Paternal stress in mice given to offspring via RNA packed into sperm | Hacker News Reader

Paternal stress in mice given to offspring via RNA packed into sperm

arstechnica.com

192 pointsshawndumas68 comments

Hello, I don't have access nor the time to grok the full paper. http://www.pnas.org/content/early/2015/10/14/1508347112.full...

Can someone give a quick ELI5 into the exact method and rough biological explanation in the study?

From what I understand roughly from the artstechnica layman explanation, the microRNA expression can be influenced by an individual's environment (in the case of the mouse, 36 hours of constant light, a 15-minute exposure to fox odor etc.) These microRNA levels act somehow as regulators/promoters to chromosome molecular structure (basically whether a particular region is wound up tightly or loosely, making that region either harder or more accessible for the DNA transcription machinery), thereby effectively regulating the accessibility and expression of the genes (in this case, genes responsible for "down regulating stress [pathways] of mice") stored in that region.

Although the innate DNA structure (source code) didn't change from parent to offspring, the environment influences (Larmakian inheritance or metaphorically the user-defined environment path) was passed down to the offspring via the microRNA (that was optimized for/influenced by the father's environment) in the father's sperm cells - such that the genes are regulated epigenetically in the child same as the father's from the get-go (e.g., inheriting the environment paths, importing the older browser's bookmarks).

I have several questions, 1) please correct my layman understanding if any of it is off (don't have access to PNAS unfortunately), 2) if someone in the field can explain how microRNA actually regulate the chromosomes and histones, 3) Even if the microRNA is passed down to the offspring, is microRNA expression level in that offspring going to remain persistent? Meaning suppose the offspring is exposed to a totally different environment in contrast to the parent, will the offspring's microRNA eventually change to match its changing environment, i.e., how does microRNA get expressed and regulated in the first place?

Thanks for posting this very interesting paper on Larmakianism making a comeback!

A quick answer to your question #1/2: microRNA (miRNA) is the substrate of a very complex piece of cell machinery that uses the miRNA sequence to find complementary messenger RNA (mRNA). When miRNA binds to its respective mRNA, the machinery (whose details I will not go into) degrades the mRNA, preventing its translation into protein. So while the DNA remains unaltered by the miRNA, protein expression is regulated on the level of mRNA degradation. MiRNA and short-hairpin RNA are tremendously useful in the laboratory setting to knock down the expression of genes without having to do gene modifications. This paper shows that miRNA can be passed from father to child through the sperm, and this miRNA can affect the way certain genes are expressed.

As for your question #3, I couldn't find any information in the paper regarding how long the miRNA persisted in the offspring. The miRNAs seem to have a long-term effect on genes in the paraventricular nucleus of the hypothalamus, but whether this is due to effects of miRNA solely in the development of the zygote, or whether the miRNA in the adult is also important, is unclear. It seems likely that changes due to the miRNA in fetal development alone could be sufficient in dramatically changing stress responsitivity, but this remains to be proven.

In another famous study, maternal nurture plays a very important role in the epigenetic development of baby mice [1]. So it could very well be that a favorable and nurturing environment may cause epigenetic changes in the offspring that might counteract the actions of the miRNA described here. Again, this is something that the paper does not show and therefore we can only speculate at this point.

Hope this helps!

[1] http://www.nature.com/neuro/journal/v7/n8/full/nn1276.html

Thank you milkcircle for your detailed and precise answers for my specific questions! And also going beyond to bring up another paper following up on nurture in terms influences epigenetic development of offsprings. Thanks for clearing up my confusion on how miRNA works ("regulate[s] on the level of mRNA degradation"). I learn something new today thanks to you!

https://en.wikipedia.org/wiki/Transgenerational_epigenetic_i...

So i guess the next question is: did the mice have different sperm characteristics because they were stressed? Or was it a long term change?

By which I mean, if the stressed mice were allowed to recover and have happy lives for a few months after the stress period, before mating, would these results still occur?

