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Tailored Hope: Personalized Gene Therapy Makes History
Curator: Dr. Sudipta Saha, Ph. D.
A groundbreaking milestone in precision medicine has been achieved by researchers supported by the National Institutes of Health (NIH), USA where a personalized gene therapy was successfully administered to an infant diagnosed with a rare and fatal genetic disorder. This therapy was developed and delivered under the NIH’s Bespoke Gene Therapy Consortium (BGTC), which focuses on accelerating gene therapy solutions for ultra-rare conditions.
The child, who had been diagnosed with a previously untreatable condition caused by mutations in the TBCK gene, was treated with a customized adeno-associated viral (AAV) vector designed specifically to address the individual’s unique mutation. This approach was enabled by rapid sequencing, vector engineering, preclinical safety testing, and regulatory approvals—all expedited within a year of diagnosis.
The therapeutic gene was administered through a single intravenous infusion. Post-treatment observations indicated stabilization in disease progression and improvement in neurological function, though ongoing monitoring is being conducted to assess long-term outcomes.
This personalized treatment was made possible by the integration of genomic diagnostics, advanced vector design, and regulatory science, marking a transformative moment in paediatric precision medicine. Ethical considerations and close family collaboration were emphasized throughout the process.
The case has highlighted the promise of tailored gene therapies for diseases too rare to be addressed by conventional clinical trials. By establishing a streamlined pathway, the NIH aims to extend this model to more patients globally.
Unlocking the Secrets of Longevity: A 117-Year-Old Woman’s Genes Defied Aging
Curator: Dr. Sudipta Saha, Ph.D.
A recent study led by the University of Barcelona has shed light on the genetic factors contributing to exceptional human longevity. The research focused on Maria Branyas Morera, who was recognized as the world’s oldest living person until her passing at age 117 in August 2024. The findings revealed that her unique genetic makeup allowed her cells to function as if they were 17 years younger, and her gut microbiota resembled that of an infant.
Branyas Morera attributed her remarkable lifespan to “luck and good genetics.” Beyond her genetic advantages, she maintained a healthy lifestyle characterized by a Mediterranean diet, regular physical activity, and strong family bonds. These factors likely contributed to her prolonged cognitive clarity and minimal health issues, primarily limited to joint pain and hearing loss.
This study adds to a growing body of research exploring the genetic foundations of longevity. For instance, the Okinawa Centenarian Study has examined over 600 centenarians from Okinawa, Japan, uncovering genetic markers associated with extended lifespan and reduced incidence of age-related diseases.
Similarly, the New England Centenarian Study has identified specific genetic variations linked to longevity, providing insights into the biological mechanisms that allow some individuals to live significantly longer than average.
Researchers hope that understanding these genetic factors can inform the development of treatments for age-related diseases, challenging the notion that aging and illness are inextricably linked. By studying individuals like Branyas Morera, scientists aim to uncover strategies to promote healthier aging across the broader population.
However, it’s important to note that while genetics play a crucial role in exceptional longevity, lifestyle factors such as diet, exercise, and social connections also significantly impact overall health and lifespan. The interplay between genetic predisposition and environmental influences continues to be a critical area of research in understanding human aging.
Science’s COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.
Researchers have used CRISPR gene-editing technology to come up with a test that detects the pandemic coronavirus in just 5 minutes. The diagnostic doesn’t require expensive lab equipment to run and could potentially be deployed at doctor’s offices, schools, and office buildings.
“It looks like they have a really rock-solid test,” says Max Wilson, a molecular biologist at the University of California (UC), Santa Barbara. “It’s really quite elegant.”
