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Tracking the Evolution of a ‘Variant of Concern’ in Brazil

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P.1 Variant of SARS-CoV-2 in the center of standard SARS-CoV-2. Arrows move out from the variant

By last October, about three out of every four residents of Manaus, Brazil already had been infected with SARS-CoV-2, the virus that causes COVID-19 [1]. And yet, despite hopes of achieving “herd immunity” in this city of 2.2 million in the Amazon region, the virus came roaring back in late 2020 and early 2021 to cause a second wave of illness and death [2]. How is this possible?

The answer offers a lesson in viral evolution, especially when an infectious virus such as SARS-CoV-2 replicates and spreads through a population largely unchecked. In a recent study in the journal Science, researchers tied the city’s resurgence of SARS-CoV-2 to the emergence and rapid spread of a new SARS-CoV-2 “variant of concern” known as P.1 [3]. This variant carries a unique constellation of mutations that allow it not only to sneak past the human immune system and re-infect people, but also to be about twice as transmissible as earlier variants.

To understand how this is possible, consider that each time the coronavirus SARS-CoV-2 makes copies of itself in an infected person, there’s a chance a mistake will be made. Each mistake can produce a new variant that may go on to make more copies of itself. In most cases, those random errors are of little to no consequence. This is evolution in action.

But sometimes a spelling change can occur that benefits the virus. In the special case of patients with suppressed immune systems, the virus can have ample opportunity to accrue an unusually high number of mutations. Variants carrying beneficial mutations can make more copies of themselves than other variants, allowing them to build their numbers and spread to cause more infection.

At this advanced stage of the COVID-19 pandemic, such rapidly spreading new variants remain cause for serious concern. That includes variants such as B.1.351, which originated in South Africa; B.1.1.7 which emerged in the United Kingdom; and now P.1 from Manaus, Brazil.

In the new study, Nuno Faria and Samir Bhatt, Imperial College London, U.K., and Ester Cerdeira Sabino, Universidade de Sao Paulo, Brazil, and their colleagues sequenced SARS-CoV-2 genomes from 184 patient samples collected in Manaus in November and December 2020. The research was conducted under the auspices of the Brazil-UK Centre for Arbovirus Discovery, Diagnosis, Genomics and Epidemiology (CADDE), a project focused on viral genomics and epidemiology for public health.

Those genomic data revealed the P.1 variant had acquired 17 new mutations. Ten were in the spike protein, which is the segment of the virus that binds onto human cells and the target of current COVID-19 vaccines. In fact, the new work reveals that three of these spike protein mutations make it easier for the P.1 spike to bind the human ACE2 receptor, which is SARS-CoV-2’s preferred entry point.

The first P.1 variant case was detected by genomic surveillance on December 6, 2020, after which it spread rapidly. Through further evolutionary analysis, the team estimates that P.1 must have emerged, undetected for a brief time, in mid-November 2020.

To understand better how the P.1 variant led to such an explosion of new COVID-19 cases, the researchers developed a mathematical model that integrated the genomic data with mortality data. The model suggests that P.1 may be 1.7 to 2.4 times more transmissible than earlier variants. They also estimate that a person previously infected with a variant other than P.1 will have only 54 percent to 79 percent protection against a subsequent infection with P.1.

The researchers also observed an increase in mortality following the emergence of the P.1 variant. However, it’s not yet clear if that’s an indication P.1 is inherently more deadly than earlier variants. It’s possible the increased mortality is related primarily to the extra stress on the healthcare system in Manaus from treating so many people with COVID-19.

These findings are yet another reminder of the importance of genomic surveillance and international data sharing for detecting and characterizing emerging SARS-CoV-2 variants quickly. It’s worth noting that at about the same time this variant was detected in Brazil, it also was reported in four individuals who had traveled to Brazil from Japan. The P.1 variant continues to spread rapidly across Brazil. It has also been detected in more than 37 countries [4], including the United States, where it now accounts for more than 1 percent of new cases [5].

