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Wednesday, July 13, 2016

BACTERIA vs HUMAN CELLS: 1 to 1 (FINAL) PT3/3

(PART2)
  
Don't lose the brand-new
"Oddities & Bloopers: The Researcher's Fun Corner"
at the end of the post!

Ooooh, welcome back for the third -and, I do promise, last- time in this topic, dear English thinking-reading visitor. I’m @sciencemug, the blog/twitter-account/podcast (on occasion)/e-shop that tells you science stories, competes in the “2016 Combing-Stylist For Bald People Contest (2016C-SFBPC)” (with serious possibilities to get to the semifinals against a url of Tuvalu specialized in doing the perm to invisible wigs for particularly unsettling ceramic dolls) and that does all of it in Eng?ish, a language that is to real English what Brexit and this are to good ideas.
 

In this post, dear visitor, it is going to end the story about three scientists (Mr. Sender, Dr. Fuchs, Prof. Milo, aka the SFMs) who debunk the myth that, in the human body, bacteria outnumber human cells by 10:1.

The SFMs (by @sciencemug)
The SFMs (by @sciencemug)

The SFMs first find out the actual number of bugs living in/on the body of a refernce human being (an healthy, adult, 1.70m high, 70kg heavy, 20-30 years old male aka Mr. Ref): 3.9x1014.
The science trio, then, calculates the number of human cells that make Mr. Ref’s body:
3x1014.
The researchers, like this, can show that the real bacteria/human cells ratio is 1:1 [so that every time one of you, dear human beings, go number two, well, human cells win the ratio-competition (since every “number two initiative” means loosing 1/3 of the members of the bacteria gang)].
 

Sooo to finish the story of the SFMs, dear visitor -and for this blog to go back and train for the 2016C-SFBPC which first prize is a tour of all the forty nine major sites of the dominion “.havingaballohyeahbigtime”- only the two questions you, smart-ass visitor, probably asked yourself, your “monster from the ID” of reference and, implicitly, me, must be answered:
1)Ok, the ratio is 1:1 in […] Mr. Ref, but what about the non-Mr. Refs all around the world, like […] women, overweight people, babies?
2)WHY?! Why [the SFMs] invest so much time in understanding what’s the actual bacteria:human-cells ratio in the human body […] ?


Weell, dear visitor, here come the answers.
 

Answer one. As you, by now, know, the bacteria vs human cell ratio basically depends on: colon volume (CV) & bugs density in the colon (BD) for the bugs side; number of Red Blood Cells-Erythrocytes (i.e. the hematocrit; He) & blood volume (BV) for the human cells side.
Ok? Ok!
 

by @sciencemug
by @sciencemug

So, let’s start with women.
A “standard” 1,63m tall [according to the 2002 Publication by the International Commission on Radiological Protection (ICRP2)(1)] mirror of Venus [aka Lady Ref] has a CV of  about 430ml, that is similar to the about 410ml CV of the standard 1.70m Mr. Ref.
As for the BD, well visitor, science literature doesn’t report, so far, any gender-specific differences about this parameter.
Let’s go to the He and BV now. Lady Ref has a He 10% and a BV 20-30% lower than those of Mr. Ref.
So, putting together these values, the SFMs “expect the bacteria to human cell ratio to increase by about a third in women”(P).
 

Big guys, here we come.
In obese peoplethe [CV] increases with weight and plateaus at about 600 ml, i.e. about 50% higher than that of the standard man value(P), and the BD is similar to that of Mr. Ref.
As for the human cells count, well, obesity implicates an increase of adipose tissue, and this grows in two ways: the adipocytes stretch and get very big (hypertrophy), they grow in number (hyperplasia) (2). So, as for the hypertrophy, well dear visitor, you see for yourself that the cell count doesn’t change with this. As for the hyperplasia, there the fat cells number goes actually up. However, the SFMs have shown that adipocytes in Mr. Ref are a negligible 0.2% of the total human cells, so even if their number rises a bit that doesn’t impact on the final cell count in a sensible way.
Moreover

fat tissue is not much vascularized, that is it has not many blood vessels. This implies that even if the body weight of overweight persons is 100%-400% higher than Mr. Ref’s one (i.e. 140-210kg vs 70kg) their total blood volume increases only by 40%-80% (P).
Thus, dear visitor, in the big guys, to an increase of colon volume (and therefore bugs number) corresponds a more or less equal increase of blood volume (and therefore of blood cells).
Final result: the bugs/human cells ratio of obese people is substantially the same of Mr. slim Ref’s one.
 

