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Next-generation sequencing (NGS) is continuously evolving. Traditional short-read DNA sequencing has encouraged break-throughs at ever-lower costs across the field of genomics. However, tumors, brains, the immune system, and other complex systems require the greater resolution and flexibility only recently introduced with single-cell sequencing. Compared to the more established bulk RNA sequencing (RNA-Seq), single-cell sequencing magnifies cellular differences to glean intel about how an individual cell functions in its environment. By sequencing individual cells to determine the base sequences, researchers can obtain genomic, transcriptomic, or multiomic data on a cell-by-cell basis, revealing details that are otherwise overlooked.

Single-cell sequencing applies to any study that requires detailed understanding of a cell population, marking tremendous potential for multiple research areas spanning a diversity of applications. This eBook highlights single-cell innovations and approaches, demonstrating how NGS identifies a neuroblastoma target and provides insights for brain rejuvenation and the development of combination therapies. We also invite researchers to explore how the Element AVITI System synthesizes quality, flexibility, and compatibility to deliver affordable single-cell sequencing at any scale so that you can own the next breakthrough.

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Modern humans (Homo sapiens) from Africa began replacing Neanderthals 40,000 years ago in the western part of the Eurasian continent where Neanderthals had lived for hundreds of thousands of years. The replacement was not sudden but took place over several millennia which resulted in the integration of Neanderthal DNA into the H. sapiens genome.

“The worldwide expansion of modern humans started before the extinction of Neanderthals (Homo neanderthalensis). Both species coexisted and interbred, leading to slightly higher introgression in East Asians than in Europeans. This distinct ancestry level has been argued to result from selection, but range expansions of modern humans could provide an alternative explanation. This hypothesis would lead to spatial introgression gradients, increasing with distance from the expansion source,” write the researchers.

“We investigate the presence of Neanderthal introgression gradients after past human expansions by analyzing Eurasian paleogenomes. We show that the out-of-Africa expansion resulted in spatial gradients of Neanderthal ancestry that persisted through time. While keeping the same gradient orientation, the expansion of early Neolithic farmers contributed decisively to reducing the Neanderthal introgression in European populations compared to Asian populations. This is because Neolithic farmers carried less Neanderthal DNA than preceding Paleolithic hunter-gatherers. This study shows that inferences about past human population dynamics can be made from the spatiotemporal variation in archaic introgression.”

Genome sequencing and comparative analysis

Due to genome sequencing and comparative analysis, it’s established that Neanderthals and Sapiens interbred and that these encounters were sometimes fruitful, leading to the presence of about two percent of DNA of Neanderthal origin in present-day Eurasians. However, this percentage varies slightly between regions of Eurasia, since DNA from Neanderthals is somewhat more abundant in the genomes of Asian populations than in those of European populations.

One hypothesis to explain this difference is that natural selection would not have had the same effect on genes of Neanderthal origin in Asian and European populations. The team of Mathias Currat, PhD, senior lecturer in the department of genetics and evolution at the UNIGE Faculty of Science, is working on another hypothesis. His previous work, based on computer simulations, suggests that such differences could be explained by migratory flows: when a migrant population hybridizes with a local population, in their area of cohabitation, the proportion of DNA of the local population tends to increase with distance from the point of departure of the migrant population.

In the case of Sapiens and Neanderthals, the hypothesis is that the further one moves away from Africa, Homo sapiens’ point of origin, the greater the proportion of DNA from Neanderthal, a population mainly located in Europe. To test this hypothesis, the authors used a database made available by Harvard Medical School that includes more than 4,000 genomes from individuals who have lived in Eurasia over the past 40 millennia.

‘‘Our study is mainly focused on European populations since we are obviously dependent on the discovery of bones and the state of conservation of DNA. It turns out that archaeological excavations have been much more numerous in Europe, which greatly facilitates the study of the genomes of European populations,’’ explains Claudio Quilodrán, PhD, senior research and teaching assistant in the department of genetics and evolution at the UNIGE Faculty of Science, and co-first author of the study.

Paleolithic hunter-gatherers

Statistical analyses revealed that, in the period following the dispersal of Homo sapiens from Africa, the genomes of Paleolithic hunter-gatherers who lived in Europe contained a slightly higher proportion of DNA of Neanderthal origin than the genomes of those who lived in Asia. This result is contrary to the current situation but in agreement with paleontological data, since the presence of Neanderthals was mainly reported in western Eurasia (no Neanderthal bones have been discovered further east than the Altai region of Siberia).

