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Among a group of cell surface proteins known as sialic-acid-binding immunoglobulin-like lectins (Siglecs), CD33-related Siglecs are found mainly on innate immune cells and are involved in cell signaling. One Siglec, however, appears to have “gone rogue” in humans, according to Ajit and Nissi Varki, a husband-and-wife team at the UC San Diego School of Medicine.

Siglec-XII, encoded by the gene SIGLEC12, no longer binds sialic acid and seems to be involved in abnormal cell signaling in humans, the researchers report. The Varkis argue that the protein plays a role in cancer progression and could help explain why humans have much higher rates of carcinoma—cancers that arise from epithelial cells, where Siglec-XII is abundant—than do other great apes.

Only about 30 percent of humans produce this rogue protein; most people have a mutation that inactivates SIGLEC12. The Varkis and their colleagues found Siglec-XII in about 80 percent of carcinoma samples but in just 35 percent of normal tissues. When they forced production of Siglec-XII in a human prostate cancer cell line, the result was higher expression of cancer progression–related genes than in prostate cancer cells that lacked the protein. And comparing cohorts of cancer patients, the team found that functional SIGLEC12was associated with poor prognosis in late-stage colorectal cancer patients.

“The study proposes very interesting hypotheses,” says Jun Wang, an immunologist at NYU Langone Health who was not involved in the research. But, he says, more evidence is needed to confirm Siglec-XII’s role in cancer progression because artificial overexpression of the protein in prostate cancer cells could differ from how the protein behaves in tumors. He notes that it would also be interesting to examine how Siglec-XII in immune cells contributes to cancer. “The cancer cell is just part of the puzzle. The whole picture is cancer and the immune system.”

Story by: Asher Jones for The Scientist

“As the world grapples with supply challenges and inequitable vaccine access on local and global scales, marginalized groups, particularly refugees, internally displaced persons and stateless persons, face a double burden of access, even within countries that are themselves marginalized on the global stage,” said Monette Zard, MA, Allan Rosenfield Associate Professor of Forced Migration & Health…

… To access the rest of the article please clink on the following link: medicalxpress.com

The ACGT hosted a webinar for the plant phenomics community on the 4^th of March 2021. The webinar was designed as a feedback session for the Wageningen University and Research (WUR) “Drones for Agriculture” online course, as well as to discuss the progress made on formation of the SA Phenomics Society and exploring collaborative funding opportunities.

The “Drones for Agriculture” course was attended by 20 participants (fully funded by the ACGT) associated with the University of Pretoria (UP), the Agricultural Research Council (ARC) and the South African Sugarcane Research Institute (SASRI).  The course was a self-paced, three-week online course facilitated by WUR’s top professors from the ‘Information Technology Group’ and the ‘Laboratory of Geo-Information Science and Remote Sensing Group’. The course was ran through the edX platform. Three participants gave feedback on the course, including Mr Phinda Magagula (UP), Dr Tingmin Yu (ARC) and Ms Natalie Hoffman (SASRI). They gave an overview of the course and also shared their highlights from the course. The participants shared how each institution hopes to implement the drone technology in advancing the plant phenotyping in their institutions. The presentations from the participants can be accessed at the link below.

Dr John Becker from the ACGT chaired the sessions on the SA Phenomics Society formation and exploring collaborative funding opportunities for the community.  It was highlighted that since the first Plant Phenotyping and Precision Agriculture meeting held in 2019, a Charter for the SA Phenomics Society was developed and has been circulated to a number of institutions for approval. More institutions were identified at this meeting and the Charter has been circulated to them.

In the last session of the webinar, the attendees were informed about the High-End Infrastructure grant application that will be submitted to the Department of Science and Innovation at the end of April 2021. This application is a collaborative effort by the ACGT, UP, the ARC and Stellenbosch University, from which national researchers stand to benefit. The community will be kept informed about the grant application progress.

