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More variants will undoubtedly emerge over time, and it is unclear how much these variants will complicate, or even set back, efforts to bring the pandemic to an end. Ongoing genomic sequencing is key in identifying the emergence of vaccine escape variants, Moi said. This makes it all the more troubling that most nations have failed to even come close to the levels of genome sequencing that may be needed.

The state of the genomic surveillance situation is grimmest in 38 countries with reported COVID-19 infections but no sequencing data shared with Gisaid. These make up some of the poorest countries in the world, such as Chad and Burundi. The African continent, as of June 27, has reported more than 5.3 million infections (3.9 million of these are confirmed), but its countries have sequenced and released only about 22,700 genomes, or at best only 0.6% of its cases. More than 40% of those genome sequences (about 9,600) come from just one country, South Africa.

The consequences of the paucity of data on Africa could be serious for people everywhere. Africa, given its human population variation, is a candidate to becoming the source of ever more pathogenic and refractory strains, said Muntasar Ibrahim, a Sudanese geneticist and professor of molecular biology at the University of Khartoum, where he leads its Institute of Endemic Diseases.

Shortfalls in sequencing cannot be blamed simply on a lack of money. (Sequencing costs about $120 per SARS-CoV-2 genome, but the costs can be significantly lowered by sequencing the genomes in large batches, according to Haussler.) Some of the poorest countries have sequenced more of their cases than some of the richest countries, so wealth cannot be the only determining factor. Gambia, for instance, at 7.8%, has sequenced more than Germany (3.6%), a country with 60 times its gross domestic product per capita.

Nor do low rates merely reflect how hard countries have been hit by the pandemic. About 10% of the U.S. population has had COVID-19, resulting in a low sequencing rate (1.7%) even though the U.S. has sequenced the most SARS-CoV-2 genomes. But the U.K., where about 7% of the population has had the disease, has sequenced more than 10% of its caseload: It has only the 13th-highest rate of sequencing in the world, but it has sequenced more virus genomes than all the countries ahead of it put together.

What really seems to have determined the genome-sequencing performance of countries during the pandemic is a combination of their strategic choices and biomedical infrastructure.

Tom Maniatis, chief executive officer of the New York Genome Center (NYGC), noted that COVID-19 surveillance in the U.S. has been compromised by a systemic lack of connections between facilities that have samples of the virus hospitals, public health laboratories and commercial testing facilities and facilities with the capacity to sequence them. Though the situation has improved, there have been persistent logistical challenges, he said.

Maniatis and Soren Germer, who leads the sequencing and analytics teams at NYGC, said that obtaining samples had been the biggest challenge in the U.S. During the early days of the pandemic when New York was particularly hard hit, even the most research-focused hospitals often did not have the resources to collect samples for research, they explained by email. We have heard stories of truly heroic efforts to save some of these samples for research and surveillance, but the severely strained hospitals had to prioritize treating patients and protecting staff. Maniatis and Germer also pointed to a lack of coordinated funding in the U.S., which has been uneven at the state and local level and has only recently begun at the federal level.

Rolf Apweiler, director of the European Bioinformatics Institute, says that the nations depositing SARS-CoV-2 sequences into the dedicated genome data platform that his organization operates also vary substantially in their ambitions. While some countries aim low or have no genomic surveillance of SARS-CoV-2, he said, countries like Denmark, Iceland, Australia and the U.K. aim to sequence between 10% of all positive samples in times of high infection rates and all positive samples technically feasible in times of low infection rates.

The genome sequencing effort may already be bearing fruit for some of the countries engaging in it most vigorously. COG-UK is a consortium of genomic experts working to track, trace and control the SARS-CoV-2 virus in the U.K. It formed when the countrys scientists took steps early in the pandemic to ensure genomic sequencing at scale, aided by 20 million from the government. Within weeks of its formation in March 2020, the consortium had made the first sampled genomes publicly available; it has now sequenced more than 450,000 virus genomes.

OGrady credits that work with helping to contain the pandemic in the U.K. Genome sequencing identified the B.1.1.7 variant, providing us with an answer as to why case numbers were increasing dramatically towards the end of 2020 and enabling us to implement successful control measures, he said. When other variants were discovered in South Africa and elsewhere, U.K. authorities increased the testing and contract tracing efforts and curtailed the spread of the variants into the country.

Many countries are now working to scale up their sequencing programs. In February, the CDC pledged $200 million as a down payment for genome surveillance. In April, the Biden administration dedicated $1.7 billion to boosting sequencing efforts and fighting variants of SARS-CoV-2. The U.S. is now investing heavily in sequencing with the realization that the gains weve made are fragile and could be upended by viral variants, OConnor said.

