Mani Family Blog!

Hello, again. Our Cobra adventure is now three days in. After the torrid rainstorm, that was the St. Louis Diwali, a bright, crisp and windy Sunday meant 2 drives with the Blue Snake.

After waiting till the sun was truly in the clear (and neighbours likely awake from their slumber), it was two pumps on the gas pedal and a push on the starter pedal to awake the beast. From the usual explosion of noise, her engine settles into a Brrump-Brrump-Brrump rhythm. Strapped in my four point harness, like a biplane pilot, I gingerly engage reverse as I crawl out onto my driveway. Pedestrians enjoying the morning walk regard me with disdain as I try to enter the roadway.

Surprisingly, the clutch is light, the transmission precise as I gently advance through first, second and third as I trudge down Wydown – just under the limit. Shouting a big “Thank you” to the county of St. Louis for fixing Big Bend, I traverse the segment from Wydown to the 40 without the usual bone-shaking that the ultra-stiff suspension of this replica of a 60s racer has. With the smoothness of a P-51 taking wing in the crisp November air, she delights as I gently advance the gas pedal to match the expressway speed as she settles into her overdrive at a meager 1800 rpm and 60 mph. Occasionally buffeted by the near gale-force winds that remained from the prior night’s storm, she continues unabated, her steering light (and a little numb – thanks to the power assistance) and drawing on easy reserves of power to climb inclines without even the thought of a downshift.

Despite the balmy 50^o weather, freezing air rips through the cabin as it creeps through the tiny spaces in the soft top. Notwithstanding my relaxed grip, my fingers are numb on the moto lita at 11 and 2 as we coast to the exit towards the Chesterfield Airport. Returning back to the expressway from the overpass, she eases into roadways speeds with the easy alacrity of an old hand, gently reminding me of how outmatched I am to what she is capable of, yet welcoming me to enjoying her thoroughbred power as she flexed her considerable muscle. Her dimunitive proportions (the same as the Mazda Miata) make her a dream to point and steer as she switches lanes accurately and without complaint.

Thundering back up our driveway, she returns to her abode with a clatter and a clang as I remove the battery-kill tag. I enter to find her angry namesake, looking in askance to being left behind. Apologies delivered, I head to work in my trusty Golf.

Returning from work, I find both ladies ready to embark again. The cobra ready to dance, and Alpana dressed in biking gear. A smile on the latter, broader than the Chesapeake Bay greets me as I start up the 4-wheeled one. Accompanied by the thunder of her exhaust, we go through a gentle drive through the quiet Clayton Sunday, as the smiles continue to grow.

Trundling home, my wife looks at me. Of all the cars I’ve had, this would be the first time, her face was both content, yet excited, as she pronounced that this was her favorite car ever.

Which would make sense.

Of all the cars I’ve owned, this is by far the prettiest, meanest, most characterful car that carries a streak of mischief but remains responsible, gentle and smart. Probably my second best choice in all my life.

BDR#2122

RT4 with an Iconic 427 ci engine. 488 bhp/533 lbft on the dyno. BMW E91 rear independent suspension with coilovers. 4 piston 13 inch brakes in front and single piston in the back. 18 inch 245/40 (front) and 295/40 (rear). Heated seats and interior with cloth soft top.

A few blogposts ago, I alluded to Fastlane Classic Cars. It is a cool place to visit and is staffed by car enthusiasts who are driven by the spirit of the car, more than fastidious adherence to purity of lineage. Dan, the general manager, was kind enough to allow me to take some pictures. These were done with my trusty old Leica SL with a 80-200 F4 ROM. All the pictures were taken at wide-open aperture and handheld. It may have been easier to take these with a wider lens, but the importance of maintaining the proportions of these beautiful cars was more imperative than just capturing the whole car.

As readers of this blog might surmise, I am an avid believer in science and keeping an open mind. Dogma is the antithesis to scientific method. The ability to accept that known science may be wrong, is the underpinning of modern scientific method. The advent of COVID19 has changed everything. The nearly 1 million deaths worldwide are a tragedy, but the impact of COVID19 may have much more far-reaching consequences. Imagine if the events of the 1918 pandemic or the Black Plague had resulted in halting of the quantum mechanics and the industrial revolution respectively. The ability of modern medicine to save lives would have been stunted, resulting in billions of deaths. A sort of “butterfly effect”.

Science is under threat today.

Evangelical and religious people are not that threat. It is possible to both be a believer and to have faith and yet, accept science. Science is under threat from within. The core of our community has significant rot, where dogma and petty cronyism as well as politics have reared their ugly head.

Let me give you an example. As the proud few, that make up the readership of this blog, will recall, I signed up to receive the Moderna vaccine against COVID 19. I did it because I went through the due diligence to assure myself that the trialists and the technology proposed made sense. I did so, not as an expert in vaccine design, but as someone that believes that there have to be scientific underpinnings to any approach. Satisfied with the propriety of methodology, I have since received both the primary and booster doses.

The greatest pushback that I have experienced about doing so, has not been from rural farmers or evangelical priests or even some of my mask-refusing compatriots, it has been from so-called people of science: doctors, nurses and self-professed scientists.