From the discussions it was highlighted the ”Drones for Agriculture” course was useful for the community. The ACGT will thus investigate whether there is enough interest to fund more participants for the course in 2021. The ACGT will also look at identifying other courses that might be beneficial for the community. The ACGT was also tasked with establishing an online discussion forum, which has been completed in the interim. This discussion forum includes participants from UP, ARC, CSIR, SASRI and Stellenbosch University. This discussion forum will be utilized by the community as a communication tool (sharing ideas, seeking assistance, etc.) around any topic within the plant phenotyping field. The community highlighted the need for a large data storage facility. The ACGT volunteered to explore data storage platforms that the community could utilize.

Presentations:

Mr P Magagula – University of Pretoria

Dr T Yu – Agricultural Research Council

Ms N Hoffman – South African Sugarcane Research Institute

Story by: the ACGT

More than 1,200 people with rare diseases have received a diagnosis thanks to the integration of large-scale genomics into the Stockholm region’s healthcare system. This is according to a study from Karolinska Institutet in Sweden that analyzed the result of the first five years of collaboration on whole genome sequencing between Karolinska University Hospital and SciLifeLab. The work, published in Genome Medicine, constitutes a major leap forward in the emerging field of precision medicine.

“We’ve established a way of working where hospital and university collaborate on sequencing each patients’ entire genome in order to find genetic explanations for different diseases,” says the paper’s first author Henrik Stranneheim, researcher at the Department of Molecular Medicine and Surgery, Karolinska Institutet. “This is an example of how precision medicine can be used to make diagnoses and tailor treatments to individual patients.”

Large-scale whole genome sequencing technology, that is the process of determining an individual’s complete set of genetic material, has made rapid advances over the recent decade. Despite this, few clinics worldwide routinely use it to diagnose patients…

Please use the following link to access the rest of the article: ScienceX

Two University of Pretoria (UP) researchers are among nine researchers in South Africa who have received funding grants from the South African Medical Research Council (SAMRC) as part of the Strategic Health Innovation Partnerships (SHIP) programme. The grants are worth approximately R3 million each and are to be used over a three-year period.

Professor Robert Millar and Dr Iman van den Bout, academics and researchers of the Centre for Neuroendocrinology in UP’s Faculty of Health Sciences, have received funding to support their research into cutting-edge solutions for the diagnosis and treatment of prostate cancer and breast cancer respectively.

Professor Tiaan de Jager, Dean of UP’s Faculty of Health Sciences, said he is delighted that two researchers from the Faculty are part of producing such important work. “At the Faculty of Health Sciences, we pride ourselves on using our research to solve today’s pressing issues in the communities we work and live in. Additionally, I am proud to hear that our Centre for Neuroendocrinology has received two grants of about R3 million each which will go into finding innovative and lasting solutions to the current challenges facing the diagnosis and treatment of cancer in SA.”

The announcement was made today (8 Feb) at a virtual ceremony. The MRC SHIP is a partnership between the SAMRC and the Department of Science and Technology that funds and manages innovative projects focused on the development of new drugs, treatments, vaccines, medical devices and prevention strategies. This partnership provides life-saving innovations to the health industry and the South African public through involvement in developing new and improved treatment options

An A-rated scientist with over 450 peer review publications, Prof Millar will continue his lifelong work by using the grant to test a new way to diagnose and stratify prostate cancer among South Africans, using a ‘liquid biopsy’ to improve outcomes.

“In South Africa, the age-standardised prostate mortality rate is one of the highest in the world. There is currently no systematic prostate cancer screening program in South Africa within the state-run healthcare system,” Professor Millar explained. “The standard diagnostic test for prostate cancer in South Africa consists of digital rectal examination and prostate specific antigen (PSA) and sometimes prostate biopsy. These tests are, however, characterised by high false-positive and false-negative values, leading to under- and over-diagnosis and consequent harm to patients, and increased costs to the healthcare system. My aim is to show that by utilising the novel state-of-the-art non-invasive genomic technology quantifying tumour mRNA in blood, PROSTATest and NETest, in South African black men, we can improve diagnosis and treatment selection and reduce costs to the healthcare system. Importantly, these tests have demonstrated the potential to identify new therapies for advanced prostate cancers which are not responsive to the major treatment –  androgen deprivation therapy – thus addressing the SHIP call for a ‘pharmacogenomics approach to failed therapies.’”