No doubt you are wondering what this means for vaccines, such as the Pfizer and Moderna mRNA vaccines, that have been used to immunize (at least one dose) over 140 million people in the United States. Here the news is encouraging. Serum from individuals who received the Pfizer vaccine had titers of neutralizing antibodies that were only slightly reduced for P.1 compared to the original SARS-CoV-2 virus [6]. Therefore, the vaccine is predicted to be highly protective. This is another example of a vaccine providing more protection than a natural infection.

The United States has made truly remarkable progress in combating COVID-19, but we must heed this lesson from Manaus: this terrible pandemic isn’t over just yet. While the P.1 variant remains at low levels here for now, the “U.K. variant” B.1.1.7 continues to spread rapidly and now is the most prevalent variant circulating in the U.S., accounting for 44 percent of new cases [6]. Fortunately, the mRNA vaccines also work well against B.1.1.7.

We must continue to do absolutely everything possible, individually and collectively, to prevent these new SARS-CoV-2 variants from slowing or even canceling the progress made over the last year. We need to remain vigilant for just a while longer, while encouraging our friends, neighbors, and loved ones to get vaccinated.

References:

[1] Three-quarters attack rate of SARS-CoV-2 in the Brazilian Amazon during a largely unmitigated epidemic. Buss, L. F., C. A. Prete, Jr., C. M. M. Abrahim, A. C. Dye, V. H. Nascimento, N. R. Faria and E. C. Sabino et al. (2021). Science 371(6526): 288-292.

[2] Resurgence of COVID-19 in Manaus, Brazil, despite high seroprevalence. Sabino EC, Buss LF, Carvalho MPS, Prete Jr CCA, Crispim MAE, Fraiji NA, Pereira RHM, Paraga KV, Peixoto PS, Kraemer MUG, Oikawa MJ, Salomon T, Cucunuba ZM, Castro MC, Santos AAAS, Nascimento VH, Pereira HS, Ferguson NM, Pybus OG, Kucharski A, Busch MP, Dye C, Faria NR Lancet. 2021 Feb 6;397(10273):452-455.

[3] Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil. Faria NR, Mellan TA, Whittaker C, Claro IM, Fraiji NA, Carvalho MDPSS, Pybus OG, Flaxman S, Bhatt S, Sabino EC et al. Science. 2021 Apr 14:eabh2644.

[4] GRINCH Global Report Investigating novel coronavirus haplotypes. PANGO Lineages.

[5] COVID Data Tracker. Variant Proportions. Centers for Disease Control and Prevention.

[6] Antibody evasion by the P.1 strain of SARS-CoV-2. Dejnirattisai W, Zhou D, Supasa P, Liu C, Mongkolsapaya J, Ren J, Stuart DI, Screaton GR, et al. Cell. 2021 Mar 30:S0092-8674(21)00428-1.

Links:

COVID-19 Research (NIH)

Brazil-UK Centre for Arbovirus Discovery, Diagnosis, Genomics and Epidemiology (CADDE)

Nuno Faria (Imperial College, London, U.K.)

Samir Bhatt (Imperial College)

Ester Cerdeira Sabino (Universidade de Sao Paulo, Brazil)

NIH Support: National Institute of Allergy and Infectious Diseases


Infections with ‘U.K. Variant’ B.1.1.7 Have Greater Risk of Mortality

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One coronavirus in a group looks different and is labeled B.1.1.7 variant. Lines radiate from Britain on a map.

Since the genome sequence of SARS-CoV-2, the virus responsible for COVID-19, was first reported in January 2020, thousands of variants have been reported. In the vast majority of cases, these variants, which arise from random genomic changes as SARS-CoV-2 makes copies of itself in an infected person, haven’t raised any alarm among public health officials. But that’s now changed with the emergence of at least three variants carrying mutations that potentially make them even more dangerous.

