Extending “Custom Made” Microscopy Limits

Researchers at the European Molecular Biology Laboratory (EMBL) say they have made an important leap forward with a novel methodology that adds an important microscopy capability to life scientists’ toolbox.

The advance represents a 1,000-fold improvement in speed and throughput in Brillouin microscopy and provides a way to view light-sensitive organisms more efficiently, according to Carlo Bevilacqua, an optical engineer in EMBL’s Prevedel Team and lead author of the study, “Full-field Brillouin microscopy based on an imaging Fourier-transform spectrometer” published in Nature Photonics.

“We were on a quest to speed up image acquisition,” said Bevilacqua. “Over the years, we have progressed from being able to see just a pixel at a time to a line of 100 pixels, to now a full plane that offers a view of approximately 10,000 pixels.”

The technology is based on a phenomenon first predicted in 1922 by French physicist Léon Brillouin. He showed that when light is shone on a material, it interacts with naturally occurring thermal vibrations within, exchanging energy and thereby slightly shifting the frequency (or color) of the light. Measuring the spectrum (colors) of the scattered light reveals information about a material’s physical characteristics.

Using Brillouin scattering for microscopy purposes came much later—in the early 2000s—when other technological advancements enabled scientists to measure tiny frequency shifts with high precision and sufficient throughput. This allowed them to compute the mechanical properties of living biological samples. However, at that point, scientists were only able to view one pixel at a time. The process was therefore quite time-consuming, and it severely limited how the microscopy method could be used in biology.

In 2022, Bevilacqua and others in the Prevedel group were able to first expand the field of view to a line, and now with this latest development, to a full 2D field of view, which also helps speed up 3D imaging.

“Just as the development of light-sheet microscopy here at EMBL marked a revolution in light microscopy because it allowed for faster, high-resolution, and minimally phototoxic imaging of biological samples, so too does this advance in the area of mechanical or Brillouin imaging,” pointed out Robert Prevedel, PhD, group leader and senior author on the paper. “We hope this new technology—with minimal light intensity—opens one more ‘window’ for life scientists’ exploration.”

Alzheimer’s Disease Could Be Influenced by HSV-1 Infections via Jumping Genes

New research from scientists at Cleveland Clinic’s Genome Center and their collaborators at other institutions describes a pathway that human herpes simplex-1 (HSV-1) can use to contribute to the development of Alzheimer’s disease. They have also identified two FDA-approved drugs that successfully reversed the pathway in the lab. Full details are published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association in a paper titled, “Human herpesvirus-associated transposable element activation in human aging brains with Alzheimer’s disease.”

Feixiong Cheng, PhD, Genome Center director and senior author on the study, claims that their findings provide concrete evidence of a possible link between human herpesviruses and Alzheimer’s disease. Many people around the world are either currently infected or will contract herpesviruses by adulthood. Some infections are asymptomatic while others cause minor illnesses. However, even after the illnesses subside, infected individuals carry the virus for the rest of their lives.

While herpesviruses are generally harmless when they are suppressed, there is evidence that shows that immune systems can lose the ability to suppress them under certain conditions including as people age. Circumstantial evidence from other studies has linked HSV-1 to Alzheimer’s disease, but the exact mechanism was not known.

Cheng and his team hypothesized that latent HPV-1 infections could trigger Alzheimer’s disease by directly activating the transposable elements that they had previously connected to disease progression in aging brains. Transposable elements are small pieces of DNA that can physically “jump” out of chromosomes and randomly move to far-away regions of our DNA.

For this study, the researchers mapped all of the transposable elements associated with Alzheimer’s disease in aging brains. The investigators then analyzed four publicly available RNA sequencing datasets from hundreds of healthy and Alzheimer’s-affected brain cells. 

They identified several transposable elements that were more highly activated in Alzheimer’s-affected brains containing HSV RNA, compared to uninfected or healthy brains. They then tested HSV-1 infected brain cells to see whether the identified transposable elements were activated. They also assessed any effects on neuroinflammation and protein accumulation, which are associated with Alzheimer’s disease.

What they found was that when people either contract HSV-1 or when latent infections become active with age, the infection is linked with the activation of transposable elements like LINE-1. Once these are activated, they disrupt important genetic processes in the brain that are associated with the accumulation of Tau and other Alzheimer’s-linked proteins which contribute to inflammation and neurodegeneration in the brain.

