally developed and applied in mice have been applied to human brains.

Three papers in the collection present the first atlas of cells in the adult human brain, mapping the transcriptional and epigenomic landscape of the brain.

In another paper, a comparison of the cellular and molecular properties of the human brain and several nonhuman primate brains (chimpanzee, gorilla, macaque, and marmoset brains) revealed clear similarities in the types, proportions, and spatial organization of cells in the cerebral cortex of humans and nonhuman primates. Examination of the genetic expression of cortical cells across species suggests that relatively small changes in gene expression in the human lineage led to changes in neuronal wiring and synaptic function that likely allowed for greater brain plasticity in humans, supporting the human brain’s ability to adapt, learn, and change.

A study exploring how cells vary in different brain regions in marmosets found a link between the properties of cells in the adult brain and the properties of those cells during development. The link suggests that developmental programming is embedded in cells when they are formed and maintained into adulthood and that some observable cellular properties in an adult may have their origins very early in life.

An exploration of the anatomy and physiology of neurons in the outermost layer of the neocortex—part of the brain involved in higher-order functions such as cognition, motor commands, and language—revealed differences in the human brain and the mouse brain that suggest this region may be an evolutionary hotspot, with changes in humans reflecting the higher demands of regulating humans’ more complex brain circuits.

Other work advances research started in 2020, by a team at the Salk, that profiled 161 types of cells in the mouse brain, based on methylation patterns. In the new paper, the researchers used the same tools to determine the methylation patterns of DNA in more than 500,000 brain cells from 46 regions in the brains of three healthy adult male organ donors. While mouse brains are largely the same from animal to animal, and contain about 80 million neurons, human brains vary much more and contain about 80 billion neurons.

“This is really the beginning of a new era in brain science, where we will be able to better understand how brains develop, age, and are affected by disease,” said Joseph Ecker, PhD, director of Salk’s Genomic Analysis Laboratory and a Howard Hughes Medical Institute investigator.

Among eight papers in the package from Science Advances, research explores how fast-spiking interneurons in humans maintain fast synchronization frequencies despite larger neuron-to-neuron distances than their rat counterparts.

Another study zeroes in on inflammation early in life—a clinically established risk factor for several neurological disorders. The impact of inflammation on human brain development is poorly understood. Focusing on the cerebellum, a brain area particularly vulnerable to postnatal perturbations, the team’s analyses reveal that inflammation is associated with changes primarily in two subtypes of inhibitory neurons: Purkinje neurons and Golgi neurons.

“This suite of studies represents a landmark achievement in illuminating the complexity of the human brain at the cellular level,” said John Ngai, PhD, director of the NIH BRAIN Initiative. “The scientific collaborations forged through BICCN are propelling the field forward at an exponential pace; the progress—and possibilities—have been simply breathtaking.”

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This work is published in Nature in the paper, “Learning from prepandemic data to forecast viral escape.”

The researchers first developed EVE (evolutionary model of variant effect) in the context of uncovering mutations that cause human diseases. The core of EVE is a generative model that learns to predict the functionality of proteins based on large-scale evolutionary data across species. In a previous study, EVE allowed researchers to discern disease-causing from benign mutations in genes implicated in various conditions, including cancers and heart rhythm disorders.

“You can use these generative models to learn amazing things from evolutionary information—the data have hidden secrets that you can reveal,” said Debora Marks, PhD, associate professor of systems biology in the Blavatnik Institute at Harvard Medical School.

During the pandemic, Marks and her team saw an opportunity to apply EVE. They took the generative model from EVE—which can predict mutations in viral proteins that won’t interfere with the virus’s function—and added biological and structural details about the virus, including information about regions most easily targeted by the immune system.

“We’re taking biological information about how the immune system works and layering it on our learnings from the broader evolutionary history of the virus,” explained co-lead author Nicole Thadani, a former research fellow in the Marks lab.

Such an approach, Marks emphasized, means that EVEscape has a flexible framework that can be easily adapted to any virus.

