Changing the thermostat

Everyone knows that the human core body temperature is supposed to be around 98.6 F.  At least, that's what we all learned in seventh grade life science, right?

A more curious question is why 98.6 and not some other temperature.  Other mammals need different core body temperatures, but the range is remarkably narrow -- from elephants (97.7 F) to goats (103.4 F), only a 5.7 degree difference overall, and the vast majority of mammal species are in the vicinity of 98-100 F.

In my biology classes, I usually did nothing more than a hand-waving explanation that "our body temperatures are what they are because that's the temperature where our enzymatic and neurochemical reactions work at their optimal rate," but that's a facile analysis at best -- a bit like saying "bake the cake at 350 F because 350 F is the best temperature at which to bake cakes."  It might be true, but it doesn't tell you anything.

Last month we got a better explanation of what's going on than what I used to give (admittedly a low bar).  A paper in Molecular Cell with the daunting title, "A Conserved Kinase-Based Body-Temperature Sensor Globally Controls Alternative Splicing and Gene Expression," by a huge team led by Tom Haltenhof of Freie Universität Berlin's Department of Biochemistry, gives us a window into why we regulate body temperature -- and why things fall apart so quickly when the temperature isn't what it should be.

The team looked at the effects of temperature change not in mammals but in turtles and crocodiles -- which are themselves poikilothermic (known in common parlance as "cold-blooded") but have a temperature-switching mechanism for sex determination.  In crocodiles, incubation of the eggs at a warmer temperature results in males; in turtles, the pattern is the opposite.  (Some lizards have an even odder pattern, where intermediate temperatures result in males, and either low or high temperatures result in females.)

The question was how this was happening.  Something about the temperature must be changing the chemical signaling that guides embryonic development; but how?

Haltenhof's team found that there is a group of enzymes called CDC-like kinases that are extremely temperature-sensitive.  Kinases in general are a hugely important enzyme family that are responsible for phosphorylation, the main way energy is transferred in living organisms.  So if you affect the reaction rate of a kinase, it results in changes in the transfer of energy -- and can have enormous impacts on the organism.

And the CDC-like kinases, Haltenhof et al. found, were acting directly on the DNA, and changing the rate of gene expression.  In crocodiles and turtles, the type of gene expression affected had to do, unsurprisingly, with embryonic development of the reproductive systems.

So far, interesting only to geneticists and herpetologists (and, presumably, to the crocodiles and turtles themselves).  But where it caught my attention was when it was pointed out that the activity of CDC-like kinases is important not only in reptiles, but in humans -- and that overexpression of one of them, cyclin E, is connected with at least one form of cancer.

So this research seems to have implications not only for embryonic development in crocodiles and turtles, but in explaining why our own body temperatures are so tightly regulated.  The authors write: "[CDC-like kinase] activity is likely to also impact on gene expression in pathological conditions such as hypothermia, septic shock, and fever, or in the slightly warmer tumor microenvironment."  And since in general, the core body temperature drops as a person ages, it also made the authors speculate that this could be the key to at least some age-related malfunctions (and perhaps suggest a way to treat them).

[Image licensed under the Creative Commons 24ngagnon, Thermostat science photo, CC BY-SA 4.0]

This also brought to mind another perplexing bit of research that came out in January -- that the average human body temperature is dropping, on the order of 0.03 C per decade.  The standard "98.6 F" was established in 1851 by Carl Reinhold August Wunderlich, who determined this by taking the axillary (armpit) temperature of 25,000 people in Leipzig (and you thought your job was boring).  But a recent study with even more measurements found that currently, the average body temperature is almost a degree cooler than Wunderlich's value.

The speculation in that paper is that the drop in temperature is due to a decrease in the inflammation caused by exposure to infectious agents.  If the 25,000 Leipzig residents were a representative sample from the mid-19th century, 3% would have had an active tuberculosis infection, and that's just one disease.  So the lower average temperature today might have to do with our lower incidence of infections of various kinds.

But it makes me wonder what effect that's having on the CDC-like kinases from the first study.  Because during our evolutionary history, the 1850s condition of harboring infections was much more the norm than our current clean, germ-free-ness.  So while losing our collection of nasty bacteria might be overall a good thing, it might have caused a drop in temperature that could affect other reactions -- ones we're only beginning to understand.

That's yet to be established, of course.  But what it does highlight is how important the body's thermostat is.  Only a four-degree drop in core body temperature is a sufficient level of hypothermia to severely endanger a person's survival; likewise, a six-degree increase would be a life-threatening fever that (if survived) could result in brain damage.  We are only beginning to understand how our temperature is regulated, and why the effects of losing that regulation are so drastic.  But what this new research shows is that our body temperature might have far more ramifications for our health than we ever imagined -- and could be the key to understanding, and perhaps treating, diseases that have up till now defied medical science.

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This week's Skeptophilia book-of-the-week is brand new -- science journalist Lydia Denworth's brilliant and insightful book Friendship: The Evolution, Biology, and Extraordinary Power of Life's Fundamental Bond.

Denworth looks at the evolutionary basis of our ability to form bonds of friendship -- comparing our capacity to that of other social primates, such as a group of monkeys in a sanctuary in Puerto Rico and a tribe of baboons in Kenya.  Our need for social bonds other than those of mating and pair-bonding is deep in our brains and in our genes, and the evidence is compelling that the strongest correlate to depression is social isolation.

Friendship examines social bonding not only from the standpoint of observational psychology, but from the perspective of neuroscience.  We have neurochemical systems in place -- mediated predominantly by oxytocin, dopamine, and endorphin -- that are specifically devoted to strengthening those bonds.

