Perspectives

Some pages with curated lists of research articles are listed below.

  1. https://www.nature.com/articles/d41586-020-00502-w
  2. https://covid19.researcher.life/
  3. https://www.cidrap.umn.edu/
  4. https://www.jhsph.edu/covid-19

 


 

The shape of a receptor on human cells that is recognized by SARS-CoV-2

Anand Vaidya, TIFR Hyderabad

Understanding any biological process, including diseases such as COVID-19, requires research at different levels of biology - at the population level to understand the spread of disease, at the individual human level, the affected organs, the cells that are involved in the disease and the protein molecules of the cells. Protein molecules are involved in various steps of viral infection and multiplication, and the knowledge about the structure of protein molecules is critical in developing vaccines and drugs for treatment. Deciphering the structure of a protein molecule is like taking a photograph of the protein molecule using X-rays and electrons beams and it eventually shows the arrangement of thousands of atoms it is made up of. In the current papers, scientists have used these techniques to decipher the structure of proteins involved in the first step of infection to answer how the SARS-Cov-19 virus specifically attaches to human cells and how an antibody blocks this step. 
 

The SARS-CoV-19 virus specifically infects humans because the hACE2 protein, which is recognized by this virus, is produced only in humans. The entire structure of this critical hACE2 protein has been elusive. A group of scientists from China managed to get the structure of hACE2 by increasing its stability using another protein B0AT1 that interacts with hACE2 (Figure). They also went a step ahead and got the structure of hACE2 attached to the 'sticky piece' of S protein from the virus; the S protein (or spike protein) on the SARS-CoV-19 virus sticks to hACE2 protein of human cells and starts the infection. They found three interesting features - (1) the hACE2 protein structure is made up of two hACE2 molecules instead of one, (2) these two molecules are arranged in two different angles resulting in two different shapes of the hACE2 - open shape and closed shape, (3) the S protein sticks to hACE2 only in the closed shape and not the open. The S protein from the virus sticking to the human hACE2 protein is similar to a key (S protein) sticking into the correct keyhole and opening a lock (hACE2). Though we expect only one lock, surprisingly, in this case, two locks (with two keyholes) were found by the scientists and these locks are at different angles. The keys can enter the keyholes only in one angle. These structures are important because other scientists can now begin to find ways of preventing the S protein from sticking to hACE2 i.e. preventing the key from opening the lock. The second group of scientists tried to do precisely this.

Antibodies are proteins generated by a patient's immune system in response to an infection. Antibodies stop the infection by sticking to the key and preventing it from opening the lock. The aim of the second study was to see if an antibody from a previous coronavirus infection (SARS outbreak in 2002) can neutralize the current coronavirus infection. If yes, then this antibody could be used as a basis for developing one general vaccine for multiple coronaviruses instead of one vaccine for each coronavirus. This group from the USA got the structure of the 'sticky piece' of S protein attached to an antibody from a patient from the previous SARS outbreak. Surprisingly, the structure reveals that the antibody cannot block the S protein from sticking to hACE2 - though it does not prevent the key from entering the keyhole, it may prevent it from turning, which eventually stops the infection. This antibody prevents previous SARS infection, but it is not clear if it would prevent the current SARS-CoV-19 infection, and if it does then how does it work. Genetically engineered mice producing hACE2 protein would be the next testing ground for this antibody.
 

[Last update 14 May 2020]
 


 

Nucleic Acid-based Diagnostic for Covid-19

Tamal Das, TIFR Hyderabad

To this day, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) remains the most widespread method for detecting SARS-Cov-2 coronavirus, whose genetic information is carried by ribonucleic acids (RNAs). In qRT-PCR, viral RNAs become templates for a specific enzyme called reverse transcriptase (RT), which generates the corresponding DNA sequences. Using this DNA as starting material, another enzyme called DNA polymerase then kick-starts a cyclic chain reaction called polymerase chain reaction or PCR. PCR eventually increases the DNA concentration by more than a billion-fold, making it detectable by a fluorescent dye. In spite of being the gold standard for the Covid-19 test, qRT- PCR has certain disadvantages. It needs pricey instruments, it needs trained man-power, and it takes hours to get the test done. With millions of people getting infected with the virus, we need a bed-side test kit, and for that, we need an instrument-independent method that is faster, cheaper, and preferably more sensitive than qRT-PCR.

One such method is RT-LAMP. In RT-LAMP, scientists do use reverse transcriptase (RT) to generate DNAs out of viral RNAs, but they replace the subsequent PCR-based DNA amplification by a different loop-mediated amplification (LAMP) reaction. While PCR requires precise up-and-down ramping of temperature in each cycle of amplification, LAMP reaction can happen under constant temperature around 70ºC. This feature liberates the test from the stringency of PCR machines and allows the reaction to happen over a simple hot plate. Another simplicity of RT-LAMP comes from its detection strategy. For the detection of DNA amplification, the reaction mixture contains a pH-sensitive dye that changes its color from red to yellow upon successful amplification. Thus, in RT-LAMP test, a yellow solution implies a COVID-positive sample while a red solution implies a negative one. Further, to make the process even simpler, researchers from Harvard Medical School have recently invented an
inexpensive pipeline that eliminates the rigorous RNA isolation step. With this invention, it looks like RT-LAMP should be able to tell us whether a person is Covid-19 positive or not within 30 minutes.