CRISPR diagnostics are just one way researchers are trying to speed coronavirus testing. The new test is the fastest CRISPR-based diagnostic yet. In May, for example, two teams reported creating CRISPR-based coronavirus tests that could detect the virus in about an hour, much faster than the 24 hours needed for conventional coronavirus diagnostic tests.CRISPR tests work by identifying a sequence of RNA—about 20 RNA bases long—that is unique to SARS-CoV-2. They do so by creating a “guide” RNA that is complementary to the target RNA sequence and, thus, will bind to it in solution. When the guide binds to its target, the CRISPR tool’s Cas13 “scissors” enzyme turns on and cuts apart any nearby single-stranded RNA. These cuts release a separately introduced fluorescent particle in the test solution. When the sample is then hit with a burst of laser light, the released fluorescent particles light up, signaling the presence of the virus. These initial CRISPR tests, however, required researchers to first amplify any potential viral RNA before running it through the diagnostic to increase their odds of spotting a signal. That added complexity, cost, and time, and put a strain on scarce chemical reagents. Now, researchers led by Jennifer Doudna, who won a share of this year’s Nobel Prize in Chemistry yesterday for her co-discovery of CRISPR, report creating a novel CRISPR diagnostic that doesn’t amplify coronavirus RNA. Instead, Doudna and her colleagues spent months testing hundreds of guide RNAs to find multiple guides that work in tandem to increase the sensitivity of the test.
That’s still not as good as the conventional coronavirus diagnostic setup, which uses expensive lab-based machines to track the virus down to one virus per microliter, says Melanie Ott, a virologist at UC San Francisco who helped lead the project with Doudna. However, she says, the new setup was able to accurately identify a batch of five positive clinical samples with perfect accuracy in just 5 minutes per test, whereas the standard test can take 1 day or more to return results.
The new test has another key advantage, Wilson says: quantifying a sample’s amount of virus. When standard coronavirus tests amplify the virus’ genetic material in order to detect it, this changes the amount of genetic material present—and thus wipes out any chance of precisely quantifying just how much virus is in the sample.
By contrast, Ott’s and Doudna’s team found that the strength of the fluorescent signal was proportional to the amount of virus in their sample. That revealed not just whether a sample was positive, but also how much virus a patient had. That information can help doctors tailor treatment decisions to each patient’s condition, Wilson says.
Doudna and Ott say they and their colleagues are now working to validate their test setup and are looking into how to commercialize it.
Most significant article published in the Society of Evolution, Medicine and Public Health won Prize: polygenic scores, polygenic adaptation, and human phenotypic differences
Reporter: Aviva Lev-Ari, PhD, RN
UPDATED on 8/30/2020
Analysis of polygenic risk score usage and performance in diverse human populations
A historical tendency to use European ancestry samples hinders medical genetics research, including the use of polygenic scores, which are individual-level metrics of genetic risk. We analyze the first decade of polygenic scoring studies (2008–2017, inclusive), and find that 67% of studies included exclusively European ancestry participants and another 19% included only East Asian ancestry participants. Only 3.8% of studies were among cohorts of African, Hispanic, or Indigenous peoples. We find that predictive performance of European ancestry-derived polygenic scores is lower in non-European ancestry samples (e.g. African ancestry samples: t = −5.97, df = 24, p = 3.7 × 10−6), and we demonstrate the effects of methodological choices in polygenic score distributions for worldwide populations. These findings highlight the need for improved treatment of linkage disequilibrium and variant frequencies when applying polygenic scoring to cohorts of non-European ancestry, and bolster the rationale for large-scale GWAS in diverse human populations.
You might be interested in the paper “interpreting polygenic scores, polygenic adaptation, and human phenotypic differences” by N. Rosenberg, M. Edge, J. Pritchard, and M. Feldman, published in Evolution, Medicine and Public Health (2019). Rosenberg and Pritchard are my former PhD students, both full professors at Stanford, and M.Edge is a student of Rosenberg.
It is my pleasure in my role as President of the International Society for Evolution, Medicine and Public Health to inform you that your 2019 EMPH article, “Interpreting polygenic scores, polygenic adaptation, and human phenotypic differences” has won The George C. Williams Prize which is awarded each year to the first author of the most significant article published in the Society’s flagship journal, Evolution, Medicine and Public Health.