At the top of this short list is a variant known as B.1.1.7, first detected in the United Kingdom in September 2020. This variant is considerably more contagious than the original virus. It has spread rapidly around the globe and likely accounts already for at least one-third of all cases in the United States [1]. Now comes more troubling news: emerging evidence indicates that infection with this B.1.1.7 variant also comes with an increased risk of severe illness and death [2].

The findings, reported in Nature, come from Nicholas Davies, Karla Diaz-Ordaz, and Ruth Keogh, London School of Hygiene and Tropical Medicine. The London team earlier showed that this new variant is 43 to 90 percent more transmissible than pre-existing variants that had been circulating in England [3]. But in the latest paper, the researchers followed up on conflicting reports about the virulence of B.1.1.7.

They did so with a large British dataset linking more than 2.2 million positive SARS-CoV-2 tests to 17,452 COVID-19 deaths from September 1, 2020, to February 14, 2021. In about half of the cases (accounting for nearly 5,000 deaths), it was possible to discern whether or not the infection had been caused by the B.1.1.7 variant.

Based on this evidence, the researchers calculated the risk of death associated with B.1.1.7 infection. Their estimates suggest that B.1.1.7 infection was associated with 55 percent greater mortality compared to other SARS-CoV-2 variants over this time period.

For a 55- to 69-year-old male, this translates to a 0.9-percent absolute, or personal, risk of death, up from 0.6 percent for the older variants. That means nine in every 1,000 people in this age group who test positive with the B.1.1.7 variant would be expected to die from COVID-19 a month later. For those infected with the original virus, that number would be six.

The U.S. percentage of B.1.1.7 started near zero on January 2, 2021 but by March 13 was over 20%.
Adapted from Centers for Disease Control and Prevention

These findings are in keeping with those of another recent study reported in the British Medical Journal [4]. In that case, researchers at the University of Exeter and the University of Bristol found that the B.1.1.7 variant was associated with a 64 percent greater chance of dying compared to earlier variants. That’s based on an analysis of data from more than 100,000 COVID-19 patients in the U.K. from October 1, 2020, to January 28, 2021.

That this variant comes with increased disease severity and mortality is particularly troubling news, given the highly contagious nature of B.1.1.7. In fact, Davies’ team has concluded that the emergence of new SARS-CoV-2 variants now threaten to slow or even cancel out improvements in COVID-19 treatment that have been made over the last year. These variants include not only B1.1.7, but also B.1.351 originating in South Africa and P.1 from Brazil.

The findings are yet another reminder that, while we’re making truly remarkable progress in the fight against COVID-19 with increasing availability of safe and effective vaccines (more than 45 million Americans are now fully immunized), now is not the time to get complacent. This devastating pandemic isn’t over yet.

The best way to continue the fight against all SARS-CoV-2 variants is for each one of us to do absolutely everything we can to stop their spread. This means that taking the opportunity to get vaccinated as soon as it is offered to you, and continuing to practice those public health measures we summarize as the three Ws: Wear a mask, Watch your distance, Wash your hands often.

References:

[1] US COVID-19 Cases Caused by Variants. Centers for Disease Control and Prevention.

[2] Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7. Davies NG, Jarvis CI; CMMID COVID-19 Working Group, Edmunds WJ, Jewell NP, Diaz-Ordaz K, Keogh RH. Nature. 2021 Mar 15.

[3] Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England. Davies NG, Abbott S, Barnard RC, Jarvis CI, Kucharski AJ, Munday JD, Pearson CAB, Russell TW, Tully DC, Washburne AD, Wenseleers T, Gimma A, Waites W, Wong KLM, van Zandvoort K, Silverman JD; CMMID COVID-19 Working Group; COVID-19 Genomics UK (COG-UK) Consortium, Diaz-Ordaz K, Keogh R, Eggo RM, Funk S, Jit M, Atkins KE, Edmunds WJ.
Science. 2021 Mar 3:eabg3055.