This is indeed a surprise.

When I signed up for this, I thought there would be a crush of those who believed in science, lining for this. In fact, my experience is to the otherwise. I do not know of any of my colleagues – in medicine or science – who have agreed to receive the trial vaccine. When asked why, the replies are variants of a single theme:

“I don’t know if it is safe and I’m not willing to take a chance.”

Really?

If people of science do not sign up to these studies, then why should your patients or the public, believe in your scientific edicts. A randomized quadruple blinded research Phase III trial is as scientific and safeguarded as it gets.

Can bad effects occur?

Absolutely.

But I would rather these occurred in a scientific study and not during a wider release of the vaccine.

Many of my colleagues are so-called clinical researchers. This involved convincing patients to try “experimental” treatments. This adds to their scientific glory and promotion prospects. Yet, none of them, are willing to consider this a scientific endeavor that is necessary to change the world.

COVID19 has changed everything. As we wait for the second surge, the IHME modeling suggests mortality this fall, that will make heart disease sink to a second place. We need ALL the tools we can get to deal with this. the first step is accepting and enjoining scientific method as the single most effective tool against this.

I am a scientist and a devout believer. I respect the faith of those who believe in the almighty’s deliverance. I believe that science is a gift to Humankind from the Divine. While the role for faith is something I cannot explain or understand, as a physician, I have seen miracles abound. It does not dim my devotion to science.

The threat to science is not from maskless Evangelicals. It is not from creationists. It is not from the rural farmer who worries about how he/she will make payroll in these times. It is from pseudo-scientists out there, who would be happy for patients to enroll in their well-paying pharma-company sponsored trial, but lack the moral turpitude to stand up for a vaccine to the greatest threat to humanity in modern times.

I’d like to publish my response to your kind comments on the prior blog post. As an SCAI member, I value my Society and your response. But I would like to point out my specific concerns and some suggestions. 

As a long time SCAI member, it pains me to say that the current activities of the society do NOT reflect my perception of what a professional society for interventional cardiologists needs to be.  In these difficult times, it is becoming increasingly hard to practice as an interventional cardiologist out in the community. With multipronged rivalry from interventional radiologists, cardiac and vascular surgery as well as their strongly supportive professional organizations, many of us face uphill battles as we deal with credentialing and new procedures as medicine evolves. The need of the hour is an advocate for our cause, not a witness for the prosecution.  

While elite operators (read: high volume, academic – not necessarily high quality) prefer that we refer our cases to them – in their cocooned environs – this comes at a cost.

Firstly, the patients often need to travel long distances, and deal with physicians and hospitals they are unfamiliar with. For instance, an 81-year old rural farmer with no family in the city, this is a major issue. On top of that, many of our patients are country folk for whom these large cities and mega hospitals are a forbidding prospect, even prior to their high-risk procedures surrounded by people they don’t know or can’t relate to.

Secondly, as you are well aware, the complexity of disease, driven by aging, obesity and diabetes has only increased. By reducing volume in the community and promoting the “high quality (i.e. high volume) referral center” model, it also means that operators in the community are less confident at dealing with these patients when they present in an emergency at 2AM on Christmas night, when the “referral center” team, tens or hundreds of miles away, is warmly tucked away.

How, then, does taking away procedures from us, the community cardiologists, help the specialty? How does it help our patients? What are the metrics that decide who gets to do what?

Here are my suggestions:

As a former member of the QI and advocacy committees, as well as working with Dawn on the PAC, I am only too keenly aware of how lacking we are in member engagement. These are the concerns that I have heard from my colleagues and in this missive, hope to transmit these to you.

1. SCAI, possibly partnering with industry, needs to take the lead in training operators in the community to enhance the procedures they perform, as well as, engage them in ensuring they have the resources to do these safely. 

2. SCAI needs to find ways to HELP interventionalists negotiate the credentialing processes in their local areas to ensure that they are able to deliver the appropriate and safe care to the patients – IN THEIR COMMUNITY.

3. Rather than focusing on volume metrics, SCAI should help operators in the community with creating QUALITY metrics to enhance the safety and appropriateness of the procedures, because we can do it BETTER than any other specialty. 

4. Mandate that at least 30% of the SCAI leadership, at any given time, consist of community cardiologists (not just academic “leaders”). This will need recruitment and engagement but it is work that needs to be done for the good of the Society and the specialty. 

I do not want this letter to come across as self-serving. I am secure in where I am and am writing to you, out of a sense of alarm, rather than a desire to look for any academic growth. While I am happy to help in ALL the society’s efforts, I do not want to seem like I am angling for a position in this. My only interest is preventing the decline in our specialty and our Society. I remain committed to the ideals of SCAI with the same enthusiasm as I did in 2006 and hope that we can reclaim this lost ground. 

Best regards,

Kartik Mani FSCAI

In the interests of keeping this an open discussion, I am highlighting the reply from the president of SCAI on the blog.