The Prize recognizes the contributions of George C. Williams to evolutionary medicine and aims to encourage and highlight important research in this growing field. It includes $5,000 and an invitation to present at the online lecture series, Club EvMed. The Prize is made possible by donations from Doris Williams, Randolph Nesse, and other supporters of EMPH.
Recent analyses of polygenic scores have opened new discussions concerning the genetic basis and evolutionary significance of differences among populations in distributions of phenotypes. Here, we highlight limitations in research on polygenic scores, polygenic adaptation and population differences. We show how genetic contributions to traits, as estimated by polygenic scores, combine with environmental contributions so that differences among populations in trait distributions need not reflect corresponding differences in genetic propensity. Under a null model in which phenotypes are selectively neutral, genetic propensity differences contributing to phenotypic differences among populations are predicted to be small. We illustrate this null hypothesis in relation to health disparities between African Americans and European Americans, discussing alternative hypotheses with selective and environmental effects. Close attention to the limitations of research on polygenic phenomena is important for the interpretation of their relationship to human population differences.
We are currently witnessing a surge in public interest in the intersection of evolutionary genetics with such topics as cognitive phenotypes, disease, race and heritability of human traits [1–7]. This attention emerges partly from recent advances in genomics, including the introduction of polygenic scores—the aggregation of estimated effects of genome-wide variants to predict the contribution of a person’s genome to a phenotypic trait [8–10]—and a new focus on polygenic adaptations, namely adaptations that have occurred by natural selection on traits influenced by many genes [11–13].
Theories involving natural selection have long been applied in the scientific literature to explain mean phenotypic differences among human populations [14–16]. Although new tools for statistical analysis of polygenic variation and polygenic adaptation provide opportunities for studying human evolution and the genetic basis of traits, they also generate potential for misinterpretation. In the past, public attention to research on human variation and its possible evolutionary basis has often been accompanied by claims that are not justified by the research findings [17]. Recognizing pitfalls in the interpretation of new research on human variation is therefore important for advancing discussions on associated sensitive and controversial topics.
The contribution of polygenic score distributions to phenotype distributions. Two populations are considered, populations 1 (red) and 2 (blue). Each population has a distribution of genetic propensities, which are treated as accurately estimated in the form of polygenic scores (left). The genetic propensity distribution and an environment distribution sum to produce a phenotype distribution (right). All plots have the same numerical scale. (A) Environmental differences amplify an underlying difference in genetic propensities. (B) Populations differ in their phenotypes despite having no differences in genetic propensity distributions. (C) Environmental differences obscure a difference in genetic propensities opposite in direction to the difference in phenotype means. (D) Similarity in phenotype distributions is achieved despite a difference in genetic propensity distributions by an intervention that reduces the environmental contribution for individuals with polygenic scores above a threshold. (E) Within populations, heritability is high, so that genetic variation explains the majority of phenotypic variation; however, the difference between populations is explained by an environmental difference. Panels (A–C and E) present independent normal distributions for genotype and environment that sum to produce normal distributions for phenotype. In (D), (genotype, environment) pairs are simulated from independent normal distributions and a negative constant—reflecting the effect of a medication or other intervention—is added to environmental contributions associated with simulated genotypic values that exceed a threshold
Summary
These limitations illustrate that much of the complexity embedded in use of polygenic scores—the effects of the environment on phenotype and its relationship to genotype, the proportion of variance explained, and the peculiarities of the underlying GWAS data that have been used to estimate effect sizes—is obscured by the apparent simplicity of the single values computed for each individual for each phenotype. Consequently, in using polygenic scores to describe genomic contributions to traits, particularly traits for which the total contribution of genetic variation to trait variation, as measured by heritability, is low—but even if it is high (Fig. 1E)—a difference in polygenic scores between populations provides little information about potential genetic bases for trait differences between those populations.