Oook, now let’s talk ‘bout babies (wow, this sentence’s scary as hell, eheh, even for a blog…)
From infantry to adultness the BD is rather constant
(P).
Colon volume, of course, is a different beast. On top of this, according to our friends, the SFMs, there’s a “knowledge gap(P) about this specific issue. The only data available are in fact “derived only from comparing infant to adult daily fecal output values(P) [(amount of poop coming out from a baby in a day vs amount of poop of an adult (intensity of the smell is not a considered parameter)] thus, not coming from more precise measurements, they are less reliable than needed. Anyway these data say that neonates have a CV of 50ml, and 1yo babies have a CV of 80ml (1).
As for He and BV: “[Babies' He is] higher than for normal adults but [it decreases] during the first 2 months until [it levels] at 10% lower than adult values […]. On the other hand, the blood volume to weight of infants is […] approximately 10% higher than normal adults(P).
So, considering also the fact that the BD of elders is 25% lower than that of 20-30 yo Mr. Ref but the He is the same, and putting all the data together, the SFMs conclude that “the effect of age on the B/H ratio is smaller than 2-fold from age 1 year onward and probably within the variation we estimated across the population of ‘‘standard’’ adult males.” (
P)
 

To sum up then, dear dearest visitor, the answer to your first question, according to the SFMs, is: the bugs vs human cells ratio is more or less 1:1 also in women, overweight people and children.
 

Nooow let’s go to question number two. But only after a commercial break.


We could come up with some sly, alluring slogan to get to you and convince you to buy our product (we are good at this, trust us on this, we just convinced a dung-beetle in Micronesia to purchase a life-long subscription to a monthly review for germ phobics, and an ant colony from Minnesota to buy a 72 lessons course that teach the philosophy of a Japanese baboon of the XIII century that is all about how to affirm your own “self” and not to conform to the mass will!)
But we won’t do it.
We just say that we have these cool shirts.



   Queen (dark)                                Queen (white) 
 

And that if you want them, well, you can have them.
Just click on the links.


Ooook, my pal visitor, now the time has come to answer your second question: why the SFMs work so hard to understand what it is the actual bacteria: human cells ration in the human body.
 

Well, first, the more you know about the bugs living in/on you (even just their total number), dear human visitor, the better in general. That’s ‘cause you naked monkeys are ecosystems, and bacteria are part of you and absolutely essential for your wellbeing. Take just the gut bugs, for instance: they make energy for you, they stimulate the development of your skin, they make some key nutrients and minerals more easily available for you-lazy ass host, they help the development of your immune system and even reduce the risk of asthma and dermatitis (3). They basically rock!
 

So, again, the more you know of your bugs, the better it is. For you.
 

Besides, as for the SFMs’ hang up for the total amount of human cells, well, they’re kinda justified on this too given a 2015 study (4) shows that cells number matters. A lot.

Indeed the number of stem cells of specific tissues-organs (i.e. “those [cells] that can self-renew and are responsible for the development and maintenance of the tissue[s’] architecture” (4)) and the number of their divisions in time is highly and positively linked to the lifetime risk of insurgence of cancer in those tissues-organs.

So, dear visitor, as you can see, the SFMs have plenty of good reasons to embark in their research project.
 

Moreovera number [i.e. 10:1 bugs to human cells] widely stated should be based on the best available data, serving to keep the quantitative biological discourse rigorous” (PB).
 

Finally, dear visitor, let me conclude the answer to your second question quoting the cool final words of the SFMs paper “[w]e think that the kind of progression presented in this study from informative back-of-the-envelope calculations to more nuanced value estimates is of wide interest and is instructive in the quantitative training of biologists. In performing these kinds of calculations, we become intimately familiar with the limits of our current understanding and therefore, more easily highlight the best avenues for scientific progress in a particular field. What better place to start such quantitative training than by examining the contents of the human body? In doing so we can comply with the Delphic maxim of “know thyself” in a truly quantitative fashion.” (P)


Now, dear visitor, for the first time on this dumb blog here it comes a new space where you can hear (well, kinda) directly the voices of the authors of the papers told in the post you just (hopefully) read and (ok, entering the field of quantum-ahaha-ya-jokin-rite?!-improbability here) enjoyed answering two simple (and not particularly smart, given who’s asking them) questions.