“As President of SCAI, I have made it my mission to represent the membership, not the elitists.
We share your concerns about the “competency” article. Let me assure you that SCAI DID NOT author this article or endorse it. Its publication was a surprise to all of us. The journal CCI publishes many independent articles, as it did in this case.
We are in the process of writing a rebuttal to this article and its harsh recommendations, and to let everyone know that SCAI HAD NOTHING TO DO WITH THIS ARTICLE
SCAI is trying to be inclusive and we’ve created an opportunity to submit cases through SCAI.org, apply for committee membership and is having several webinars where you can give commentary.
Please let me know how we can do a better job.
Cindy Grines”

The society for coronary angiographers and interventionalists is a medical professionals group that portrays itself as a representative for the interventional cardiology community – both in the US and abroad. Things could not be further from the truth. As a card-carrying member of the organization, I would like to bring to light exactly how bad things are. Even if you are not an interventional cardiologist, you may want to read this, just to see how a “professional society” devolves from high ideals to petty protectionism and selfish elitism.

I joined SCAI as a wide-eyed interventional cardiology trainee in 2006. I was dazzled by the camaraderie and focus on quality. A determined effort to maintain high procedural quality and an academic approach – alone – even in the face of strong commercial and industry influence taking over many others. Over the years, as a member, subsequently a Fellow and committee member, I have seen with dismay as the society has devolved into an elitist club, focused more on pet agendas of “leadership” as well as promoting their own, with no emphasis on trying to honestly represent the large body of interventional cardiologists in the community.

For years SCAI has pushed an agenda portraying themselves as representing the interests of patients’ as purveyors and guardians of procedural quality. While this may have held true in yesteryear, the present sings a different story. Most present “multi-society” documents, no longer include SCAI, partly because of their vanishing relevance. Whether in discussion of outpatient surgery centers, high risk coronary procedures, valve procedures, the society is lead by individuals who believe that they are the only people capable of doing these procedures. Akin to royalty, they do dole out permissions to the humble average board certified interventional cardiologist out there, but the paying procedures (that the SCAI fights for expanded reimbursement using society money at the national level) should be preferentially sent to “quality” operators (per their own self affirming guidelines).

Take for instance the most recent”competencies” document they have generated.

https://onlinelibrary.wiley.com/doi/abs/10.1002/ccd.29229?campaign=wolearlyview

In this wondrous piece of work, the authoritarian authors promulgate that training for high-risk PCI be driven by numbers that would result in less people available to do these procedures than are currently out there. Without delving into details, their guidelines are clearly likely to benefit the authors of the document. Rather than focusing on improving the standards of procedures performed in the patient’s neighborhood by focusing on education and engagement of the society’s membership, the statement is to put unrealistic numbers to prevent “low-volume” operators. Of course this is put out in the guise of a training document, i.e. applicable to training of new operators, but it is a short hop from these becoming standards that hospitals use to determine privileges and renewal thereof in existing operators. For example they recommend 150 CTO procedures at a minimum to be considered competent. The number of such centers that do 150 CTO procedures nationally is tiny. Then, they insist on technical aspects to further limit access. What broke the camel’s back was the fact that in order to qualify as a “high risk operator” a physician had to be reckless enough with at least 15 patients to have to demonstrate competence in rescuing a ruptured coronary artery with injecting fat or a plastic covered metal coil or a possibly dangerous heart support device (where significant safety questions have been raised by 2 independent non-industry funded studies).

In all of this, where is the patient, you ask? Nowhere, there are no mentions of outcome metrics with these procedures. There is no mention of metrics to ensure that appropriate medical therapy is ascertained. There are no metrics of procedural followup of these patients. It makes me wonder why the focus is only on things which can be billed for?

Is this what we have become? Is this who we are? As an interventional cardiologist and a Fellow of the Society, it pains to me to see this. I could quit the Society. But how would that help. No. The society won’t be rid of me that easy. I will stay and fight. I will be the thorn in their side, till every last one of them cries uncle. I will be there until the best outcome for the patient and the MAJORITY of interventional cardiologists, is back at the center of the discussion.

Why the majority?

Most interventional cardiologists, unlike the ivory tower elitists running the society, are regular folk. They are part of the continuum of the patient’s life. They have to live with their decisions WITH their patients, unlike the elite who deign to touch the patients and return to eliteland, never to see the patient again. The regular interventionalist knows his patient, their families and their social fabric. These elite don’t.

And yet, the elite are the one’s making decisions on how the regular interventionalist cares for his patients. In other words, they are trying to take away the patient’s own decision making by substituting their own.

This has to stop.

I may be one voice. I may be shunted aside. But it will not be for a lack of trying. Join me. Retweet this. Share this. Email this. Print this and post on your notice board.

We will not be silenced.

Readers of this blog will have noticed my repeated references to a very pretty Guards Red Carrera Targa. To say that I was enamored of it might be an understatement. However, living in a family with 3 others who lacked any real enthusiasm for it, can get a little exhausting. Still, the sunday morning blasts and the rare car event, made it worthwhile.

A few weeks ago, on a whim, I was visiting a classic showroom. I happened to see a really cool looking Dodge Viper. It had many of the things that would make owning a classic, fun. Air conditioning. A water cooled engine that mechanic joe in any small town garage, would be able to set right. A noise that was exhilarating and a menace in it’s appearance that would ensure you knew that messing with the owner was not cool.