In the new study, the team turned the clock back to January 2020, just before the COVID-19 pandemic started. Then they asked EVEscape to predict what would happen with SARS-CoV-2.

“It’s as if you have a time machine. You go back to day one, and you say, I only have that data, what am I going to say is happening?” Marks said.

EVEscape predicted which SARS-CoV-2 mutations would occur during the pandemic with accuracy similar to this of experimental approaches that test the virus’s ability to bind to antibodies made by the immune system. EVEscape outperformed experimental approaches in predicting which of those mutations would be most prevalent. More importantly, EVEscape could make its predictions more quickly and efficiently than lab-based testing since it didn’t need to wait for relevant antibodies to arise in the population and become available for testing.

The researchers are now using EVEscape to look ahead at SARS-CoV-2 and predict future variants of concern; every two weeks, they release a ranking of new variants. Eventually, this information could help scientists develop more effective vaccines and therapies. The team is also broadening the work to include more viruses as they demonstrated that EVEscape could be generalized to other viruses, including HIV and influenza.

“We want to know if we can anticipate the variation in viruses and forecast new variants— because if we can, that’s going to be extremely important for designing vaccines and therapies,” notes Marks.

Additionally, EVEscape predicted which antibody-based therapies would lose their efficacy as the pandemic progressed and the virus developed mutations to escape these treatments. The tool was also able to sift through the tens of thousands of new SARS-CoV-2 variants produced each week and identify the ones most likely to become problematic.

“By rapidly determining the threat level of new variants, we can help inform earlier public health decisions,” said Sarah Gurev, a graduate student in the Marks lab from the Electrical Engineering and Computer Science program at MIT.

The team is now applying EVEscape to SARS-CoV-2 in real time, using all of the information available to make predictions about how it might evolve next. They are also testing EVEscape on understudied viruses such as Lassa and Nipah, two pathogens of pandemic potential for which relatively little information exists. Such less-studied viruses can have a huge impact on human health across the globe, the researchers noted.

The researchers publish a biweekly ranking of new SARS-CoV-2 variants on their website and share this information with entities such as the World Health Organization. The complete code for EVEscape is also freely available online.

Another important application of EVEscape would be to evaluate vaccines and therapies against current and future viral variants. The ability to do so can help scientists design treatments that are able to withstand the escape mechanisms a virus acquires.

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Now, for the first time, genome editing has generated chickens partially resistant to infection by influenza virus A. The findings, which indicate that multiple genetic modifications would be required to curtail viral escape, present a potential strategy to help mitigate the spread of avian influenza into farmed poultry from wild bird sources.

This work was published in Nature Communications in the paper, “Creating resistance to avian influenza infection through genome editing of the ANP32 gene family.”

Avian influenza is widely dispersed across Asia, Europe, Africa, and the Americas representing a threat to wild bird species, economic costs to farmers, and risk to human health. Poultry vaccination against avian influenza has not yet been reliable due to the rapid antigenic drift of field viruses and is controversial owing to political and economic implications. In chickens, avian influenza relies on the host protein ANP32A for its life cycle, which represents a potential target for creating virus-resistant birds.

Researchers edited the ANP32A gene in chicken germ cells to restrict influenza A activity. More specifically, the authors used CRISPR/Cas9 to generate homozygous gene-edited chickens containing two ANP32A amino acid substitutions that prevent viral polymerase interaction. They found that fully-grown chickens were resistant to a physiological dose of influenza A exposure from other infected birds and displayed increased resilience. After a challenge with influenza A virus, nine of the ten edited chickens remained uninfected.

However, when the researchers infected with a higher dose (1,000 times higher,) breakthrough infections occurred. The influenza virus, they found, had mutated to be able to use the edited chicken ANP32A. Unexpectedly, the authors wrote, “this virus also replicated in chicken embryos edited to remove the entire ANP32A gene and instead co-opted alternative ANP32 protein family members, chicken ANP32B and ANP32E.”

The birds showed no adverse health or egg-laying productivity effects when monitored for over two years. The authors suggest that additional editing and deletion of the other associated genes (ANP32B and ANP32E) in chicken cells would prevent virus replication.

