Sometimes, one can feel disheartened that people who identify as scientists nevertheless react with priestly outrage whenever anyone dare attempt falsify their pet theorems, or even question some of their assumptions.

We all understand the motivations behind such defensiveness, as exemplified so perfectly by Rory Collins and his ilk; however, we must remember that we do also find true scientists, with properly inquisitive minds, prepared to react and adapt to new information, and to the clarifications of old assumptions.

Molecule of the Month

As part of my research into an upcoming post to explain in laypersons’ terms how statins work, I have looked into the molecules involved in the statin-affected metabolic pathway. I sought a model of one of these molecules, Acetyl Coenzyme-A, and stumbled upon a page which had just what I needed in a post at Bristol University’s Molecule of the Month series.

This laudable (and gloriously old-school styled) web-series has run for more than a decade. It picks a molecule, which it explores, in friendly and delectably understandable terms.

The Molecule of the Month page on Acetyl Coenzyme-A, written by Professor Paul May, describes nicely some of the important metabolic processes in which the co-enzyme involves itself. It discusses how it helps to provide energy directly to our cells, convert food to appropriate storage forms, and how to release energy from these pre-existing stores when needed.

A Problem of Excess and Suffering

The Acetyl CoA Molecule of the Month concluded with a paragraph on the molecule’s use in fatty acid metabolism

The text describes how acetyl CoA gets used in lipolysis, where fats get used for energy. The text then says the following:

In cases of starvation, or where the person has a low carbohydrate diet (such as the Atkins Diet), this process can occur to excess.

The piece then continues, to describe the production of ketone bodies when one burns fat, concluding:

In this situation, the person is said to be suffering from ketosis

Of course, we find a number of inaccuracies here.

Firstly, the paragraph conflates starvation and nutritional ketosis. Secondly, it perhaps has as a subtext a confusion of ketosis and diebetic ketoacidosis. Finally, it begs the question that we should consider a body using fat as its primary energy substrate as somehow behaving “excessively”, with owner of said body “suffering” from that “excess”.

Email to the Author

Rather than just shrug my shoulders, or whine about this, I decided to get in touch with the author, Professor May. I sent him the following Email:

Dear Professor May,

Re: Molecule of the month:
http://www.chm.bris.ac.uk/motm/acetylcoa/acoajs.htm

I recently visited your molecule of the month, from over ten years ago, on Acetyl CoA. I found it a well-written example of science communication; however, I did have one issue:

On the page, you suggest that lipolysis can "occur to excess", and that the ketogenesis therefrom leads to the person's "suffering" from ketosis.

Could you please let me know how you qualify this "excess"? And could you explain the nature of said "suffering"?  Humans can thrive perfectly well on a zero-carbohydrate diet and, as an ice-age, big brained species, we spent plenty of evolutionarily significant time so doing.

I agree that for Type 1 diabetics, whose beta-cells cannot ensure ketone homeostasis via an insulin brake, runaway ketogenesis could lead to ketoacidosis. This does not concern anyone who has a working pancreas, though.

I hope that, as a man of science, you'll not resent this intrusion from a stranger.

Warm regards,

Nick Mailer
London

The Initial Response

To my surprise, Professor May responded within minutes. He has kindly allowed me to share his correspondence:

Hi Nick,

The term 'to excess' described what may happen with people suffering from starvation, or who were on low carbohydrate diets.  In these cases, where the stores of fat or glycogen have been completely used up, the body's cells are so deficient in sugar that lipolysis now occurs on the essential fats surrounding organs or within muscles. If this situation continues for long enough, this can ultimately lead to muscle wasting and organ failure.

The term 'suffers from' was not meant to imply that the person's ability was impaired or that they were somehow in distress as a result of ketosis.  In hindsight, perhaps 'exhibits ketosis' would have been a less judgmental choice of words.

regards,

Paul

My Clarification

I then replied once again, to deal with some of the points that Professor May brought up:

Hi Paul,

Thank you for taking the time to respond.