Unlike heritability, which ranges from 0 to 1 and therefore makes it obvious that the remaining contribution to phenotypic variation is summarized by its difference from 1, the limited explanatory role of genetics is not embedded in the nature of the polygenic scores themselves. Although polygenic scores encode knowledge about specific genetic correlates of trait variation, they do not change the conceptual framework for genetic and environmental contribution to population differences. Attributions of phenotypic differences among populations to genetic differences should therefore be treated with as much caution as similar genetic attributions from heritability in the pre-genomic era.
National Public Radio interview with Dr. Anthony Fauci on his optimism on a COVID-19 vaccine by early 2021
Reporter: Stephen J. Williams, PhD
Below I am giving a link to an important interview by NPR’s Judy Woodruff with Dr. Anthony Fauci on his thoughts regarding the recent spikes in cases, the potential for a COVID-19 vaccine by next year, and promising therapeutics in the pipeline. The interview link is given below however I will summarize a few of the highlights of the interview.
Some notes on the interview
Judy Woodruff began her report with some up to date news regarding the recent spike and that Miami Florida has just ordered the additional use of facemasks. She asked Dr. Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases (NIAD), about if the measures currently in use are enough to bring this spike down. Dr. Fauci said that we need to reboot our efforts, mainly because people are not doing three things which could have prevented this spike mainly
We have to use the tests we have out there efficiently and effectively And we have to get them out to the right people who can do the proper identification, isolation, and do proper contract tracing and need to test more widely in a surveillance way to get a feel of the extent and penetrance of this community spread. there needs to be support and money for these testing labs
We have a problem and we need to admit and own it but we need to do the things we know are effective to turn this thing around.
On Vaccines
“May be later this year”
His response to Merck’s CEO Ken Frazer who said officials are giving false hop if they say ‘end of year’ but Dr. Fauci disagrees. He says a year end goal is not outlandish.
What we have been doing is putting certain things in line with each other in an unprecedented way.
Dr. Fauci went on to say that, in the past yes, it took a long time, even years to develop a vaccine but now they have been able to go from sequence of virus to a vaccine development program in days, which is unheard of. Sixty two days later we have gone into phase 1 trials. the speed at which this is occurring is so much faster. He says that generally it would take a couple of years to get a neutralizing antibody but we are already there. Another candidate will be undergoing phase 3 trials by end of this month (July 2020).
He is “cautiously optimistic” that we will have one or more vaccines to give to patients by end of year because given the amount of cases it will be able to get a handle on safety and efficacy by late fall.
Now he says the game changer is that the government is working with companies to ramp up the production of doses of the candidate vaccines so when we find which one works we will have ample doses on hand. He is worried about the anti vaccine movement derailing vaccine testing and vaccinations but says if we keep on informing the public we can combat this.
Going back to school
Dr. Fauci is concerned for the safety of the vulnerable in schools, including students and staff. He wants the US to get down to a reasonable baseline of cases but in the US that baseline after the first wave was still significantly higher than in most countries, where the baseline was more like tens of cases not hundreds of cases.
For more information on COVID-19 Please go to our Coronavirus Portal at
The Wide Variability in Reported COVID-19 Epidemiologic Data May Suggest That Personalized Omic Testing May Be Needed to Identify At-Risk Populations
Curator: Stephen J. Williams, PhD
I constantly check the Youtube uploads from Dr. John Campbell, who is a wonderful immunologist and gives daily reports on new findings on COVID-19 from the scientific literature. His reporting is extremely insightful and easily understandable. This is quite a feat as it seems the scientific field has been inundated with a plethora of papers, mostly reported clinical data from small retrospective studies, and many which are being put on preprint servers, and not peer reviewed.
