Welcome to Doughnuts with drugs

DOUGHNUTS WITH DRUGS

After Sushant Singh Rajput’s demise, Koffee with Karan was criticized at many levels. Being called the ‘flag-bearer of nepotism’, Karan Johar might ban his own show. As my fellow netizens might refrain from watching the show again, I would like to take the opportunity and entertain you with ‘Doughnuts with drugs’. Unlike KWK, this is a one-day affair. It will not be aired for decades and does not support any form of discrimination in the name of ‘hot brewing gossip’. So, feel free to read on.

For months now, it has been known that the drugs- Dexamethasone and Remedesvir have shown potential in the treatment of Covid-19 patients. Dexamethasone is the first drug to show a reduction in the number of deaths. With a new case just a few houses from mine, I would like to dive deeper and understand these drugs better. Would you like to join me in this quest and develop a better understanding?

Firstly, what is dexamethasone?
It is a synthetic glucocorticoid belonging to the steroid class of drugs. It has anti-inflammatory and immunosuppressive properties and has been shown to reduce deaths by one-third in Covid-19 patients on ventilators. Its potential was discovered in the RECOVERY trial that had been launched in March to test various potential therapies. Its effect on critically ill patients was note-worthy and thus, has been claimed to be a ‘breakthrough’.

“It is a major breakthrough,” says Peter Horby, an infectious-disease specialist at the University of Oxford, UK, and a chief investigator on the trial. 

What are glucocorticoids?
These are hormones produced in the adrenal cortex (present in the periphery of the adrenal gland) and secreted into the blood. Glucocorticoids inhibit many molecules that are associated with inflammation like cytokines, chemokines, etc. Often, anti-inflammatory mediators are upregulated by glucocorticoids.

What is its mechanism of action?
Our body is made of cells which are like little houses having rooms for various actions. The rooms or organelles float on an aqueous medium called the cytoplasm. Glucorticoids bind to glucocorticoid receptors(GR) present in the cytoplasm. GR stays in a complex with hsp90,hsp70 and hsp56. These are heat shock proteins and hsp 90 and hsp 56 leave the complex when glucocorticoid passively diffuses into the cell and binds with GR. The activated GR complex moves into the nucleus where hsp 70 leaves the complex.

Figure showing Signal transduction by GR – Garabedian et. al, F1000 Research,2017

Glucocorticoids have the following actions:

  1. They prevent the transcription (refer to the first blog) of cytokines and chemokines.
  2. They reduce the neurokinin receptor expression. This prevents its action as mediators of the effects of Substance P.
  3. Glucocorticoids inhibit the synthesis of inducible nitric oxide synthase. They also inhibit gene expression of Phospholipase A2 and cyclooxygenase-2 which results in the reduction of prostaglandins and thromboxanes production.
  4. They also reduce the surface expression of adhesion molecules.
  5.  They inhibit the overactivation of macrophages.

All the aforementioned effects play a role in reducing inflammatory responses.

As I had mentioned about the cytokine storm in my previous posts, Dexamethasone’s anti-inflammatory role helps reduce death caused by it. It has been shown that the drug reduces death from 40% to around 28% in critically ill patients. It is cheap and can be administered orally and intravenously. Like most drugs, this drug also has side effects but its clinical benefits are more overpowering.

What is Remedesvir?
It is a broad-spectrum antiviral prodrug (present in an inactive form but gets activated inside the host cell). It was developed by Gilead Sciences and is a nucleotide analog (specifically, adenosine analog). It was designed primarily for treating Ebola virus.

How does it work?
Remedesvir resembles adenosine and its active form gets incorporated into the RNA of the virus. This terminates genome replication. It has also been observed that this drug plays a role in the evasion of proofreading activity of the viral exoribonuclease. This promotes mutation in the viral RNA. It has been shown to reduce SARS-Cov-2 replication in Rhesus monkey and thus, shows promise. However, being a broad-spectrum drug, scientists are worried about its harmful side effects like antiviral resistance.