Subsequently, during the transition to the Neolithic, i.e., the transition from the hunter-gatherer lifestyle to the farmer lifestyle, 10,000 to 5,000 years ago, the study shows a decline in the proportion of DNA of Neanderthal origin in the genomes of European populations, resulting in a slightly lower percentage than that of Asian populations (as currently observed). This decrease coincided with the arrival in Europe of the first farmers from Anatolia (Turkey’s western peninsula) and the Aegean area, who themselves carried a lower proportion of DNA of Neanderthal origin than the inhabitants of Europe at the same time. By mixing with the populations of Europe, the genomes of farmers from Anatolia “diluted’’ Neanderthal DNA a little more.

The study shows that the analysis of ancient genomes, coupled with archaeological data, makes it possible to trace different stages in the history of hybridized species. ‘‘In addition, we are beginning to have enough data to describe more and more precisely the percentage of DNA of Neanderthal origin in the genome of Sapiens at certain periods of prehistory. Our work can therefore serve as a reference for future studies to more easily detect genetic profiles that deviate from the average and might therefore disclose an advantageous or disadvantageous effect,’’ notes Currat, last author of the study.

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Broadcast Date: November 9, 2023
Time: 9:00 am PT, 12:00 pm ET, 18:00 CET

The human brain has ~170 billion cells, with roughly 170 trillion synaptic connections, organized into distinct regions, structures, and cortical layers. This complex intersection between cellular connectivity and neuroanatomy has made it challenging to untangle discrete functions in health and disease. Spatial profiling at the single cell level makes it possible to move beyond deductive science and delve into the gene expression changes occurring in tissue micro environments during disease development and therapeutic response more directly.  

In this GEN webinar, our distinguished speaker Dr. Simon Gregory will demonstrate how 10x Genomics’ Xenium Mouse Brain Gene Expression Panel and a Custom Add-on Panel can be used to characterize therapeutic response in brain cancer and white matter injury repair. He will demonstrate the use of single cell spatial imaging with these panels to examine pathological processes associated with the development of diffuse midline glioma, and tumor response to a novel therapeutic intervention. He will also share results assessing the impact of a new oxysterol therapy on an intestinal perforation model of cerebral palsy. 

A live Q&A session will follow the presentation, offering you a chance to pose questions to our expert panelist.

Webinar produced with support from:

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Carl C. Icahn has launched the next phase of his campaign for change at Illumina through a lawsuit filed this week in Delaware against former CEO Francis deSouza and board members.

Icahn’s lawsuit alleges that deSouza and board members breached their financial duty by directing Illumina’s three-year effort to acquire cancer blood test developer Grail, as well as the company’s defense of the $7.1 billion deal in the face of opposition from U.S. and European regulators.

The lawsuit comes four months after deSouza resigned as CEO following a proxy challenge from the activist investor that was partly successful. Shareholders of the sequencing giant ousted a deSouza ally as chair and elected to the board one of three allies nominated by Icahn.

The lawsuit was filed Tuesday in Delaware Chancery Court. However, the complaint on which the suit is based is not public and will not be until next week. The court allows complaints to be kept confidential pending potential redactions to be proposed by lawyers for Icahn and the defendants.

Illumina spokesman David McAlpine told GEN today that Illumina was reviewing the complaint.

Illumina investors appeared somewhat fazed by news of Icahn’s lawsuit. Shares of Illumina fell nearly 6% today, from $131.87 to $124.45. Shares of Icahn’s publicly-traded Icahn Enterprises stayed flat, inching up 0.5%, from $17.77 to $17.86.

Icahn disclosed his lawsuit yesterday during a “fireside chat at the 13D Monitor Active-Passive Investor Summit, a conference focused on shareholder activism; corporate governance; environmental, social, and governance (ESG) concerns.

“Throughout my long, long career as an activist, I have never found it necessary, until today, to sue a board of directors in this manner,” Icahn told the conference, according to Bloomberg News. “I continue to believe in the company’s long-term potential and I have full faith in Illumina’s new CEO, and its employees.”

In a statement Wednesday, Icahn said he decided to pursue the lawsuit because of “the board’s unconscionable and egregious actions relating to closing the acquisition of Grail without regulatory approval, thus putting Illumina, a great company, in harm’s way.”