I agree with you that when one starves, the body uses whatever
endogenous substrate it can - muscles, essential fats and so forth - and will eventually catabolise itself to death.

However, research has found that low-carbohydrate milieus with otherwise nutritional sufficiency do not exhibit this characteristic. Humans have a unique ability, amongst all species, to continue ketogenesis even when replete with sufficient protein and calories. As the US Institute of Medicine put it: 
"The lower limit of dietary carbohydrate compatible with life
apparently is zero, provided that adequate amounts of protein and fat are consumed" [1]

How does the human species achieve this? Firstly, the metabolism down-regulates its requirements for glucose substantially. Very few cells actually demand glucose: red blood cells do, because they transport oxygen, and so cannot afford to burn the furniture for their own energy, so to speak; and certain brain cells require glucose too. Almost all other cells can use ketones and FFAs perfectly well and, indeed, more efficiently. [2]

Secondly, to provide the remaining glucose that the few glucose-
dependent cells still do require, the metabolism uses the glycerol from the triglycerides (as you illustrate in your piece), and engages in gluconeogenesis from ingested amino acids. [3] It thus need not draw down on its essential endogenous substrates at all.

Thus, the combination of the body's down-regulating its glucose
requirements, and the ability indefinitely to manufacture glucose
hepatically, means that the body can continue in this mode
indefinitely, and perfectly healthfully [4]. Thus, I think the notion of "excess" or suffering has little scientific merit :-)

Of course, when one considers our evolution, this makes sense. As a
fatty-brained, ice-aged species, we spent much of our time without
ready sources of digestible carbohydrate to hand. Stable isotopic
analysis of human bone-collagen remains confirm that we often exhibited a carb-free carnivory that exceeded that of foxes or wolves! [5] As such, we perhaps do not appropriately use the term "excess" or "suffering" to describe the state in which we probably spent most of our evolutionary time. 

Refs:

[1] https://www.nal.usda.gov/sites/default/files/fnic_uploads/energy_fu
ll_report.pdf

[2] http://www.ketotic.org/2013/09/the-ketogenic-diet-reverses-indicato
rs.html

[3] https://www.ncbi.nlm.nih.gov/pubmed/7351177

[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716748/

[5] http://www.primalbody-primalmind.com/fish-didnt-build-big-brains/

At this point, things could have  gone one of two ways. Professor May could have rejected me as an annoying crank for pestering him about an 11-year-old web-page; or he could have responded positively.

Professor May Responds Again

I received the following reply to my clarification:

Hi Nick,

The good thing about publishing documents on the web is that if any mistakes are found they can easily be rectified.  I've changed the online version to now read 'more readily and extensively' rather than 'to excess',  and 'exhibits' rather than 'suffers from'.

regards,

Paul

What a lovely response! And, indeed, Professor May has changed the page’s wording. No longer do people who burn fat “suffer” from ketosis, and nor does the page describe their state as “excessive”.

Note that, as a true scientist, he revels in setting the record straight.

I finally asked Professor May whether I could quote his correspondence, as I have just done. He affirmed:

Hi Nick,

Of course, no problem.   

Did you ever think of writing up your piece on statins as a Molecule of the Month contribution?

regards,
Paul

So now mevalonic acid could even have its 15 minutes of fame at Bristol!

Lesson Learned

We can suffer despondency when we continually encounter people who refuse to listen even to polite, reasoned argument. Their entrenched worldviews, or their hidden insecurities, or their corrupting  conflicts of interest, can make changing even a few neurons in a mind fraught.

My little episode here reminds us that we can still find people of science – true science, rather than a rigid chimera of science. These people continue to listen, continue to want to learn and continue to adapt. So, if you notice something awry in the public discourse, don’t let it lie. Send off a polite email, with references and reasoning and, who knows, maybe you too will receive the joy of a response from a person of honour like Paul May.