Mea culpa, mice!

Animal research is purportedly protected by university and broader review and approval criteria.  The relevant IACUC (Institutional Animal Care and Use Committee) approval committees meet regularly, go over research and/or grant applications their faculty wish to submit for funding to the feds, and so on, and approve them for humane handling and other criteria; approval is required before the work can go on. 

Approval?  Well, what I have seen over many years, is not that 'anything goes', but lots of bending to allow scientists to act like Frankensteins so long as the victims--and that's what they are--can't protest.  We define what is 'humane' for them.  That makes it 'ethical' research.  And, no surprise, it does not require that whatever be approved is something we would voluntarily undergo ourselves (for knowledge's sake!).  Well, maybe the Nazis did that....

I am writing this to express my own very deep regrets for my many years of research on mice.  Mice were almost my only victims (no guinea pigs, etc., baboons once or twice briefly), but they were many.  And they did not have to sign any informed consent!  We did to them what our purportedly protecting IACUC approved, and deemed 'humane' and 'justified' for the new knowledge we would gain.  Note the 'we' here.  This was entirely selfish.

A lab mouse (source: cdn9wn.com)

And, dare one ask: what fraction of the knowledge gained by animal research is really of any substantial value to humans (none, of course, to the animals' own species)?  By what 'right' do we enslave and torment (if not, often, horrify and torture) innocent animals, to build our careers?  Because it is score-counting for our own selfish interest that is part of the story, even if, of course, that story also includes the desire for genuine new knowledge, which we hope will lead to improvements of some kind (for us).

Well, they're 'just animals', we rationalize (I think, a rationale conveniently provided by Descartes, who judged all but we soul-bearers to be no more than autonomous machines).  IACUC restrictions mean that we don't torture them (well, we pretend so, at least, using our not their definition; and we certainly do do things to them we'd be jailed, or even executed, for doing to humans).  Animal research is, after all, for our own good (note, again, the 'our' in this excuse).

What is the reality of the IACUC protection system?  It may avert the worst tortures, but it rationalizes much that is so gruesome that if the public knew of it......  For example, we can 'humanely' make transgenic mice who suffer--even from conception--some serious physical, health or behavioral defect, by investing them with, say, some known serious gene defect so that, hopefully, 'we' can figure out how to fix it (in humans, not in the victims from whom we learned the tactic).  I have been present at a purported meeting about research ethics, where a prominent university official bemoaned the care (already minimal, really, from the victims' viewpoint) that his IACUC committee exercised.  Why?  Because, he said, their Committee sometimes turned down faculty proposals that might, if funded, have brought in significant overhead funds to the University.  I mean, really!

A clear statement of the problem, for those humane enough to listen
There is a poignant, indeed deeply disquieting article in The Atlantic ("Scientists Are Totally Rethinking Animal Cognition", Ross Andersen, March, 2019).  Animals of all sorts, including even invertebrates, have self-awareness of one kind or another, essentially a sense of 'me'.  They presumably generally don't know about the inevitable finiteness of life, including their lives, so are saved from at least some of the abstract fears and fearful knowledge we humans may uniquely understand.  But they are not just things, cellular machines, and they do have fears, experience pain, and so on.  And yet.....

And yet, we noble university professors, not to mention those working in industry and agriculture, do to animals what we would not do to ourselves or each other (well, about what we do to each other one can say much that is just as sad as my reflections on animal research here).

So, to the mice (and those insects I've knowingly destroyed, and countless animals that I've eaten), I offer my mea culpa!  Sometimes, one must kill.  Life is an evolutionary phenomenon most of whose actors must, because of their evolutionary history, dine on objects of similar makeup.  Meat is one form, but do we too easily dismiss plants?  There are recent reports showing that plants are far more social, sentient, and aware than is convenient for us to think about with ease, as we munch away on our daily salad or fruit and veggies.

Darwin saw in his way what is to blame.  Life evolved as a self-renewing chemical phenomenon, and species evolved to dine on each other because, in a sense, we're all made of the same stuff.  It is a cruel truth of living existence, and that is one reason Darwin's work was controversial and is still resisted by those who wish for comforting theological accounts of reality and a joyful forever-after.  But we know--even they know--some of the harsh realities of life here and now.

We researchers always have some sort of justifying rationale for what we do to animals.  We have the approval of a committee, after all!  We're doing it for the good of humanity, to understand life, or for some other self-advancing careerist reason, including bringing in money to the university.  But, the bottom line is: we do, in fact, do it.

Fare thee well...
So, you countless mice, whose lives I terminated so I could get ahead, even if doing so as 'humanely' as possible after selfishly using them as I did, here's my apology.  I can't take back what I did to you, all within our acceptable research standards (note, mice, I said 'our', not 'your' acceptable standards).  Even where I could find, or construct, some rationale for my work, such as health-related discovery, basic knowledge, and so on, the payoff for us is small, and the cost to you, mice, was total and involuntary.  And one can debate how valuable the knowledge really was in the grand scheme of things.  How many of these must suffer before even one serious benefit, even one just for humankind, be gained?   I, and my lab group over the years, didn't really 'need' to do it, except  mainly for our careers. Was it enough that I did, after all, give you life, some sort of short life at least?

I so wish there were some way I could make it up to you.

Obesity and diabetes: Actual epigenetics or just IVF?

This press release that appeared in my newsfeed titled "You are what your parents ate!" caught my eye because I'm a new mom of a new human and also because I study and teach human evolution.

So I clicked on it.

And after that title primed me to think about me!, the photo further encouraged my assumption that this is really all about humans.

"You are what your parents ate!"