It has become a challenge for many scientists, already inundated with expanding peer reviewed literature in their own fields, as well as the many requests to review papers, to keep up with all these COVID related literature. Especially when it is up to the reader to do their own detailed peer review. So many thanks to people like Dr. Campbell who is an expert in his field for doing this.
However the other day he had posted a video which I found a bit disturbing, as a central theme of the video was that many expert committee could not find any reliable epidemiologic study concerning transmission or even incidence of the disease. In all studies, as Dr. Campell alluded to, there is such a tremendous variability in the reported statistics, whether one is looking at percentage of people testing positive who are symptomatic, the percentage of asymptomatic which may be carriers, the transmission of the disease, and even the percentage of people who recover.
With all the studies being done it would appear that, even if a careful meta analysis were done using all available studies, and assuming their validity before peer review, that there would be a tighter consensus on some of these metrics of disease spread, incidence and prevalence.
Below is the video from Dr. Campbell and the topic is on percentage of asymptomatic carriers of the COVID-19 virus. This was posted last week but later in this post there will be updated information and views by the WHO on this matter as well as other literature (which still shows to my point that this wide variability in reported data may be adding to the policy confusion with respect to asymptomatic versus symptomatic people and why genetic testing might be needed to further discriminate these cohorts of people.
“There is not a single reliable study to determine the number of asymptomatic infections”
And this is very troubling as this means there is no reliable testing resulting in any meaningful data.
As Dr. Campell says
” This is not good enough. There needs to be some sort of coordinated research program it seems all ad hoc”
A few other notes from post and Oxford Center for Evidence Based Medicine:
Symptom based screening will miss a lot of asymptomatic and presymptomatic cases
Some asymptomatic cases will become symptomatic over next week (these people were technically presymptomatic but do we know the %?)
We need a population based antibody screening program
An Italian study of all 3,000 people in city of Vo’Euganeo revealed that 50-75% of those who tested positive were asymptomatic and authors concluded that asymptomatic represents “a formidable source of infection”; Dr. Campbell feels this was a reliable study
Another study from a Washington state nursing facility showed while 56% of positive cases were asymptomatic, 75% of these asymptomatic developed symptoms within a week. Symptom based screening missed half of cases.
Other studies do not follow-up on the positive cases to determine in presymptomatic
It also appears discrepancies between data from different agencies (like CDC, WHO) on who is shedding virus as different tests used (PCR vs antibody)
Recent Studies Conflict Concerning Asymptomatic, Presymtomatic and Viral Transmission
‘We don’t actually have that answer yet’: WHO clarifies comments on asymptomatic spread of Covid-19
From StatNews
A top World Health Organization official clarified on Tuesday that scientists have not determined yet how frequently people with asymptomatic cases of Covid-19 pass the disease on to others, a day after suggesting that such spread is “very rare.”
The clarification comes after the WHO’s original comments incited strong pushback from outside public health experts, who suggested the agency had erred, or at least miscommunicated, when it said people who didn’t show symptoms were unlikely to spread the virus.
Maria Van Kerkhove, the WHO’s technical lead on the Covid-19 pandemic, made it very clear Tuesday that the actual rates of asymptomatic transmission aren’t yet known.
Some of the confusion boiled down to the details of what an asymptomatic infection actually is, and the different ways the term is used. While some cases of Covid-19 are fully asymptomatic, sometimes the word is also used to describe people who haven’t started showing symptoms yet, when they are presymptomatic. Research has shown that people become infectious before they start feeling sick, during that presymptomatic period.
At one of the WHO’s thrice-weekly press briefings Monday, Van Kerkhove noted that when health officials review cases that are initially reported to be asymptomatic, “we find out that many have really mild disease.” There are some infected people who are “truly asymptomatic,” she said, but countries that are doing detailed contact tracing are “not finding secondary transmission onward” from those cases. “It’s very rare,” she said.
