Research Is Done One Question At A Time: Whether It’s Formaldehyde Or Plantar Fasciitis

“Learning how to sell your product is your single most important job as an entrepreneur.” The Reluctant Entrepreneur, Michael Masterson.

“Learning how to sell your ideas is your single most important job as a scientist.” FitOldDog

“Research is done one question at a time, so choose your questions wisely.” FitOldDog

I was recently asked for details concerning my research on formaldehyde toxicity and carcinogenesis (induction of cancer), for human risk assessment. This was such a saga, spanning almost 20 years, that I thought I should tell it as a short timeline, here, as it will clarify why we chose the approach we did for our ongoing work on curing plantar fasciitis.

If you so desire, you can sign up for the FitOldDog Plantar Fasciitis Newsletter, at this link.

FitOldDog (aka Dr. Dr. Morgan) Tells His Formaldehyde Story (Briefly!)

Note: while I was doing this work, with the help of many great people, others were pursuing their parallel research on the challenge of the relevance of cancer in rat’s noses for human risk, such as Jim’s work on DNA adducts, Henry and Mercedes’s studies of DNA-protein cross-links, Andy’s investigations of sister-chromatid exchanges, and so forth – at the time, there was tremendous energy around this issue, and the work continues to this day.

Jim gave me the opportunity of a life-time, to study the nose for 16 years, in Research Triangle Park, NC, USA, and a lot of guidance and mentorship, much of which came from watching how he handled his thinking and communication.

1978, or was it 1979, Jim Swenberg (an important mentor to FitOldDog as a young veterinary pathologist), working at the Chemical Industry Institute of Toxicology (CIIT), Research Triangle Park, North Carolina, USA, published a short paper that had a major impact on many chemical products, essentially destroying the urea-formaldehyde foam industry overnight. He described the induction of tumors in the noses of rats exposed for 6 hrs/ day, for up to 2 years, to 15 ppm (i.e. 15 parts formaldehyde, the simplest aldehyde, per million parts of air; enough to make your eyes water, and nose sting). These tumors, highly dangerous squamous cell carcinomas, common in humans, occurred in about 50% of the rats exposed. Such cancers are rarely seen in rats living a healthy, normal life. Is life normal for a rat in a cage? I think not, and the sooner this can be reduced and finally eliminated the better – I like rats! Jim’s article created a furor in the Chemical Industry, triggering much needed research on the value of the rat as a model for humans.

1981, a young, fresh-faced, FitOldDog, straight from Geneva, Switzerland, with a background in Neuropathology, and pretty well nothing else, arrives to work at CIIT. Within a couple of months, as I pass Jim’s office door, he calls me in and says, “Kevin, are you interested in the toxicology of the nose? I don’t have time for it!” I replied, “Why not! Sounds interesting!” With these few words, I started a journey that took me beyond the microscope, around the World, and from one scientific discipline to another.

Here you see a much younger FitOldDog (right), with his colleague, Dan, back in the early 1980s, studying mucociliary function – been a splitter all my life. Felt that I had come home when I entered research. Now for plantar fasciitis (osis? – that’s not right, either!).

Fuzzy Question – can I learn something by re-examining the nasal tumors?

NOTE: You won’t get a grant approved by writing things like this, you just do it and don’t tell anyone until something interesting turns up!

1982 Onwards I became obsessed with understanding how the nose, or more precisely the nasal passageways and their linings, actually work. My first move was to re-examine all of the nasal sections from the study reported by Jim, in order to find where exactly the tumors arose. I don’t like killing animals for research, but I’d rather experiment on a rat, if I have to, than experiment on people by doing nothing. That said, one should try to extract as much information as possible from any rat you kill for this purpose, and furthermore, try to find alternatives, such as mathematical modeling – maybe you won’t need to kill that lovely, interesting, affectionate rat. I examined over 1,000 microscope slides from any formaldehyde nose study I could find. After months of microscopy I came to four critical conclusions for my future research into formaldehyde-induced carcinogenicity and human risk assessment:

Click image for interactive map – all about plantar fasciitis, not formaldehyde. Created by FitOldDog.

1. The distribution of these cancers in the nose is specific, they aren’t just randomly distributed, but I won’t bore you with the anatomical details.

2. The early nasal lesions are VERY precisely demarcated, as if the epithelial lining was cut with a knife.

3. Emotions play a role in one’s enthusiasm, and endurance, for solving a disease problem. I lost a close family member, and a cat that I dearly loved, to the principal tumor type present in these rats, the squamous cell carcinoma.

4. You have to find, work with, and reward good people, if you really want to make progress, as you can’t achieve much in the way of biological research nowadays without a great team behind you, which was important as,

the squamous cell carcinoma is a formidable enemy.

I lost Alobar to cancer, a squamous cell carcinoma of the throat, when he was 18 years old.