But it's about mice. Yes, evolution, I know, I know. We share common ancestry with mice which is why they can be good experimental models for understanding our own biology. But we have been evolving separately from mice for a combined total of over 100 million years. Evolution means we're similar, yes, but evolution also means we're different.

Bah. It's still fascinating, mice or men, womice or women! So I kept reading and learned how new mice made with IVF--that is, made of eggs and sperm from lab-induced obese and diabetic mouse parents, but born of healthy moms--inherited the metabolic troubles of their biological parents. And by inherited, we're not talking genetically, because these phenotypes are lab-induced. We're talking epigenetically. So the eggs and sperm did it, but not the genomes they carry!

This isn't so surprising if you've been following the burgeoning field of epigenetics, but it's hard to look away. This fits with how we see secular increases in human obesity and adult-onset diabetes--it can't be genomic evolution, it must be epigenetic evolution, whatever that means!

As the press release says...

"From the perspective of basic research, this study is so important because it proves for the first time that an acquired metabolic disorder can be passed on epigenetically to the offspring via oocytes and sperm- similar to the ideas of Lamarck and Darwin," said Professor ...

Whole new ways of thinking are so exciting.

Except when you remember a two-year-old piece by Bethany Brookshire (because you use it to teach a course on sex and reproduction) which explained something that suggests we may have a major experimental problem with the study above.

In IVF, the sperm gets isolated (or "washed") from the semen.

You know what happens, to mice in particular, when there's no semen? Obesity and other symptoms of metabolic syndrome! There are placental differences too. This was published in PNAS.

"Offspring of male mice without seminal fluid had bigger placentas (top right) and increased body fat (bottom right) compared with offspring of normal male mice (left images)" from The fluid part of semen plays a seminal role by Bethany Brookshire.

So I went back to look at the original paper that the press release with the donut lady was about. I wanted to see if they are aware of this potential problem with IVF and whether it explains their findings, rather than the trendy concept of epigenetics...

So even though they titled it "Epigenetic germline inheritance of diet-induced obesity and insulin resistance," I wanted to see if they at least accounted for this trouble with semen, like how it's probably important, how its absence may bring about the same phenotypes they're tracking, and how IVF doesn't use semen.

But I don't have access to Nature Genetics.

Who has access to Nature Genetics, can check out the paper, and wants to write the ending of this blog post?

Step right up! Post your work in the comments (or email me holly_dunsworth@uri.edu, and please include a pdf of the paper so I can see too) and I'll paste it right here.

Update 12:19 pm
Two very good comments below are helpful. Please read those.

I'll add that I now have the pdf of the paper (but not the Supplemental portion where all the methods live and other important information resides). This quote from the second paragraph implies they do not agree with the finding of (or have forgotten about) the phenotypic variation apparently caused by sperm washed of their seminal fluid:

"The use of IVF enabled us to ensure that any inherited phenotype was exclusively transmitted via gametes."

As the second commenter (Anonymous) pointed out below, there does not appear to be a comparison of development or behavior between any of the IVF mice and mice made by mouse sex. So there is no way to tell whether their IVF mice exhibit the same metabolic changes that the semen/semenless study found. Therefore, it is neither possible to work the semen issue into the explanation nor to rule out its effects. Seems like a missed opportunity.

Completely unrelated and inescapable... I'm a little curious about how the authors decided to visualize their data like this:

Health story of the day -- Java jolt cures Alzheimer's!

Here's a particularly cruel health result of the day, it seems to us. The BBC reports that coffee may reverse the symptoms of Alzheimer's, at least in mice force-fed the equivalent of 5 cups a day (or 2 lattes, 14 cups of tea, or 20 soft drinks -- wait, didn't we recently learn from the BBC that people who drink that much cola are susceptible to hypokalemic periodic paralysis?).

The new story says that caffeine seems to prevent plaques from forming in the brain, the 'hallmark' of the disease, or reduce those already there. Oddly, other researchers have found that these plaques are neither always found in people who had been given a diagnosis of Alzheimer's, nor are they always associated with dementia when they are found. So reporters aren't doing their job and/or researchers enjoying the limelight aren't coming clean (assuming they at least know their job).

This is a perfect example of a story prematurely reported about a scary disease, and thus that will sell. Because it will sell. Everyone fears losing their memory as they age, and quick and easy cures are surely eagerly sought by caretakers and the affected alike. Many have seen the awfulness of close and loved relatives with this disorder.

But mice are not people, and the dementia bred into an inbred strain of mice cannot be assumed to be the dementia any of our grandparents suffer or suffered from. As with all 'simple' diseases, the more researchers learn about dementias in people, the more questions they have--indeed, 'Alzheimer's' has always been a diagnosis of exclusion (that is, impossible to confirm until after death), and the signature amyloid plaques in the brain that were assumed to confirm the diagnosis on autopsy have been shown to be non-confirmatory after all. The idea of Alzheimer's itself as a single definable disease is fading within the research community as more is learned about dementias (unless perhaps your lab is committed to the line of inbred Alzheimeric mice it took you years to breed).

So, once again, scientists prematurely rush to the press with a story that may well cause caretakers to force-feed elderly patients with caffeine at best, and at worse cruelly encourage hope of a cure where in fact there is none. We write often about oversimplifying genetic determinism, but this is a case about oversimplifying environmental determinism--a problem that actually predated genetic determinism in the history of 20th century epidemiology. Surely by now both researcher and media should know better than to hype such claims.

There are many ways to get dementia. There are also many ways to get your morning energy boost even if tea, say, won't help your state of mind without drowining you or making you park all day in the bathroom. And there are many ways to spin a story to the news media.

But don't forget to have your coffee....or you'll forget to have your coffee!

Right.