Icahn has voiced public support for deSouza’s successor Jacob Thaysen, PhD, who became Illumina’s CEO effective September 25. While some market watchers questioned Thaysen’s lack of past CEO experience, Icahn posted on X, formerly Twitter:  “I think he will do an excellent job and he has my full support.”

deSouza’s resignation marked the second victory for Icahn in his effort to change the direction of Illumina’s management by reshaping its board. The first came in May, when Illumina shareholders ousted chairman John W. Thompson, who had ties to deSouza, and instead elected to Illumina’s board Andrew J. Teno, a portfolio manager at Icahn’s investment management firm Icahn Capital since October 2020.

Icahn’s case for change

During more than two months of open letters to Illumina shareholders—and in an exclusive interview on GEN’s “Close to the Edge” video series, Icahn and Teno stated their case for change at Illumina. That case rested on three key arguments:

• Illumina drained itself of resources by acquiring Grail and challenging regulators.
• Illumina’s stock price had shrunk to the point where the company had lost some $50 billion in market capitalization—the share price times the number of outstanding shares of a public company.
• Illumina’s board nearly doubled deSouza’s total compensation last year, to almost $27 million, with much of that increase based on stock options.

Speaking with GEN in April, Icahn cited an instance of what he considered a breach of duty by Illumina’s board—its decision to increase its insurance protection to board members before they approved the purchase to what he has termed an unprecedented level. That decision, Icahn concluded in March, reflected board reluctance to support the Grail acquisition absent additional personal liability protection above existing protections.

“This board realized—they must have—how crazy this was. So, they’re supposed to use their business judgment, their duty of loyalty, their duty of care. They didn’t use it,” Icahn said.

“If they were really lax to do a business judgment, and so if that is found, insurers may not cover them. But the board doesn’t seem to care,” Icahn lamented. “It’s a very, very interesting and strange situation. I’ve never seen one as bad as this, and I’ve been around a long time.”

Potential conflicts

Icahn has also raised the question of potential conflicts by deSouza and Illumina’s board between their duty to shareholders and their actions in the Grail acquisition—potential conflicts that he told shareholders on May 8 justified requesting a fairness opinion from an independent financial expert.

Icahn cited as one example deSouza’s years of personal friendship and professional relationships with John W. Thompson, a Grail shareholder who served as Illumina’s board chair from 2021 until he was ousted by shareholders in May.

Another example was Goldman Sachs’ role as Illumina’s financial advisor after having served as a lead underwriter for Grail in an attempted initial public offering (IPO) that it aborted when Illumina agreed to buy the company in 2020, saying the deal would accelerate the commercialization of its Galleri blood detection test, then being planned for launch in 2021.

In his May 8th letter, Icahn also introduced the possibility of a lawsuit: “We believe there are likely many more red flags [emphasis in original] that will be revealed if and when the members of Team Francis are forced to sit for depositions.”

During the GEN interview, Teno contrasted deSouza’s relationships with Thompson and the presence on the board of other deSouza allies with the traditional separation of powers between CEOs and board chairs: “Francis is picking the people he wants to be on the board and pushing them through his committee.”

Asked if the moves constituted too close a link between chairman and CEO, and thus a breach of fiduciary duty, Teno replied: “If you hired your friend of 20 years, you’ve known someone for 20 years, do you think they treat them a little differently than you treat someone you don’t know? I think the answer is absolutely. That’s why they have the separation of powers.”

Alex Philippidis is Senior Business Editor of GEN.

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Reporting in ACS Central Science (“Deep Learning-Predicted Dihydroarteminsinin Rescues Osteoporosis by Maintaining Mesenchymal Stem Cell Stemness through Activating Histone 3 Lys 9 Acetylation,”) the team said their collective studies suggested that “… DHA could be a promising therapeutic agent for treating osteoporosis by maintaining BMMSC stemness.”

Osteoporosis is a degenerative disease that affects the skeletal system and is characterized by the loss of bone density and destruction of the bone microstructure. In healthy people, there is a balance between the osteoblasts that build new bone and osteoclasts that break it down. But when the “demolition crew” becomes overactive, it can result in bone loss and osteoporosis, which typically affects older adults. BMMSCs, which are the precursors of osteoblasts, play a crucial role in osteoporosis, the authors wrote. “BMMSCs maintain a constant flow of functional osteoblasts by committed differentiation and a local population through steady proliferation and refreshment, which together constitute the stemness of BMMSCs under physiological motion.” Maintaining the stemness of BMMSCs is thus “crucial for bone homeostasis and regeneration,” they continued.

