Monday, March 15, 2021

mRNA vaccines: A brief history of time


Covid-19 pandemic has ravaged the world throughout 2020. Amidst public health measures that varied across the globe, from full compliance to calling Covid19 a hoax, the scientific community was quietly working on the development of a vaccine for Covid-19. Here is a summary of vaccines for SARS-Cov-2, both approved and in development.

Vaccines Approved

Vaccines in Development

Pfizer, BioNTech’s BNT162b2

Bharat Biotech’s Covaxin

Moderna’s mRNA-1273

Univ of Oxford-AstraZeneca’s AZD1222

Sinovac’s CoronaVac

...

Russia’s Sputnik-V

...

Russia’s EpiVacCorona


China’s BBIBP-CorV



mRNA vaccines give our immune system genetic instructions to recognize the virus, without at any point in time introducing the virus (dead or alive or part or weakened) itself! An mRNA sequence is synthesized for virus’s spike protein (S-protein) and this sequence is introduced into our cellular mechanism to allow our cells to make the spike protein and thereby induce an immune response. The synthetic mRNA is packaged in a lipid nanoparticle that delivers the instructions to the cells. Once inside the cell, cellular machinery follows mRNA instructions to produce the viral spike protein, which then induces an immune response. This is not science fiction – this is real life! We insert instructions to our cells to make a protein from it that looks like a virus protein. The body then builds an immune response to that protein, so in future, if you are ever exposed to the virus, the immune system recognizes that spike protein on the virus and then destroys it before it can enter the cells!

I decided to put together a history in timeline for two most popular vaccines today, Moderna’s and Pfizer’s, which are both mRNA based vaccines.

What you may have heard or read:

Time

Description

64 days

Time it took Moderna to develop their vaccine and launch phase I trial

Jul 2020

Phase III trials began

Dec 2020

The vaccines were ready for deployment and around 3million people worldwide have already been vaccinated.


While everything you have heard and read is correct, the devil though is in the detail and there is a need to understand and appreciate the background work carried out by many scientists and particularly Katalin Kariko in most adverse conditions. In any scientific endeavour, there are hundreds and thousands of scientific researchers who give their everything and largely go unnamed, but in the success of both Moderna and Pfizer is one individual – Katalin Kariko!

I have tried to take descriptive narration out and summarize the history in a tabular form captured as a timeline. Hopefully this is useful, readable and informative.

Time

Description

1961

Messenger RNA (mRNA for short) was discovered by 9 scientists including Francis Crick (of the Crick-Watson double helix fame), Jacob, Brenner and Meselson (of the famous Meselson-Stahl experiment)

1976

Kariko first came to know mRNA in details after attending seminar in Hungary and became inspired to use it for therapeutics

1985

She moved to US from Hungary and joined Temple University as faculty

1990

Kariko moved to Univ of Pennsylvania (Upenn) following a dispute with her boss at Temple University who threatened to deport her.

1995

Through early nineties, she continued her work on using mRNA for drugs and therapeutics, but was not able to generate funding, as all her grant applications were rejected. Eventually, UPenn gave her 2 options – either leave or prepare for demotion

1995

Same year, she was diagnosed with Cancer – so given her circumstances and her desire to pursue research for using mRNA for therapeutics, she decided to stay on and take the humiliation of a demotion at Upenn

1997

In front of a largely dysfunctional copier machine, she met Drew Weissman, who had recently joined Upenn and had approved grants. He became interested in her work and decided to partly fund her experiments and started a partnership

2005

Kariko and Weissman published a paper announcing a modified form mRNA – which is congenial to easy acceptance by the immune system. Normally, we know of 4 bases in DNA, namely, A, T, C and G. In RNA, the T is replaced by a U. Their paper talked of replacing the U with 1-methyl-3’-pseudouridylyl in a synthetically created mRNA. This is generally denoted by greek letter, ψ.

For next 5 years, no additional funding came, not much interest was generated.

2010

Derrick Rossi got inspired by her paper and founded Moderna

2010

Kariko and Weissman licensed their technology to small German company BioNTech.

2012

UPenn refused to renew her faculty contract (since demotion) and told her “she was not faculty quality”

2013

Kariko accepted senior VP role at BioNTech

2017

Moderna began developing Zika virus vaccine based on mRNA

2018

BioNTech and Pfizer started co-working on development of mRNA vaccine for influenza. The landmark paper of 2005 and use of ψ is an integral part of the Pfizer’s vaccine.

Jan 2020

Within weeks, Chinese scientists had sequenced the SARS-Cov-2 virus. A synthetic mRNA sequence is extracted that corresponds to the spike protein.