"Therapeutic remdesivir treatment initiated early during infection had a clinical benefit in SARS-CoV-2-infected rhesus macaques."-Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2,Nature,2020
Figure: Remdesivir- Potential Repurposed Drug Candidate for COVID-19. Image created with biorender.com

With this, we come to the end of Doughnuts with drugs. A shout out to all the frontline workers including Debdutta Ray (our college alumnus) who has recently lost her life while tending migrant workers. The fight against the pandemic is getting worse day-by-day. I urge all the readers to not take this virus lightly. Please wash your hands before eating doughnuts, wear your PPEs, and try to stay indoors.

The Royal Vaccine Hunt

(Copyrights held by Royal Collection Trust)

The scene in the courtroom…

Minister 1: “The fort is under attack. We have to do something to save the kingdom in some way or the other.”

Minister 2: “But what can be done to protect the kingdom? The virus is killing at a death rate of about 2 to 5%.”

Minister 1: “We are in grave danger. We have to think of a solution as soon as possible.”

Scientist: “What about a vaccine? “

All the ministers stare at the scientist.

Minister 3: “Vaccine? It will take years to make a vaccine. The kingdom will be doomed by then.”

Scientist: “Not if we speed up the process. Let me start right now. I will get in touch with the other kingdoms and see if I can get some help.”

Continuing the concept of ‘Akraman’ from my previous blog, today I am going to write about one of the ways our army is fighting against Covid-19 – finding a suitable VACCINE. As is apparent from the numerous headlines that pop up on our smartphone screens, scientists across the globe are working on developing a vaccine against SARS-CoV-2. But why are they working on vaccines? And which vaccine has proved to be the most successful as of now? How do these vaccines work? If these questions pique your interest, then keep reading.

What are the vaccines?

Vaccines are forms of the pathogen that are incapable of causing disease.They prevent the disease by training our immune system against a foreign pathogen. It is like training an army against an enemy by showing them visuals of the enemy so that the warriors are aware of the enemy and its characteristics.   

We have 2 types of immunity- innate and adaptive. The innate immunity is like a beagle. Beagles, although very cute, generally are very barky. They bark at everyone without any specificity. On the other hand, trained dogs only bark at strangers or a specific type of people. Likewise, the innate immunity can fight against a broad spectrum of foreign pathogens that invade our body and lack specificity. On the other hand, adaptive immunity recognizes a specific pathogen and fights against it.

Certain cells belong to the adaptive immunity called B-cells and T-cells. The B-cells have the capability of producing antibodies against a specific part of the pathogen called the antigen. These antibodies have various functions that ultimately eradicate the pathogen from the body. A subset of these B-cells can memorize the type of pathogen they have encountered and can facilitate immediate antibody production if the same invader attacks again. A similar function is also seen in T-cells that kill the target cells but do not produce antibodies. These subsets of b- and t-cells are called memory B-cells and T-cells. Vaccines induce the formation of these memory cells in the body so that when the real pathogens enter, the immune system can start immediate action by producing antibodies against the specific pathogen, employing T-cells to kill that pathogen, etc.

Illustration of vaccine by Maki Naro

The development of new vaccines takes a long time as it is a very long and complicated process. So, what are the scientists doing to speed up the process during the pandemic?

We need to understand that designing and manufacturing a new vaccine for the mass is not an easy task. Conventionally, it takes more than one year to carry out the process. The different stages of clinical trials take a lot of time as monitoring the safety and efficacy of the vaccine is crucial. The different stages of vaccine development are as shown below:

The stages of vaccine clinical trials. Image adapted from: Australian Academy of Science

To increase the pace of vaccine development, various approaches may be taken like carrying out the different vaccine developmental stages simultaneously, increasing vaccine manufacturing sites globally, funding a variety of potential vaccines, carrying out clinical trials in most countries (not only in high-income countries), etc. Different companies are using a combination of approaches to accelerate the process. Organizations like Bill and Melinda Gates Foundation, Wellcome, Mastercard have come forward to fund new therapeutics, prepare for manufacturing, and catalyze the development of the potential drugs and vaccines to eradicate Covid-19. The U.S. government has selected 5 vaccine projects that will receive billions of dollars to allow progress without monetary obstacles.