Next, the scientists analyzed publicly available health records to see if people who were prescribed antiviral herpes medications were less likely to be diagnosed with Alzheimer’s later in life. They found evidence suggesting that two herpes medications, valacyclovir and acyclovir, were associated with significantly reduced instances of Alzheimer’s disease. When they tested the drugs in virus-infected human brain organoid models, they seemed to successfully reverse the activation of transposable elements that impact the Alzheimer’s disease pathway.

Commenting on the study, Cheng noted that their findings could open a door to “new strategies for treating other neurological diseases associated with herpesviruses or other viruses.”

Genome-edited rice shows resistance to bacterial blight in East Africa

The international Healthy Crops consortium has developed an innovative strategy to combat the disease bacterial blight (for short: BB) in rice using genome editing technology. If approved for use by farmers in Kenya, the BB-resistant rice varieties are expected to reduce yield losses associated with the disease in the affected rice growing regions and increase productivity. The work is a collaboration between Kenya Agricultural and Livestock Research Organization (KALRO) and Heinrich Heine University Düsseldorf (HHU).

Rice production is of central importance for food security and economic development in many countries, in particular in low- and medium-income countries. Rice is the second most important staple food in East Africa, with 1.8 million tonnes consumed every year in the countries of the East African Community (for short: EAC).

In 2019, members of the Healthy Crops team identified an outbreak of BB in Tanzania caused by invasive Asian variants of the bacterium Xanthomonas oryzae pv. oryzae (Xoo). The bacterium is spreading rapidly and causing estimated yield losses of 13–20%.

Dr. Emily Gichuhi from KALRO explains, “Due to climate change, incidences of rice diseases including BB have been on the rise in Kenyan rice growing areas. This has increased the cost of production among rice farmers, thereby reducing their returns.”

Dr. Daigo Makihara and Dr. Moto Ashikari from Nagoya University (NU) in Japan, researchers from the Wonder Rice Initiative for Food Security and Health (WISH), are working closely with Dr. Gichuhi and her team to develop new African rice varieties. Dr. Makihara explains, “As a result of the international spread of different crop plant varieties, we are increasingly finding ourselves confronted with outbreaks of plant diseases in regions where they have not previously played a role.”

The starting point for the researchers from Healthy Crops is the nutrient supply of the bacteria. The Xoo bacteria possess a set of “keys” which can open the “pantry” of the plants: When the bacterium injects one of these “key” proteins into rice cells, it leads to increased production of a transporter, which releases sugar in the neighborhood of the bacteria. This sugar serves as nutrition and is essential for the multiplication and virulence of the bacteria. However, when the bacteria utilize the sugar, there is none left for the plant, which ultimately dies as a result

The research team has succeeded in changing the “locks” via genome editing, making the plants resistant to all known Xoo strains currently prevalent in Asia and Africa.

Professor Bing Yang, University of Missouri, who developed the editing approach, states: “The combination of two different sets of enzymes for editing enabled us to develop a robust resistance.”

The import of these edited elite rice varieties has been made possible due to the availability of genome editing guidelines developed by the National Biosafety Authority (NBA) of Kenya and published in 2022.

Dr. Marcel Buchholzer, coordinator of the Healthy Crops project at HHU, explains, “It is now possible to evaluate these rice lines, developed using advanced biotechnology methods at HHU, in Kenya.”

Professor Dr. Wolf B. Frommer, spokesperson for the project at HHU explains, “This project aims to protect smallholder farmers from crop yield losses through knowledge-based approaches to fighting plant diseases.”

Circular mRNA produces 200 times more protein, enhancing precision therapy potential

Imagine a breakthrough in cancer treatment where only malignant cells are targeted, sparing healthy host cells; or patients with abnormal protein synthesis are treated to produce a healthy protein. Hiroshi Abe and his colleagues at Nagoya University have identified two applications, among others, in a new study.

Their innovative approach, reported in Nature Biotechnology, called the Internal Cap-Initiated Translation (ICIT) mechanism, introduces a novel way to “switch on” protein synthesis only in target cells, creating healthy proteins to treat illnesses or toxic proteins to kill unwanted cells.

Capping circular mRNA in a new way

ICIT builds on the promise of circular mRNAs, a new generation of mRNA treatments known for their stability and reduced inflammatory effects compared to traditional linear mRNAs.

Unlike linear mRNAs, circular mRNAs are less susceptible to enzymatic degradation because of their lack of terminal structures, offering a sustained translation process.