Vaccine’s trick #1: A clever lipid packaging system delivers this (synthetic) mRNA into our cells.

Feb 2020

Pfizer’s vaccine development revolved around the use of ψ in mRNA sequence.

Vaccine’s trick #2: Cells are extremely unenthusiastic about foreign RNA and try hard to destroy it before it does anything. But the vaccine needs to go past immune system. The use of placates the immune system and interestingly it is however treated as a normal U by relevant parts of the cell.

Mar 2020

In 64 days, Moderna had completed the development of their mRNA vaccine and BioNTech had also reached similar completion stage.

Jul 2020

Phase III trials began

Nov / Dec 2020

The world is ready for vaccination with two leading mRNA vaccines that are 95% efficacious!


In scientific pursuit, never follow only the news in the media – it serves us better to find the whole truth. The vaccines were not developed in one year, as claimed – they are largely a result of tireless pursuit of one woman over 3 decades along with other inspired scientists who ensured that the recipe was ready, come Jan 2020. Technically speaking, we have waited 59 years since 1961 for this day! Yes, the arrival of SARS-Cov-2 virus definitely fast paced the latter development.

Katalin Kariko is directly responsible for the Pfizer vaccine, while an inspiration to Rossi and why Moderna was created! Remember the name, she might just feature in the news as a future Nobel Laureate!

Monday, March 8, 2021

FC1 and FC2 - a tale of two genes

This short article is largely my fictional essay. When the scientific community first put together the human genome in early 2000 and published subsequently, we suddenly discovered that there are more than 20,000 genes in our genome. We are still discovering new genes and their functions through a rigorous scientific protocol. These genes are either named based on their location, or their function. They are appended with a number if there are more genes doing the same thing but with a small difference. Metaphorically speaking, humans are discovering newer genes also based on human behaviour. While there is a MAGA gene doing rounds lately in the other half of the world, in our own backyard, two genes were unearthed during these last 6 months of the pandemic. Based on location and function, I choose to call them FC1 and FC2. Their resemblance to our WhatsApp group names is purely coincidental. Other than location and function, these 2 genes also have another attribute – behaviour!

Some of the most fundamental questions concerning our evolutionary origins, our social relations, and the organization of society are centred around the issues of altruism and selfishness. Experimental evidence indicates that human altruism is a powerful force and is unique in the animal world. However, there is much individual heterogeneity and the interaction between altruists and selfish individuals is vital to human cooperation. Depending on the environment and circumstances, a minority of altruists can force a majority of selfish individuals to cooperate or, conversely, a few egoists can induce a large number of altruists to defect. Current gene-based evolutionary theories cannot explain important patterns of human altruism, pointing towards the importance of both theories of cultural evolution as well as gene–culture co-evolution.

In evolutionary biology, an organism is said to behave altruistically when its behaviour benefits other organisms, at a cost to itself. Altruistic behaviour is largely considered more surreal and noble in nature, whereas its opposite, the selfish behaviour is more common in animal world. In everyday parlance, an action would only be called ‘altruistic’ if it was done with the conscious intention of helping another. But in the biological sense there is no such requirement. Indeed, some of the most interesting examples of biological altruism are found among creatures that are (presumably) not capable of conscious thought at all, e.g. insects.

Altruistic behaviour is common throughout the animal kingdom, particularly in species with complex social structures. There are plenty of examples of vampire bats, vervet monkeys, helper birds, meercats volunteering an individual to watch out for a predator essentially putting its life at risk. Such behaviour is maximally altruistic. From a Darwinian viewpoint, existence of altruism is puzzling. Natural selection leads us to expect animals to behave in ways that increase their own chances of survival.

Human societies represent a huge anomaly in the animal world. They are based on a detailed division of labour and cooperation between genetically unrelated individuals in large groups. This is obviously true for modern societies like ours. Why are humans so unusual among animals in this respect? Human altruism goes far beyond that which has been observed in the animal world. Among animals, fitness-reducing acts that confer fitness benefits on other individuals are largely restricted to kin groups. On the other hand, humans have the unique ability to form and cooperate within large social groups, which include many genetic strangers. For example, humans invest time and energy in helping other members in their neighborhood and make frequent donations to charity. They come to each other’s rescue in crises and disasters. They respond to appeals to sacrifice for their country during a war, and they put their lives at risk by helping complete strangers in an emergency.

Plato argues in his treatise, ‘The Republic’, that the soul comprises of three parts, rational, appetitive and spirit. He says, for a community to be just, every element has to perform the role to the best ability. He combined the concept of soul as defined by Socrates and Pythagoras before him.