For Dr van den Bout this project forms part of work that began 20 years ago. He will use his grant to initiate and develop the first breast cancer organoid biobank, which will be used to develop better prediction tools for South African women’s response to standard chemotherapy regimens offered in the public health system.

“As I keep developing the project, I feel very strongly that this project will establish a resource and knowledge base that will be of immense value to local cancer scientists in their quest to improve breast cancer patient care in our country,” Dr van den Bout said. “It is already known that a significant percentage of African breast cancer patients that are treated with the standard chemotherapies available in the public health system fail to respond well. In this study we seek to develop a way to test living cells from the tumours of these patients for their reaction to the therapies in the lab, and to see if this will predict how the patient will respond to the treatment. Eventually, we hope that our research will lead to clinical tools with which we can assess each incoming breast cancer patient to determine what therapies will be most effective for them.”

Professor Tawana Kupe, UP Vice-Chancellor and Principal, said the two researchers embody UP’s vision of being the leading research-intensive university on the African continent. “Cancer in South Africa and on the African continent remains one of the most devastating diseases. I am proud that two of our researchers are leading the quest to find lasting and more effective solutions in the diagnosis and treatment of breast cancer and prostate cancer. It proves that at UP, we are committed to producing research that is relevant, innovative and that will improve the lives of ordinary people across Africa and the world.”

Story by: Masego Panyane, for the University of Pretoria 

In February 2021, the African Centre for Gene Technologies (ACGT) and INSERM Toulouse (France) organized a virtual Lipidomics workshop. Lipidomics is a newly emerged discipline that studies cellular lipids on a large scale, based on analytical chemistry principles and technological tools, particularly mass spectrometry.

Following from rapid advances in genomics, transcriptomics and proteomics, Lipidomics similarly seeks to elucidate the role of fats and lipids, especially in the context of a range of human diseases, at a high coverage and throughput rate. Due to the range of fatty acid length, conjugation and saturation status, it has been challenging to study all lipids in a single experiment. The event outlined different approaches to analysing different classes of lipids in targeted and untargeted approaches.

The workshop consisted of online lectures, a seminar and interactive discussions. The event was intended to ignite a deeper interest in Lipidomics and add more interesting research avenues to those who are already working on Lipidomics and related disciplines. The workshop covered topics that included: Introduction to Lipidomics, how Lipidomics converges with and complements other “-omics” technologies, analytical flow in global and targeted quantitative Lipidomics, as well as applications of Lipidomics. The latter had a specific focus on inflammation; as highlighted in a research case study, with high development potential, in treating inflammation.

The seminar highlighted that lipids play many essential roles in cellular functions, including cellular barriers, membrane matrices, signalling, and energy depots. As a result, the ACGT is reassured that Lipidomics is a fast-growing field not only in the world, but also in South Africa. The participants of the workshop were from various research institutions spread across South Africa and also included a few delegates from the rest of Africa. Potential international and local collaborative efforts were also evaluated. Plans are being put into place to have similar workshops in future and complementary Lipidomics-related capacity building efforts.

The ACGT would like to thank the INSERM Toulouse team of Dr Justine Bertrand-Michel, Dr Pauline Le Faouder and Dr Cénac Nicolas for facilitating this event. The ACGT and the 35 participants of the workshop thank the delegates for generously donating their time in preparing and in facilitating the talks.

For further information about developments in this field, contact Mr Molati Nonyane, ACGT Liaison Scientist, and visit the MSA website.