However, one significant challenge with circular mRNAs has been the inefficiency of their translation inside living organisms.

Previous methods relied on long internal ribosome entry sites (IRES) for introducing the mRNA, which were difficult to optimize and often inefficient. Abe’s team overcame this hurdle by introducing a cap structure into the circular mRNA itself.

This internal cap structure triggers translation initiation, bypassing the need for IRES sequences, and significantly improves the efficiency of protein synthesis.

Precision therapy

Abe and his colleagues developed two designs. Among these, Cap-circRNA demonstrated superior performance, synthesizing up to 200 times more protein than commonly used circular mRNAs with IRES sequences. Importantly, this synthesis persisted for an extended period, even after traditional mRNA structures began to degrade.

This stability and ability to selectively target cells make Cap-circRNA an ideal candidate for developing precision therapies.

“This technology is expected to revolutionize mRNA medicine, including antibody therapy, genome editing, and protein replacement therapy,” Abe said.

“Current mRNA is fundamentally unstable, requiring constant injections to be used for treatments such as protein replacement, a problem that our technique overcomes. Using this, we could treat diseases caused by abnormal protein synthesis, such as Duchenne muscular dystrophy.”

Targeting cancer cells

The ICIT mechanism’s ability to control protein translation at the single-cell level also offers a transformative approach to the treatment of cancers and other tissue-specific diseases. By targeting specific RNA markers that are highly expressed in diseased cells, such as those found in liver cancer, the mRNA can instruct protein synthesis only in target cells.

This precision reduces the risk of off-target effects and side reactions, which are common challenges in current treatments. To test its efficacy, the team designed a circular RNA using ICIT to target HULC lncRNA, an RNA that is commonly found in liver cancer cells.

Bacterial cellulose promotes plant tissue regeneration, study shows

A study has elucidated the mechanism by which bacterial cellulose mediates plant tissue regeneration. The work has been published today in the journal Science Advances and includes collaborations with researchers of the Institute of Materials Science of Barcelona (ICMAB-CSIC) and Colorado State University.

Bacterial cellulose (BC), synthesized by certain bacteria as a biofilm, consists of highly pure cellulose fibers. BC has been widely used in human biomedical applications showing a high degree of biocompatibility, but its potential healing effects in plants were unknown.

In this work, scientists have demonstrated that BC patches induce plant tissue regeneration and have identified for the first time the precise molecular mechanism underlying the process. Wounded leaves of the model plants Nicotiana benthamiana and Arabidopsis thaliana were covered with BC patches and formation of new cells on both sides of the cut was observed two days post-wounding, reaching complete wound closure after seven days.

This wound healing process was promoted by BC but not by other structurally similar matrixes such as plant cellulose, indicating that BC had specific features beyond preventing dehydration or promoting physical contact.

Scientists discovered that BC patches contain cytokinins, a class of hormones involved in plant development.

“Plants with defective cytokinin signaling did not respond to BC patches, confirming that cytokinins are crucial for triggering regeneration,” explains Nerea Ruiz-Solaní, a co-first author of the study.

The team also identified production of oxidative stress (ROS) at the wound sites upon BC application. Genomic and bioinformatic analyses enabled scientists to identify the specific genes involved in the process, which are typically associated with biotic responses, i.e. defense mechanisms against pathogens. The transcription factor WRKY8, which regulates defense responses, was found to interact directly with the promoter of GSTF7 gene leading to ROS accumulation.

Importantly, it is the concurrent activation of both the cytokinin and defense signaling pathways that results in the observed tissue regeneration, a novel finding since these mechanisms were previously studied independently. Further research would be needed to fully elucidate the pathways leading to cell cycle activation and functional differentiation during regeneration.

“Bacterial cellulose triggers a unique transcriptional program that differs from typical wounding-and callus-induced regeneration,” states Miguel Moreno-Risueño, co-leader of the study and an expert in plant regeneration at the CBGP.

This research holds significant implications for agricultural practices, including wound healing to prevent infections, and applications in grafting, pruning, and ornamental plant care, particularly in vineyards, rose cultivation, and stone pine production.

This work started a few years ago, back in 2016, with joint projects between CRAG and ICMAB-CSIC research groups led by Núria Sánchez Coll and Anna Laromaine, respectively, and in collaboration with companies such as AGROMILLORA and Forestal Catalana S.A. (Plant Healing and Plant Nanohealing projects), which conducted preliminary field trials.