[4] Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study. Challen R, Brooks-Pollock E, Read JM, Dyson L, Tsaneva-Atanasova K, Danon L. BMJ. 2021 Mar 9;372:n579.

Links:

COVID-19 Research (NIH)

Nicholas Davies (London School of Hygiene and Tropical Medicine, U.K.)

Ruth Keogh (London School of Hygiene and Tropical Medicine, U.K.)


On-the-Spot Gene Readouts Offer Clues to How Cells Work

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Credit: MIT and Harvard Medical School, Cambridge, MA

Just as two companies can merge to expand their capabilities, two technologies can become more powerful when integrated into one. That’s why researchers recently merged two breakthrough technologies into one super powerful new method called ExSeq. The two-in-one technology enables researchers for the first time to study an intact tissue sample and track genetic activity on the spot within a cell’s tiniest recesses, or microenvironments—areas that have been largely out of reach until now.

ExSeq, which is described in a paper in the journal Science [1], will unleash many new experimental applications. Beyond enabling more precise analysis of the basic building blocks of life, these applications include analyzing tumor biopsies more comprehensively and even unlocking mysteries of how the brain works. The latter use is on display in this colorful cross-section of a mouse’s hippocampus, a region of the brain involved in the memory of facts and events.

Here you can see in precise and unprecedented detail the areas where genes are activated (magenta) in the brain’s neurons (green). In this particular example, the genes are working within subregions of the hippocampus called the CA1 and dentate gyrus regions (white, bottom and top left).

ExSeq is a joint effort from NIH grantees Ed Boyden, Massachusetts Institute of Technology (MIT), Cambridge, and George Church, Harvard Medical School, Boston. The new method combines a technology called tissue expansion with an in situ sequencing approach.

Tissue expansion swells the contents of tissue sections up to 100 times their normal size but retains their same physical structure [2]. It’s sort of like increasing the font size and line spacing on a hard-to-read document. It makes cellular details that were outside the resolution range of the light microscope suddenly accessible.

With the information inside cells now easier to see, the next step involves a technique called FISSEQ (fluorescent in situ sequencing), which generates readouts of thousands of mRNA molecules in cells [3]. FISSEQ works by detecting individual RNA molecules where they are inside cells and amplifying them into “nanoballs,” or rolled-up copies of themselves. Each nanoball can be read using standard sequencing methods and a fluorescence microscope.

Using the combined ExSeq approach, the team can analyze precisely where gene activity changes within tiny cellular microenvironments. Or, it can compile a more-comprehensive readout of gene activity within cells by analyzing as many gene readouts as detectable. When used in the hippocampus, this untargeted, “agnostic” approach led to some surprises—revealing unusual forms of RNA and, by association, genes for proteins not previously linked with communication between neurons.

Like many technology developments, the scientists envision that ExSeq can be used in many ways, including for more precise analysis of tumor biopsies. To illustrate this point, the researchers analyzed breast cancer metastases, which are cells from breast tumors that have spread to other areas in the body. Metastases contain many different cell types, including cancer cells and immune cells.

Using ExSeq, Boyden and Church learned that these distinct cell types can behave differently depending on where they are inside a tumor. They discovered, for example, that immune B cells near tumor cells expressed certain inflammatory genes at a higher level than immune B cells that were further away. Precise information about a tumor’s composition and activity may lead to development of more targeted approaches to attack it.

Many discoveries come on the heels of transformative new technologies. ExSeq shines a much brighter light on the world of the very small. And that should help us better understand how different parts of cells work together, as well as how cells work with each other in the brain, in cancer, and throughout the body.

References:

[1] Expansion sequencing: Spatially precise in situ transcriptomics in intact biological systems. Alon S, Goodwin DR, Sinha A, Wassie AT, et al. Science. 2021 Jan 29;37:eaax2656.