The findings suggest gene editing as a possible route to create chickens resistant to infection by avian influenza. However, the authors caution that further study is needed to ensure animal health is not impacted and that multiple edits to the ANP32 family of genes might be required to eliminate the possibility of viral evolution.

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Ultima Genomics has been quiet since the June 2022 Advances in Genome Biology and Technology (AGBT) conference, where the company boldly entered the next-generation sequencing (NGS) world by introducing the UG 100 sequencing instrument. At that AGBT meeting, the UG 100, which was ensconced in Ultima’s suite, attracted a swarm of onlookers. The instrument was one of several new tools introduced last year, including platforms from more established companies.

At this year’s AGBT conference, Ultima was anything but conspicuous. There was no instrument, no suite, no swarm of onlookers. Yet I managed to get an update, if only by chance, from Gilad Almogy, PhD, the company’s CEO.

Almogy had been riding an elevator, likely heading to or from an AGBT-related meeting, when I greeted him and proposed an impromptu interview. Happily, Almogy agreed. Even better, when we met later, he responded to my questions with straightforward answers. (On this occasion, he was unaccompanied by staff members interested in translating his answers into marketing speak.)

In a disarmingly earnest manner, Almogy told me that his company’s lack of fanfare did not indicate a lack of progress. He explained that Ultima had been holding closed-door meetings and staging events to learn what early-access customers had to say about the UG 100.

I asked Almogy, who studied quantum optics and spent years developing semiconductor-based diagnostic instruments, how he felt about his new field, genomics. He responded quickly, “I love it.” The world of semiconductors, he said, was great fun because it was constantly moving. That world would transform every two years. But he grew ever more detached from the applications. He found it hard to feel excited about developing a better inspection tool that would, for example, allow people to program better games for teenagers.

Almogy doubts he’ll miss the thrilling speed of the semiconductor field now that the genomics field is becoming increasingly competitive. “It’s a technological arms race,” he said. It’s not only challenging and exciting from a technological view, but it is paired with customers that are “insanely smart” and working on gratifying projects.

Almogy likens himself to the proverbial kid in the toy store. Genomics, he points out, is where everything converges: biology, data, and technology. “Maybe I’m biased,” he continued, “but I couldn’t imagine being anywhere more exciting.”

In that same conversation, Almogy invited GEN to visit Ultima in South San Francisco. A few months later, I found myself pulling up to the Ultima building.

Seeing the tools

When I reached Ultima’s facility in Fremont, CA, I wondered if I was in the right place. I had started to think that everything about the company was big. It had a staff of 400 people. It had raised $600 million since 2016. It had built a machine that was large enough to command attention. So, I had expected to see a big, impressive building. Instead, I saw a nondescript, single-story building in an industrial park.

Almogy soon arrived and told me that Ultima is in transition. For the past few years, the company has been renting space in Newark, CA. Soon, all company activities will move to new headquarters in Fremont—near the production site that I was visiting. It was modest, but Almogy was unapologetic.

“[I thought] it was more important for you to see the tools than the [corporate headquarters],” he said. “We like to spend our resources where it matters.”

At some point during our conversation, Almogy decided to show me a wafer from one of the company’s instruments. (An Ultima wafer is akin to other sequencing companies’ flow cells.) He reached into his bag, apparently expecting to find one in there. The gesture looked perfectly natural. If you sleep, eat, and breathe DNA sequencing, why not carry it around, too?

The beginning

When Almogy first had the idea to build a DNA sequencer, he asked for input from NGS users. They provided “screaming feedback” about the need for “more data” and “lower costs.”

Upon starting Ultima, Almogy had a basic understanding of what was needed to build a sequencer that could shake up the high-throughput sequencing space. He needed to make two fundamental changes to existing platforms: faster chemistry and a flow-based system with no fluorescent terminator. He leaned into his background in diagnostics and semiconductor chips. In his old field, he developed systems (still in use today around the world) that were fast and, thanks to the design of the underlying architecture, capable of becoming faster every few years.

