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  Science smudges forwards.  

 

Only very occasionally does Science advance by lightening strikes that land right in the middle of the researcher's logbook.

 

Instead, its progress arises in the stains and crumpled edges. Spots that originally were thought to be an unfortunate result of a moment’s inattention. The bottom of a coffee cup that left a curved stain that connected two words on different lines. And in that moment, in that crescent stain and the words that get noticed, Science smudges forwards. Some will use the word serendipity.

 

Others may quote Louis Pasteur:  "Chance favors the prepared mind."

 

Here's how that came about:

 

On December 7, 1854, as dean of the brand new Faculty of Sciences at Lille, Louis Pasteur gave the opening speech in which he said, “in the fields of observation, chance only favours the mind which is prepared…” Pasteur was speaking of Danish physicist Oersted and the almost “accidental” way in which he discovered the basic principles of electro-magnetism.

 

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So next I will share with you some of my personal "smudges."

 

Soon, I will be inviting you to share some of your own "smudges" here so we can all stare at them and find what's missing about "long-term" COVID-19.

 

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One day in 1977, I was listening to a Professor (his name was Kenneth L. Becker, MD) lecture my Medical School Class about the thyroid gland, as part of our class in Endocrinology.

 

And after he had covered and we had taken notes on the anterior pituitary, and its TSH hormone, and the thyroid that releases thyroxin hormone into the blood in response to TSH, and all the other stuff that starts simple, then becomes complicated enough to drive any simple thinking person a little mad ...,

well he moved on. 

 

He started covering other cells found in the thyroid. The "C-cells" so named because they secrete calcitonin and help to regulate blood calcium levels. Too high a calcium, and the blood bathing those C-cells prompts a "that's too high!" reaction and those cells dump some calcitonin into the blood. 

 

It works on the bones, and on the kidneys, and maybe elsewhere. In the bone it tells the osteoblasts to lay down calcium in the matrix. It yells at the osteoclasts quite loudly to stop chewing up bone which releases calcium. And it tells tubular cells in the nephron of the kidney to stop reabsorbing calcium and to just, well, ... pee it out.

 

And then the calcium level comes down. And of course this is all controlled in a balanced way with the 4 or sometimes 5 tiny parathyroid glands that you have stuck on the back and sides of your thyroid gland (if you still have one). Those glands do the opposite. Low calcium? The parathyroids get bathed by that low-calcium blood, they yell out, "Hey! We need more calcium here for Godssake!" They then release parathormone (PTH) which works on bone, and kidney and elsewhere, and does just the opposite of calcitonin. 

 

And that's what Dr. Becker was telling us while everybody around me was bent over scribbling in their notebook.  On that day, it didn't sink in completely, (it never did on the first day), and probably 70% of the class was lost as you might be now. And as Dr. Becker waited, seeing the frantic writing activity in front of him, pausing to let us catch up, I had an idea. That idea became a question. I raised my hand while others continued to draw pituitary glands and thyroids and scribble words on their drawings.

These were later highlighted in several different fluorescent colors to get ready before the exam.

 

I had raised my hand and been acknowledged with a quiet "Yes?"

 

"Dr. Becker, our classes in Embryology last year helped us to understand how embryonic cells migrate from where they begin to where they wind up in the body. That migration was also explained for the thyroid, and also its C-cells. But do these C-cells ever wind up elsewhere in the body besides the thyroid?"

 

The guy next to me started shaking his head while he continued to take notes. His body language was saying: "He just told us calcitonin comes from the thyroid, dummy! Lets just leave it at that. Why are you trying to make something that's already complicated enough, even more complicated?"

 

His body language was saying all of that as he scribbled. 

 

I just looked at Dr. Becker. And on first hearing the question, he had squiggled up his mouth, then broke into a smile. "In our lab at the VA we're working on that very idea. So when you rotate through next year, come and see me and we'll talk about that. Now let's move on."

 

So we moved on.

 

--------

 

 

Mentioning all the steps in between will take up too much time and space here.

 

But one day, while still in Medical School, I was working in the Surgical Research Lab. I had eventually migrated there out of personal interests. I had by then imbibed, digested, memorized, regurgitated and otherwise experienced many medical topics. Many topics besides calcitonin and the thyroid's C-cells.