[2] Expansion microscopy. Chen F, Tillberg PW, Boyden ES. Science. 2015;347:543-548.

[3]. Highly multiplexed subcellular RNA sequencing in situ. Lee JH, Daugharthy ER, Scheiman J, Kalhor R, et al. Science. 2014;343:1360-1363.

Links:

Ribonucleic Acid (RNA) (National Human Genome Research Institute/NIH)

Synthetic Neurobiology Group (Massachusetts Institute of Technology, Cambridge)

George Church (Harvard Medical School, Boston)

NIH Support: National Human Genome Research Institute; National Cancer Institute; National Institute of Biomedical Imaging and Bioengineering; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke


Fueling the Next Genomic Revolution

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Genomics Research Panel Discussion
I recently enjoyed taking part in a video discussion of the future of genomics with Eric Lander, Broad Institute of MIT and Harvard (lower left); Charles Rotimi, NIH’s National Human Genome Research Institute; and Claire Fraser, University of Maryland’s Institute for Genome Sciences. The Jan. 13, 2021 event celebrated the 25th anniversary of the first complete bacterial genome, the 20th anniversary of the publication of the human genome, and the 15th anniversary of the first human metagenome. I’m also excited to report that two days later, President-elect Joe Biden asked me to stay on as NIH Director and nominated Lander to lead the White House Office of Science and Technology Policy and serve as our nation’s first Cabinet-level Science Adviser.


DNA Base Editing May Treat Progeria, Study in Mice Shows

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Sam Berns with personalized snare drum carrier
Credit: Progeria Research Foundation

My good friend Sam Berns was born with a rare genetic condition that causes rapid premature aging. Though Sam passed away in his teens from complications of this condition, called Hutchinson-Gilford progeria syndrome, he’s remembered today for his truly positive outlook on life. Sam expressed it, in part, by his willingness to make adjustments that allowed him, in his words, to put things that he always wanted to do in the “can do” category.

In this same spirit on behalf of the several hundred kids worldwide with progeria and their families, a research collaboration, including my NIH lab, has now achieved a key technical advance to move non-heritable gene editing another step closer to the “can do” category to treat progeria. As published in the journal Nature, our team took advantage of new gene-editing tools to correct for the first time a single genetic misspelling responsible for progeria in a mouse model, with dramatically beneficial effects [1, 2]. This work also has implications for correcting similar single-base typos that cause other inherited genetic disorders.

The outcome of this work is incredibly gratifying for me. In 2003, my NIH lab discovered the DNA mutation that causes progeria. One seemingly small glitch—swapping a “T” in place of a “C” in a gene called lamin A (LMNA)—leads to the production of a toxic protein now known as progerin. Without treatment, children with progeria develop normally intellectually but age at an exceedingly rapid pace, usually dying prematurely from heart attacks or strokes in their early teens.

The discovery raised the possibility that correcting this single-letter typo might one day help or even cure children with progeria. But back then, we lacked the needed tools to edit DNA safely and precisely. To be honest, I didn’t think that would be possible in my lifetime. Now, thanks to advances in basic genomic research, including work that led to the 2020 Nobel Prize in Chemistry, that’s changed. In fact, there’s been substantial progress toward using gene-editing technologies, such as the CRISPR editing system, for treating or even curing a wide range of devastating genetic conditions, such as sickle cell disease and muscular dystrophy

It turns out that the original CRISPR system, as powerful as it is, works better at knocking out genes than correcting them. That’s what makes some more recently developed DNA editing agents and approaches so important. One of them, which was developed by David R. Liu, Broad Institute of MIT and Harvard, Cambridge, MA, and his lab members, is key to these latest findings on progeria, reported by a team including my lab in NIH’s National Human Genome Research Institute and Jonathan Brown, Vanderbilt University Medical Center, Nashville, TN.