However, during osteoporosis, these multipotent cells tend to turn into fat-creating adipocytes and have “diminished regenerative potential,” the authors continued. “Because BMMSCs provide a continuous supply of osteoblasts for bone repair, it is critical to find ways to restore their functions.”

Previously, Zhengwei Xie, PhD, at Peking University, and colleagues, trained a deep learning algorithm to predict cellular responses with drug treatment and eventually accurately predicted the efficacies of new drugs by comparing the changes in gene expression profiles of diseased and drug-treated cells. “This deep learning-based efficacy prediction system (DLEPS) has already been successful in discovering new drugs for a range of diseases, including obesity, hyperuricemia, and NASH.” For their newly reported study, the investigators, joined by Yan Liu, PhD, and Weiran Li, PhD, at Peking University School and Hospital for Stomatology, wanted to use the algorithm to find a new treatment strategy for osteoporosis that focused on BMMSCs.

The team ran the program on a profile of differently expressed genes (DEGs) in newborn and adult mice. One of the top-ranked compounds identified was DHA, a derivative of artemisinin and a key component of malaria treatments. “From the top-ranked candidates, we identified dihydroartemisinin (DHA), a traditional Chinese herbal extract that can promote BMMSC stemness, which is beneficial for establishing healthier bone homeostasis,” the investigators noted.

In vivo studies showed that administering DHA extract for six weeks to an ovariectomized (OVX) mouse model of osteoporosis significantly reduced bone loss in the animals’ femurs and nearly completely preserved bone structure. “In general, oral administration of DHA rescued endogenous mBMMSC stemness in OVX mice, while correcting the biased differentiation inclination from adipogenesis to osteogenesis,” the scientists explained.

“Taken together, the therapeutic effect of MSN-ALN@DHA on osteoporosis was mainly achieved by the protection effect of DHA on the stemness of BMMSCs, while both MSN-ALN and DHA also played a certain role in inhibiting osteoclastic activity,” they wrote. “The use of the bone-targeting carrier, MSN-ALN, has improved the therapeutic efficacy of DHA. Compared to oral administration of DHA, the application of MSN-ALN@DHA ensures treatment efficacy while reducing the frequency of drug administration.”

The researchers say that this work demonstrates that DHA is a promising therapeutic agent for osteoporosis. “These findings also demonstrate the potential of deep learning approaches to accelerate drug development and facilitate precision medicine,” they commented in their paper.

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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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Thermo Fisher Scientific has agreed to acquire Olink Holding for approximately $3.1 billion, the companies said today, in a deal intended to expand the buyer’s presence in proteomics.

Headquartered in Uppsala, Sweden, with offices in Boston, Shanghai, Singapore, and Tokyo, Olink was founded as Olink Proteomics in 2004. The company spun out of the Uppsala University lab of Ulf Landegren, MD, PhD, a professor of molecular medicine whose research focuses on developing and applying advanced molecular tools for precision medicine at levels of nucleic acids and proteins.

Olink offers a platform of proteomics-focused products and services—the best-known of which is its proximity extension assay (PEA) technology, designed to enable high-throughput, multiplex immunoassays of proteins using minimal volumes of serum, plasma, or almost any other type of biological sample.

Based on Landegren’s earlier proximity ligation assay (PLA), PEA has evolved since its first publication in 2011, and its first protein panel two years later, to provide protein analysis for qPCR and next-generation sequencing readout systems. PEA has a library of more than 5,300 validated protein biomarker targets, and citations in more than 1,400 scientific publications.

“The acquisition of Olink underscores the profound impact that proteomics is having as our customers continue to advance life science research and precision medicine,” Thermo Fisher chairman, president, and CEO Marc N. Casper said in a statement. “Olink’s proven and transformative innovation is highly complementary to our leading mass spectrometry and life sciences platforms.”

Olink investors embraced the Thermo Fisher acquisition with a buying surge that sent Olink share prices soaring 66.5% Tuesday, to $24.94 as of 1:52 p.m. ET. Thermo Fisher shares stayed all but flat, dipping 0.61% to $485.56 after peaking at $489.88 at 12:26 p.m. ET, an 0.8% gain.

Reflecting that sense of caution on Thermo Fisher, one analyst—Tycho Peterson of J.P. Morgan—lowered his firm’s 12-month price target on the company’s shares by 6%, from $670 to $630. Peterson, however, maintained J.P. Morgan’s “Overweight” rating on the stock.