However, further field studies are still needed to confirm the efficacy of BC patches in grafting. More technology transfer resources are needed to bridge the gap between fundamental research and the productive sector, with significant economic implications.

Núria Sanchez Coll, CSIC researcher at CRAG and co-leading author, highlights the collaborative nature of this research, saying, “This work has fostered very interesting collaborations with other research groups as well as industry, paving the way for further studies on plant regeneration mechanisms and potential biotechnological applications.”

Acidification kills H5N1 in waste milk, reducing risk of bird flu

Pasteurization is the only widely recognized method of killing H5N1, the virus that causes bird flu, in milk. However, pasteurization can be expensive and fewer than 50% of large dairy farms pasteurize waste milk.

Waste milk includes colostrum, the first milk after calving; milk from cows treated with antibiotics or other drugs; or any other factor that can make milk unsuitable and unsellable for human consumption. On farms, raw waste milk poses a potential risk of spreading avian flu, which so far has been confirmed in dairy cattle in 16 states.

University of California, Davis, researchers have found that acidification can kill H5N1 in waste milk, providing dairy farmers an affordable, easy-to-use alternative to pasteurization of waste milk. The Journal of Dairy Science published the study.

“There can be a quite significant cost to have pasteurization as an option on the farm,” said co-corresponding author and veterinary epidemiologist Richard Van Vleck Pereira, with the UC Davis School of Veterinary Medicine. “In our laboratory tests, we found that acidifying milk to a pH of 4.1 to 4.2 with citric acid effectively deactivates the virus.”

The UC Davis research team will next conduct on-farm testing of milk acidification in waste milk containing H5N1. They will develop practical guidelines for farmers to implement acidification of waste milk as a protocol on the farm.

A sustainable solution

Pereira said citric acid is inexpensive. Acidified waste milk is also safe to be used to feed pre-weaned calves. The acidification process takes only six hours to fully kill the virus and doesn’t require refrigeration, further reducing costs and increasing safety of farm workers handling milk.

Hobby farmers milking one or two cows or large commercial dairy farms could implement milk acidification without having to invest in large equipment.

“When we started this project, we were carefully thinking about not just deactivating the virus but developing a method that could be affordable, accessible and sustainable for farmers to use,” he said.

Some U.S. dairy farms already practice milk acidification. Lowering milk pH to a level unsuitable for bacterial growth can kill bad bugs and prevent contamination without causing health issues in calves.

“We believe acidification is a novel and effective way to contain the spread of H5N1 on dairy farms and help protect livestock, pets and people,” Periera said.

Zika Virus Creates Tunnels to Cross Placenta in Stealth Mode and Infect Fetus

Infection with Zika virus (ZIKV) in pregnancy can lead to neurological disorders, fetal abnormalities, and fetal death. Until now it’s not been clear how the virus manages to cross the placenta, which forms a strong barrier against microbes and chemicals that could harm the fetus. The results of a laboratory study carried out by researchers at Baylor College of Medicine, in collaboration with a team at Pennsylvania State University, have identified a strategy that Zika virus uses to covertly spread in placental cells, raising little alarm in the immune system. The team suggests their findings could point to new therapeutic strategies against the virus.

“The Zika virus, which is transmitted by mosquitoes, triggered an epidemic in the Americas that began in 2015 and by 2018 had reached as many as 30 million cases,” said Indira Mysorekar, PhD, E.I. Wagner Endowed, M.D., Chair Internal Medicine II, chief of basic and translational research and professor of medicine–infectious diseases at Baylor. “Understanding how Zika virus spreads through the human placenta and reaches the fetus is critical to prevent or control this devastating condition.

Zika virus is a mosquito-borne virus in the Flaviviridae family, and infection can lead to neurological disorders and fetal abnormalities such as microcephaly, and fetal death, “collectively known as congenital Zika syndrome,” the authors explained. “The propensity for horizontal and vertical transmission, and the ability to traverse blood-tissue barriers, including the blood-placental barrier, of ZIKV are unique among Flaviviridae.” The researchers noted that their own studies in mice, and work by others, have shown that ZIKV can infect fetal trophoblasts and endothelial cells of the placenta, which form the primary barrier between the maternal and fetal circulations. By infecting these cells the virus can enter the fetal circulation.