Ultima, Almogy decided, would blaze a path different from that taken by other NGS companies. Ultima would build an economical and automated sequencer, one that would be capable of continuous operations and suitable for high-volume users. It wouldn’t even look like a regular sequencer. Shrugging, Almogy acknowledged, “We took on a lot.”

Now, Ultima is in the last stages of its early-access program, with plans to launch by the end of 2023. When that happens, the time for tweaking, fine tuning, and responding to the suggestions of early-access customers will end. The UG 100 specifications will be locked in. And Ultima will wait to see how the market responds.

Quantity means quality

Ultima declined to share its complete list of early-access customers. However, the company did say that the number of customers on the list was in the mid-teens. The company also disclosed that customers on the list included Genome Insight, the Broad Institute, Baylor University, the New York Genome Center, Exact Sciences, and Regeneron Pharmaceuticals.

All of the early-access customers (and other potential customers) are gated by their current scale of sequencing, Almogy remarked. He observed that although everyone wants to pay less, the opportunity is driven more by customers’ desire to do more. He elaborated, “I haven’t yet come across any field where people don’t want more data.”

“Every [person] will have a whole genome sequence—that’s a given,” he insisted. But that’s someone’s germline—the DNA sequence they’re born with—not how it’s changing. What is happening to your mutation profile or methylation profile—that’s not static. And that data, Almogy stressed, will become a bigger and bigger part of healthcare.

This cost of sequencing will have a big impact on moving this field forward. Ultima believes that cost is the biggest pain point. That might not be the case if you’re running a flow cell every other week. But for high-volume users, cost is a major concern. And it’s one that might justify the cost and inconvenience of switching to a new instrument.

According to Almogy, sequencing will be here for a very long time. Indeed, he pointed out that many trends are driving the need for much more sequencing. He predicted that the amount of sequencing that will be generated annually in the future will increase this year’s figure by orders of magnitude.

Ups and downs

When Ultima first unveiled the UG 100 some 15 months ago, the instrument sparked a lot of interest—and a healthy amount of skepticism. Some questioned whether the UG 100 would be able to accurately sequence longer homopolymer regions. But Ultima insists that the version of the UG 100 that will hit the market shortly will be much better than the 2022 version. How much better? Without offering details, Almogy assured me that I won’t be writing about homopolymers next year.

Almogy also touted the sequencing accuracy on single-nucleotide polymorphisms (SNPs.) “We have higher accuracy than every other sequencing platform when it comes to SNPs,” he asserted. In other sequencing platforms, the four bases flow together, and the instrument identifies or “calls” the nucleotide. But if it is wrong, there is no going back. There’s a single shot on goal. By contrast, the UG 100 has multiple shots on goal because it is flow based.

Another advantage (for high-volume users) is that the instrument will be able to run continuously, 24/7. Rather than just one box, the UG 100 has a separate prep box for DNA amplification. Although some may view this as a disadvantage, Almogy notes that this feature allows users to amplify whenever they want. And because multiple samples can be loaded into the UG 100, it will pick them up and start a run—even in the middle of the night.

Ultima has yet to release a lot of specifications. But it notes that the run times are less than 20 hours, the average read length is around 300 base pairs, the accuracy is Q30 > 85%, and the cost is $1.00/Gb. Almogy credited a series of advances with bringing the UG 100 to this point—improvements in chemistry, coverage (accessing more of the genome), base-calling algorithms, and variant calling.

Almogy stated that Ultima is not a one-trick pony, and that it is not stopping at the UG 100. The company, he pointed out, will take advantage of the scalable architecture it has developed—an architecture that could help DNA sequencing sustain its march down the cost curve.

I asked Almogy if he has his sights set on other omics fields like spatial omics or proteomics. “Our core strength,” he answered, “is making sequencing cheaper and cheaper and better and better. That’s what we do.” When Almogy showed me the production floor, his demeanor lightened for a moment as he explained the inner workings of the instruments. The “kid in a toy store” saying comes to mind. And his smile lets you know that he has relaxed—just a little.