–ooOoo–

A PLANTAR FASCIITIS ASIDE (my current obsession): In the case of formaldehyde, I gained a key research clue, the precise location of nasal lesions, from looking at the microscope slides (seen by many already – remember that great quote, “The task is not to see what has never been seen before, but to think what has never been thought before….” Erwin Schrodinger. In the case of plantar fasciitis, I’m right where I was with formaldehyde nasal tumors, back in 1981, except instead of microscope slides as my datasource, I have people’s plantar fasciitis stories, some of which are presented in our latest book.

–ooOoo–

When I looked under the microscope at tissues from rats that had only been exposed for a day or so, it looked as if the damaged nasal lining had been very precisely excised from the adjacent, unaffected areas. You could go from visibly normal, to completely dead epithelium, back to normal again, with a sharp line of demarcation between them.

WHY SO SHARP?

I spent the next 15 years tackling that problem, because it was extremely important for assessing human risks AND even more important for the researcher, IT WAS INTERESTING.

1986 We published this observation (takes ages to do that in science, or should I say Science?), in the following paper:

Morgan, K. T., Jiang, X. Z., Starr, T. B., and Kerns, W. D. (1986). More precise localization of nasal tumors associated with chronic exposure of F-344 rats to formaldehyde gas. Toxicol. Appl. Pharmacol. 82, 264–271.

In the meantime, I thought day and night about that question, “Why so precise a cut?” Being a little OCD is helpful in scientific research. I started with the second protective layer between the formaldehyde-laden inspired air and the delicate nasal lining (the first I was unaware of at the time – read on), the slime that lines the nose, known affectionately as snot or boogers (this is not what it really looks like in life), nasal mucus; it’s time for you to watch our mucus movie (YES, YOU TOO RORY) and see what inhaled formaldehyde does to this protective river of slime, forever flowing in your nose:

Question – does nasal mucociliary function account for the precise nature of lesion location by functioning as a local formaldehyde barrier of regionally specific effectiveness?

1982 – 1990: We studied nasal mucus for it’s role in formaldehyde lesion location, mapping out the entire flow field, describing all the rivers and tributaries in the rat’s nose, exploring the diffusion of radioactive formaldehyde through human nasal mucus (I got good at collecting it), running computational models to assess whether the mucus provided any significant protection, and if it could account for the precise lesion location, and concluded – NO! A blind alley, but what fun, and I learned so much about mucus and thixotropy!

What next? Science can be full of blind alleys – in fact you can spend your whole life up a blind alley, if you’re not careful.

I was fortunate to have a number of Biochemists in my team, in the form of post-docs and visiting scientists (can’t give all their names, or there is no way you’ll read this stuff [bet you’re yawning, already!], but they were great, including…forget it, I’ll leave one out by mistake, and they’ll have hurt feelings). They helped me to fail faster, the best reward in science and business.

Betsy, of all the people involved in my research life, was the person who contributed most to my enjoyment of science – Betsy is a problem solver, extraordinaire. Frame from the mucus movie.

Question – does regional nasal formaldehyde catabolism (chemical destruction) account of the precise nature of lesion location?

Spent about four years trying to answer that one, which yielded a paper that pretty well laid that idea to rest, another blind alley, whilst triggering a bunch of unrelated nasal histochemical studies and publications, NEXT:

Histochemical localization of formaldehyde dehydrogenase in the rat. Douglas A. Keller; Henry d’A. Heck; Holly W. Randall; Kevin T. Morgan, Toxicology and Applied Pharmacology, (1990), 106, 311-326.

Then we finally got on the right track.

AIRFLOW? I couldn’t believe airflow patterns in the nose could possibly account for the precise nature of local formaldehyde dose (the dose makes the poison): WRONG!

I was saved from my impressive ignorance by:

An Artist, Andy – best nasal models, ever.

A Differential Geometer, Julie – computational fluid dynamics, and great teacher.

A Chemical Engineer, Jim – boundary layer theory, and thinker.

A great pathology team, Tom and Betsy – pathology data generation, and interpretation.

A mathematical modeler/risk assessor, Rory – believed in us and created a safety risk assessment.

And lots of other people, of course, but I have to stop somewhere, but it went like this (in brief).

I was looking up these references, when my grandson’s face appeared in the middle of my screen. He’s in Japan, and we talk on Face Time. Boy, the World has changed. Screen shot by FitOldDog.

10 Years Work: Studies of inspiratory airflow patterns in the nasal passages of the F344 rat and rhesus monkey using nasal molds: relevance to formaldehyde toxicity. Morgan, K.T., Kimbell, J.S., Monticello, T.M., Patra, A.L. and Fleishman, A. (1991). Toxicol. Appl. Pharmacol, 110, 223-240.

Julie introduced me to the value of mathematics in the form of computational fluid dynamics, which caused me to spend about 5 years of my life doing almost nothing but studying mathematics, though that came much later, and is another story, entirely.