 

But one day, who should walk into the lab, accompanied by a Professor of Surgery? You guessed it: Dr. Kenneth L. Becker, MD. The guy to whom just a year or so before, I had asked my dumb calcitonin question. And very soon, here were the three of us, talking about, you guessed it: calcitonin. 

 

Very, very briefly: Dr. Becker had already learned that when the Professor of Surgery who walking in with him that day, operated on one of his patients and completely removed their entire thyroid gland for one disease or another (often a cancer), the calcitonin levels in the patient's blood did not drop to zero (0). 

 

You recall perhaps if still following to this point, that I (and thousands of medical students in 104 medical schools in the US at that time, and throughout the world) had learned that the thyroid is the source of calcitonin. And also that it is an important regulator of too high calcium levels in the blood. Becker and the Surgeon had been puzzled or rather intrigued to observe then confirm that these patients with no thyroid glands (no C-cells?) were not dying of hypercalcemia. And as said, these patients still had measurable calcitonin in their blood. 

 

  Now why would that be?  

 

So the three of us were now going to work on answering that question.

Wow! I was part of a team!

 

One quick way would have been to euthanize all the thyroidectomy patients after getting written permission to do an autopsy, cut up little bits of all their organs, and measure in the lab to see if those little bits of lung, liver, skin, brain, kidney, adrenal, you name it, ... contained calcitonin or not. 

 

We got another idea. This idea also got us around having to ask patients who had survived their thyroidectomies (100% by the way), what they thought about being euthanized and autopsied. Never asked a one. We can be delicate when needed.

 

Instead, we asked some Rhesus macacca monkeys who lived in the lab at that time, if they would be willing to participate, and they agreed.

 

Looking back, I still feel that the work was important (it proved to be) and that the animals were always well treated (I used to play my violin for them in the room where they lived in cages. They seemed to enjoy the music. It made them blink their eyes rapidly and show their huge canines. I took this as an applause-equivalent gesture. Maybe not). And when it came time to finish their research days as research associates and sacrifice them, that was done with the utmost concern for their lives and comfort. They are not forgotten. I still remember most of the names I had given them. 

 

Some parts of rolling the Science Ball forward are not easy.

 

--------

 

So very soon, I was anesthetizing "Old Split Nose" and others, and the Professor of Surgery was teaching me how to do a total thyroidectomy using sterile technique just like in an OR for human primates. Our goal was to carefully remove, absolutely all of the thyroid tissue from each monkey. For some pre-reviewers of our project, that would imply removing all C-cells, and all of the monkey's calcitonin. Unless of course, he had some C-cells hidden away somewhere else. If that were the case, they'd still have some calcitonin measurable in blood and/ or urine.

 

I'll skip an explanation of the following words: immunocalcitonin, immunoassay, thyroid scan, radio-isotope, nuclear medicine, dark room film development, Ketamine, Halothane, nitrous oxide, hemostasis, neck dissection, external laryngeal nerve, parathyroid glands, strap muscles, surgical skin clips, and others ...

 

But we got it done. 

The hospital had an old nuclear medicine scanner. I pushed it across the street and got it set up. I set up a darkroom for film development.

I did thyroid scans of our monkeys. The point was to prove they each had a thyroid gland before we opened their neck to remove it. Then develop the images, carry them across the street, and get an interpretation from the docs in Nuclear Medicine. Turns out they thought the images weren't dark enough to be sure. I tried again, based on their instructions, changed isotope dosages based on weight.

 

Still not dark enough. I made other changes to get the little thyroids to show up as little black fuzzy blobs on the films.

 

"Still not dark enough."

"You know, that's quite an old machine that we gave you for the lab ..."

 

So one day, one of the technicians in Nuc.Med. suggested that we bring the monkeys over to the hospital and scan them using the more modern machine used for humans. He was laughing when he said that. The Nuc.Med. doc was not laughing when he said: "Sure. Why Not? Hell yes! Bring 'em over!"

 

So soon I was placing an anesthetized monkey on a cart like the one I used to push when I was a Nursing Assistant back in the ER. I would cover the monkey with a sheet, so no one would have the least suspicion about our monkey business. And monkey and I wheeled across the street, passed the Guard with a cheery wave, into the elevator, and down the hall to Nuclear Medicine. 