Meeting with the crew at Fast Lane Cars, I wandered through their huge collection of American muscle and, was amazed at the ingenuity of my own country’s ponies. For years, the lackluster 80s, 90s and 00s, with the exception of an occasional flash of brilliance, US made cars represented the dreary and mediocre. As a formative car enthusiast in these years, I gravitated to fantasize about wildly stylish Italian, the staid and precise weapon-like German and, yes, even some mad high revving Japanese cars. Unsurprisingly, my car history is checkered by a series of German and British cars, buying American never an option.

As I walked through this temple of chrome, tuned to the sonorous drumbeat of thundering engines, I stood amazed, in wonder. The beauty, and artistry of manufacture of these wonderful wonderful machines. The ability to distill the American spirit into a tonne of chrome and steel is truly incredible. To embody our own brutish, boyish, rebellious, devil-may-care and ferocious yet lovable, simple and easy to please nature into 4 wheels and a transmission, is art. These cars are who we are. The ones’ that noone thought was really capable, but in a pinch would be the only ones to count on. America, indeed.

I just had to bring my wife, another firm believer, in the American ideals to see this (and that Viper).

That did not go as I expected. Having dragged her to innumerable car shows with her “Yes, Dear.” expression plastered to the face, I expected the same lack of enthusiasm, despite my own Ameri-car-na Epiphany. She did not disappoint.

The puckering of the lips and wide eyed shock, as well as the disdain for the “old look (read 1980s look)” flashed across her visage. Even sitting in the aforesaid large cushy seat in this north american serpent car did little to assuage her complete disinterest.

Until…

To watch the transformation of facial expressions from “the unsweetened lime juice” look to one of slack-jawed wonder is an interesting sight. After 3 decades of traveling through life together, it isn’t often that we surprise each other, but this is one that surprised me. This Porsche Blue replica car with stainless steel side exhausts had her smiling with a longing that I have never seen with ANY vehicle. Ever.

Comfortably sliding into it, she looks at me and says, “This is what we should get.”

Imagine that.

Even in my wildest dreams, the original Snake was always out of reach.

Of course, we could not afford this (no, not even the replica!) at this time without dipping into our savings. But to find something unexpectedly that we both liked and enjoyed, after nearly 30 years, 6 homes, 12 cars, 2 children and a dog, was a shock of unimaginable proportions.

So. Here we are. We have decided to put an end to my dalliance with the Europeans and stick with our own this time. The Red One, bids us adieu as we look to save up for Venomous Vixen, somewhere in the future.

8/29/2020

Fun day with the family. Vaccine far from my thoughts. No news to report. Doing my reports regularly.

8/28/2020

How good must you be doing to forget to update the blog?

That good. Dreams are better. Back to work as usual. Busy clinic day. Congratulated by patients for working towards making myself safer by getting vaccinated. Frustrated by peoples’ dogmatic fear of the unknown. Still, when my patients, the Veterans, signed up to fight, it was to die for the nation. This is such a tiny effort by comparison. I feel ashamed when people call me brave, because I take care of the truly brave, and I am no match for them. If there is a downfall to the idea of America, like there was Rome, it is because we, the people, have become way too comfortable. Who stands up for what is right? That which is uncomfortable? Like many things, Science matters. Next time you check your smartphone or device, get an antibiotic for an infection or a medical procedure, remember that it needed a scientific study to create and test. Now, if you are paid to do any of those things (as an engineer, scientist or physician), you are even more indebted to the research. Think about that, the next time you cringe at a vaccine.

Slower, but getting there…

8/27/2020

First day back to exercising today. Times on the rower are longer but within acceptable ranges. 7:44 2K. Some photography with the SL. Usual caseload at work. Couple of meetings. Mentally back to firing on all cylinders. Met with friend at SLU who, it turns out is a vaccine skeptic. Sad.

It remains frustrating to see how people are willing to ask others for money for science, but not support science’s efforts to save lives. C’est la vie.

Have to keep the enthusiasm up. This blog helps with that.

I’m Back!!!

8/26/2020

What a relief to be back. After the fog I was living in over the last two days, today was a breath of fresh air. I completed by NIH progress report for my grant, did a 60mm CTO, organized experiments in the lab and still had enough energy to play with the dog.

Last night was awful. Tried to work last night. Could not even sit. Got dizzy. Had an awful headache. Needed an NSAID. Slept ok. Bad nightmares, very vivid. Very action movie. Really a comedy type, myself. Did not like the pace of the dream/nightmare. NOt sure if it was vaccine or just hypoglycemia from my loss of appetite.

Today, much brighter.

Definitely taking time off for the booster dose. Bit close to my R01 submission, but too late to change my mind now.

Did get a phone call from the vaccine research center after logging in the symptoms. No advice regarding my COVID19 NP swab. Which must mean that it was negative. Which is a good thing.