However, two other analysts were more positive about the deal.

Brandon Couillard, a senior analyst, equity research with Jefferies covering healthcare / dental, diagnostics and life science tools, observed in a research note that Olink brings to Thermo Fisher a leading player in proteomics, especially on the research side, with PEA differentiated fomr the proteomics platforms of competitors by delivering “high-throughput protein analysis that is highly complementary to TMO’s existing mass spec & life science reagents platforms.

“Over time, we expect it will be able to leverage TMO’s leading qPCR [quantitative polymerase chain reaction] franchise & NGS [next=-generation sequencing] installed base to accelerate meaningful discovery work, removing a prior hurdle (dependent on third-party read-out instruments = don’t control own destiny),” Couillard wrote.

Puneet Souda, a senior research analyst at Leerink Partners covering Life Science Tools and Diagnostics, was more positive about the deal: “TMO, we believe, can scale OLK’s business up significantly and drive penetration into new markets, while strengthening its proteomics franchise of an already strong lineup of Orbitrap mass specs.”

Growing footprint

The Olink acquisition comes some four months after Thermo Fisher grew its footprint of proteomic products by unveiling its Thermo Scientific Orbitrap Astral mass spectrometer at the American Society for Mass Spectrometry, held June 4–8 in Houston.

Orbitrap Astral is designed to help researchers find proteins that had previously evaded detection by offering what the company said was up to two times deeper proteome coverage and up to four times more throughput than current mass spectrometers.

“We’ve already started to deliver the Astral to our customers, and we’re very pleased with the strong bookings performance to date,” Casper told analysts July 26 during the company’s quarterly earnings call, without furnishing details.

In announcing the acquisition, Thermo Fisher said Olink was on track to generate more than $200 million in revenue in 2024. Olink has guided investors to a projection of between $192 million to $200 million in revenues this year—between 37% and 43% annual growth.

Thermo Fisher projected that Olink will grow by a “mid-teens” percentage organically. The deal is expected to lower Thermo’s “adjusted” (excluding certain acquisition-related costs) earnings per share (EPS) by 17 cents in the first full year of ownership—but is also expected to add to EPS by 10 cents a share.

By the fifth year following completion of the acquisition, Thermo Fisher said, it expects to realize approximately $125 million of adjusted operating income through from revenue and cost “synergies.”

“The expected strong long-term business growth and synergy realization profile make the financial returns on the transaction very compelling,” Thermo Fisher added in its announcement.

However, Couillard of Jefferies cautioned that the synergies projection “seems high to us,” since it equates to ~80% of Olink’s estimated 2023 operating expenses of about $150 million, based on a workforce of about 300 commercial and research-and-development (R&D) full-time equivalent employees. “We think >50% of targeted synergies may come from revenues.”

Olink is Thermo Fisher’s second acquisition since July. The first was CorEvitas, a clinical data intelligence company acquired for $912.5 million cash, in a deal completed in August.

Growing net losses, revenue

Olink finished the first six months of this year with a net loss that grew 31% year-over-year to $22.231 million, up from a net loss of $16.992 million in January–June 2022.  That includes a second-quarter net loss of $8.274 million, up about 72% from a $4.822 million net loss in Q2 of last year.

The company’s total revenue grew 13% in the first half of 2023, to $56.893 million from $50.191 million, with Q2 revenue rising 7% year-over-year, to $29.436 million from $27.514 million.

The acquisition deal is expected to be completed by mid-2024, subject to customary closing conditions that inclulde receipt of applicable regulatory approvals, and completion of the tender offer.

In 2019, Summa Equity acquired Olink for an undisclosed price, becoming Olink’s largest shareholder. Summa Equity and additional Olink shareholders and management—which combined hold more than 63% of Olink’s common shares—have entered into support agreements agreeing to tender their shares into a tender offer to be commenced by Thermo Fisher to acquire all outstanding Olink common shares and ADS shares.

The $3.1 billion purchase price includes net cash of approximately $143 million. At $26 a share cash, the purchase price represents $26 per American depositary share (ADS) cash—a 74% premium to Olink’s closing price Monday of $14.98.

Thermo Fisher said it expects to fund the acquisition using cash on hand and debt financing. Upon completion, Olink will become part of Thermo Fisher’s Life Sciences Solutions segment.

“Thermo Fisher’s deep life sciences expertise, global reach and proven operational excellence will enable significant opportunities for both customers and colleagues, while also providing immediate value to our shareholders,” Olink CEO Jon Heimer stated.