A summary of the approaches that can accelerate vaccine development, Image Credits: The New York Times

The incident related to the abandonment of the first mass vaccination program against poliovirus tells us the importance of a safe vaccine. If few reports related to the side effects or the negative impacts on public health are overlooked in this quest to develop a vaccine, then it can claim the lives of many and also leave thousands with life-long disabilities. Naturally, I had presented my skepticism in front of the Godmother of India’s vaccine, Dr. Gagandeep Kang, during a webinar. She affirmed that the safety of a new vaccine is checked thoroughly at every stage of a clinical trial, such that chances of the vaccine having a negative effect are very low. Nevertheless, the pace at which the community is working is highly appreciable.

What are the different potential vaccine candidates?

As per the coronavirus vaccine tracker by Jonathan Corum and Carl Zimmer, there are more than 125 vaccines that are yet to enter clinical trials. Two vaccines have already reached phase III of clinical trials.  

AZD1222 (previously called ChAdOx1 nCoV-19) is a vaccine that is in phase III at present. It is being developed by the collaboration of Oxford University and AstraZeneca Company. It was discovered by Oxford University’s Jenner Institute working with the Oxford Vaccine Group. It is known to use a Chimpanzee adenoviral vector that cannot replicate itself. The adenoviral vector is a genetically engineered Adenovirus in which a set of viral genes has been replaced by our gene of interest. In this case, the gene of interest is that of the SARS-CoV-2 spike protein. The mRNA is embedded in lipid. After this vaccine is employed, spike protein is produced in the body. This trains the immune system against the spike protein. The utility of this is: when a SARS-CoV-2 attacks a vaccinated human, the immune system will recognize the virus’s spike protein and will be activated very quickly. Thus, the body can itself fight the virus without further medical intervention.  

Image courtesy: Oxford University

Beth Israel Deaconess Medical Center and Johnson & Johnson are also a part of this quest. Their vaccine candidate uses an adenoviral vector like AZD1222. It is still in its preclinical stages but is one of the 5 drugs chosen by the U.S. government for adequate funding. 

Another candidate in phase III is the BCG vaccine. Murdoch Children’s Research Institute has started a program to check if Bacillus Calmette Guerin(BCG) vaccine can be used against Covid-19. It is based on the observation that the incidence of Covid-19 infection is low in countries having strong BCG vaccination policies. It is known that the vaccine provides a certain level of protection against a broad range of respiratory diseases as it has off-target effects. This vaccine is a disabled form of the bacteria Mycobacterium bovis and is primarily used against tuberculosis. Since it is a disabled form of the bacteria, it can mimic the real pathogen better. It is like training medical students with cadavers. They can see, touch, and understand the human body and experiment on the corpse so that when they have to deal with live human bodies, they are more comfortable and confident.  

mRNA-1273 is the vaccine that has reached Phase II. It has been discovered by the company Moderna. The vaccine uses a very innovative approach to tackle coronavirus. mRNA is a stretch of single-stranded RNA that directs protein synthesis in the cell. This vaccine is the mRNA that produces the Spike protein of the virus. Thus, when administered, cells produce this protein and express it on their surface. The cells of the immune system learn about this protein and train themselves against it. This enhances their action on exposure to SARS-CoV-2.

Photo courtesy of Moderna, Inc.

The vaccine candidate being developed by BioNTech, Pfizer and Fosun Pharma is another mRNA vaccine. The working principle is similar to that of Modern’s mRNA-1273. The companies are focusing on mRNA vaccines because their development time is less compared to conventional vaccines like BCG which took 13 years to develop.