In January, the Indian government set up the Indian SARS-CoV-2 Genomics Consortium to expedite the gene sequencing effort through a growing network of institutions. The nationally coordinated genome-sequencing program has sequenced more than 15,000 genomes in about three months, said Anurag Agrawal, a senior scientist with the consortium and director of the CSIR-Institute of Genomics and Integrative Biology in New Delhi, one of the participating institutions. I expect the numbers to keep getting better, he said.

The situation is improving in Africa, too. Segun Fatumo, an assistant professor of genetic epidemiology and bioinformatics at the Medical Research Council/Uganda Virus Research Institute, said that African governments urgently need to provide funding for relevant research and infrastructure. But he also noted that Africa has been moderately successful in the fight against the coronavirus, and genome sequencing has greatly contributed to this.

The WHO has established a network of COVID-19 genomic sequencing laboratories across Africa in 18 countries, he said. Africa is central to human origin and disease susceptibility, so large-scale genomic study in populations of African descent might yield potential therapeutic strategies.

Apweiler feels that a pandemic can be successfully managed only if it is tackled at a global level with as much coordination and collaboration as possible. A problematic new lineage of SARS-CoV-2 in one country may become a worldwide problem very quickly, he said. Our response to the pandemic will be globally only as strong as the weakest part of the global efforts.

Moi agrees about the importance of sequencing, but also suggests that it will always be necessary to balance that effort against other local priorities to ensure the best public health impact. Particularly during large outbreaks, sequencing large numbers of virus [genomes] may not be practical and could increase the burdens on laboratories and medical facilities that are already under pressure, she said. But she is also confident that with optimal sequencing strategies in place, powerful insights can still be achieved with well-planned sampling and testing.

Had the pandemic happened even five years ago, it would have been a lot more difficult to implement genomic surveillance programs at scale, OConnor said. The technologies to democratize sequencing and make it available to small laboratories and public health authorities simply werent available.

The infrastructure and technology developed to map the virus could also be beneficial beyond COVID-19. Our next hope is that the detailed observation of viral evolution during the pandemic and the research will help with the more rapid development of targeted therapeutics in future pandemics, Maniatis said.

To him, the real question is whether the informational networks and infrastructure will enable viral surveillance to become routine, so that the discovery of the next potential pandemic virus can be a normal part of the public health system. The WHO has called the integration of genome sequencing into the regular practices of the global health community a must in preparations for future threats.

Haussler agreed that building global pathogen sequencing and genome sharing capability could help prevent future viral outbreaks. It is one of the most important investments the world can make at this point, he said. It is likely to save many lives and many trillions of dollars in the long run.

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A Lack of COVID-19 Genomes Could Prolong the Pandemic Quanta Magazine - Quanta Magazine

Drugs that slow tumor growth by targeting genetic abnormalities in the cancer itself are now well established in oncology. But what if doctors could treat cancer by altering gene activity throughout the body, tricking it into fighting off the disease?

A handful of startups and academics are working towardthat goal. Its not gene therapy in the traditional sense, because theyre not removing or replacing disease-causing genes. Rather, theyre using novel drugs to turn the expression of certain genes up or down to achieve an anti-cancer effect.

Were unlocking new biological pathways so we can go after undruggable targets and treat diseases in very new ways, said Robert Habib, chief executive officer of London-based MiNA Therapeutics, in an interview. MiNA is developing a pipeline of small activating RNAs (saRNAs), which are short, double-stranded oligonucleotides designed to enter cells and boost the activity of target genes to achieve a therapeutic effect.

In September, MiNA raised about $30 million to advance its lead asset, MTL-CEBPA, into a phase 2 trial. The saRNA drug is designed to target the gene CEBPA, which encodes a transcription factor thats key to the bodys production of cancer-fighting myeloid cells. These cells can be depleted in the tumor microenvironment, contributing to drug resistance in cancer.

MTL-CEBPA enters the cell nucleus and uses RNA activation to boost levels of the CEBPA protein. MiNAs drug is in testing alongside Bayers Nexavar, initially in liver cancer, though Habib and his colleagues believe its unique mechanism of action could prove useful across a range of solid tumors.

Myeloid cells are a problem in liver cancer but also in many other solid tumors, he said.

MiNA is now planning a second clinical trialin combination with Mercks immuno-oncology blockbuster Keytruda in a broader set of solid tumors, Habib said.

RELATED: MiNA raises $30M to take small activating RNA into phase 2

A related technology called small interfering RNAs (siRNAs) has long been of interest for its potential to shut down cancer-promoting genes, but translating it into therapies has been challenging. It has been hindered by tissue bio-accumulationmaking sure the delivery system is safe and provides a wide enough therapeutic window in tissues beyond the liver, said Anna Perdrix Rosell, Ph.D., co-founder and managing director of London-based Sixfold Biosciences, in an interview.