Was called by a colleague from Med School. Thought I was “brave”. Disabused him of that. Entering an NIH funded trial for a vaccine that has completed Phase 1 and 2 trials and is unlikely to be available in time for the winter is not “brave”. I would argue that even the 50% chance that I DID get the vaccine, is a sign that I am not brave enough to risk a COVID exposure and infection when the next surge happens. And it looks like with slow recruitment, it will be mid October before this trial stops recruiting. Which means that the second dose for a large number of patients will be in November. Which also means we won’t have results of anything till mid December. Which would, of course, be too late to vaccinate people against a predicted surge beginning in November.

This is so stupid of people to take this attitude. With a disease as dangerous as COVID19, which has a mortality of 0.5% in someone with my health status (156 lbs, 6′, BMI 21, Body Fat 7%, 7’26” 2K Row) as compared to close to ZERO if I don’t get it, this paranoid and implanted fear of a remarkable vaccine trial is as much as a rejection of “earth is round” or “wash your hands” concepts.

If people of science and education resort to such base nonsense, how on earth do we expect those without the requisite knowledge or education to follow science?

Or even wear a mask.

To all those people that cry “foul” at those that don’t wear a mask, but fear the vaccine trial, I would like to point out their delightful clay feet.

8/25/2020

Meh Day!

Full day of work today. Achiness in weird places besides my left arm. Somewhat foggy today. Luckily, doesn’t seem to impair my ability to function. Some NSAIDs last night to deal with pain. No fever. Seems to be like what was published in the Phase I data. Plan on taking time off for booster dose.

8/24/2020

Vaccine day!

And so, it begins.

At St. Louis U at 8AM today to the vaccine center. Was not busy at all. Went right in. About 2 hours total – including screening examination, labs and consent. Received something (vaccine or placebo). 27Ga needle with about 0.7mL vaccine. Painless injection.

Noticed some achiness about two hours later. No fever. No chills yet. (3:21PM). Finished my E-diary for the trial.

Donating proceeds from trial to kids to pick their favorite charity. This has to be about the science, not the reimbursement. Tempting as it is.

Schedule of phone visits, every week for the first few weeks – then less frequently for 2 years.

Also got an NP swab. Always pleasant. Feels like my memory is improved by the brain cleaning. 😦

All else is good. Will update tomorrow.

Shout out to Ali Javaheri for his support.

Also to family for dealing with this.

08/23/2020

Prologue

I signed up from a link on the CDC website to be a volunteer for the vaccine. As a physician, scientist and responsible citizen, I felt it to be my duty to support solid scientific method over the profusion of hokum cures that have spread like raging wildfires in the wake of this unheralded virus. It goes without saying that this vaccine (Moderna) is the world’s first RNA vaccine. In this first blog post, I am going to go over some basics for non-experts on how viruses and anti-virus vaccines work (in completely layman terms), what RNA is (and why it may be a revolution), the due diligence I did before choosing to participate as well as the reasons why scientific methods in US funded research is protected by incredible safeguards. (In the interest of full disclosure though, being a research fanboy may make me blind to people disguised as scientists or those who subvert the organizations that keep us safe, but if that occurs who is safe after all?) By means of this blog, I want to keep a running record of my experience with the build up to getting the vaccine, people’s reactions to my volunteering, as well as a real time account of both the trial as well as my own reactions to the vaccine. Whether successful or not, this vaccine will be a game-changer and a first person account of a recipient may be of value.

In the next few sections, I will start with defining what a virus is. But, to help you understand how they work or cause damage, I will review what a cell is and how it came to be (including a basic primer on genetics). I will keep it extremely easy (at the 10-year old level– which may have something to do with my own level of maturity) and it will be helpful if you could imagine it being read to you by Stephen Fry (as he did in the Hitchhiker’s Guide to the Galaxy). It is important to understand cells because that will make it easier to understand COVID-19 and thus why the vaccine and the reasons why it might be amazing…or a bust. It will also give you an idea of why I chose to sign up to be a volunteer in this effort.

Viruses, viruses everywhere….

SARS-Cov-2 (a.k.a novel coronavirus, the virus causing COVID-19) is a novel virus that affects small mammals and has made the jump to humans and other primates. It has killed a quarter of a million people worldwide via infection and a likely far larger number (both until now and in the future) by the economic fallout. This brings us to the question, what is a virus?

Viruses are extremely tiny quasi-living things, that take simple living to the limit. They vary greatly from tiny particles consisting of a small piece of genetic information protected by a shell of proteins to nearly visible complex structures consisting of multiple proteins, a lipid envelope and a large genetic storehouse. Unlike the concept of a “cell” seen from ancient bacteria to man, these simple beings make up for the lack of sophistication of structure with the elegant effectiveness of their ability to survive and propagate, their only purpose. Like all other life-forms, the virus’ genetic material is its identity, the protective shell is its body. Lacking in their own machinery to build anything, viruses commandeer the machinery of the cells they manage to get into, to generate new proteins (made from sources in their ‘host’), to make new copies of the their genetic identity, to assemble these into progeny virus particles and then leave the cell (either by activating cellular self destruct signals or by allowing the cell to survive and using export pathways to leave the cell).

That is all very nice, but what exactly is a cell??