INO-4800 by Inovio is a synthetic DNA vaccine in phase I. It gives rise to SARS-CoV-2 spike protein and RNA in the host cell. This induces immunity and provides protection. The vaccine uses a plasmid vector which is a circular form of DNA containing the alphabets (as explained in the first blog) for the production of the spike protein. When this plasmid enters the cell, it merges with the host chromosome or lives independently and eventually enhances the immune system.

The red part shown with an arrow is the DNA encoding Spike protein (Image courtesy: The New York Times)

Various other vaccines are in progress, some using novel approaches. It is difficult to say which vaccine will be successful as all the candidates have their pros and cons. In the present scenario, one can only be hopeful that at least one succeeds and saves humankind. Till then, let us maintain proper hand hygiene and wear our PPEs as prevention is better than cure.

The scene in the courtroom continued…

Scientist: “A lot of kingdoms are ready to help us. They have come up with brilliant strategies.”

Minister 1: “That is great. But, what I understand is that vaccines are useful in prevention but not in treating those who are already affected. How can we protect them?”

Minister 2: “Didn’t somebody say something about drugs? Can’t we use them?”

Scientist: “ I have already thought about drugs. I will discuss them in the next courtroom session.”

Minister 3: “That sounds like a plan.”

Keep following this site for more posts on other ways the kingdom is preparing its army against ‘akraman’ by the enemies.

AKRAMAN

Battlefield from Chronicles of Narnia (Credits:Tumblr)

‘Akraman’ is a Hindi word which means invasion. In many Bollywood periodic movies, we have heard the war men cry out this word before attacking their enemy. Nowadays, whenever I hear someone coughing or sneezing around me, my brain automatically screams ‘akraman’ on behalf of the number of viruses, especially SARS-CoV-2, that may be present. If we think about the current pandemic, it does feel like a war where the virus is attacking us and we are frantically searching for vaccines and drugs to fight it. So, today I am going to write about the part played by Coronavirus in this war.
It is known that bats are reservoirs of Coronavirus. The relatives of SARS-COV-2: SARS Coronavirus and MERS Coronavirus had attacked mankind before and their origins are known to us. Both had originated in bats though humans received the virus from Civet cats and dromedary camels in the case of SARS Coronavirus and MERS Coronavirus, respectively. It is expected that the virus responsible for Covid-19 also originated in bats but the animal that passed it to humans is still unknown. There is a debate that pangolins may have been the intermediate host.

Possible transmission routes ,Yifei Xu,2020

What are the intermediate hosts?
Let us imagine that coronavirus is someone who wants to take revenge against us. We are the king of this kingdom where we do not let outsiders enter without a proper reference. So, the coronavirus has to find a way to enter the kingdom without being recognized by anyone. It achieves it by carrying out a series of events. It disguises as an attractive woman and befriends the guards of the kingdom. The guards eventually allow her to enter as she is their friend now. Then the coronavirus changes its looks again to befriend the king’s most trusted friend and come closer to the king.Now, the virus has full access to the king’s palace and can roam around freely. Here, the guards are like the hosts or bats and the king’s best friend is the intermediate host or Civet cats, dromedary camels, and pangolins. In real life, the virus changes itself employing mutations which is a change in the nucleotide bases or the alphabets that I had explained in the first blog.
The war…
It is like a stealthy war plan where the enemy enters the room of the king and kills it (the room here refers to the human cells) instead of fighting on the battlefield. The virus is extremely smart and has the key to the king’s room- the Spike protein. The key fits into the lock and the virus gets a free pass to enter the room. The lock is the ACE2 (Angiotensin Converting Enzyme) receptor found in the cells present in many organs of the human body. The Spike protein attaches to the ACE2 receptor and the virus is internalized into the cell by a process called receptor-mediated endocytosis.
Considering that the cell is our pet dog’s mouth and we are playing with it, we see that the dog has a common tendency to engulf our hand in its mouth. So, the sequence is like this:

  1. We put our hand on the dog’s tongue
  2. The dog closes its mouth with the hand inside it
  3. The game starts where we want to free our hand but our playful dog won’t allow it
    The same thing happens with the virus. The Spike protein (hand) sits on the ACE2 receptor (tongue) and the cell internalizes the virus ( the dog closing its mouth with the hand inside it). The whole process is called receptor-mediated endocytosis as it involves the ACE2 receptor and the virus is engulfed by the cell (endocytosis). The only difference is that the cell does not want to free itself from the virus like we want to free our hand from the dog’s mouth.
Life cycle of SARS-CoV-2 in host cell where event 1 shows endocytosis as explained, Lo’ai Alanagreh et al,2020


After the virus is inside the cell, it starts replicating or making babies. The whole motive behind entering the human cell is to take the help of our cell machinery and replicate itself. As I had explained that the virus has a small genome and thus cannot make all the proteins needed, it requires the help of the host cells (here, human cells) to procreate. The virus hijacks the cell and reprogrammes it in such a way that the host cell makes more viral products than its own.
The primary target of our enemy is lung cells called pneumocytes. After entering the respiratory tract, the virus enters the pneumocytes and the positive single-stranded RNA uses the host ribosome to make the enzymes responsible for copying the RNA and synthesizing other proteins required by the virus. The RNA copies and the protein structures combine to give rise to viral babies or progenies. Thus, the enemy creates its battle army inside the king’s room and then bursts out from that room to attack other rooms or cells.
The thousands of virus particles produced during replication rupture the cell in the process of leaving it. This cell rupturing alarms the body that something is wrong, like the sound of a conch shell. It signals the guards that the body is under attack. As a result, the immune system (guard) gets activated. The cells comprising the immune system reach the ruptured pneumocytes and release signals in the form of cytokines. As the cytokines are released the blood vessels get dilated (vasodilation) to allow more blood to enter (thus allowing more immune cells to reach faster). The blood vessel permeability also increases to allow immune cells to reach the site of infection. Imagine that there is a tremendous traffic jam on the main road and the ambulance is stuck in it. To let the ambulance pass, the policemen are trying to open a bypass to allow the ambulance to leave the main road and enter the bypass. Just like that, the blood vessel permeability increases to create gaps like bypasses for important cells to reach the area.

Inflammatory responses showing cells entering through gaps (Credits: Hack Dentistry)


Pneumocytes are present in structures called alveoli in the lung. The alveoli are like balloons that inflate and deflate to allow gas exchange in the lungs,i.e., removal of carbon dioxide and release of oxygen. Sometimes, the increase in permeability of capillaries causes the plasma ( blood without cells) to seep into the alveolar spaces. The immune cells’ mechanisms, like the production of reactive oxygen species by neutrophils, may also disrupt the alveolar structure and allow the fluid to seep into them. The plasma or fluid accumulation interferes with the proper functioning of the alveoli which eventually collapses. This explains the deaths due to pneumonia and respiratory distress in Covid-19 patients.

Pneumonal alveoli (Credits: Primal Pictures)


Like pneumocytes, ACE2 receptors are present on many cells like those involved in our gastrointestinal system. Also, the ACE2 receptor is involved in the Renin Angiotensin System(RAS) that involves major organs in the body like heart, kidney, etc. Dysregulation of this system due to the viral attack may also explain the heart and renal problems seen in Covid-19 patients.
Also, high levels of signaling molecules like cytokines and chemokines which induce inflammation, hence the name proinflammatory cytokines, leads to aberrant functioning of the immune cells. In some cases, the immune cells start attacking the body which eventually leads to multiple organ failures. It is like releasing 1000 hungry tigers into the battlefield instead of 100 and getting eaten by your tigers. The increased secretion of proinflammatory cytokines into the blood refers to what is known as the cytokine storm.

This is how the novel Coronavirus attacks different organs and creates medical complications. How humans are fighting against the virus ‘akraman’ will be described in the next blog. So, keep following to know about your army’s role in this war.

COVID-19 and nature

Maybe COVID-19 is God’s way of protecting the environment.