Therefore the problems have been in coordinating the testing results, which types of tests conducted, and the symptomology results. As Dr. Campbell previously stated it appears more ‘ad hoc’ than coordinated research program. In addition, defining the presymptomatic and measuring this group have been challenging.
However, an alternative explanation to the wide variability in the data may be we need to redefine the cohorts of patients we are evaluating and the retrospective data we are collecting. It is feasible that sub groups, potentially defined by genetic background may be identified and data re-evaluated based on personalized omic data, in essence creating new cohorts based on biomarker data.
From a Perspective in The Lancet about a worldwide proteomic effort (COVID-19 MS Coalition) to discover biomarkers related to COVID19 infection risk, by identifying COVID-related antigens.
The COVID-19 MS Coalition is a collective mass spectrometry effort that will provide molecular level information on SARS-CoV-2 in the human host and reveal pathophysiological and structural information to treat and minimise COVID-19 infection. Collaboration with colleagues at pace involves sharing of optimised methods for sample collection and data generation, processing and formatting for maximal information gain. Open datasets will enable ready access to this valuable information by the computational community to help understand antigen response mechanisms, inform vaccine development, and enable antiviral drug design. As countries across the world increase widespread testing to confirm SARS-CoV-2 exposure and assess immunity, mass spectrometry has a significant role in fighting the disease. Through collaborative actions, and the collective efforts of the COVID-19 MS Coalition, a molecular level quantitative understanding of SARS-CoV-2 and its effect will benefit all.
In an ACS Perspective below, Morteza Mahmoudi suggests a few possible nanobased technologies (i.e., protein corona sensor array and magnetic levitation) that could discriminate COVID-19-infected people at high risk of death while still in the early stages of infection.
Emerging Biomolecular Testing to Assess the Risk of Mortality from COVID-19 Infection
Lancet Oncol. 2020 Mar; 21(3): 335–337. Published online 2020 Feb 14. doi: 10.1016/S1470-2045(20)30096-6
PMCID: PMC7159000
The National Clinical Research Center for Respiratory Disease and the National Health Commission of the People’s Republic of China collaborated to establish a prospective cohort to monitor COVID-19 cases in China. As on Jan31, 20202007 cases have been collected and analyzed with confirmed COVID-19 infection in these cohorts.
Results: 18 or 1% of COVID-19 cases had a history of cancer (the overall average cancer incidence in the overall China population is 0.29%) {2015 statistics}. It appeared that cancer patients had an observable higher risk of COVID related complications upon hospitalization. However, this was a higher risk compared with the general population. There was no comparison between cancer patients not diagnosed with COVID-19 and an assessment of their risk of infection. Interestingly those who were also cancer survivors showed an increased incidence of COVID related severe complications compared to the no cancer group.
Although this study could have compared the risk within a cancer group, the authors still felt the results warranted precautions when dealing with cancer patients and issued recommendations including:
Postponing of adjuvant chemotherapy or elective surgery for stable cancer should be considered
Stronger personal protection for cancer patients
More intensive surveillance or treatment should be considered when patients with cancer are infected, especially in older patients
Further studies will need to address the risk added by specific types of chemotherapy: cytolytic versus immunotherapy e.g.
Preparedness for COVID-19 in the oncology community in Africa
Africa has a heterogeneity of cultures, economies and disease patterns however fortunately it is one of the last countries to be hit by the COVID-19 pandemic, which allows some time for preparation by the African nations. The authors note that with Africa’s previous experiences with epidemics, namely ebola and cholera, Africa should be prepared for this pandemic.
However, as a result of poor economic discipline, weak health systems, and poor health-seeking behaviors across the continent, outcomes could be dismal. Poverty, low health literacy rates, and cultural practices that negatively affect cancer outcomes will result in poor assimilation of COVID-19 containment strategies in Africa.”