Sixfold is working on a siRNA technology called Mergo, which it aims to prove can deliver siRNAs to cancer cells within specific organs while leaving healthy tissues alone. The companys preclinical testing issupported by an Innovate UK Smart Grant, and the companyis now working to define its lead cancer targets, with the goal of moving into clinical trials in 2022, Rosell said.

Gene-silencing specialistSirnaomicsis working on several RNA-interfering drugs to treat solid tumors. Its lead asset, STP705, uses a polypeptide nanoparticle to deliver two siRNAs targeting the genes TGFB1 and COX-2.

Suppressing those genes inhibits cancer-associated fibroblasts, which are cells in the tumor microenvironment that promote tumor growth, the Gaithersburg, Maryland, company has set out to show. It is in early clinical trials in solid liver tumors, squamous cell carcinoma and basal cell carcinoma.

Another gene-directed approach involves injecting DNA into tumors with the goal of making them more responsive to immunotherapyor turning them from cold tumors to hot ones. One company working on this technology is Pennington, New Jersey-based OncoSec Immunotherapies. Its lead technology, called tavokinogene telseplasmid (TAVO), uses electrical pulses to temporarily open cancer cell membranes, after which DNA is injected into them.

The DNA makes IL-12, a naturally occurring, immune-stimulating protein that the companys scientists believe could help overcome resistance to checkpoint inhibitors like Keytruda, a PD-1 blocker. Its a common problem in cancer care: An estimated 60% to 80% of melanoma patients, for example, do not respond to PD-1 blockade. And IL-12 cant be given systemically because it causes toxic side effects.

OncoSecs DNA-delivery system is designed to prompt the body to make more of its own IL-12. The DNA essentially co-opts the cells function to cause it to make IL-12, explained Daniel OConnor, CEO off OncoSec, in an interview.

OncoSec has partnered with Merck to test TAVO in combination with Keytruda in advanced melanoma and triple-negative breast cancer. TAVO is given every six weeks as an injection into tumors, though not every tumor has to be medicated, OConnor said. We see shrinkage in the tumors that are treated, but also in those that are untreated, he said. In April, OncoSec presented interim data from the melanoma trial, reporting an overall response rate of 30%, with some complete responses and no serious side effects.

RELATED: Omega grabs $126M to bring 'genome-tuning' cancer treatment into the clinic

Investors continue to show enthusiasm for the idea of manipulating gene activity to achieve an anti-cancer response. One recent beneficiary of their largesse was Omega Therapeutics, a Cambridge, Massachusetts-based company that raised $126 million in March to advance its genome-tuning drugs, including its lead treatment for liver cancer, OTX-2002.

Omega refers to the drug as an epigenetic controller, because its designed to control the expression of the cancer-promoting gene C-MYC. The companys technology tunes gene expression up or down without permanently changing DNA, and it does so by targeting regulatory factors in loops of DNA known as Insulated Genomic Domains (IGDs), CEO Mahesh Karande explained to Fierce Biotech in March.

We treat diseases created by functional or structural changes in IGDs, Karande said at the time.

Meanwhile, in academia, researchers are continuously searching for new technologies to make the process of adjusting gene activity safer and applicable to a wider variety of tumor types.

In May, for example, researchers at MUSC Hollings Cancer Centerdescribed a peptide theyre designing that can deliver aSiRNA into cells by adhering to antennae-like protrusions on cell surfaces known as filopodia. The researchers are initially developing the technology to target oral cancers, which typically have high levels of filopodia.

The MUSC researcher leading the effort, Andrew Jakymiw, Ph.D., an associate professor of oral health sciences, said in an interview that if the filopodia-targeted SiRNA delivery system pans out, it could prove applicable to a range of cancers.

Many invasive carcinomashave high levels of filopodia, while normal cells typically have very few, Jakymiw said. So this could potentially be used as a strategy to target more aggressive forms of this type of cancer.

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Outsmarting cancer with RNA, 'genome-tuning' drugs and other gene-altering therapies - FierceBiotech

WHEN THE Mutambaras first son was a about 18 months old they began to worry about his hearing. The toddler did not respond when asked to come to Mama. He was soon diagnosed as deaf, though no doctor could tell the Zimbabwean couple the cause. Several years later their second son was also born deaf.

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This time a doctor referred them to Hearing Impairment Genetics Studies in Africa (HI-GENES), set up in 2018 by Ambroise Wonkam, a Cameroonian professor of genetics now at the University of Cape Town. The project is sequencing the genomes of Africans with hearing loss in seven countries to learn why six babies in every 1,000 are born deaf in Africa, a rate six times that in America. In Cape Town, where Mr and Mrs Mutambara (not their real names) live, a counsellor explained that the boys deafness is caused by genetic variants rarely found outside Africa.