For decades, researchers have viewed synonymous mutations as inconsequential quirks of the genome. Due to the way the genetic code is set up—where multiple three-base-pair codons can encode the same amino acid—mutations can arise that don’t change a protein’s amino acid sequence. Scientists have largely dismissed these anomalies as harmless oddities.

But like other historically underappreciated aspects of the genome, scientists are realizing that many “silent” mutations might not be so silent after all. Research suggests they’re often subject to selective pressure and could play a role in cancer, autism, and schizophrenia.

A study published online last week (February 12) in iScience adds to the mounting evidence that synonymous variants can have consequences. The authors describe a synonymous mutation in the gene BAP1 that was associated with a worse-than-expected prognosis in a kidney cancer patient. Their subsequent experiments suggest that the mutation has this effect by disrupting cells’ RNA splicing process, by which freshly transcribed messenger RNA (mRNA) is converted into digestible fragments ready to be translated into protein. Because the cancer patient lacked a second healthy copy of the gene, the silent mutation may have resulted in a complete loss of function of BAP1.

“To my knowledge, tying a specific synonymous mutation [to] a clinical outcome [in cancer] is a novelty,” remarks Fran Supek, a cancer geneticist at the Institute for Research and Biomedicine in Barcelona who wasn’t involved in the study. “I’m always glad to see that researchers are thinking a bit outside the box . . . and looking at understudied classes of genetic changes that may help us solve a certain number of patients with genetic diseases or with cancer.”

While combing through The Cancer Genome Atlas(TCGA)—a public database of genomic samples from more than 11,000 patients around the world—Samuel Peña-Llopis and his colleagues discovered an entry from a patient with an unusual course of disease. The 73-year-old Caucasian woman had clear-cell renal cell carcinoma, the most common form of kidney cancer, with a mutation in PBRM1, a gene involved in chromatin remodeling.

Although PBRM1 mutations are normally associated with relatively good clinical outcomes in such patients—with a median survival of 117 months, according to TCGA data—the patient died only 56 months after diagnosis, says Peña-Llopis, a cancer geneticist specializing in kidney cancer and uveal melanoma with the German Cancer Consortium at the University Hospital Essen in Germany.

The team noticed that she also had a synonymous mutation in BAP1, which encodes an enzyme involved in regulating the degradation of proteins. The mutation changes a thymine to a guanine, which still results in the same amino acid, glycine, encoded both by GGT and GGG. Curiously, the patient also had very low abundance of BAP1 protein, in fact, it was on par with renal cell carcinoma patients who have nonsynonymous loss-of-function mutations in BAP1, which tend to be linked to severe outcomes. The team suspected that the silent BAP1 mutation might somehow affect the gene’s transformation into protein.

The path by which DNA turns into protein is a long and winding one. First, double-stranded DNA is teased apart and the strands are individually transcribed into single strings of pre-mRNA, a rough draft of the instructions needed to turn it into protein. Then it must be spliced, whereby various proteins bind to different sites across the pre-mRNA and cut out noncoding nucleotide sequences—introns—and fuse the coding parts—exons—together. Only then is the mRNA ready for other cellular machinists to translate it into protein.

One way by which synonymous mutations can perturb this process, previous research suggested, is by altering the specific binding sites of RNA splicing proteins, which are required to properly integrate different exons. If they can’t bind—or the altered codon causes the wrong proteins to bind—they might end up skipping over important bits of genetic code—called “exon skipping”—which can result in a dysfunctional protein. Because the synonymous mutation located in BAP1’s exon 11 was close to a splice site critical for joining this exon to the next, “we thought that maybe the splicing system was affected,” Peña-Llopis recalls.

To find out, the team conducted a series of experiments with genetic constructs containing BAP1’s exon 11, into which they had inserted fluorescent proteins. They expressed the construct in a human cancer cell line. Based on the color that emerged under a microscope, they could tell if the exon was being integrated or skipped. They observed nearly 100 percent skipping when the construct contained the synonymous mutation, significantly more than when using the construct based on the unmutated version of BAP1.