A few days back I went to the medicine shop with my father and I was not allowed inside to avoid crowding. Since the medicine shop was in a containment zone then, I could walk on the road without fearing about bumping into vehicles. As I was walking down the road, nature’s beauty struck me. Never had I seen the trees along the road look so beautiful. Leaves were devoid of dust, flowers were in full bloom and there was this cool breeze. At that point, I realized what this havoc creating virus had done to nature. There is less pollution, the air that I breathe feels fresh, the bird songs which were lost amidst noisy city life can be heard again.

What I saw outside the medicine shop.

There are not many research articles claiming the direct relationship between COVID-19 and the environment. But, of the very few that have been published, one reports that daily global CO2 emission has decreased by 17%. Before the lockdown policies were implemented across the globe, the math was a 1% increase in global CO2 emission per year. Does this not point out clearly that if given a chance, nature can heal itself very rapidly? So, why do we hesitate to plant trees when we know that it can help purify the air? Why do we choose ventilators over the natural oxygen producers?

This lockdown has allowed us to step back and realize what could have been done differently to avoid the following things:

1.The large ozone hole that we have created

  1. Global warning
  2. The amount of biodiversity we have lost due to poaching, fun, fashion, etc.
  3. The vast expanses of ocean that we have destroyed
  4. The forests that we have slashed down without mercy
    6.,7., ………the list seems to go on.

When I was reading the very famous Shiva trilogy by Amish, a thought occurred to me: Isn’t development like Somras that we are utilizing for our benefit at the cost of other living beings (Nagas) who share this planet? All the plastic we generate for our convenience, the organisms we kill in the name of scientific research, the e-waste we generate because a new tech gadget has been launched and the one we are using is outdated are just like Somras.

How my neighbourhood looks after lockdown.


I am not sure about the authenticity of news like: ‘Extinct species can be seen again’, ‘Swans in canals, dolphins at empty cruise ports and even wild boar in cobbled streets prove how fast nature can reclaim the world’. Nevertheless, I can say with full confidence that my neighborhood is much cleaner, greener and cooler, signs good enough for me to claim that Coronavirus is a boon for our environment.

On World Environment Day, let us ask a few questions to ourselves: Why do we need activists to tell us that we need to protect our environment? Why does our conscience not hurt when we destroy biodiversity? Why do we not plant more trees? Why do we pollute every new tourist spot that we visit? Why do we not love the concept of ‘sustainability’? If we ponder over these questions, realize our wrongdoings, and try to make it better for every species (discovered or undiscovered) living on this planet then maybe God will not send another SARS-CoV-2 to save its creation.

Understanding our enemy

As the number of days staying confined in these four walls keeps increasing, I try my best to sustain my sanity and turn the mundane days into productive ones. I am neither a doctor nor someone who can help people during their time of distress. Nevertheless, I can try working as a science communicator (virtually) and help in containing this infodemic while fighting the pandemic. I know that the prospect of herd immunity is questionable but we can try and increase nerd immunity.

With a good motive, I write my first blog today on the current superstar ,or shall I say supervillain who is claiming so many lives every day. Let us all know more about this virus and understand our enemy together. The objective of writing this blog and all the subsequent pieces that follow is to help us understand science in the simplest way possible. Science is easy if one understands it. There are times we fail to grasp the simplest of concepts because of so many jargon that look scary. So, I will try to explain each jargon in a way that we can understand hoping that this will make us capable of identifying misinformation and understand why we think it is a ‘misinformation’.

CDC’s rendition of SARS-CoV-2

First, let us look into the virus’s genome…

If I am asked what a genome is, I would respond by saying that it is our manipulator. We are who we are because of our genome. It is a huge database of all the information that is required to build and maintain an organism. In scientific words, it is a complete set of DNA or RNA including all its genes. For simple understanding let us think that genes are the pieces of information and DNA/ RNA is the database. Now, what is the kind of information that I am talking about? What makes our genome control us? The answer to that would be- let us consider the genes as chefs who can direct the type of proteins that can be made in our body. So, they have the recipe to make these proteins and transport them wherever required. If our chefs fail to function properly then we may end up being a different version of the conventional pizza that we cannot live without.