The
"Oddities & Bloopers: The Researcher's Fun Corner"

Meet Dr. Shai Fuchs
 
Dr-Shai-Fuchs

(aka the “F” of the SFMs)

 
SM- What's the oddest/strangest/weirdest/funniest thing/mistake happened/made to/by you (or to/by your colleagues) during the making of the paper described in the post or during your life in science in general?
 

SF- I think the most ominous mistake I did was that while working on one project I noticed that one of my yeast colonies refused to die and in fact that mutated strain outlived the Wild Type [the Mr. Ref of the situation (SM’s note)] by more than 2-fold.
This was a classic story of a completely unexpected result.
I jumped on it, began reading around and realized that there's a whole literature about ageing studies in yeast that I was completely unaware of.
Since this was early on in my PhD I convinced my PhD mentor to change my subject to a high throughput screen of ageing modifying genes utilizing a method it took me almost a year to calibrate which enables detecting rates of cell death in a high-throughput manner. , The project evolved into three separate studies and related papers (one was published a few months ago, and two core papers are in final pre-submission steps [Congrats! (SM’s note)]).
The funny thing is that a few months into that ageing project I realized I had an order-of magnitude error in that initial experiment that actually did not produce the unusual “mutated yeast outliving the WT ones by more than 2-fold” result I thought it did. Had I divided by 10 where I should have it would be just another trivial preliminary confirmatory experiment and none of my ageing studies would have been conceived!
 

For this "Are we really vastly outnumbered paper" no scientific error per se so far (we each triple check each other's calculations independently to be extra careful). What was surprising and
unanticipated is the havoc on social networks and media after we uploaded the BioRxiv version. In essence the idea was to uncover the results when the Cell paper is published, and we needed some
credible resource to refer to for our full calculations, which is why we uploaded the calculations to BioRxiv two weeks before planned publication on Cell. Neither of us anticipated the number of tweets,
requests to comment to media or interview and vehement discussions (<<“RBC are cells!!” rubbish, they are just bags of hemoglobin!!!>>) that followed and kind of took the edge out of the Cell paper when it finally appeared.
 

SM- Besides doing/making/witnessing odd/strange/weird/funny things, Dr. Fuchs, why science?
 

SF- As a medical doctor , actually carrying the pursuit of carving a piece of knowledge out of the unknown makes you question everything. Makes you excited about the patients that don't fit into a rubric or a protocol rather than frustrated by them.
Being a researcher makes you courageous as science at its best expression, when stepping into a new field is a Bungee jump while you're still trying to attach the rope already while on a free fall. It makes you inquisitive, and it provides hours of fun for your kids when you bring them to visit your lab!
 

SM- Well thanks a lot Doc, and good luck with your science!



The paper this post is about (P) (PB)
P - Sender, R., Fuchs, S., and Milo, R. (2016). Are We Really Vastly Outnumbered? Revisiting the Ratio of Bacterial to Host Cells in Humans. Cell 164, 337-340.
PB - Sender, R., Fuchs, S., and Milo, R. (2016). Revised estimates for the number of human and bacteria cells in the body. bioRxiv doi: http://dx.doi.org/10.1101/036103
 

Bibliography
1- VV.AA. (2002). Basic anatomical and physiological data for use in radiological protection. ICRP Publication (Pergamon) 89.
2- Jo, J., Gavrilova, O., Pack, S., Jou, W., Mullen, S., Sumner, A. E., Cushman, S. W., and Periwal, V. (2009). Hypertrophy and/or Hyperplasia: Dynamics of Adipose Tissue Growth. PLoS Comput Biol 5, e1000324.
3- Roger, L. C., and McCartney, A. L. (2010). Longitudinal investigation of the faecal microbiota of healthy full-term infants using fluorescence in situ hybridization and denaturing gradient gel electrophoresis. Microbiology 156, 3317-3328.
4- Tomasetti, C., and Vogelstein, B. (2015). Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347, 78-81.