If exon 11 is skipped, that likely causes a loss of BAP1 for that gene copy, Peña-Llopis explains. Because that exon has 185 base pairs—which is not a multiple of three—losing it will cause a shift of the three-base-pair reading frame that enzymes use for protein translation. That, in turn, would cause a codon further down the line to be misread as a stop codon, signaling the protein translation machinery to terminate. mRNA transcripts containing premature stop codons are typically degraded by the cell. In this particular patient, this likely led to a complete loss of BAP1 because she had lost her second copy due to a deletion of a small chromosome segment, which is common in that cancer subtype.

Synonymous mutations in kidney cancer patients

Back in the TCGA database, which includes nearly 500 clear-cell renal cell carcinoma patients, the team found another eight patients who had synonymous mutations in BAP1 exons near sites important for splicing, two of which were located inside the sites necessary for gluing exons 10 and 11 together. Considering that there are 32 splicing sites across the 17 exons that make up BAP1, finding two out of eight is a significant number, Peña-Llopis says, “suggesting that this is a hotspot for inactivation of BAP1.” However, the two patients had very different clinical outcomes, suggesting that other genetic alterations also play a role in the prognosis.

“I think this is an important finding,” remarks James Brugarolas, a physician-scientist and oncologist who directs the kidney cancer program at the University of Texas Medical Center. BAP1 is mutated in around 10–15 percent of all clear-cell renal cell carcinomas, mostly through nonsynonymous alterations. “The study provides relatively convincing evidence that . . . mutations that do not affect the protein sequence in BAP1could be pathogenic driver mutations, leading to the inactivation of the tumor suppressor protein,” adds Brugarolas, who has collaborated with Peña-Llopis in the past but wasn’t involved in the new research.

Brugarolas says that the data would have been even more convincing had there been more RNA sequencing and immunohistochemistry data from the patients’ tumor available, which could yield more definitive evidence of exon skipping. And, of course, such findings can always be better supported by larger sample sizes and replication in independent datasets, Supek adds. That said, “I think the in vitro experiments that they [did] suggest that the mutation they’ve identified has the potential to alter splicing. And clearly, exon 11 escaping would result in a nonfunctional protein due to a premature stop codon. One could make a very convincing argument for that,” Brugarolas says.

The clinical relevance of the finding is not yet apparent. Targeting loss-of-function mutations in tumor suppressor genes such as BAP1 has lagged behind targeting gain-of-function mutations, for instance, in enzymes that control cell growth and function, Brugarolas says; it’s generally easier to inhibit misfit proteins than to correct something that has been already abolished by mutation. It’s also unclear if BAP1 mutations could be used as biomarkers to predict patients’ responsiveness to therapies. “How mutations in BAP1[should] be leveraged for therapy remains unknown,” Brugarolas adds.

On the whole, the findings indicate that researchers should be paying more attention to synonymous mutations, notes Thomas Mitchell, a clinician-scientist focusing on kidney cancer at the Wellcome Sanger Institute in the UK. “[There is] little awareness of synonymous mutations and their role in cancer. In general, they are ignored in sequencing studies as it has been felt that they are very unlikely to be drivers.”

Nevertheless, larger studies in the past have predicted that synonymous mutations could have pathogenic effects. In 2014, Supek and colleagues estimated that around 6–8 percent of pathogenic single-nucleotide mutations in cancer genes are synonymous mutations. Taken together with other studies, research seems to converge on an estimate of 5 percent of all driver mutations being synonymous mutations—a “non-negligible amount” that may be quite significant for some individual cancer patients, Supek says. Exon skipping is one mechanism by which such mutations could have deleterious effects, “but it’s probably going to be different for every synonymous mutation.”

Understanding silent mutations, along with other overlooked genetic alterations, could help unlock the underlying causes of disease for many individual patients for whom mutations don’t clearly fall into the nonsynonymous bucket, and open the door to finding treatments. “The human genome is a very complex thing, and there are many ways in which it can break and result in disease,” Supek says.