Unlike the English recipe books that we read having words from the 26 alphabets, the gene has only words made from the 4 alphabets- A, T, G, and C in case of DNA and A,U,G,C for RNA. It is important to understand that not all genes make food (proteins) , some assist in helping in the process of cooking or do not help in a significant way at all (RNA). These alphabets are like ingredients to the dish and the jargon used for them by scientists is ‘Nucleotide’.

Our genome is made up of DNA but our enemy’s genome is made of RNA. We have 3.3×10^9 alphabets in our cookbook while coronavirus has 27000 to 31000 alphabets only. Such a miniscule virus creating havoc reminds me of ‘The elephant and ant story’ that my mom used to tell me when I was a kid. Another difference in our genomes is that our DNA is double-stranded (looks like two ropes intertwined) and the virus’s RNA is single-stranded.

Daenerys’s locks showing the difference between single stranded RNA and double stranded DNA.
Image taken from Pinterest

Now, let us try to understand how these viruses increase their army size and make more proteins…

Common sense says that such a small cookbook cannot have all the recipes to kill giants like us. It must have a hidden arsenal to deal with humans. That is exactly what happens.

In our case, the DNA is first made into DNA, a process called replication. The DNA is then converted into RNA by a process known as transcription. This RNA is further made into proteins by translation. The whole pathway from DNA to protein is called CENTRAL DOGMA. Since Coronavirus has a genome made of RNA and not DNA so it cannot follow the central dogma. Its process is a bit different from ours and let us see if we can understand it.

RNA strand that can make proteins is called a positive strand while the strand incapable of making proteins is called a negative strand. Coronavirus has a single positive strand of RNA. Thus, it can make proteins directly. But it has to make a lot of proteins from that small RNA genome.

Suppose, we have a bar of chocolate, mangoes, and some leftover vanilla pudding but we want to make chocolate pudding, and mango pudding. Also, our sibling wants to have hot chocolate, vanilla pudding with mangoes . So, what can be done when so many dishes have to be made out of the little number of ingredients that you have? We can take a bit of the vanilla pudding and mix it with chocolate to make chocolate pudding. Likewise, we can add mangoes instead of chocolate to make mango pudding.  We can melt the leftover chocolate to serve hot chocolate and cut mangoes over the vanilla pudding to make our sibling happy. As we can see, the same ingredients are being used in different ways to make a large number of dishes. Let us take this idea and try to imagine how viruses can use this concept to make more proteins from the limited number of alphabets.

We divide the virus’s RNA into many small parts and think of them as ingredients.  The first ingredient is mixed with a part of the second ingredient to make a dish. Similarly, a part of the second ingredient is mixed with a part of the third ingredient to make a second dish. This goes on to make many dishes. These ingredients are called OPEN READING FRAMES (ORF)  by the science community. The starting point of one ORF is referred to as 3′ and the endpoint is called 5′, i.e. , the chef’s assistant (a structure called ribosome) starts with 3′ and ends at  5′.The use of different ORFS to make a single protein (like mixing of ingredients) is called RIBOSOMAL FRAMESHIFTING. The transition from one ORF to another is facilitated by a structure called PSEUDOKNOT in the viral RNA.

Schematic representation of the SARS-CoV-2 (our enemy) genome organization and the different protein templates made from it. gRNA refers to genomic RNA while S,E,M,N are various proteins. the image has been taken from Kim et al., CellPress, 2020.

To make more viruses like it, Coronavirus has to make more positive stranded RNA genome. It achieves that by making a negative stranded RNA as an intermediate using the positive strand as a template (like a picture of the cake that we use as a reference to make our cake) and then again a positive strand of RNA by using a tool called RNA-dependent RNA polymerase. This is how the viral genome replicates.

How the viral structure assembles and makes the virus capable of infecting humans will be discussed in my next blog. Stay tuned till then.