What is true of deafness is true of other conditions. The 3bn pairs of nucleotide bases that make up human DNA were first fully mapped in 2003 by the Human Genome Project. Since then scientists have made publicly available the sequencing of around 1m genomes as part of an effort to refine the reference genome, a blueprint used by researchers. But less than 2% of all sequenced genomes are African, though Africans are 17% of the worlds population (see chart). We must fill the gap, argues Dr Wonkam, who has proposed an initiative to do just thatThree Million African Genomes (3MAG).

The evolutionary line leading to Homo sapiens diverged 5m-6m years ago from that leading to chimpanzees, and for almost all that time the ancestors of modern humans lived in Africa.

Only about 60,000 years ago did Homo sapiens venture widely beyond the continent, in small bands of adventurers. Most of humanitys genetic diversity, under-sampled though it is, is therefore found in Africa. Unfortunately, that diversity is also reflected in the greater variety of genetic illnesses found there.

The bias in sequencing leads to under-diagnosis of diseases in people of (relatively recent) African descent. Genetic causes of heart failure, such as the one that caused the ultimately fatal collapse of Marc-Vivien Fo, a Cameroonian football player, during a game in 2003, are poorly understood. The variation present in most non-Africans with cystic fibrosis is responsible for only about 30% of cases in people of African origin. This is one reason, along with its relative rarity, that the illness is often missed in black children. Standard genetic tests for hearing loss would not have picked up the Mutambara boys variations. And such is the diversity within the continent that tests in some countries would be irrelevant in others. In Ghana HI-GENES found one mutation responsible for 40% of inherited deafness. The same variation has not been found in South Africa.

Bias also means that little is known about how variations elsewhere in the genome modify conditions. With sickle-cell disease, red blood cells look like bananas rather than, as is normal, round cushions. About 75% of the 300,000 babies born every year with sickle-cell disease are African. The high share reflects a bittersweet twist in the evolutionary tale; sickle-cell genes can confer a degree of protection against malaria. Other mutations are known to lessen sickle-cells impact, but most knowledge of genetic modifiers is particular to Europeans.

Quicker and more accurate diagnosis would mean better treatment. The sooner parents know their children are deaf, the sooner they can begin sign language. Algorithms that incorporate genetic information, such as one for measuring doses of warfarin, a blood-thinner, are often inappropriately calibrated for Africans.

Knowing more about Africans genomes will benefit the whole world. The continents genetic diversity makes it easier to find rare causes of common diseases. Last year researchers investigating schizophrenia sequenced the genomes of about 900 Xhosas (a South African ethnic group) with the psychiatric disorder. They found some of the same mutations that a team had discovered in Swedes four years earlier. But those researchers had to analyse four times as many of the homogeneous Scandinavians to find it. Research by Olufunmilayo Olopade, a Nigerian-born oncologist, into why breast cancer is relatively common in Nigerian women, has revealed broad insights into tumour growth.

Dr Wonkams vision for 3MAG, as outlined in Nature, a scientific journal, is for 300,000 African genomes to be sequenced per year over a decade. That is the minimum needed to capture the continents diversity. He notes that the UK biobank is sequencing 500,000 genomes, though Britains population is a twentieth the size of Africas. The plummeting cost of technology makes 3MAG possible. Sequencing the first genome cost $300m; today the cost of sequencing is around $1,000. If data from people of African descent in similar projects, like the UK biobank, were shared with 3MAG, that would help. So too would collaboration with genetics firms, such as 54Gene, a Nigerian start-up.

The 3MAG project is building on firm foundations. Over the past decade the Human Heredity and Health in Africa consortium, sponsored by Americas National Institutes of Health and the Wellcome Trust, a British charity, has supported research institutes in 30 African countries. It has funded local laboratories for world-class scientists such as Dr Wonkam and Christian Happi, a Nigerian geneticist.

There are practical issues to iron out. One is figuring out how to store the vast amounts of data. Another is rules around consent and data use, especially if 3MAG will involve firms understandably keen to commercialise the findings. Dr Wonkam wants to see an ethics committee set up to review this and other matters.

At times he has wondered whether his plan is too big, too crazy and too expensive. But similar things were said about the Human Genome Project. Its researchers used the Rosetta Stone as a metaphor for the initiative and its ambition. In a subtle nod, Dr Wonkam has a miniature of the obelisk on a shelf in his office. It is also a reminder of how understanding African languages, whether spoken or genetic, can enlighten all of humanity.

This article appeared in the Middle East & Africa section of the print edition under the headline "The African genome project"

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The promise of the African genome project - The Economist