J. Niersch et al., “A BAP1 synonymous mutation results in exon skipping, loss of function and worse patient prognosis,” iScience, doi:10.1016/j.isci.2021.102173.

Story by: Kararina Zimmer, for The Scientist

Researchers in the UK have identified a new SARS-CoV-2 variant with mutations that could allow it to evade immunity-conferring neutralizing antibodies.

Known as B.1.525, the variant was first detected in the UK and Nigeria in December. It’s since been found in 11 other countries, including Denmark, the US, and Australia.

B.1.525 sports a handful of mutations, including one on the spike protein called E484K. This mutation is also found in variants that emerged in South Africa and Brazil and seems to help the virus evade antibodies, The Guardian reports. In addition, B.1.525 has similarities to the highly transmissible B.1.1.7 variant that also emerged in the UK.

“We don’t yet know how well this [new] variant will spread, but if it is successful it can be presumed that immunity from any vaccine or previous infection will be blunted,” Simon Clarke, an associate professor of cellular microbiology at the University of Reading in the UK, tells The Guardian.

Moderna and Pfizer are already working to develop booster shots to give vaccines an edge against the slew of new virus variants. The good news is that because many of the variants share the same mutations, new vaccine versions are likely to confer immunity to multiple versions, according to The Guardian. “This [E484K] change seems to be the key change at the moment to allow escape, so that’s the one you put into the tweaked vaccine,” Jonathan Stoye, a group leader at the Francis Crick Institute, tells the news outlet.

Story by: Asher Jones, for The Scientist

The University of Pretoria (UP) has discovered new potent chemical compounds that show potential as candidates for both the treatment and elimination of malaria.

Professor Lyn-Marie Birkholtz, Professor in Biochemistry and South African Research Chair in Sustainable Malaria Control (part of the South African Research Chair Initiative, SARChI), was part of an international team that published this discovery in the journal Nature Communications on 11 January. “The breakthrough involves the identification of unique compounds that are able to kill several stages of the malaria-causing parasite and can block the transmission of the parasite between humans and mosquitoes,” she explained.

The deadly human malaria parasite Plasmodium falciparum occurs in South Africa. These parasites are transmitted to humans by female Anopheles mosquitoes. The only means of killing the parasite itself is to use chemical drugs, but new antimalarial drugs are urgently needed to address the growing concern of antimalarial drug resistance.

Prof Birkholtz describes the parasite as a “shape shifter” since it can take on multiple forms while in humans. Some of the forms cause disease and others allow the parasite to be transmitted back to mosquitoes to continue the life cycle. Prof Birkholtz states: “To eliminate malaria, it is essential that we have the necessary tools to kill all these different forms of the parasite. We can then cure patients of the disease but, importantly, also block the malaria transmission cycle. This is the only way to achieve malaria elimination.

South Africa is leading regional malaria elimination efforts as part of four frontline countries in southern Africa including Namibia, Botswana and Eswatini.

In an innovative strategy, the team looked for new chemical compounds that can do exactly this, but that are completely new so that the parasite does not have resistance against them. The team runs a unique research platform on the African continent, in which all of these stages of the malaria parasite can be produced in the lab and be used to test chemical compounds. The team discovered compounds that kill the disease-causing form and compounds that blocked the parasite from infecting mosquitoes in the lab.

Two potent compounds target processes essential to the parasite’s survival: one is a clinical candidate against tuberculosis and blocks cell membrane synthesis and another is an anti-cancer candidate that targets epigenetic mechanisms (mechanisms that control cell fate beyond the genome). “This is the first time that these compounds were shown to have activity against malaria parasites and since they are not toxic to humans, they show the potential to be developed as antimalarials for both the treatment and elimination of the disease,” said Prof Birkholtz.