Sigmund Freud presented an alternative theory of ego, superego and id. The id is trying to get you to do things and the superego is trying to get you to make good decisions and be an upstanding person. So the id and superego are always fighting with each other and the ego steps in between the two.

Both of the above abstractions, try to explain human behaviour at an individual and community level.

In the literature, two largely eminent theories of altruism are discussed, which are both mathematically founded and have overwhelming empirical evidence. They are the ‘kin selection theory’ and ‘reciprocal altruism theory’. The kin selection theory says that natural selection would favour behaviours that benefit those organisms or others who share their genes, e.g. closely related kins. On the other hand, reciprocal altruism involves shared altruism between neighbours as a reciprocal act of kindness either directly or at some point in time in future. ‘Competitive altruism theory’ explains other forms of altruism that can not be explained by these two theories. For example, acts of volunteering and charity for non-kin groups.

To some extent, the idea that kin-directed altruism is not ‘real’ has been fostered by the use of the ‘selfish gene’ terminology used by Richard Dawkins in his famous book by same name. A ‘selfish gene’ story can by definition be told about any trait, including a behavioural trait.

The origin of “The Selfish Gene” is intriguing. Dawkins revealed in the first volume of his memoirs, “An Appetite for Wonder”, that the idea of selfish genes was born ten years before the book was published. The Dutch biologist Niko Tinbergen asked Dawkins, then a research assistant with a new doctorate in animal behaviour, to give some lectures in his stead. Inspired by Hamilton, Dawkins wrote in his notes (reproduced in An Appetite for Wonder): “Genes are in a sense immortal. They pass through the generations, reshuffling themselves each time they pass from parent to offspring ... Natural selection will favour those genes which build themselves a body which is most likely to succeed in handing down safely to the next generation a large number of replicas of those genes ... our basic expectation on the basis of the orthodox, neo-Darwinian theory of evolution is that Genes will be 'selfish'.”

As an example of how the book changed science as well as explained it, a throwaway remark by Dawkins led to an entirely new theory in genomics. In the third chapter, he raised the then-new conundrum of excess DNA. It was dawning on molecular biologists that humans possessed 30–50 times more DNA than they needed for protein-coding genes; some species, such as lungfish, had even more. About the usefulness of this “apparently surplus DNA”, Dawkins wrote that “from the point of view of the selfish genes themselves there is no paradox. The true 'purpose' of DNA is to survive, no more and no less. The simplest way to explain the surplus DNA is to suppose that it is a parasite.” Four years later, two pairs of scientists published papers in Nature magazine formally setting out this theory of “selfish DNA”.

So, as a corollary to the competitive altruism theory, I can think of a theory that explains selfishness rather than altruism, which I can best describe as ‘competitive selfishness theory’.

I think we carry these altruist and selfish genes together in our DNA. They get expressed depending on the environment and circumstances. Let’s say FC1 is the altruist gene. It gets expressed routinely for our near and dear ones and those in immediate family (as per all theories mentioned above such as the kin selection, reciprocal altruism and competitive altruism). FC2, on the other hand, let’s say is the selfish gene. It gets expressed routinely for community related issues. Clearly, we have both of them. It is just their amount of gene expression depends on environment and context. Largely, the empirical evidence witnessed during the last 6 months of the pandemic speaks volumes of which gene is expressed more. It is also true, that we have seen both get expressed simultaneously. What else explains a behaviour when the individual is altruistic in his/her environment but clearly selfish for the same issue when it comes to community?

If humans are the most evolved form in animal kingdom and the only form capable of cognitive thinking, then we need to do much better than just expressing the FC2 gene most of the time. That is a behaviour genetically coded in us, by just virtue of us being the living species of animal kingdom. Every other species does that too. While a noble, just, fair and charitable community is clearly a Utopian idea, should the FC1 in us not get expressed at least as much as FC2, if not more? I think it should. What do you think?

Sunday, March 7, 2021

New beginning

March  2021 is not just a new month/year - its a year after the pandemic set foot on this planet and changed all of us - whether we liked it or not, whether we agreed with it or not.

So, my thought too is to revive my blog series. You would see I made many attempts before (since 2010) and have largely got caught up in following dilemmas:

  1.  Should I publish only after I write a meaningful post? The problem with this is it cant be periodic, but I have control over what I publish.
  2. Should I publish periodically with  not-so-great contents ? The problem is obvious.

I have decided to find the middle ground and decided to start publishing, both periodically and not wait for a long article, but publish one liners, paras, pages or articles as they appear important to me at that time. So, here is going to be another start on the lines of Hugh Prather's - "Notes to myself".