The researchers’ newly reported laboratory study has now discovered that Zika virus builds underground tunnels, a series of tiny tubes called tunneling nanotubes TNTs, in the placental trophoblasts, which facilitate the transfer of viral particles to neighboring uninfected cells. This ability is reliant on a viral protein NS1. “TNT formation is driven exclusively via ZIKV non-structural protein 1 (NS1),” they wrote.

“Zika is the only virus in its family, which includes dengue and West Nile viruses among others, whose NS1 protein triggers the formation of tunnels in multiple cell types,” Michita said. “Other viruses unrelated to Zika, such as HIV, herpes, influenza A, and SARS-CoV-2, the virus that causes COVID-19, also can induce tiny tunnels in cells they infect and use the tunnels to spread to uninfected cells. This is the first time that tunneling has been shown by Zika virus infection in placental cells.”

Interestingly, the tiny conduits provided a means to transport not only viral particles, but also RNA, proteins, and mitochondria, a cell’s main source of energy, from infected to neighboring cells. “We demonstrate that ZIKV infection or NS1 expression induces elevated mitochondria levels in trophoblasts and that mitochondria are siphoned via TNTs from healthy to ZIKV-infected cells,” the team wrote. Added co-author Long B. Tran, a graduate student in the Mysorekar lab, “We propose that transporting mitochondria through the tunnels may provide an energetic boost to virus-infected cells to promote viral replication.”

The study findings showed how TNT-mediated trafficking also allows Zika cell-to-cell transmission that is “camouflaged from host defenses.” Michita further commented, “We also show that traveling through the tiny tunnels can potentially help Zika virus avoid the activation of large-scale antiviral responses, such as interferon lambda (IFN-lambda) defenses implemented by the placenta. Mutant Zika viruses that do not make tiny tunnels induce robust antiviral IFN-lambda response that can potentially limit the spread of the virus.”

Mysorekar continued, “Altogether, we show that Zika virus uses a tunneling strategy to covertly spread the infection in the placenta while hijacking mitochondria to augment its propagation and survival. We propose that this strategy also protects the virus from the immune response. These findings offer vital insights that could be used to develop therapeutic strategies targeted against this stealth transmission mode.”

In their paper, the team concluded, “Our investigation reveals a previously unknown mechanism of intercellular transmission exploited by ZIKV, setting it apart from other orthoflaviviruses  … Together our findings identify a stealth mechanism that ZIKV employs for intercellular spread among placental trophoblasts, evasion of antiviral interferon response, and the hijacking of mitochondria to augment its propagation and survival and offers a basis for novel therapeutic developments targeting these interactions to limit ZIKV dissemination.”

The team acknowledged that further research will be needed to investigate the molecular mechanism by which ZIKV NS1 induces TNTs, and whether monoclonal antibodies or NS1-based vaccines target TNT formation in ZIKV-infected cells, to potentially limit viral infection and spread.

From farmland to construction: Bacteria strains offer sustainable biocement solution

A recent study examines the effectiveness of environmental strains for the production of biocement. The study’s lead author, Dimitrios Terzis, is an EPFL senior scientist and a co-founder of Medusoil, a company that produces organic binders and that opened a production plant in Vaud in 2024.

“For me, it’s essential to keep conducting fundamental research,” says Terzis, a civil engineer at EPFL’s Soil Mechanics Laboratory. His company Medusoil produces organic binders that are similar to biocement.

For the study published recently in Scientific Reports, Terzis worked with scientists from the University of Applied Sciences and Arts of Southern Switzerland to analyze 50 bacteria strains sourced from farmland in Ticino canton. This land is used for grazing dairy cattle and has shown to be particularly well suited for the production of Medusoil’s biocement due to the widely available presence of calcium.

Biocementation relies on stimulating a natural process: The secretion by microorganisms of an enzyme that triggers the formation of carbonate, which then binds with the calcium largely present in the soil to form calcite, a natural cement.

The study identified which naturally occurring strains fabricate the enzyme required for carbonate formation and can be fermented—two factors that make them prime candidates for biocement production. The scientists created a culture of the most promising strain, which was inoculated in a 1.5-meter-high column of sand.

After 24 hours of infiltration, the column was strong enough to sustain its weight and to be used in a variety of geotechnical engineering and geoenvironmental applications, like erosion. The scientists also found that using this strain could cut production costs by 40%.