 

If somewhere along that path, the monkey stuck a hand out from under the covers and began pulling at the sheet (perhaps Old Split Nose was cold?) I would reach into my scrub shirt pocket for a syringe I had prefilled with Ketamine, and nail him in whatever muscle presented itself. Took about 4 minutes for his giving me the finger gestures to stop.

 

Eventually we would scan the monkey. Eventually, one by one, all of the monkeys had thyroid scans. And we proved with beautiful, high quality scans that they all had normal thyroid glands. And subsequently, one by one, I took out all their thyroid glands. Guided by the able hands and patient instructions of my then and two years later and after, Professor of Surgery.

 

Often at this time in my life, I found myself first thinking then saying: "If we knew what we were doing, it wouldn't be research." I even wrote that down on a piece of cardboard box, and nailed it above my desk in the lab.

 

 

  Here's the rest, in abbreviated form:  

 

• • • • scanned the monkeys' thyroids and measured calcitonin, PTH, calcium, phosphate, TSH, T3, T4, in blood and urine. You name it. We measured it.
      • removed their thyroids surgically. I had 100% survival (at that point).
      • waited for them to recover while checking labs weekly
      • Once Dr. Becker had given the endocrine go ahead, we remeasured all the same labs.

 

Turns out that the monkeys still had calcitonin in their blood and urine. Wow!

We took out the "only" source of their calcitonin hormone, and they still had some of the stuff...

Wow!

 

Maybe the monkeys had a bad surgeon (me)? Maybe I had left behind some calcitonin secreting C-cells?

• • • • more road trips across the street to Nuc.Med. with each monkey and plenty of Ketamine in my pockets just in case. (Actually no, though the Ketamine came in handy on more than one occasion, we never had an incident).
      • all the repeat postoperative scans, interpreted by the same guys who interpreted the human scans, and reviewed by our Veterinarian, were all negative - no thyroid left.
      • more lab work: calcitonin still present in our subhuman primate research associates.

 

So we could now believe it. 

 

After removing the supposed only source of calcitonin in these animals, they still had calcitonin in their bodies. My question a few years before in Endocrinology lecture now seemed less dumb. Even seemed rather insightful for a newbie.

 

We did make the assumption that no one was sneaking in and injecting them with salmon calcitonin at night. The whole lab and animal care area was alarmed to protect all of our non-human associates, from the mice to baboons.

 

  Next came the hard part for the monkeys  

 

• • • • Without telling them ahead of time here is what we did:
        • We anesthetized them with Somlethal (Nembutal) to the point of euthanasia
        • We did their autopsy
        • We took samples of all (meaning every one) of their organs and tissues, blood and urine samples
        • Dr. Becker's lab staff (Charlie and Dick) did immunoassays for immunocalcitonin (iCT) after extract it from all the bits of tissue I had provided.
        • One after another, I now no longer had a single survivor of my operations (0%).
        • The night before the above events, I never failed to play my violin one last time for the monkeys.

 

And lo and behold, many organs and tissues still had calcitonin!

Wow!

We discovered that as an intact organ, there is more calcitonin in the lung, than in the thyroid. Thyroid per gram, still has the most calcitonin. Had these other organs simply stored for a long time, calcitonin from the thyroid? I'll skip the proofs, but no, they were making the stuff. 

 

"Wow!" is what we all said to each other, several times.

 

----------

 

 

  Science smudges forwards.  

 

 

So what did we do?

The only thing that 3 self-respecting medical researchers can and will do. We published it.

Here it is, a scientific treasure just a click away.

 

Calcitonin Studies in the Rhesus Monkey.

 

And frankly, I was proud of the work that we had done together. Happy to see it in print.

 

Now, because at the time I was still a Medical Student and not yet an MD, it was decided that placing me first in the list of authors, with my measly BA degree might not present much clout.

 

So the Surgeon and the Endocrinologist with their MD degrees got position 1 and 2, and I got position 3.  I was still proud and happy to be in position 3. All this also an example of initiation into the publish or perish silliness that still goes on to this day.

 

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  Science smudges forwards.  