Because if not, then it opens the possibility that just being incredibly stressed out altered the production of sperm in some temporal manner.

Great. Another thing to worry about when trying to start a family...

Starting a family isn't rocket science. Look at the world around you. It's amazing. And it was built by people whose parents didn't wear them around in a pouch until they were five, who fed them formula, who didn't eat a bunch of fish oil while pregnant, and who (gasp!) smoked or drank during pregnancy.

Parenting science is like nutrition science. Lots of studies, little consensus. Just ignore it.

FWIW I (GP) have two kids and totally agree with this:

"Parenting science is like nutrition science. Lots of studies, little consensus. Just ignore it".

I'm just too weak to resist such low hanging joke opportunities.

Survivorship Bias [0].

[0] https://en.wikipedia.org/wiki/Survivorship_bias

They also had horrific infant mortality rate and ridiculous risk of death during childbirth, for both mother and child.

There isn't as much clear cut answers about parenting as we would like, but there is much evidence backed science which tells us what to do.

Your "Just ignore it." comment is pretty close to what the anti-vaxxers argue.

I'm pretty sure all of that drop in infant and maternal mortality rate was due to "real science" (antibiotics, surgical techniques, heroic efforts to save pre-term babies), and not the "pop science" that bombards parents-to-be. There is little scientific evidence that stuff leads to materially (not just measurably) better outcomes.

That means the advice reduces to "Pay attention to the real science, and ignore the pop science". Unfortunately that asks too much of a general audience (presupposes the ability to differentiate, which we know even PhDs occasionally have trouble with).

The real science is the stuff the powers that be will take care of for you. Just say "yes" when the doctor asks to vaccinate your kid or rush her to the NICU.

That's IMO the core of the anti-vaxx issue. The real reason is not rejection of the real science (even if it manifests this way) - it's the lack of trust in the way "powers that be will take care of (...) you" will be good for you. Politicians, pharma companies and all those scientists publishing bullshit for career/grant money fucked that up.

It's really hard to argue with the track-record of those politicians, pharma companies, and bought scientists. Infant mortality rate is one-third of what it was even in 1970. And that didn't happen from "empowered parents" making decisions based on advice they read on the internet. It was the medical industrial complex--including those companies selling NICU equipment for a few hundred grand per bed--saved all those lives.

> It's really hard to argue with the track-record of those politicians, pharma companies, and bought scientists.

As a lawyer, you should know it's pretty easy:

"Past performance is not necessarily indicative of future results."

Quod erat demonstrandum.

It's simpler than that. Past performance is something you get used to, and if you grow up around something working, you sort of assume it's always been like that. Part of the reason why every new generation wants to dismantle the systems set up by their grandparents.

I'm not denying that. Science, industry and politics did a hell of a great job. My point is, there were so many bad apples in those fields that society is rapidly losing its collective trust in authority - and this breeds all that anti-vaxx nonsense. I believe this rampant lying to be an actual existential threat to civilization - and I don't mean it as a hyperbole.

How about we stop jailing people for cannabis possession and instead start putting behind the bars journalists, politicians and "scientists" that push the most obvious bullshit for money?

"there were so many bad apples in those fields that society is rapidly losing its collective trust in authority"

Assumes facts not in evidence. I think it's fair to say that some of the tribalism currently evident in social and political argument is expressed as a broad based distrust and disregard for science, but that doesn't seem to be based on any rational analysis or actual knowledge, but more on internally propagated mythology.

Assumes facts visible to naked eye if you just go out and talk to normal people.

> I think it's fair to say that some of the tribalism currently evident in social and political argument is expressed as a broad based distrust and disregard for science, but that doesn't seem to be based on any rational analysis or actual knowledge, but more on internally propagated mythology.