A paradigm shift

Medusoil, founded seven years ago, supplies organic binders whose carbon impact is at least 55% lower than that of standard cement, which is made by heating an 80% limestone/20% clay mixture to high temperatures. Biocement can be used in a number of geotechnical and building applications, such as to reinforce dams, prevent soil erosion by wind and help protect areas subject to landslides, earthquakes or cyclic loads induced by road and railway traffic.

To test yet another application, the company’s biocement was used in a project in Geneva to recover concrete aggregates from demolished buildings. And because biocement can be employed several times, it supports the circular economy.

In the Scientific Reports study, the authors note that this naturally occurring biocementation process can be applied on a large scale and can help drive a paradigm shift towards greater sustainability in the construction industry.

New production plant

Medusoil reached a new milestone in 2024 with the opening of a production plant in Molondin, near Yverdon-les-Bains. “The plant can generate 400,000 liters of biocement per year, which is enough to stabilize five kilometers of riverbank against erosion,” says Vincent Laurençon, Medusoil’s head of manufacturing.

The company also has a mobile biocementation plant designed to make use of local raw materials. It was recently transported by truck to Romania, for example, where it was employed to reinforce roads. The firm intends to pursue its cutting-edge R&D and has projects lined up this year in France, the Middle East and the Netherlands.

Decoding emotions in seven hoofed species with AI

Can artificial intelligence help us understand what animals feel? A pioneering study suggests the answer is yes. Researchers from the Department of Biology at the University of Copenhagen have successfully trained a machine-learning model to distinguish between positive and negative emotions in seven different ungulate species, including cows, pigs, and wild boars. By analyzing the acoustic patterns of their vocalizations, the model achieved an impressive accuracy of 89.49%, marking the first cross-species study to detect emotional valence using AI.

“This breakthrough provides solid evidence that AI can decode emotions across multiple species based on vocal patterns. It has the potential to revolutionize animal welfare, livestock management, and conservation, allowing us to monitor animals’ emotions in real time,” says Élodie F. Briefer, Associate Professor at the Department of Biology and last author of the study.

The work is published in the journal iScience.

AI as a universal animal emotion translator

By analyzing thousands of vocalizations from ungulates in different emotional states, the researchers identified key acoustic indicators of emotional valence. The most important predictors of whether an emotion was positive or negative included changes in duration, energy distribution, fundamental frequency, and amplitude modulation. Remarkably, these patterns were somewhat consistent across species, suggesting that fundamental vocal expressions of emotions are evolutionarily conserved.

The study’s findings have far-reaching implications. The AI-powered classification model could be used to develop automated tools for real-time monitoring of animal emotions, transforming the way we approach livestock management, veterinary care, and conservation efforts. Briefer explains, “Understanding how animals express emotions can help us improve their well-being. If we can detect stress or discomfort early, we can intervene before it escalates. Equally important, we could also promote positive emotions. This would be a game-changer for animal welfare.”

Key findings include:

  • High accuracy—The AI model classified emotional valence with an overall accuracy of 89.49%, demonstrating its strong ability to distinguish between positive and negative states.
  • Universal acoustic patterns—Key predictors of emotional valence were consistent across species, indicating an evolutionarily conserved emotional expression system.
  • New perspectives on emotional communication—This research offers insights into the evolutionary origins of human language and could reshape our understanding of animal emotions.

To support further studies, the researchers have made their database of labeled emotional calls from the seven ungulate species publicly available.

“We want this to be a resource for other scientists. By making the data open access, we hope to accelerate research into how AI can help us better understand animals and improve their welfare,” Briefer concludes.

This study brings us one step closer to a future where technology allows us to understand and respond to animal emotions—offering exciting new possibilities for science, animal welfare, and conservation.

Roche Announces SBX Technology, Creates Sequencing Buzz

A few years ago, a new NGS platform being announced at the Advances in Genome Biology and Technology (AGBT) meeting would not have been a surprise; multiple new instruments entered the NGS arena over the span of a few years. In turn, the genomics community has grown used to teams touting their “game-changing” platforms, with promises of either lower cost, longer reads, higher accuracy, more throughput (or all of the above!) But those days had settled down. Or so we thought.

This week, Roche made it feel like 2022 again. Just days before the AGBT meeting kicks off in Marco Island, FL, the company hosted a much-anticipated webinar to offer a technical introduction to their sequencing expansion technology (SBX): a coming together of two companies that Roche had previously acquired—Stratos Genomics and Genia Technologies.