Denworth's book is both scientifically fascinating and also reassuringly optimistic -- stressing to the reader that we're built to be cooperative.  Something that we could all do with a reminder of during these fractious times.

[Note: if you purchase this book using the image/link below, part of the proceeds goes to support Skeptophilia!]

Reconsidering the junk

Regular readers of Skeptophilia know how much I respect science, and the women and men who have devoted their lives to increasing our understanding of how things work.  The curiosity, drive, intelligence, and creativity of scientists have provided us not only with stunning technological and medical advances, but basic knowledge about everything from the origins of life to the bizarre and counterintuitive behavior of the subatomic particles that make up all the matter in the universe.

Still, scientists are only human.  They make mistakes, misunderstand what the data mean, follow leads in the wrong direction.

Fortunately, science self-corrects.  It still baffles me when people think self-correction in science is a weakness; I call this the "Everything About This Could Be Proven Wrong Tomorrow" argument.  Why anyone would think that a system of knowledge that either couldn't detect errors, or else simply ignored them, would be preferable, is beyond me.

We had a great example of science's capacity to self-correct just this week, in a paper that came out in the journal Cell.  "Sensing Self and Foreign Circular RNAs by Intron Identity," by Y. Grace Chen, Myoungjoo V. Kim, Xingqi Chen, Pedro J. Batista, Saeko Aoyama, Jeremy E. Wilusz, Akiko Iwasaki, and Howard Y. Chang, of Stanford University, the Yale School of Medicine, and the University of Pennsylvania, sounds at first like something that would only be interesting to genetics geeks like myself.  To see why it's much more than this will take a bit of background explanation.

Our traits, and the traits of every living thing on Earth, arise through a pair of processes called transcription and translation.  DNA, as you undoubtedly know, is the master set of instructions for building everything in your body; but somehow, that information has to then direct our cells to produce brown hair or A+ blood type or resistance to malaria or any of a thousand different other features of our bodies.

The way it does that is through synthesizing proteins that then are responsible for guiding everything.  The synthesis of these proteins takes two steps.  The first, transcription, is a little like making a temporary copy (called mRNA) of the instructions from a single page of a cookbook (the DNA).  Then, a structure in the cell called the ribosome reads the copied page (the mRNA), and makes the chocolate cake or honey-glazed spare ribs or eggs Benedict -- whatever the instructions say (those finished dishes represent the proteins).

A diagram showing the process of translation [image courtesy of the Wikimedia Commons]

Our master cookbook -- the DNA in every single cell in our body -- has, according to most estimates, about 30,000 different recipes.  This gives you an idea of how genetic disorders occur -- they happen when one of the recipes has a mistake, produces too much of its final product, or doesn't get read at all.

Anyhow, back in the 1950s and 1960s, when scientists were first figuring out how all of this worked, they assumed that most of the DNA was made up of actual, readable recipes, that produced something essential for the cell.  Otherwise, why would it be there?

So it came as a bit of surprise when it was found that a significant portion of your DNA -- early estimates said it could be as much as 40% -- is "noncoding."  In other words, it's made up of recipes that don't make anything.  This noncoding DNA was derisively labeled "junk DNA" -- although why such a high proportion of our genetic material would have no function whatsoever was a considerable mystery.

I was pretty skeptical about the "junk" epithet right from the get-go.  For one thing, you'd think that stretches of DNA that had no function would eventually get scrambled by random mutations, but at least some of them have patterns (such as the tandem repeat sequences -- regions of DNA that have the same base sequence repeated over and over, and which are remarkably similar even in distantly-related species).  The fact that these patterns get preserved through millions of years of evolutionary distance indicates that changing them causes problems -- i.e., they do have some function, even if we don't know what it is.

Some "junk DNA" probably does deserve the title, of course.  We have old, damaged copies of genes floating around in our DNA, which don't ever get transcribed and simply are hangers-on from our distant ancestors.  We also have odd things called transposons, which are genes that almost act like independent life forms, copying themselves and splicing the copies elsewhere in our genomes.  (Some of those transposons are functional in switching genes on and off, but others are more like intranuclear parasites.)

Anyhow, my point is that I've long suspected that most of the noncoding DNA would turn out not to be useless after all.  And the paper by Chen et al. has just shown us that some of what seemed to be the junkiest of junk DNA -- the introns, pieces of DNA that are transcribed into mRNA but then cut out before the process of translation -- might have a function that is downright critical.

What the paper in Cell suggests is that these introns -- the leftovers bits of RNA after they're spliced out following transcription -- could have a role in the detection of "non-self" -- i.e., the basis of our immune systems.  Chen et al. write:

Circular RNAs (circRNAs) are single-stranded RNAs that are joined head to tail with largely unknown functions.  Here we show that transfection of purified in vitro generated circRNA into mammalian cells led to potent induction of innate immunity genes and confers protection against viral infection...  These results reveal innate immune sensing of circRNA and highlight introns—the predominant output of mammalian transcription—as arbiters of self-nonself identity.

Which I think is astonishing.  These chunks of RNA, which have been compared to the full-page advertisements in a magazine article that you can tear out and throw away without losing any information, might well have a role in protecting us from infection by viruses.  How exactly they do this is beyond the scope of the current study; but just the fact that this is possible will open up huge avenues for research, possibly even leading to treatments for hitherto intractable viral infections.

So what were once derisively considered useless stretches of DNA now appear to be downright critical.  All of which brings me back to my original point; that science is powerful because it has a methodology for sifting out and correcting errors or misunderstandings.  Without that, there would be no progress -- no way, in fact, for us to discern and excise the junk in our knowledge about the universe.