Alex Philippidis is Senior Business Editor of GEN.

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“Single-cell sequencing technology is helping us look at the biology of neurons in much more detail than has ever been possible, and this study really demonstrates that capability,” said senior author Binhai Zheng, PhD, professor in the Department of Neurosciences at UC San Diego School of Medicine. “What we’ve discovered here could be just the beginning of a new generation of sophisticated biomarkers based on single-cell data.” Zheng and colleagues reported on their findings in Neuron, in a paper titled “Deep scRNA sequencing reveals a broadly applicable Regeneration Classifier and implicates antioxidant response in corticospinal axon regeneration.” In their paper the team concluded, “Our data demonstrate a universal transcriptomic signature underlying the regenerative potential of vastly different neuronalpopulations and illustrate that deep sequencing of only hundreds of phenotypically identified neurons has the power to advance regenerative biology.”

Neurons are among the slowest cells to regenerate after an injury. While scientists have made progress in understanding neuronal regeneration, it remains unknown why some neurons regenerate and others do not.

For their study the researchers focused on neurons of the corticospinal tract, which is a critical part of the central nervous system that helps control movement. After injury, these neurons are among the least likely to regenerate axons—the long, thin structures that neurons use to communicate with one another. This is why injuries to the brain and spinal cord are so devastating. As the authors noted, “Despite substantial progress in understanding the biology of axon regeneration in the CNS, our ability to promote regeneration of the clinically important corticospinal tract (CST) after spinal cord injury remains limited.”

First author Hugo Kim, PhD, a postdoctoral fellow in the Zheng lab, added, “If you get an injury in your arm or your leg, those nerves can regenerate and it’s often possible to make a full functional recovery, but this isn’t the case for the central nervous system. It’s extremely difficult to recover from most brain and spinal cord injuries because those cells have very limited regenerative capacity. Once they’re gone, they’re gone.”

To carry out their investigations the researchers used Patch-based single-cell RNA sequencing to analyze gene expression in neurons from mice with spinal cord injuries. They encouraged these neurons to regenerate using established molecular techniques, but ultimately, this only worked for a portion of the cells. This experimental setup allowed the researchers to compare sequencing data from regenerating and non-regenerating neurons.

Further, by focusing on a relatively small number of cells—just over 300—the researchers were able to look extremely closely at each individual cell. “Just like how every person is different, every cell has its own unique biology,” said Zheng. “Exploring minute differences between cells can tell us a lot about how those cells work.”

Using a computer algorithm to analyze their sequencing data the researchers identified a unique pattern of gene expression that can predict whether or not an individual neuron will ultimately regenerate after an injury. The pattern also included some genes that had never been previously implicated in neuronal regeneration. “It’s like a molecular fingerprint for regenerating neurons,” commented Zheng.

To validate their findings the researchers tested this molecular fingerprint, which they named the Regeneration Classifier, on 26 published single-cell RNA sequencing datasets. These datasets included neurons from various parts of the nervous system and at different developmental stages.

The team found that with few exceptions, the Regeneration Classifier successfully predicted the regeneration potential of individual neurons and was able to reproduce known trends from previous research, such as a sharp decrease in neuronal regeneration just after birth.  “We found that our Regeneration Classifier can be applied in an unbiased manner to characterize any published scRNA-seq dataset,” the team commented. “This generated a pattern of regeneration classification for various neuronal populations that remarkably reflects prior knowledge on their regenerative potential based on the neuronal type and developmental stage.”

Zheng added, “Validating the results against many sets of data from completely different lines of research tells us that we’ve uncovered something fundamental about the underlying biology of neuronal regeneration,” said Zheng. “We need to do more work to refine our approach, but I think we’ve come across a pattern that could be universal to all regenerating neurons.” In their paper the investigators stated, “It has been extensively shown in the literature that neurons undergo a developmental stage-dependent decline in regenerative abilities. However, our data provide, for the first time to our knowledge, a transcriptomic basis for this phenomenon across vastly different neuronal types.”

A closer evaluation of differentially expressed genes, and gene network analyses, highlighted a gene called NFE2L2 (nuclear-factor-erythroid-derived-2-like 2) also known as NRF2 (nuclear-factor erythroid-2-related factor 2), as a potential regulator of differentially expressed genes in regenerating, compared with non-regenerating CST neurons. NFE2L2 encodes a transcription factor that activates antioxidant genes that are under oxidative stress in response to injury and inflammation. Tests in engineered mice indicated that NFE2L2 acted as a positive regulator of CST regeneration. The team said the findings “… validate our Patch-seq approach in discovering new regeneration regulators.”