We’ve talked about “cells”, but what exactly does that term mean? Each currently existing lifeform (viruses and prions excluded) consists of an organized compartmentalization into individual units called cells. In fact, the converse way of looking at it would be that an individual being is the result of billions of these units coming together. Each of these cells has an oil-lining (lipid bilayer to you technical folk) which holds a little water-based chamber containing protein, oil and sugar (carbohydrate) based structures. These are arranged in unique patterns and the manner of arrangement is determined by the type of function needed by the cells. Some cells are tiny and others are huge, some ephemeral lasting days or weeks while others span the lifetime of a being. Each of these cells have, during at least some portion of their lifespan, a complete storehouse of genetic information for the entire organism stored in a digital-esque format on an organic platform of a single chain of compounds known as nucleic acids. (Hmmm… or maybe computer memory is genetic-like, not sure.)

These “nucleic acids” are named for where they were first found, the nucleus. Early scientists noted that all cells had a ‘dot’ in the center, filled with organic material composed of sugars, and specific benzene-ring like circular acidic molecules containing a combination of carbon, hydrogen and nitrogen. Turns out that, in the interest of simplicity, the body selected four such molecules, Adenine (A), Thymine (T), Guanine (G) and Cytosine (C). When arranged in pairs, the molecules are peculiar in partnering with each other as A-T and G-C linkages. By arranging this alphabet on a chain formed by a backbone of a sugar (deoxyribose) and phosphates (from ATP – yes, from all those energy drink ads) gives rise to one of the single largest molecules in existence, deoxyribo-nucleic acid or your DNA. An that is exactly what it is, an entire library of all the information that it takes to be YOU. All written in the long-hand of a 4-letter alphabet, with 3-letter syllables. Despite small differences, this arrangement of genetic identification information is preserved through ancient times to the present. Every organism carries in its DNA all the information of all its ancestors and its history to try to deal with every eventuality. DNA allows a cell to pass on this information to the next generation. While life is so much larger than the DNA itself, life as we know it requires the DNA-based information to construct the cell, use historical information stored to react to the environment and ultimately, to pass it on to the next generation. But why did it have to be thus?

The origin of life

In the beginning (more than a billion years prior), when the primordial ocean soup existed on Earth, simple organic (i.e. carbon-based, not something to do hippies and Whole Foods) molecules formed. This likely occurred under the influence of solar and extrasolar radiation as well as local random factors leading to this happy happenstance. These carbon-based entities (likely primordial protein-like molecules) were the first form of life, and had the capacity to assemble and transform their environment. Unfortunately for them, they were continuously under attack from the same environment that brought them into existence. Over the next millions of years, some lucky molecules were enveloped in oils which formed a protective barrier around them. This had both advantages and disadvantages. The big plus, obviously, was that these early “living molecules” were now isolated from the harms of the environment. The big downside, equally obviously, was that being isolated from the environment limited their ability to modify it (a key feature of being ‘alive’). Somewhere in that ancient history, some water managed to creep into the protein containing oil droplets, creating a microcosm of the environment within the droplet and thus creating the first cell. The next step was to use the protein molecule to allow selective entry of water and solutes to maintain a unique environment inside this primordial cell. Somewhere along the course of history, the meeting of two different oil bubbles with different proteins resulted in the formation of a bigger bubble that had more proteins and thus greater functionality. In this next phase, an accretion of bubbles lead to growth to the point where the chaos ensuing from the size of the bubble resulted in the bubble breaking apart into “daughter” cells. In this phase, the daughter cells with the most symmetric distribution of resources had an advantage and survived. By “sticking” together ( a result of surface tension of the oil and water interface), they could now help or protect each other. The big problem in this was how to store the information they had to be able to pass it on to the next generation. To do so, would take another eon, when using the template of the “living” proteins, these primordial cells could put together simple codes to memorize them in a linear chain, the primordial “nucleic” acids (a misnomer because there was no nucleus at that time). To keep things simple our ancient ancestor had defined a code to signify individual protein constituents – one that has continued through every life-form since on this planet.

Viruses, again!

Which brings us to viruses. It is not clear if viruses represent a truly ancient form of life or are the product of later species. Although previously believed to be the former, modern biology seems to indicate that they are the latter. Each one, a product of the species that it gravitates to. This also explains the fact that they can be benign to some, yet amazing dangerous to others. Causing a common cold to a bat, while resulting in deaths of millions of humans. In fact, new data indicate that all beings generate protein-nucleic acid-lipid complexes (known as membrane-less organelles) that have critical in the stress-response mechanisms in cells. The similarity in organization and structure as well as appearance to viruses is remarkable.

In every cell, from the library book of DNA, the cell transcribes a copy onto a Post-it! (the RNA or Ribonucleic acid). Unlike the remarkably durable DNA, that is compactly stored in duplicate (the famous double helix), RNA is a linear strand that is relatively evanescent. With an extremely short span of existence, the RNA, once transcribed, is “translated” by the cells’ 3-d printers into the proteins that define their every single aspect. Unlike the stability required for the DNA (to endure across generations), the function of the RNA is to be a temporary copy of genetic message, that tells the cell machinery what needs to be made. Using a system of feedback loops (driven by so-called “transcription factors”), the passage of messages between the cellular machinery and its central library defines the normal functioning of all cells, be they bacterial, murine or human.