Why now for the technology unveiling? “It just felt like this was the right timing based on where we were, and our comfort with where we are with the technology which we’re very excited about,” noted Mark Kokoris, vice president, head of SBX technology RS.

Kokoris, who co-founded Stratos Genomics in 2007 and served as the company’s CEO until the acquisition, invented SBX technology. The webinar was designed to be “a heavy dive in on the technical,” he told GEN, with less focus on the timeline of the instrument launch and more focus on “the technology, what we’re putting forward, and what we’re seeing.”

The technology

“Our approach to efficiently sequencing DNA is to not sequence DNA,” Kokoris told GEN, chuckling. Instead, he explained, they created and innovated a biochemical conversion process to change DNA into an expanded surrogate molecule with the idea to rescale the signal-to-noise problem. He brought the idea to his friend Bob McRuer, Stratos’ former CTO, almost 20 years ago, who loved it because it simplified measurement. Then, Kokoris had to figure out how to make the chemistry come together without a roadmap.

Nothing existed, he remembers, to explain how to build a cleavable X-NTP (one of the keys to the technology). When you see the structure of an X-NTP, Kokoris asserted, you probably think, this is crazy! “And I knew it was going to require innovation in protein engineering, molecular engineering, and developing chemistries that didn’t exist. And there was a bunch of other stuff that we didn’t realize at the time that we had to innovate.”

SBX creates a surrogate molecule called an Xpandomer (which is 50 times longer than target DNA) and encodes the DNA sequence information in large, high signal-to-noise reporters. The backbone of the Xpandomer is X-NTPs, which are linked along a target DNA template. The DNA sequence is represented in the X-NTP sequence. The four X-NTP types have a tether that is linked between the base and the alpha phosphate. In the process, the DNA template is degraded and the backbone expands, becoming an Xpandomer which is pulled through a nanopore. This is performed in millions of wells on a CMOS-based sensor.

“When we got to the other side of [building the technology] it was exactly what we had thought. We had solved that single molecule signal to noise. And now that we have transitioned that to a large, 8 million array. It’s bonkers.”

Not Roche’s first rodeo  

Roche is not a newcomer to the sequencing space: the company bought Jonathan Rothberg’s 454 in 2007 for $140 million. 454 had just announced the completion of Jim Watson’s genome (in May 2007) and published in Nature the following the year. But it was evident that 454’s platform could not get the WGS price down significantly, while competition from Illumina and others was rapidly intensifying (PacBio launched at AGBT in 2008). The writing was on the wall when Nature published three back-to-back landmark NGS papers in November 2008—the first African genome, the first Asian genome, and the first cancer genome—all featuring the Illumina platform.

Roche shut down the 454 program in 2013. Meanwhile, Roche had taken a shine to Genia Technologies, the developer of a single molecule, semiconductor-based, DNA sequencing platform using nanopore technology. Roche eventually bought Genia for $350M in 2014.

A crazy idea 

At this point, a new NGS technology has to offer something new or different to users to get noticed. What are the advantages of SBX? Is it read length, cost, accuracy? According to Kokoris, the cost, scale, throughput, and accuracy have all been considered. (The data from the webinar suggested that read accuracy and speed are strengths of the system.) But the one thing that was always the focus—even back when McRuer and he would meet at Starbucks on First Avenue (in Seattle) for six-hour sessions back in 2007—was flexible operation. That was at the top of mind then and “hasn’t changed one bit in 18 years,” noted Kokoris.

“We envisioned a platform that can sequence up and down the throughput spectrum with impunity,” Kokoris explained. “In other words, one system where someone could do four minutes, 40 minutes, or four hours depending on your throughput. That’s what I wanted on one system. And that is why we did single molecule.”

The technology will be released as research use only, but Kokoris noted that there are future ambitions to take it to the clinical setting. This year will be early access, with the plan to commercialize in 2026. No other details on pricing or sample prep were offered at this time.

At the end of the webinar, Kokoris thanked his team and many others. And he thanked those who believed in this when “it seemed like a crazy idea.” Although Kokoris was referring to the technology, it might also seem crazy to some to launch a new NGS technology into an already extremely crowded market. Time will tell. But the SBX announcement has succeeded in creating a buzz that the NGS community hasn’t experienced for a few years. And in the words of Peter Diamandis, MD: “The day before something is a breakthrough, it’s a crazy idea.”

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