Work Spanning 5 Years: Application of computational fluid dynamics to regional dosimetry of inhaled chemicals in the upper respiratory tract of the rat. Kimbell, J.S., Gross, E.A., Joyner, D.R., Godo, M.N. and Morgan, K.T. (1993). Toxicol. Appl. Pharmacol., 121, 253-263.

Jim helped me to solve the problem of relating boundary conditions in the air phase to local mass flux patterns, in the lab, providing enough insight to convince me that such boundary layer effects can be as precise as those lesions in the nose.

I was going to put a nice picture of mass flux predictions in the nose, but I don’t want to pay $35 for my own article. Didn’t seem right!

Work Spanning 3 Years: A photographic method for the visualization of mass uptake patterns in aqueous systems. Dasgupta, A., Guenard, P., Ultman, J.S., Kimbell, J.S., and Morgan, K.T. (1992). Int. J. Heat Mass Transfer, 36, 453-462.

Conclusion: the key variable responsible for the precise location of formaldehyde-induced lesions in the nose of the rat is the air phase boundary layer structure, knowledge of which can lead you to meaningful tissue response distribution research and a solid, scientifically (as opposed to safety factor)-based risk assessment, upon which wise societal decisions can be made.

Tom and Betsy – waded through mountains of data generation, analysis and interpretation, leading to the PWULLI (Population Weighted Unit Length Labeling Index) approach to exposure response assessment, with respect to regional cell replication.

Work Spanning 8 Years: Once we established the distribution of high exposure areas in the nose, this permitted us to study the relationship between estimated local dose of formaldehyde to the target cell population, lying in different regions of the respiratory epithelium lining the nose. This took us to site-specific studies of a key cancer variable for risk, cell replication (cell division) rate, and finally a paper relating local cell replication rate to target cell population size and the subsequent cancer incidence in relation to airborne concentration of the gas and regional delivery in the nose.

Correlation of regional and nonlinear formaldehyde-induced cancer with proliferating populations of cells. Monticello, T.M., Swenberg, J.A., Gross, E.A., Leininger, J.R., Kimbell, J.S., Seilkop, S.K., Starr, T.B., Gibson, J.E. and Morgan, K.T. (1996).  Cancer Res, 56, 1012-1022.

Rory (right) and FitOldDog heading out on a planned 80-mile bike ride. Note, Rory is carrying food in the form of Spiz on his bike, and FitOldDog is carrying food in his Paleo-adapted body (storage fat).

Rory taught me to ride a bike, and he generated a scientifically-based human risk assessment, which in part was supported by our foregoing research results.

Work Spanning 8 Years:

What is the point of all this? It helps you extrapolate from animal data (better still non-animal, say in vitro), and computer studies, to create effective human risk calculations. This is really important stuff, which is summarized in this reference, by my cycling coach and buddy, Rory:

Human Respiratory Tract Cancer Risks of Inhaled Formaldehyde: Dose-Response Predictions Derived From Biologically-Motivated Computational Modeling of a Combined Rodent and Human Dataset. Rory B. Conolly,1 Julia S. Kimbell, Derek Janszen,3 Paul M. Schlosser, Darin Kalisak,, Julian Preston,2 and Frederick J. Miller

When it comes to chemical exposures, you have to make choices, such as: Should we deal with the use of chemical X, by (a) ensuring safe exposure levels, using protective equipment, or by (b) closing down an industry that depends on the use of chemical X. Tough choices indeed, especially if it’s your job on the line, and one that is full of ethical pitfalls. Reliable data, combined with knowledge and wisdom, is the way to go, in my opinion.

So, what  has this got to do with so-called plantar fasciitis?

When it comes to plantar fasciitis, you also have to make choices, treatment choices.

Click on this link for the interactive map.

We want to optimize these choices for people with this horrible condition.

As an alternative to prayer, and if you are not on statins, you might consider our wonderful road map.

I’m approaching this mystery in the same way as I did the formaldehyde-induced tumors in rats, all those years (>30 years) ago. Instead of using microscope slides for the generation of key insights, I’m employing case histories – people’s plantar fasciitis stories, such as:

“Had a severe reactions to cortisone, face flushing, not feeling well. After that past, about a week. It only lasted about a month for me! I have it in both feet!”

 “I have been suffering with PF over a year. Night braces, orthotics, PT, two Ossatron shockwaves, now cortisone shots. Have gained 30 lbs, and don’t consider myself to be a runner any more. Any advice? Thanks.”

Then there’s Matt and his foot, at this link, which is, in part, why I fight this battle.

What I love about this research is that I don’t have to kill any rats, and it is teaching me all about business.

Want to buy our latest book?

You can have it at a discount, if you use this promo code KM07VWJS at this link – first 18, no, 17, no 16, comers first.