Viruses, as we discussed before, come in various kinds. Some (like the virus causing Hepatitis B) use DNA as their source of genetic material (and thus can be very robust). The problem with this, is the limitations of how they get into the cell and the difficulties they encounter in starting the process of subverting the cell to their own agenda, as the transcription and translation machinery clearly prefers the host DNA to the viral one. To subvert this, some viruses, like our bete noire, SARS-Cov-2, use RNA. The advantage to this is that they are able to easily subvert the cell’s protein printing machinery to their own direction by bypassing the need for transcription. The obvious downside, is the fragility of RNA itself. Which is why SARS-Cov-2 has a strong protective protein coat (the N protein) AND a lipid envelope made from the cells own lipid membranes. Furthermore, by putting sticky anchors and stabilizers on the envelope (the Spike and Envelope proteins respectively), it is able to easily enter a variety of cells by binding to receptors on the surface of the cell that normally act as gatekeepers for blood borne messages. In the case of SARS-Cov-2, this receptor appears to be the ACE2 receptor that is important in the sensing of a polypeptide hormone – angiotensin II.

By coopting the cells’ tendency to internalize the activated receptor complex to repair and replenish it, the virus gains entry into the cells, where the breakdown of the outer structures – rather than damaging it – releases the viral RNA into the cell, thus unleashing its fury. In addition, to triggering its own replication, the upregulation of an immune respone paradoxically drives inflammation, coughing and thus viral shedding to new hosts. When exaggerated, the combination of viral injury and inflammation result in death of the human host, while the virus moves on to the next.

Immunity. Not just in a court-room…

While this paints a bleak picture, it is worthwhile to note that humans have a remarkable ability to counteract viruses. Except in the case of HIV, where the immune system is targeted, most viruses can trigger the formation of an immune response consisting of a combined cellular and antibody-mediated response. This activation results in rapid recognition of the virus as a foreign threat and a brisk elimination from the system. To put this immunity in perspective, it is worthwhile to note, that most people think nothing of measles and chicken-pox, in non-immune populations, these are often lethal. While generalized inflammation as well as specific immune responses can be triggered by the cells’ innate ability to sense foreign genetic materiel, the body’s virus specific systemic immune response requires priming to specific and easily found proteins and features on the surface of the viral particles.

A Brief History of Vaccines

Through their history, from the effects of Pasteur’s initial efforts, vaccines have used the presence of inactivated or non-lethal virus proteins to be sensed by the body’s immune system to develop a memory and resistance to future infection. By recognizing a milkmaid’s resistance to small-pox from a prior exposure to cowpox, humans have been able to train and marshal the immune system, to the detriment of polio, smallpox and a host of viral infections. In turn, naturally mischievous viruses like influenza, are able to survive this challenge by continuously changing their surface protein combinations (the H and N proteins) to stymie the antibody and cell response. This is why people need a new flu shot every year, while the vaccination course for polio, measles and hepatitis B is more durable. From the injection of digested tissue (animal or human) to the development of cell culture based vaccines to the development of synthetic viral proteins, it has been possible to dramatically augment the safety and cost and thus, the availability of safe “cures” for these scourges.

The whole point of a vaccine is to mimic a viral infection, without the risk of viral injury. The problem with using proteins to do so is manifold. Firstly, the proteins need to be stable enough and “clean” enough to avoid replacing one one infection with another. The second is to generate an immune response without an exaggerated inflammatory response that may result if the body senses a large amount of foreign protein. To avoid this, live attenuated viruses (like the oral polio (Sabin) vaccine) can be used that trigger an immune response. Often, these can be less effective, but are more protection than nothing.

The other big problem is the timeline. To develop an immune response is something that takes days or weeks. As we find out differently every year on the effectiveness of that year’s flu shot, testing the immune effect of a give vaccine is a slow and tedious process. Thus, developing a new vaccine, against a hitherto unknown pathogen, poses unique challenges. Firstly, traditional approaches of using subunit proteins alone is plagued by the issue of making enough it on the scale of billions of people. More importantly, to be sure that it works and can be stably delivered with an acceptable adverse effect profile.

RNA Vaccines. The Way of the Future?

Enter the concept of the RNA vaccine. Never previously tried in humans on any large scale in the past, this is a novel approach, borne of the need for a speedy response to COVID19. The Moderna mRNA1273 vaccine is the RNA sequence coding for the Spike and associated proteins covered in an oil globule (called a liposome). The science behind this approach is that RNA enters the cells (using the liposome) and results in triggering the body to produce just the viral protein without the viral RNA or the protective coat (N-protein). When produced by the cell, particularly macrophages (specialized cells responsible for local cleanup in tissues), pieces of these proteins (a.ka. antigens) are displayed on the surface to trigger an immune response in B- and T- immune lymphocyte cells. Unlike in the real infection, where in addition to producing these proteins, the virus itself is replicating and up to additional damaging activities, the vaccine is only limited to these proteins. In contrast to protein based vaccines, where the bacterial origin of recombinant proteins carries the risk of non-specific inflammation, the RNA vaccine uses protein made by the host itself. Unlike attenuated live or killed viruses, there is no full length genetic materiel that could integrate itself into the host’s gene structure – possibly resulting in undesirable issues at a later time. Finally and most significantly, it is easy, quick and relatively cheap to produce as well as package the RNA fragment, completely synthetically. This has allowed development of a vaccine candidate within 3 months of the onset of the pandemic.