You know that, I know that. People who are not really into science/tech don't know that. Most people know only what they hear on the news. And what they hear is that every single thing causes cancer - on Mondays, Wednesdays and Fridays, because that same thing cures cancer on Tuesdays, Thursdays and Saturdays. What they hear is that their government panicks about some flu, buys shots, those shots are not used and then questions are asked, politicians lose seats, etc.

Add to that that almost every single company is out there to fuck you over (mom&pop are the worst, actually), there's shit ton of FUD in media about everything related to biology (GMOs, vaccines, drugs, etc.), and are you really going to tell me there is no loss of general trust in scientific establishment? Go ask your non-tech family members and friends.

But yeah, it's easier to just assume instead that all "those people" must be just stupid.

   Assumes fact visible to the naked eye if you just go out and took to normal people.

Well, no, which was the point. Some normal people, absolutely. Others, not at all. To characterize this as "society" is inept. One of the problems with making sense of society as a concept is that these sort of generalizations tend to have little value as they occlude more than they illuminate.

>>And what they hear is that every single thing causes cancer

http://www.nbcnews.com/health/cancer/processed-meat-causes-c...

...you're so right it's painful. =/

There's a point I keep beating into people whenever someone utters the word "cancer" within my earshot. Actually, two related points:

- Just ignore the news; if Commonly Used Thing X was Actually Dangerous, you'd see people around you dying from cancer clearly tied to it.

- If you really have to go into it, demand to know actual values - not that something "causes cancer", but how it adjusts the probability, and then factor in the base probability. Something increasing cancer risk 100x may sound dangerous until you realize we're talking about increase from 0.00005% to 0.0005%, at which point you can, once again, just completely ignore it.

Anti-vaxxers argue against something that's proven all over and pretty much obvious if you had biology classes in high school[0]. OTOH, "nutrition science" is some small core of facts and good studies, covered by layers and layers of lies, bullshit, misperceptions, bad statistics and normal people acting like idiots. It's not worth the time.

[0] - then again, many if not most anti-vaxxers are only showing their lack of trust in the medical establishment, for which I do not blame them in the least, because of all the shenanigans doctors, scientists, pharma corps and politicians keep doing. And yes, "nutrition science" is a big part of that, too. <insert my standard rant about people who lie being responsible for all the blood that will be shed when society dissolves and civilization collapses />

You're going to like the NYT article[1,2] about the state of nutritional research... It speaks directly to your point _and_ rayiner's, in that the definitive research is limited, and the mass-media interpretation of said research is overblown.

[1] NYT Article: http://www.nytimes.com/2015/10/27/upshot/surprising-honey-st... [2] HN Submission: https://news.ycombinator.com/item?id=10453401

"Horrific" enough to have our population approach the carrying capacity of the planet, though I guess that doesn't take the danger away on an individual level.

That said, I think "just ignore it" is the proper thing to do in this case.

Sure, throw enough bodies at something and they'll get it done. But I don't think most parents are looking to play the odds so brashly, nor most modern organizers of any activity or goal.

Look at it from the bright side. You can now blame your parents for your crippling anxiety and stress.

and http://ww2.kqed.org/mindshift/2015/09/28/what-parents-can-do...

It is also reinforced by their actions, so nature and nurture.

Think about the conditions our ancestors dealt with.

"Stress" meant a broken bone, a fever, or a predator (if you go back far enough) could all be the source of life-changing (or ending) events.

We've evolved to adapt to harsh conditions and conditions have never been this good for a significant portion of the global population (especially for those of us reading Hacker News).

Your kids will be fine.

This raises an interesting thought in my mind. While the stresses of long-ago might have been more easily life ending, I wonder if people of long-ago laid in bed at night worrying about getting a broken bone.

Lethal stresses have the added benefit of preventing further reproduction, so we probably don't need to consider them in this scope.

While I agree conditions are pretty good for a lot of people, especially in countries like Australia where I live, people do seem to find a lot to worry about.

The non-lethal stressors are the ones we have to worry about. Or shouldn't worry about, as the evidence may suggest.