Another top candidate PPARGC1A (or PGC-1α), encodes a master regulator of mitochondrial biogenesis, but the role of PGC-1α in CST regeneration has yet to be validated in vivo, the authors noted. Nevertheless, they stated, “… our observation that these two genes (NFE2L2 and PPARGC1A) sit at the top of the regulatory network in regenerating neurons highlights the importance of both antioxidative response and mitochondrial biogenesis.”

While the results in mice are promising, the researchers caution that at present, the Regeneration Classifier is a tool to help neuroscience researchers in the lab rather than a diagnostic test for patients in the clinic. “For preclinical studies, a Regeneration Classifier may serve as a biomarker to predict the likelihood of success for candidate regenerative therapies. In this regard, our approach will likely have broad applicability in studying many other neurological conditions,” the scientists stated.

“There are still a lot of barriers to using single-cell sequencing in clinical contexts, such as high cost, difficulty analyzing large amounts of data and, most importantly, accessibility to tissues of interest,” said Zheng. “For now, we’re interested in exploring how we can use the Regeneration Classifier in preclinical contexts to predict the effectiveness of new regenerative therapies and help move those treatments closer to clinical trials.”

The post Gene Expression Pattern Predicts Which Neurons Will Regenerate after Injury appeared first on GEN - Genetic Engineering and Biotechnology News.

Over the past decade, single-cell biology and spatial biology have revolutionized how researchers understand biological processes. Single cell has made, according to an editorial in Molecular Systems Biology, important contributions to our understanding of cell types, cell states, cell–cell interactions, and tissue architecture—while spatial biology also promises to transform biology and especially pathology by measuring physical tissue structure and molecular characteristics at the same time, as a recent review article in Science has noted.

Playing leading roles in the development of both technologies have been 10x Genomics and its co-founder and CEO, Serge Saxonov, PhD, who discusses his career in genomics and science on GEN’s Close to the Edge.

After discussing how he developed a lifelong interest in genomics and science, Saxonov shares how as founding architect and director of R&D at 23andMe, he defined the initial conception of its product, built many elements of the technology, and drove strategy and execution of R&D functions as the direct-to-consumer genetic testing company scaled.

As VP of applications at QuantaLife, which Bio-Rad acquired in 2011 for $162 million, Saxonov was responsible for building content, driving new applications, and identifying key diagnostics opportunities for the core droplet digital PCR (ddPCR) technology.

In 2012, Serge co-founded 10x Genomics with Ben Hindson and Kevin Ness. As the company’s CEO, Saxonov defined 10x’s vision and strategy, contributed to core inventions, and has led the company since its inception. In 2016, Saxonov was honored as one of Goldman Sachs’ 100 Most Intriguing Entrepreneurs of the Year.

Alex Philippidis is senior business editor of GEN. Jonathan Grinstein, PhD, is senior editor of GEN.

The post Space Race: 10x CEO Serge Saxonov Discusses Single Cell and Spatial Biology on “Close to the Edge” appeared first on GEN - Genetic Engineering and Biotechnology News.

Illumina responded Friday to the European Commission (EC)’s order to divest itself of cancer blood test developer Grail by saying it will comply should it lose its European court appeal of the directive—or lose an appeal it is pursuing of a separate U.S. order to divest.

The EC’s order, issued Thursday, requires Illumina to dissolve or “unwind” its purchase of Grail, now a subsidiary, so that Grail has the same independence from Illumina that it had before the deal was announced in 2020.

The sequencing giant is still fighting the order by appealing the jurisdiction of the EC over Grail to the European Court of Justice (ECJ). Illumina has said in the past it will pursue a jurisdictional appeal even as it works to divest Grail in accordance with the EC.

In a statement, Illumina disclosed that it would have 12 months to divest of Grail, with a three-month extension possible. Illumina also confirmed an earlier EC statement by saying it will be permitted to explore a range of options for carrying out the divestiture, including but not limited to a third-party sale or a capital markets transaction.

Should Illumina choose to divest of Grail via a capital markets transaction, Illumina must capitalize Grail with two-and-a-half years of funding based on the cancer blood test developer’s long-range plan.