Clinical Trials, and the evidence so far

The data that has been published thus far is promising. In the initial Phase 1 study on human volunteers to look at doses and toxicity, all three doses tested resulted in an immune response after a second booster dose in 28days. The best profile of effectiveness as compared to the inflammatory side effects of an acute fever and muscle pain was found at the 100 microgram dose given in an intramuscular manner. Phase II trials are currently ongoing and I am signing up the NIAID sponsored (https://clinicaltrials.gov/ct2/show/NCT04470427) Phase III trials where at-risk individuals receive either vaccine or placebo and are studied to see if they develop an immune response and/or if they develop COVID19 despite the use of standard preventive measures.

At this point, I would like to talk briefly (not my forte, i.e. being brief) about clinical trials. As the quintessence of modern therapeutic testing, double blinded randomized control trials when properly conducted in the appropriate population have resulted in the elimination of biased assessment as well as ratification of therapies that have durably stood the test of time. In this approach, each entrant is randomly distributed into either a test group (drug) or a ‘control’ group (placebo). The best trials are conducted in a blinded fashion, where the person administering it as well as the patient and the person analysing the results are blinded to the treatment. In addition, all clinical trials must follow principles of beneficence, justice, and a respect for persons as well as to allow for the autonomy of choice of the participants. These failsafes and essential values are what stand between ethical research that I ascribe to, and the human experimentation with scant regard for ethics that have tainted clinical studies through history.

In each of these tainted events, the driving force for the taint is frequently the sponsor of the study and a drive for secondary gain, even at the cost of the subjects. I am proud to say, that the epitome of ethical standards in this regard, worldwide, has been the US research community that I am proud to be part of. Nowhere else in the world, has the focus of adhering to essential values been more firm that here. Within the US medical research community, the pinnacles of ethical research remain the Universities and the NIH. Despite the values demanded of all clinical studies in the US, the commercial biases often cloud the role of industry in clinical trials. In this instance, partnership between industry at building the vaccine and the NIH-based mechanism in conducting the trial provides the essential failsafe to deem the trial safe in my assessment.

Finally…

When my family and friends heard that I was taking part in the trial, I was greeted by a puzzling cacophony of responses that varied from support (a minority), to shock-fear-trepidation-panic, as well as humor and derision. As a physician and scientist, this method of developing a cure to a clinical problem remains key to my own approach to my patients. If people like me don’t show our trust in the approach, how do I justify using it? After all, if it is too risky for me, by what basis do I prescribe this to my patients? As schools reopen and the virus surges again, I am hearing of more and more acquaintances that are either testing positive for the virus or suffering from COVID19. In my mind, the off-chance (50%) that I get the vaccine, and develop an immunity to the virus, I stand to benefit far more. Furthermore, with frequent checks for the antibody as well as the virus by PCR (built into the study itself), I will be more likely to be forewarned of an unanticipated exposure to the virus, allowing me to respond early. Finally, as a relatively young, and healthy man, if there is anyone who would withstand an untoward vaccine effect, it has to be someone like me. This information will help further improve the care delivery that I count on everyday as a physician.

It is up to all of us to stand with good science. To support efforts to fight this modern scourge. To avoid giving in to the cynicism and resistance to change. To face the unknown, not with blind faith but with armed with the calculated risk-taking borne of thinking and knowledge. May God be with us all and I pray that we prevail.

Of all the misnomers and worst understood things out there, without doubt the most significant offender out there is the “the Big Bang!” In fact, other than the cataclysmic significance of the event, there was nothing “big” (in fact, infinitesimally small) about it, nor was there any sort of “bang” (in the absence of air, sound really has no meaning). In fact, even light did not come into existence millions of years into its existence. As a non-physicist and science-enthusiast, I like to believe that I owe it to people to clarify this fact. Of course, if you are left agape by this arrogance, feel free to peruse a different corner of the internet.

Here goes my theory, based on the available established knowledge as I understand it. There was no real beginning. Because time did not exist and therefore the whole concept of a beginning is meaningless. From the void of existence, came forth something. A zero-sum situation wherein the separation of positive and negative energy resulted in the creation of space and time. Given the infinite nature of the void, the energies endowed this “universe” were vast (and beyond our simplistic comprehension). As time beyond its inexorable journey, space unfolded itself, in tiny increments initially but eventually at a pace that staggers the mind to fill the universe as we know it. Given that it remains a zero-sum game, the universe is really a thing that is imaginary. One imagined by a collective consciousness that belies imagination. Thus, space and time, critical features of the universe as we know it are equally thus. Every single unit of this Universe is linked to that primordial void and Consciousness – individually aware of its nature, its position, and its fate. From tiny neutrinos flitting about the universe at frightening velocity to the blazing light that pervades the universe against the dark that represents the other half of that zero-sum, everything is both conscious and unconscious.