In general African oncologists are following COVID-19 guidelines from other high-income countries, but as this writer acknowledges in previous posts, there was a significant lag from first cases in the United States to the concrete formulation of guidelines for both oncologists and patients with regard to this pandemic. African oncologist are delaying the start of adjuvant therapies and switching more to oral therapies and rethink palliative care.
However the authors still have many more questions than answers, however even among countries that have dealt with this pandemic before Africa (like Italy and US), oncologists across the globe still have not been able to answer questions like: what if my patient develops a fever, what do I do during a period of neutropenia, to their satisfaction or the satisfaction of the patient. These are questions even oncologists who are dealing in COVID hotspots are still trying to answer including what constitutes a necessary surgical procedure? As I have highlighted in recent posts, oncologists in New York have all but shut down all surgical procedures and relying on liquid biopsies taken in the at-home setting. But does Africa have this capability of access to at home liquid biopsy procedures?
In addition, as I had just highlighted in a recent posting, there exists extreme cancer health disparities across the African continent, as well as the COVID responses. In West Africa, COVID-19 protocols are defined at individual institutions. This is more like the American system where even NCI designated centers were left to fashion some of their own guidelines initially, although individual oncologists had banded together to do impromptu meetings to discuss best practices. However this is fine for big institutions, but as in the US, there is a large rural population on the African continent with geographical barriers to these big centers. Elective procedures have been cancelled and small number of patients are seen by day. This remote strategy actually may be well suited for African versus more developed nations, as highlighted in a post I did about mobile health app use in oncology, as this telemedicine strategy is rather new among US oncologists (reference my posts with the Town Hall meetings).
The situation is more complicated in South Africa where they are dealing with an HIV epidemic, where about 8 million are infected with HIV. Oncology services here are still expecting to run at full capacity as the local hospitals deal with the first signs of the COVID outbreak. In Sudan, despite low COVID numbers, cancer centers have developed contingency plans. and are deferring new referrals except for emergency cases. Training sessions for staff have been developed.
For more articles in this online open access journal on Cancer and COVID-19 please see our
We investigated SARS-CoV-2 potential tropism by surveying expression of viral entry-associated genes in single-cell RNA-sequencing data from multiple tissues from healthy human donors. We co-detected these transcripts in specific respiratory, corneal and intestinal epithelial cells, potentially explaining the high efficiency of SARS-CoV-2 transmission. These genes are co-expressed in nasal epithelial cells with genes involved in innate immunity, highlighting the cells’ potential role in initial viral infection, spread and clearance. The study offers a useful resource for further lines of inquiry with valuable clinical samples from COVID-19 patients and we provide our data in a comprehensive, open and user-friendly fashion at www.covid19cellatlas.org.
To further characterize specific epithelial cell types expressing ACE2, we evaluated ACE2 expression within the lung and airway epithelium. We found that, despite a low level of expression overall, ACE2 was expressed in multiple epithelial cell types across the airway, as well as in alveolar epithelial type II cells in the parenchyma, consistently with previous studies9,10,11. Notably, nasal epithelial cells, including two previously described clusters of goblet cells and one cluster of ciliated cells, show the highest expression among all investigated cells in the respiratory tree (Fig. 1b). We confirmed enriched ACE2 expression in nasal epithelial cells in an independent scRNA-seq study that includes nasal brushings and biopsies. The results were consistent; we found the highest expression of ACE2 in nasal secretory cells (equivalent to the two goblet cell clusters in the previous dataset) and ciliated cells (Fig. 1b).
In addition, scRNA-seq data from an in vitro epithelial regeneration system from nasal epithelial cells corroborated the expression of ACE2 in goblet/secretory cells and ciliated cells in air–liquid interface cultures (Extended Data Fig. 1). Notably, the differentiating cells in the air–liquid interface acquire progressively more ACE2 (Extended Data Fig. 1). The results also suggest that this in vitro culture system may be biologically relevant for the study of SARS-CoV-2 pathogenesis.