The discovery was made possible by the team’s use of an open-source chemical compound set called the Pandemic Response Box, developed by the Switzerland-based Medicines for Malaria Venture (MMV) and the Drugs for Neglected Diseases Initiative (DNDi). This compound box contains compounds that can be used for drug repurposing/repositioning, a process where drugs that have activity against a specific disease (e.g. cancer) can be reused for another disease (e.g. malaria). Dr James Duffy, MMV Project Director, describes the discovery “as an important breakthrough that emphasises the potential to use existing drugs as inspiration for drug discovery projects targeting different diseases. Never before has this been more important than in light of current outbreaks, where the rapid response to discover new chemicals able to kill infectious organisms is essential.”

Prof Birkholtz directs the parasite cluster of the UP Institute for Sustainable Malaria Control (ISMC), a multidisciplinary institute with a focus on integrated innovations towards malaria elimination in South Africa. Professor Tiaan de Jager, Director of the ISMC and Dean of Health Sciences at UP, said: “A discovery of this kind attests to the leading expertise in antimalarial drug discovery at UP, and in South Africa, addressing African-centred societal challenges. This work also shows the commitment of scientists at UP to contribute to the United Nation’s Sustainable Development Goal for Good Health and Wellbeing.”

Prof Birkholtz’s team led the transmission-blocking drug discovery effort as partner in the South African Malaria Drug Discovery Consortium (SAMDD) that includes two other South African Research Chairs, Professor Kelly Chibale (Chair in Drug Discovery at the Drug Discovery and Development Centre, H3D, at the University of Cape Town) and Professor Lizette Koekemoer (Chair in Medical Entomology at the WITS Institute for Research on Malaria at the University of the Witwatersrand) as well as scientists from the Council for Scientific and Industrial Research and international partners from the USA and Spain. The work has benefitted from sustained funding from the MMV and the Medical Research Council’s Strategic Health Innovation Programme (SHIP) and affirms that investments in health innovations places South Africa at the forefront of discovery.

Story by: The University of Pretoria 

Ever since the virus now known as SARS-CoV-2 was first identified and sequenced by researchers in China a year ago, a tidal wave of research on the pathogen and its associated disease, COVID-19, has swamped the scientific literature. Indeed, an analysis posted as a preprint last month found that more than 84,000 papers related to COVID-19 were published in the first 11 months of 2020.

Even given that output and the recent rollout of vaccines against the disease, researchers who study the virus aren’t ready to put it on ice and move on to other problems. Here are some of the key areas where we’re likely to see advances in understanding this year.

Where did it come from?

Teasing out SARS-CoV-2’s origin is important, says disease ecologist Jonathan Epstein of EcoHealth Alliance, because knowing how the virus got into humans could yield clues about how to avoid future spillovers. The SARS outbreaks of 2003 and 2004 spurred research (of which Epstein was a part) that identified horseshoe bats as a reservoir for this family of coronaviruses, he notes, but it’s still not known exactly how either virus made it from bats to people. Understanding whether SARS-CoV-2 jumped directly from bats into people, or whether it first infected a wild or domesticated intermediary species, would help in pinpointing particular human activities that could be putting us at risk of future zoonotic events, he says.

The World Health Organization (WHO) has convenened a team to investigate the virus’s origins that began traveling to China early this month, WHO head Tedros Adhanom Ghebreyesus said in a January 5 briefing. According to WHO spokesperson Tarik Jašarević, the team’s plans include reviewing hospital records from late 2019 to identify illnesses that might have been COVID-19, interviewing people who were the first known cases, and finding out what animals were traded at a market in Wuhan associated with some early infections, and possibly other local markets around the time of the outbreak, and where those animals came from. Jašarević did not say when the team’s findings might be made available.

In addition to prevention, another benefit of knowing the animal origins of coronaviruses is the opportunity to design medicines against them in advance, namely, “broadly neutralizing antibodies that can hit not just SARS-2, but other related coronaviruses that we know are in animal reservoirs,” says virologist Kartik Chandran of Albert Einstein College of Medicine in New York. That’s a long-term goal of his current work on identifying effective antibodies that can be used as a COVID-19 drug. And, he says, it will also be important to figure out how to develop vaccines that confer protection against a broad swath of such coronaviruses. “From a research standpoint, in the next few years, that’s going to be a major challenge.”