 

Next, we went back to the human primates. We had considered rats or rabbits, but decided not to march backwards down the phylogenetic scale. "Hey. Let's do humans. They're all around us."

 

Dr. Becker had already studied clinical situations where calcitonin is elevated.

The best known is a cancer of the thyroid gland called medullary thyroid carcinoma.

It has huge calcitonin levels.

 

But some lab results that didn't make sense were calling out. Science was trying to smudge forwards once again.

 

If only we talked less and listened more. Epictectus suggested that since we have two ears but only one mouth, listening more than talking should come naturally, perhaps twice as often.

Not everyone has read Epictectus.

 

So it seemed that those who did not have a proven recurrence of cancer after a total thyroidectomy for a medullary, sometimes nevertheless had elevated calcitonin. Metastases still secrete calcitonin. Did they have metastases? No. None found. 

 

Ah. But some of these patients, some smokers some not, also sometimes had pneumonia or other pulmonary diseases.

 

Aha. A smudge on our neat research logbook.

 

Increased Serum and Urinary Calcitonin Levels in Patients With Pulmonary Disease.

 

----------

 

   Life Move On   

            ... which is nice.

 

So there I was, a Surgical Resident. Also married, and a Dad of great twins.

And I had just begun a Rotation in the Burn Unit.

A different hospital. A need to discover where the stairs towards home after a 12 hour shift, the bathroom and the CBC blood tubes were located all over again. Happens each new Rotation.

 

There I was. In a big city's specialized care ICU, where patients usually had to have at least 50% of their body burned to get in. Less than that, and they were admitted to the Stepdown Unit for continued burn care. The helicopters brought us The Big Burns. They were not pretty.

 

Nurses in Burns usually last either 6 days, 6 weeks max, or they hang in there and are still there 6 years later because they have the hugest hearts you can find. They love their patients one dressing change after another, washing their burns every 8 hours in "the tub." 

 

Burns are awful. Patients scream through their head and neck dressings, plastered with white silver sulfadiazine, "Just let me die!" and they mean it. We don't. We try not to listen. Burn Nurses have the hugest hearts of all the people that I met in Medicine. If you ever meet a Burn Nurse, take a moment and give her/ him a big hug.

 

------

 

Burn patients also frequently present with varying levels of inhalation injury. Frequently associated with various plastics and other materials burning in a fire and getting breathed in. A patient with even a very small burn (5-10%) might die due to inhalational injury. Death rates go up with burn size and age. So a person 55 years old with a small burn, but an important inhalational injury is very likely to die on day 3 to 5 after sustaining the burn. They often need, 24 to 36 hours after admission, to be intubated, mechanically ventilated, may survive, often did not. They get what looks like an airway injury, then bronchial injury, then pneumonia, then ARDS. Then they die. Much too often.

 

And at first, those caring for them may be surprised by that outcome because, well "Hell. She just ahd a small burn !?"

 

I rarely stop thinking around medical topics. Always looking to learn something new.

What a helluva habit.

 

So there I was in a Burn Unit, surrounded by humans with large burns, and some with probable inhalational injury. Soot in the mouth of patients and other findings noted in the Admitting Area correlated very poorly with who was going to develop respiratory failure and go down the tubes.

 

Inhalational injury. Hmmm. 

 

We had already learned (see above if you skipped ahead) that patients with pulmonary diseases have increased calcitonin levels.

Was this yet another opportunity to smudge forwards and learn something new?

 

So, ... you guessed it: I decided it might be instructive to measure calcitonin in burn patients.

Next thought: surely somebody had already done that. Medicine is filled with novel good ideas that 100's of researchers have already proven or disproven.

 

So I searched. Found nothing. 

Talked to the Surgeon who was Director of the Burn Unit. (He used to play a mean standup bass).

He said "OK. Go for it."

 

And I did.

Here is the result.

 

 

I'd give you a clearer reprint of this entire article, but I don't keep one in my back pocket.

In the past, one could go pick it up at the library, and after a quick stop at the copy machine, have it to add to a file.

 

Today, at Elsevere, I could have purchased a copy of the article I wrote in September and October of 1992 for a mere 48 €uros. I decided not to pay that amount. The copy machine used to cost a nickel a page.