“Notably, the terms of the order provide for flexibility in transaction structure, an encouraging outcome from Illumina’s ongoing dialogue with the EC,” Illumina stated.

The order also calls for Illumina to retain a stake in Grail of up to 14.5%—the stake it had before acquiring the company—and reestablish a royalty arrangement it previously had in place with Grail.

Illumina said that with help from financial and legal advisors, it has already begun preparatory work necessary for divesting of Grail “if needed.” The divestiture process will be led by Illumina.

“Most negative” scenario

“For long-term shareholders, we think a quick sale to a competitor may be the most negative divestiture scenario, given weak market sentiment and tax obligations that could cut into the $68 per share of value that we place on Grail,” Morningstar analyst Julie Utterback commented on the firm’s website.

If Illumina is able to spin off Grail to shareholders in a tax-free manner—as Danaher recently did when it spun out Veralto, which has nearly $5 billion in sales, into a public company—Morningstar’s fair value estimate of Grail may remain roughly intact until the spinoff is complete, Utterback continued. She added that the intrinsic value of Grail to Illumina shareholders would remain largely the same minus dilution to help fund Grail’s operations.

“If a spinoff to shareholders is completed, Illumina’s fair value estimate will likely revert to the value of the genomic sequencing business, which we currently estimate at $201 per share or well above recent prices,” Utterback commented. “Positively, with a divestiture, Illumina’s intrinsic value may be easier for the market to recognize without Grail’s ongoing losses overshadowing the results of the legacy business.”

Morningstar’s estimate is just above the $200 12-month price target set for Illumina shares by Stifel. On Thursday, Dan Arias, managing director, life sciences & diagnostics with Stifel, reiterated the firm’s “Buy” rating and $200 price target on Illumina.

Illumina said it is required to continue funding Grail until any divestiture occurs.

“Illumina is committed to resolving all issues regarding Grail in a timely manner, with the objective of achieving the maximum value for shareholders and the best outcome for Grail,” the company added.

Illumina announced its plan to buy Grail in September 2020, saying the deal would accelerate commercialization of the Grail-developed Galleri cancer blood test, then being planned for launch in 2021. According to Illumina, Galleri can detect more than 50 cancers across all stages and has correctly identified the tissue of origin in 93% of positive results, with >99% specificity.

Illumina disclosed the deal as being $8 billion but still had a stake in Grail, reducing its value to $7.1 billion.

Angering regulators

The U.S. Federal Trade Commission (FTC) began challenging Illumina’s purchase of Grail in March 2021. Five months later, Illumina completed its purchase of Grail despite the FTC challenge and the EC’s antitrust review of the deal, angering both regulators.

Illumina is also appealing an FTC Opinion and Order to divest itself of Grail, issued in April. The order contended that an Illumina merger would lessen innovation in the U.S. market for multi-cancer early detection (MCED) tests like those marketed by the cancer blood test developer, since Illumina is the nation’s only provider of DNA sequencing that is a viable option for MCED liquid biopsy tests.

In challenging the FTC order, Illumina has argued that the leadership structure of the FTC violates the U.S. Constitution because FTC commissioners can only be removed for cause in violation of the Constitution’s Article II, which vests executive power in the President. Illumina has also contended that the FTC violated due process by depriving Illumina and Grail of a fair proceeding before an impartial tribunal.

But if it loses a final decision of the U.S. Fifth Circuit Court of Appeals, Illumina acknowledged, it will divest of Grail.

In August upon releasing second-quarter results, Illumina tucked within its Form 10-Q quarterly filing a terse acknowledgment that staffers from the U.S. Securities and Exchange Commission had been “requesting documents and communications primarily related to Illumina’s acquisition of GRAIL and certain statements and disclosures concerning GRAIL, its products and its acquisition, and related to the conduct and compensation of certain members of Illumina and GRAIL management, among other things.”

“Illumina is cooperating with the SEC in this investigation,” the company stated.

Illumina’s execution of its Grail acquisition emerged as a key argument made by activist investor Carl C. Icahn during his partially successful proxy campaign last spring—a campaign that involved several letters to shareholders and an exclusive GEN interview. Icahn asserted that Illumina’s insistence on carrying out the acquisition despite regulator opposition drained the company of resources, an argument that Illumina has rejected.

Illumina said it will answer further questions about the Grail divestiture from analysts when it releases third-quarter 2023 earnings, which is scheduled for November 9.

Alex Philippidis is senior business editor of GEN.

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