A crowded field

When asked about the competition, specifically the arrival of two high-throughput systems (Complete Genomics’ T20x2 and Illumina’s NovaseqX) over the past year, Almogy responded that “it’s great for the industry.”

Ultima doesn’t pay much attention to the mid-throughput sequencing competition. “They don’t pay attention to us either,” Almogy remarked. But Ultima’s chief financial officer, David Peoples, sees it a little differently. “I think they pay attention to us because we’re driving the cost of sequencing down, which could have a broader impact on the market.”

The cost of DNA sequencing is finally going to get unstuck, Almogy maintained. This will accelerate the transition to larger panels and deeper sequencing. It also pushes the notion that we’re not happy with the amount of sequencing we have and that we need more sequencing. Illumina dropping its price by a meaningful factor does not mean that people will spend a lot less money with them. They’ll just consume a lot more genomic information.

“I think it’s great that we’ve maybe played our part in stoking competition,” Almogy declared. “And if we played a small role in [pushing prices down], I’m very proud of that.”

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Through their groundbreaking findings, which fundamentally changed our understanding of how mRNA interacts with our immune system, Karikó and Weismann contributed to the unprecedented rate of vaccine development during the COVID-19 pandemic—one of the greatest threats to human health in modern times.

The use of mRNA technologies for vaccines and therapeutic purposes came into focus in the 1980s, in large part due to the introduction of efficient methods for producing mRNA without cell culture. But there were challenges. In vitro transcribed mRNA was unstable and challenging to deliver, requiring the development of sophisticated carrier lipid systems to encapsulate the mRNA. In addition, in vitro-produced mRNA gave rise to inflammatory reactions. Enthusiasm for developing the mRNA technology for clinical purposes wained.

These obstacles did not discourage the Hungarian biochemist Karikó, who was devoted to developing methods to use mRNA for therapy. During the early 1990s, while an assistant professor at the University of Pennsylvania, she remained true to her vision of realizing mRNA as a therapeutic despite encountering difficulties in convincing research funders of the significance of her project. Weissman, a new colleague of Karikó’s, was interested in dendritic cells, which have important functions in immune surveillance and the activation of vaccine-induced immune responses. Spurred by new ideas, a fruitful collaboration between the two soon began, focusing on how different RNA types interact with the immune system.

Karikó and Weissman discovered that dendritic cells recognize in vitro transcribed mRNA as a foreign substance, which leads to their activation and the release of inflammatory signaling molecules. They wondered why the in vitro transcribed mRNA was recognized as foreign while mRNA from mammalian cells did not give rise to the same reaction. Karikó and Weissman realized that critical properties must distinguish the different types of mRNA.

Karikó and Weissman knew that bases in RNA from mammalian cells are frequently chemically modified, while in vitro transcribed mRNA is not. They sought to understand if the absence of altered bases in the in vitro transcribed RNA could explain the unwanted inflammatory reaction. To investigate this, they produced different variants of mRNA, each with unique chemical alterations in their bases, which they delivered to dendritic cells. The inflammatory response was almost abolished when base modifications were included in the mRNA. This was a paradigm change in the understanding of how cells recognize and respond to different forms of mRNA. Karikó and Weissman understood that their discovery had profound significance for using mRNA as therapy. These seminal results were published in Immunity, in the 2005 paper, “Suppression of RNA Recognition by Toll-like Receptors: The impact of nucleoside modification and the evolutionary origin of RNA.”  

In further studies published over the next several years, Karikó and Weissman showed that the delivery of mRNA generated with base modifications markedly increased protein production compared to unmodified mRNA. The effect was due to the reduced activation of an enzyme that regulates protein production. Through their discoveries that base modifications both reduced inflammatory responses and increased protein production, Karikó and Weissman had eliminated critical obstacles on the way to clinical applications of mRNA.