The relatively new gene-editing system moves beyond knock-outs to knock-ins [3,4]. Here’s how it works: Instead of cutting DNA as CRISPR does, base editors directly convert one DNA letter to another by enzymatically changing one DNA base to become a different base. The result is much like the find-and-replace function used to fix a typo in a word processor. What’s more, the gene editor does this without cutting the DNA.

Our three labs (Liu, Brown, and Collins) first teamed up with the Progeria Research Foundation, Peabody, MA, to obtain skin cells from kids with progeria. In lab studies, we found that base editors, targeted by an appropriate RNA guide, could successfully correct the LMNA gene in those connective tissue cells. The treatment converted the mutation back to the normal gene sequence in an impressive 90 percent of the cells.

But would it work in a living animal? To get the answer, we delivered a single injection of the DNA-editing apparatus into nearly a dozen mice either three or 14 days after birth, which corresponds in maturation level roughly to a 1-year-old or 5-year-old human. To ensure the findings in mice would be as relevant as possible to a future treatment for use in humans, we took advantage of a mouse model of progeria developed in my NIH lab in which the mice carry two copies of the human LMNA gene variant that causes the condition. Those mice develop nearly all of the features of the human illness

In the live mice, the base-editing treatment successfully edited in the gene’s healthy DNA sequence in 20 to 60 percent of cells across many organs. Many cell types maintained the corrected DNA sequence for at least six months—in fact, the most vulnerable cells in large arteries actually showed an almost 100 percent correction at 6 months, apparently because the corrected cells had compensated for the uncorrected cells that had died out. What’s more, the lifespan of the treated animals increased from seven to almost 18 months. In healthy mice, that’s approximately the beginning of old age.

This is the second notable advance in therapeutics for progeria in just three months. Last November, based on preclinical work from my lab and clinical trials conducted by the Progeria Research Foundation in Boston, the Food and Drug Administration (FDA) approved the first treatment for the condition. It is a drug called Zokinvy, and works by reducing the accumulation of progerin [5]. With long-term treatment, the drug is capable of extending the life of kids with progeria by 2.5 years and sometimes more. But it is not a cure.

We are hopeful this gene editing work might eventually lead to a cure for progeria. But mice certainly aren’t humans, and there are still important steps that need to be completed before such a gene-editing treatment could be tried safely in people. In the meantime, base editors and other gene editing approaches keep getting better—with potential application to thousands of genetic diseases where we know the exact gene misspelling. As we look ahead to 2021, the dream envisioned all those years ago about fixing the tiny DNA typo responsible for progeria is now within our grasp and getting closer to landing in the “can do” category.

References:

[1] In vivo base editing rescues Hutchinson-Gilford Progeria Syndrome in mice. Koblan LW et al. Nature. 2021 Jan 6.

[2] Base editor repairs mutation found in the premature-ageing syndrome progeria. Vermeij WP, Hoeijmakers JHJ. Nature. 6 Jan 2021.

[3] Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR. Nature. 2016 May 19;533(7603):420-424.

[4] Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Gaudelli NM, Komor AC, Rees HA, Packer MS, Badran AH, Bryson DI, Liu DR. Nature. 2017 Nov 23;551(7681):464-471.

[5] FDA approves first treatment for Hutchinson-Gilford progeria syndrome and some progeroid laminopathies. Food and Drug Administration. 2020 Nov 20.

Links:

Progeria (Genetic and Rare Diseases Information Center/NIH)

What are Genome Editing and CRISPR-Cas9? (National Library of Medicine/NIH)

Somatic Cell Genome Editing Program (Common Fund/NIH)

David R. Liu (Harvard University, Cambridge, MA)

Collins Group (National Human Genome Research Institute/NIH)

Jonathan Brown (Vanderbilt University Medical Center, Nashville, TN)

NIH Support: National Human Genome Research Institute; National Center for Advancing Translational Sciences; National Institute of Biomedical Imaging and Bioengineering; National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences; Common Fund


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