Other than RT-LAMP, there is, of course, another method that promises to transcend the disadvantages of qRT-PCR. This method reengineers the CRISPR-based gene editing technology for viral diagnostic and is called S​pecific ​H​igh ​S​ensitivity ​E​nzymatic ​Reporter Un​LOCK​ing or SHERLOCK – an acronym inspired by the famous fictional detective character. SHERLOCK does not generate DNAs, but here viral RNAs get directly amplified and then, get detected by an enzyme called Cas13. This entire RNA amplification-detection process can take place in a commercially-available paper dipstick, making it perfect for bedside testing. To make it even faster, researchers at MIT have recently come up with a step SHERLOCK test, called STOPCovid. Interestingly, we also have an indigenous version of SHERLOCK. A team of scientists based on CSIR-IGIB in Delhi is now proposing a rapid FNCAS9 Editor Linked Uniform Detection Assay or ‘FELUDA’, after the fictional detective character of Satyajit Ray. In the latest development, Tata Sons have agreed to help in commercializing the FELUDA paper test kit and make it available for public use by June this year.

[Last update 14 May 2020]
 

Contact tracing using mobile phones

Venky Krishnan, TIFR CAM
 

[General illustration of Contact Tracing based off of CDC-material. CREDIT - CFCF, CDC]

 
In order to arrest the spread of a pandemic such as the one caused  by SARS-CoV-2 (the novel coronavirus), rapid deployment of tools such as contact tracing, physical distancing, and quarantine measures is extremely important. It is even more so in the case of this virus as recent research has shown that contribution to the basic reproduction number (the average number of new individuals that an infected person can spread the disease to) from presymptomatic individuals (infected individuals capable of transmission before they experience noticeable symptoms) is high. In this context, digital technology, more specifically smartphones, has turned out to be an excellent tool as it helps governments access a large population in quick time. Apps such as Arogya Setu developed by the Government of India and  others developed elsewhere in the world [2,3] use bluetooth and GPS features of the smartphone to instantly notify individuals in the contact list of an infected individual as well as other users of the app who have been in close proximity to an infected individual to immediately undertake self-quarantine measures.

[Last update 11 May 2020]


Is there a vaccine for COVID-19?

Aswin Seshasayee, NCBS-TIFR;  Mohak Sharda, NCBS-TIFR, Archit Sharda, Srishti School of Design
 

Medical professionals and scientists are testing a variety of current drugs and vaccines for efficacy against the novel coronavirus. Among the treatment options being considered are drugs normally used to combat HIV, influenza, and malaria, at times in combination with antibiotics to prevent bacterial superinfection. Results of such research are coming in fast. Basic research on how the virus interacts with human proteins can also help identify drugs and vaccines. These are, however, initial indications, and the efficacy of these drugs will need more time and trials to be validated. Therefore do not consume medications not recommended by your doctor.

Research to develop COVID-19 vaccine is proceeding at an unprecedented speed

[Last update 11 May 2020]


Is the coronavirus a lab-made virus? 

Mohak Sharda, NCBS-TIFR
 

A comparison of coronaviruses present in different animals have suggested that bats and pangolins are the most recent intermediaries in the origin of SARS-CoV2. Six mutations in the viral protein required for human-ACE2 protein binding are identical in Pangolin-CoV and SARS-CoV2 but differ by four mutations in Bat-CoV. These mutations cause weaker binding to the human protein when compared to the previously studied 2003 SARS-CoV sequence. This suggests that it is highly unlikely that the current pandemic was a result of purposeful manipulations. A lack of previous studies reporting any progenitors of SARS-CoV2 further reduces the possibility of an inadvertent laboratory release of the virus. Instead two most likely explanations of origin, both explained by natural selection, emerge: 1) the virus adapted in an animal host highly similar to humans before transferring into the latter and/or 2) the SARS-CoV2 viral progenitor jumped into humans first and acquired the desired features to adapt during undetected human to human transmissions.

This is only one example of infections moving from animals to humans, and re-emphasises the importance of “one-health”, which aims to achieve “optimal health outcomes recognizing the interconnection between people, animals, plants, and their shared environment”.

[Last update 11 May 2020]


 

The effectiveness of containment measures

Aswin Seshasayee, NCBS-TIFR; Vijay Krishnamurthy, ICTS-TIFR
 

How effective are containment measures in mitigating spread of the coronavirus? Using real-time data on the mobility of people and the spread of the infection, a group of scientists show that infection spread correlated strongly with mobility in the initial days of the epidemic in China. With the imposition of containment measures, the growth rate of the infection became negative. A high level of compliance with containment measures is necessary. This emphasizes, in no uncertain terms, the importance of containment in mitigating the spread of this virus. A recent modeling study estimates that if such non-pharmaceutical interventions were not implemented, the number of infections could have risen by many folds in China. Early detection and containment of infectious cases play a vital role in reducing the spread of the COVID-19.
 

[Last update 11 May 2020]


Effect of temperature on the spread of COVID-19

Nitish Malhotra, NCBS-TIFR; Swagatha Adhikari inSTEM; Deepti Trivedi NCBS-TIFR
 

High temperature and high humidity may decrease the rate of transmission of the coronavirus. However, the contribution of these weather factors to reducing transmission is small. However, it is too early to conclude whether there are seasonal variations in the infectiousness of SAR-CoV-2. Social distancing and good (hand and respiratory) hygiene are major factors that reduce transmission. Medical professionals and scientists are working to make effective drugs and vaccines to curb the virus.

[Last update 05 April 2020]


How are COVID-19 vaccines being developed?

Aswin Seshasayee, NCBS-TIFR;  Mohak Sharda, NCBS-TIFR, Archit Sharda, Srishti School of Design
 

The novel coronavirus-2 uses one of its proteins to bind to a molecular receptor on human cells. This interaction is critical to successful infection. The human immune system produces “antibodies” in response to infections. Antibodies naturally produced by our immune system against the novel coronavirus reduce the interaction of the virus with its human receptor. This provides ideas and candidates for drug as well as vaccine development.

[Last update 05 April 2020]