If you read the article, there was nothing of the sort involved in this test. And it explicitly notes that the hormonal stress indicators in the mice are in fact quite common in modern men.

Take a two month long vacation[1], and then do it somewhere toward the end.

[1]: Yes yes, not everyone has the luxury to be able to do that. But frankly, I've found that with a healthy amount of planning it is possible. E.g. I'm planning to take a 2 month long vacation next summer... I know already my boss probably won't let me, but I don't care! I'll quit if I have to! Already have an eye out for new gigs! This is like what people say about exercising -- you don't have time? Make time for it. The POTUS can find time to exercise, probably you can too.

Most people can't afford to take a 2 month vacation unless they already have a high paying job. Sure, most people can reduce their living expenses a lot but only so much.

That's not even considering the fact that planning a pregnancy like that isn't feasible, especially for older couples - who are the ones who had enough time to save up for a two month vacation. Pregnancy doesn't work like that, it can take months to years and that's not even considering 10-20% of known pregnancies end in miscarriage.

The idea pregnancy should be instant is harmful and leads to anxiety in itself.

I don't have a very high-paying job. I'm able to take the vacation because of (a) specifically saving for it and (b) planning a lot; took care of airfare almost an year earlier (in fact the location I chose was because of airfare deals), arranged place to live, and so on forth.

> That's not even considering the fact that planning a pregnancy like that isn't feasible, especially for older couples

I'm getting off-topic here but I really want to say this: the biggest reason I see Valley as being evil is it forces everyone to delay having kids. Have kids early, there will be less problems. https://en.wikipedia.org/wiki/Down_syndrome#/media/File:Down... There's a huge amount of research that suggests having kids earlier (e.g. at age 30 or earlier vs. age 40) is better for so many reasons.

I'm sure you have a job that's higher than median income because most of us here do.

So you are expected to have a life partner AND save up enough for a long vacation all before you are 30. That's a ton of pressure to put on young person.

Delaying childbearing has quite a bit of disadvantages but also its advantages. Even young people can't snap their fingers and instantly have a healthy pregnancy. That's not how pregnancy works.

As a person who started a family later in life (33), I agree with the OP that starting sooner would be good for more people. I wish I had.

Yes it's hard to find a life mate, but many generations did it before us.

The challenge is what policy levers are there to make it workable? My pet peeve is housing cost. In the Valley, NYC, and Boston, housing is so expensive that you need a career that can pay large salaries. Places like Austin, this is much less of a problem.

Also, I think it would be smart for a more frank discussion about the challenges of delayed parenthood. It's great that Facebook is paying for egg-freezing, but IVF is still super risky, financially impactful, stressful in its own right, and very uncomfortable.

Well, b) is what's hard for most people. You can only plan so many things before life overwhelms you. I personally know I can't plan shit.

But many in Europe can take at least 1 month.

I doubt this will work, given that it usually takes multiple attempts to concieve.

The two month vacation would be nice, but there's nothing to guarantee that the child will be concieved at the 'correct' time.

Pre-paternity leave

I wanted to make the same pun.

More proof that genetics is not read-only.

No, this doesn't permanently alter the DNA sequence.

Doesn't matter. It's the "reflections on trusting trust" kind of thing - we, our parents, grandparents, etc. form a chain; some runtime modifications to replication mechanism could propagate forward indefinitely, without changing the DNA in the process.

Nice insight. To save a few clicks to those remembering this classic (or reading for the first time!):

https://www.ece.cmu.edu/~ganger/712.fall02/papers/p761-thomp...

But, it is like commenting out regions in code. You are factually right, in that there is no editing of the DNA sequence i.e. no mutations. But this phenomenon exerts a similar end effect.

Not "end", exactly - at least, not if you look past N generations.

The question is, how many generations does it take for this to wear off? Or is it "good until cancelled"?