 

Some things change. What are the principle drivers changing Medicine and Medical Research today?

 

Clearly, "my" article is no longer mine.

 

It's more than just a reason to get pissed off. It puts the brakes on smudging forwards.

 

------------

 

 

So what we were able to demonstrate, apparently for the first time, was that burn patients have elevated calcitonin levels in their blood and urine. It is correlated with burn size and mortality. Highest in those who died early in their course. It was also higher in those with suspected inhalational injury. Particularly high in those who died. I tried to push that point. The other authors hedged about saying that at that time with the data we had.

 

That would come later. It was just a bit too big at the time to start shouting in front of a crowd.

 

----------

 

Well, what do you know?

 

 

  Science smudges forwards.  

 

So a few years later, a post-doc in Dr. Becker's lab at the VAH, by the name of Eric Nylan had an idea as well.

Would a precursor of calcitonin called procalcitonin, also be elevated in these same burn patients?

 

So Charlie and Dick got the samples that I had drawn on all my patients out of the freezer (the samples, not the patients) and they set up and ran the assay for immuno-procalcitonin.

 

And sure enough: procalcitonin levels were elevated.

And my idea about inhalational injury, added to the idea of pulmonary sources of calcitonin that Dr. Becker had hit on, and not overlooking the monkeys' contributions ... just kept on moving along.

 

  Spinoffs of an idea one evening in a Burn Unit ...  

 

Late pulmonary sequela following burns - persistence of hyperprocalcitonemia.

 

I'll comment only on this one above. Using the samples I had drawn 7 or 8 years before, Eric got some fresh samples from some of the same patients I had cared for. What he found was that their procalcitonin levels were still not down to baseline after all that time. The effects of not only inhalational injury on the airway but also infectious diseases can be a challenge that the body may have to work on for years.

 

(Wow! And completely as an aside... Imagine if those who become infected with the SARS-CoV-2 virus develop a syndrome that takes years to resolve? Maybe it's not 'an aside').

 

PCT kinetics in the first week post-burn for sepsis diagnosis and death prognosis – an accuracy study.

 

Procalcitonin, a new diagnostic and prognostic marker for severe infections.

 

Procalcitonin - how a hormone became a marker and mediator of sepsis.

 

Here are a few more ...

 

Goodness! They're even quoting us in China and the Soviet Union.

 

 

 

 

Say, How's your Russian?

 

 

Let me help ...

 

"Assicot et al suggested Procalcitonin (PCT) as an inflammatory marker for the differential diagnosis of bacterial from viral infections in neonates and children. This based on work of Nylan, Becker, Snider, Moore, O'Neill, et al. in burn patients with inhalational injury. PCT is a prehormone of calcitonin which is produced by monocytes and liver cells that are triggered by an endotoxin or proinflammatory cytokines during systemic bacterial infections."

 

"In conclusion, the data of our study suggest that PCT is a good marker for the differential diagnosis of bacterial versus viral infections and has increased specificity and sensitivity even in children with or without immunosuppression. PCT is also a reliable marker for monitoring the course of infection, evaluating the response to treatment during the first 48 hours after its beginning and for estimating the prognosis of the bacterial infection.”

 

Becker KL, Nylen E, Thompson K. Preferential hypersecretion of procalcitonin and its precursors in pneumonitis: a cytokine-induced phenomenon? Endotoxemia and Sepsis Congress 1995; (Abstract) Philadelphia, USA

 

Nylen E, Snider R, Thompson KA, Rohatgi P, Becker KL. Pneumonitis-associated hyperprocalcitoninemia. Am J Med Sci 1996; 312:12-18

 

Nylen E, Muller B, Snider R, Vath S, Wagner K, White J, Zulewsk H, Vannier E, Habener J, Becker K. Pathophysiological significance of calcitonin precursors in sepsis and systemic inflammation. Shock 1999; 12 Suppl.:14

 

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It even became a Journey into Calcitonin's Past.

(If that's not a movie in the making, well I don't know what).

 

You've heard the expression: "Let sleeping dogs lie."

The article that follows is a wonderful journey.

It's also 14 pages. Perhaps a return at some later time.