Coronavirus Entry Genes Highly Expressed in Two Nasal Epithelial Cell Types
This story has been updated to include information on a related study appearing in Cell.
NEW YORK – Two types of cells inside the nose express high levels of the genes encoding proteins the SARS-CoV-2 uses to enter cells, suggesting they are the likely entry points for the virus.
SARS-CoV-2, the virus that causes COVID-19, uses its spike protein to bind to cellular receptors in the human body. The virus relies on the ACE2 receptor protein and the TMPRSS2 protease to enter cells, but which cells are initially infected has been unclear.
An international team of researchers used single-cell RNA sequencing datasets put together by the Human Cell Atlas consortium to search for cell types that express both the ACE2 and TMPRSS2 genes. As they reported in Nature Medicine Thursday, they found a number of cells in different organs express the genes encoding these proteins, but they homed in on cells of the respiratory system, especially goblet cells and ciliated cells in the nose.
“Mucus-producing goblet cells and ciliated cells in the nose had the highest levels of both these [genes], of all cells in the airways,” first author Waradon Sungnak from the Wellcome Sanger Institute said in a statement. “This makes these cells the most likely initial infection route for the virus.”
Using the Human Cell Atlas dataset, Sungnak and his colleagues analyzed ACE2 and TMPRSS2 expression in a range of tissues, including not only respiratory tissue — previous analyses using immunohistochemistry had detected both ACE2 and TMPRSS2 in the nasal and bronchial epithelium — but also tissue from the eyes, digestive tract, muscle, and more.
ACE2 gene expression was generally low across the datasets analyzed, while TMPRSS2 was more broadly expressed, the researchers found. This suggested that ACE2 expression might be the limiting factor for viral entry in initial infections.
However, ACE2 was expressed in a number of epithelial cell types of respiratory tissues, and its expression was particularly high among goblet cells and ciliated cells of the nose. The researchers confirmed this finding using data from two other scRNA-seq studies.
Other genes often co-expressed alongside ACE2 in the respiratory system included ones involved in carbohydrate metabolism — possibly due to their role in goblet cell mucin synthesis — and those involved in innate and antiviral immune functions.
The ACE2 and TMPRSS2 genes were also expressed outside of the respiratory system, including by cells of the cornea and the lining of the intestine, which the researchers noted is in line with some clinical reports suggesting fecal shedding of the virus.
Where these viral entry receptor genes are expressed in the respiratory system could influence how transmissible a virus is. The researchers compared the tissue expression patterns of these viral receptor genes to those of receptor genes used by other coronaviruses and influenza viruses. The receptors used by highly infectious viruses like influenza were expressed more in the upper airway, while receptors for less infectious viruses like MERSCoV were expressed in the lower airway. This indicated to the researchers that the spatial distribution of the viral receptors may influence how transmissible a virus is.
“This is the first time these particular cells in the nose have been associated with COVID-19,” study co-author Martijn Nawijn from the University Medical Center Groningen and the HCA Lung Biological Network said in a statement. “The location of these cells on the surface of the inside of the nose make them highly accessible to the virus, and also may assist with transmission to other people.”
Another study that appeared as a preprint at Cell also used single-cell RNA-sequencing datasets from humans, nonhuman primates, and mice to examine where cells expressing both the ACE2 and TMPRSS2 genes are located. Those researchers, led by the Broad Institute’s Jose Ordovas-Montanes, found both genes were expressed among type II pneumocytes and ileal absorptive enterocytes as well as among nasal goblet secretory cells.
Sungnak, W., Huang, N., Bécavin, C. et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med (2020). https://doi.org/10.1038/s41591-020-0868-6
AAAS Science Podcast: Why some diseases are seasonal and some are not: Coronaviruses and more
Reporter: Stephen J. Williams, PhD
The following podcast from the American Association for Advancement of Science (AAAS) discusses the seasonality of some viruses while other viruses are able to manifest themselves in different seasons over the globe.
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