Interest in mRNA technology began to pick up, and in 2010, several companies were working on developing the method for vaccine production against Zika virus and MERS-CoV. But it was the two base-modified mRNA vaccines encoding the SARS-CoV-2 surface protein, developed at record speed, that drove mRNA technology into the limelight. Protective effects of around 95% were reported, and both vaccines were approved as early as December 2020. The vaccines have saved millions of lives and prevented severe disease in many more, allowing societies to open and return to normal conditions.

Through their fundamental discoveries of the importance of base modifications in mRNA, Karikó and Weissman critically contributed to this transformative development during one of the biggest health crises of our time.

The impressive flexibility and speed with which mRNA vaccines can be developed pave the way for using the new platform for vaccines against other infectious diseases. In the future, the technology may also be used to deliver therapeutic proteins and treat cancer.

In 2021, GEN and the Rosalind Franklin Society hosted a webinar in which Katalin Karikó, PhD, walked through the history of mRNA and the advances that led to its role in the COVID-19 vaccine, including the discovery of the critically important modifications. 

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“We’re thrilled to announce this recent support from ARPA-H. This funding will empower us to reshape drug development by harnessing cutting-edge advancements in thymus biology, iPSC technology, and machine learning,” said Stan Wang, MD, PhD, founder & CEO of Thymmune. “Drawing from decades of dedicated research on the thymus gland, our approach has the potential to revolutionize immunology through the creation of innovative therapies for patients in need with a range of immune system disorders.”

Thymmune is developing a machine learning-enabled thymic cell engineering platform to restore normal immune function in aging and disease. The Cambridge, MA-based company uses iPSC-thymic cell manufacturing to generate off-the-shelf cells at scale. It is developing a pipeline of therapies to treat immunodeficiencies, transplant related, and autoimmune diseases.

The thymus is not only responsible for supporting normal immune cell development, but may also potentially restore immune system function as people age. More than 10,000 new patients are diagnosed each year with a thymus disorder, often related to congenital defects or cancer treatments. More broadly, thymus function naturally declines with age, which can contribute to poorer immune system function, and lead to increased vulnerability to illness and poorer health outcomes.

The thymus is a critical organ in the immune system that regulates and develops T cells, which are essential for fighting infection and disease, along with mounting effective responses to vaccines. As part of the natural aging process, the functional thymus begins to shrink and its ability to produce naïve T cells decreases, leading to immune dysfunction and disease. For children born without a thymus, those with thymus defects, and elderly patients with failing immune function, restoring thymus function could be a game changer in their health and quality of life.

Thymmune Therapeutics is developing scalable thymic cell therapies to restore immune function in aging and disease through the Thymus Rejuvenation project which aims to restore damaged or non-functional thymus tissue. The Thymus Rejuvenation project is divided into two phases. The goal of the first phase is to make best-in-class human induced pluripotent stem cell-derived thymic epithelial cells (iPS-TECs) to restore T-cell development in thymic deficient animals, and slow immune decline in animal models of aging. In the second phase, Thymmune plans to scale up the production of iPS-TECs for transplantation and engraftment in animal models to achieve effective immune function, demonstrating a clinical pathway to treat patients lacking a functional thymus.

“For children born without a thymus, those with thymus defects, and elderly patients with failing immune function, restoring thymus function could be a game changer in their health and quality of life,” explained Amy Jenkins, PhD, director of the ARPA-H Health Science Futures office. “ARPA-H looks to support cutting-edge technologies like this one that, if successful, could have applications beyond just one disease.”

Thymmune’s disease-agnostic approach to combat thymus dysfunction by bolstering immune responses against pathogens, cancer, and vaccines presents a potentially revolutionary means to reboot immunity. Thymmune has the potential to rescue patients lacking a functional thymus from morbidity and mortality and address a crucial unmet need to rejuvenate immunity in the aging population.

This is the first industry project funded by the ARPA-H Open Broad Agency Announcement (Open BAA) which seeks transformative ideas for health research or technology breakthroughs. Continued support of each award is contingent on projects meeting aggressive milestones. The Open BAA began accepting abstracts in March 2023 and is open until March 2024. Future projects will be funded on a rolling basis.

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