 

Procalcitonin and the Calcitonin Gene Family of Peptides in Inflammation, Infection, and Sepsis - a Journey from Calcitonin Back too Its Precursors.

 

It was penned by K.L. Becker (no surprise), Eric Nylen (mentioned above), Jon C. White (we had been Surgical Residents together, then he did Transplants at Hopkins. He returned to become head of ICU at the VA Hospital, and just down the hall from Becker's Ofc. so his appearance here is not surprising, becoming my replacement of sorts in the title line), Beat Müller of then Switzerland, now Heidelberg,  and Dick Snider, chemist for many years in Becker's Lab at the VA Hospital in DC).

 

 

  So what?  

 

Why,  Fame and Fortune of course.

Actually not.

 

Rather than moving into a nice University position and just staying in the Surgical Research Lab and finally cleaning it up, the next venue was the Private Practice of Surgery.

 

No remorse. No regrets. I learned once again. Learned a principle that doesn't require "peer-reviewed" publication but just daily dedication, which teaches the fundamental target of practice: relieve suffering, and heal the sick where possible. I think a Burn Nurse or two taught me that.

 

-------

 

One of the names authoring the above article is that of Dr. Beat Müller.

 

What an amazing guy!  I get at least 3 notices a month saying he's published yet another article.

I'm sure I miss some that he has cranked out.

Why, he even paired up with Dr. Kenneth L. Becker, MD, so Beat is also part of the calcitonin inhalational injury legacy and descendance. 

 

That leads to his polite introduction, like this:

 

"Director, Medical Univ. Dept., Kantonsspital Aarau AG, and Full Professor of Medicine and Endocrinology, Medical Faculty, University of Basel, Switzerland. Studied medicine in Berne, Switzerland & South-Africa. PostDoc at the Mass. Gen. Hospt., Harvard Medical School, Boston, MA, USA. Clinical and research interests focus on pragmatic outcome and quality control studies using hormonal biomarkers in general medicine, endocrinology, infectious diseases, critical illness and pulmonology."

 

Beat has picked up the calcitonin/ procalcitonin ball and is still running with it.

He lives and works in Heidelberg, not too far away. I'll have to go say "Hi" one day.

 

Here are some of his related publications:

 

Narrative Review for Clinical Microbiology and Infection “how to” How to - Implement procalcitonin testing in my practice.

 

Procalcitonin to guide antibiotic decision making.

 

Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections..

 

Characteristics, predictors and outcomes among 99 patients hospitalised with COVID-19 in a tertiary care centre in Switzerland: an observational analysis.

 

And if you'd like to march to Beat's drum even more, here is a page with his other publications.

 

So from a Burn Unit and "calcitonin in inhalation injury" to "99 patients hospitalized with COVID-19" and their procalcitonin levels, ... is quite a voyage. Took years. That's Science most of the time. Development of vaccines at "Warp Speed" is quite unusual. 

 

But one very special and important lesson to be learned in Surgery and its technique, is when to go slow, and when to go fast. Don't get these confused.

 

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  Science smudges forwards.  

 

I have been privileged to watch from both the inside and the outside how imagination and serendipity can in fact lead to discoveries that save lives. Privileged to see how new ideas emerge from the old, and how the baton gets carefully passed. 

 

In our Google, iPhone, Smart-Watch world, discoveries still nevertheless usually translate into action at a slow pace. That protects those on the receiving end that used to be called patients but have now transitioned to become consumers of healthcare. The slow pace adds to the lists of side-effects and complications of procedures, so those doing the healing can have the required full suit of informational armor when the next "chief complaint" arrives at the triage window.

 

--------

 

  Here's The Finish Line  

                          ... you made it.

 

These anecdotes were pulled from the past to share not only some examples of how Science moves, not always gracefully, but also to help bring back the focal point on the present. To keep it moving today.

 

I apologize to readers for verbosity. Sometimes I control it a little better than in this article.

But perhaps now one can find at least a small bit of Medical Science behind our current claims and proposed studies of "long-term" COVID-19 as published on this site. Also, as further pursued at StudyLTCOVID.com to keep the smudge moving.

 

And now, with "long-term" COVID-19 patients in need of a cure still waiting patiently, it's time to get a move on.

 

 

 

Thanks for all you did.

 

 

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