More treatment options

Even with effective vaccines, humanity is likely stuck with SARS-CoV-2, much like the cold-causing coronaviruses and influenza, Chandran says. That means there’s an ongoing need for effective treatments for the disease. One issue with current monoclonal antibody treatments, he notes, is that they require large volumes to be administered by IV, creating logistical challenges. “If we can get these things to be potent enough, we ideally would be able to give them by intramuscular injection, rather than giving them IV—that would make a huge difference,” he says. “But that’s going to require a jump in potency that’s quite significant.”

So far, one standalone monoclonal antibody, bamlanivimab, and a combination of two, casirivimab and imdevimab, have received emergency use authorization from the US Food and Drug Administration (FDA). Both treatments were tested in clinical trials on people with mild or moderate disease, and the studies found that those who received them had about one-third the risk of visiting the ER or being hospitalized in the following four weeks compared with patients who got a placebo. Other currently available treatments include the antiviral remdesivir and the steroid dexamethasone, each of which are used for some hospitalized patients, and convalescent plasma, which, according to a small trial published this week, halved the risk of severe respiratory illness when given within three days of the onset of symptoms.

“We were encouraged to see the quick pace of development of the monoclonal antibodies,” says Esther Krofah, the executive director of the FasterCures center at the nonprofit Milken Institute. “But I think there’s still a lot more to be done, particularly in an outpatient setting.” In particular, a small-molecule drug that could be taken by patients at home to reduce their chances of hospitalization would alleviate some of the pressure on the healthcare system. One such drug she’s keeping an eye on, camostat mesilate, is a protease inhibitor currently being tested in multiple clinical trials.

FasterCures is tracking more than 300 prospective vaccines and treatments for COVID-19 that are in various stages of development. Krofah says she expects many current clinical trials not to yield conclusive results due to poor design or problems recruiting enough patients. One promising tack, she says, are the so-called master protocol studies that compare different treatments both with each other and with a placebo.

A series of such trials sponsored by the National Institutes of Health, for example, several of which are expected to be completed later this year, are testing immune modulators, monoclonal antibodies, and blood thinners in groups of COVID-19 patients. In other trials, some repurposed antibiotics and an antifungal have also shown promise and could make it to the clinic this year, says Yasmeen Long, also of FasterCures.

Variant surveillance

As SARS-CoV-2 continues to mutate, researchers will need to determine whether available vaccines are effective against newer variants, Chandran says, such as the B.1.1.7 and 501.V2 variants that have drawn much attention in recent weeks. Akiko Iwasaki, an immunologist at Yale University, says that while current variants are “likely going to be covered by the existing vaccines, in the future, there may be new variants that can emerge that would evade the current vaccine”—meaning surveillance of viral variants should be a priority.

To date, the US has sequenced 58,560 SARS-CoV-2 samples, compared to the UK’s 209,038, The New York Times reports, but a Centers for Disease Control and Prevention official tells CNN that the agency and its partners are working to double the number of viral sequences they post publicly each week to about 6,500.

The long haul

One of Iwasaki’s current projects is profiling the immune responses of people whose COVID-19 symptoms have lasted for months, a phenomenon known as long COVID. “Right now, there are thousands of people suffering from long COVID,” she says. “But there’s very little insight as to how the disease is caused and prolonged for so many people.”

Understanding the mechanism of the disease could point the way to ways of treating it, she says, and might also shed light on other cases of chronic disease associated with an initial viral infection. In particular, after recently finding that hospitalized COVID-19 patients harbor distinct antibodies against their own proteins, known as autoantibodies, she and her colleagues have begun investigating whether such autoantibodies are at play in long COVID.

Story by Shawna Williams, for The Scientist