That's interesting that the mice with stressed parents dealt better with stress. I've typically interpreted this strain of study as a sort of depressing, "rich get richer" of biology concept where every generation gets more stressed out until they somehow get removed from the gene pool. But it seems like the exact opposite is the case, that there is an adaptive numbing effect

>That's interesting that the mice with stressed parents dealt better with stress

It doesn't say they dealt with stress better. They had a blunted stress response, and in humans that might lead to depression, etc.

Presumably there must be an evolutionary reason. If the environment is very stressful, it's perhaps better to have a lower HPA axis response to stress, otherwise you would be at risk of various diseases.

"Dealt better with stress" is not the conclusion (inference) that concerns them in the paper:

"This is relevant, and problematic, because blunted stress responses in humans are associated with neuropsychiatric disorders like depression, schizophrenia, and autism." (emphasis mine).

I interpreted it to mean that they have a blunted stress response, nothing more. Maybe a lot of people that undergo stress have a twofold reaction: 1. downregulate the response to similar stressors 2. still have some bad feelings about what happened

I would rather have 1 & 2 than just 2 alone. So yeah, when they say "associated with" they aren't saying "caused"

I suggest this review, published in Cell from 2014: "Transgenerational Epigenetic Inheritance: Myths and Mechanisms" http://www.sciencedirect.com/science/article/pii/S0092867414... (Open access)

and this series Kevin Mitchell: http://www.wiringthebrain.com/2013/01/the-trouble-with-epige... (The Trouble with Epigenetics)

They chose to show the cortisol data from the last paper[1] as a schematic...strange choice. Compare Fig 1F in this new one to Fig 1 from the previous work. The unexplained difference between control groups from the two papers is bigger than the effect they see due to injecting micro RNAs.

[1] http://www.jneurosci.org/content/33/21/9003.abstract

I extracted the data from the two figures and made a plot: http://s21.postimg.org/8it9wt9ut/Cort.png

At least the 2013 Control and 2015 PBS (the control for the current study) should be similar. They need to explain why the results are so different and figure out what is required to get reproducible results before they conclude the treatment is responsible here.

Also, in the supplemental methods they write: "Data greater than 2 SDs above each group mean were removed from analyses". That is not a legitimate reason to drop animals from the study. It appears they dropped four mice only to create the impression of less variable outcomes (and to help get "significance").

I am not confident this effect would replicate in an independent lab, they seem to be playing games with the analysis.

Also Starvation is genetically encoded

"Aftermath of hunger affects three generations in study of epigenetic changes."

http://www.nature.com/news/starvation-in-pregnant-mice-marks...

I wonder if there is some sort of evolutionary force at work here. Sort of some kind of heads up that you're coming into the world at a stressful time, better bring your best game kind of thing. Do we also father more aggressive children when we perceive we are threatened?

https://en.wikipedia.org/wiki/Lamarckism

Deleted comment

This generic critique doesn't seem to apply here. According to the article, the researchers were able to reliably reproduce the inherited stress response by artificially injecting a zygote with the extra RNA they suspected was responsible for the observed effect. That is a pretty compelling causality result.

Awesome. I guess my daughters will need SSRIs and assorted drugs to get them through life. Just bleeping great.

Same problem here. What can I say. It's tough man, but you just have to pull through it.

At least we are lucky, that we were born at a time where there's medication that makes you feel at least semi-normal. By the time I decide to have children, I hope humanity will be better equipped to handle the various mental illnesses.

miRNA here refers to microRNA, and that mRNA refers to messengerRNA ?

Yes, mRNA <always> refers to messenger RNA. miRNA nearly always refers to microRNA.

https://en.wikipedia.org/wiki/List_of_RNAs

I usually just call them 'miRs' to prevent confusion and misuse of both terms.

The equivalent of those mice experiments in human would be a tiger chasing you around for two weeks, and you finally managing to escape and reproduce. Modern men have nothing to worry about here.

This makes complete sense with me and my dad.

Reply on news.ycombinator.com