Being Human and Struggling with Entropy

Sysiphus Meets our Social Brains

Get up. Go to work. Go home. Go to bed. This tropes permeates our culture — plot-lines in advertisements, movies, books, TV shows, and even conversation — it describes the mundanity of our daily existence. A woman might wake up in the morning, perform her morning routine to ready herself for work and her household for the day, commute the same route to a workplace to perform tasks that amount to the same repetitions that she did yesterday (send emails, prepare documents, perform calculations, meet with people), and then go home, perform an evening routine. And the cycle repeats itself. Continue reading

Letting Go of the Once & Future Self

Starting my freshman year in college, I kept all of my class notes, organized in binders and arranged on shelves. They were all nearly the same: the course syllabus on the front as if it were a table of contents (with check marks as each week or assignment ticked by), followed by the the exams (as if it were an executive summary), followed by my notes in loose-leaf paper (with the dates marked in the upper right-hand corners), then handouts, then homework, then quizzes. The binders were color-coded by field: Chemistry – Black; Evolution Ecology & Organismal Biology – Green; Biochemistry and Molecular Genetics – Blue; Immunology – Red; Math/Calc – Burgundy; Non-science (general ed. curriculum) – light blue or yellow. They were not organized by date, but rather by clustered together by field. I carried this through graduate school and kept all these notes from 1999 to 2015.

IMG_1179
The stack of papers that I unceremoniously threw into the recycle bin on February 28, 2015, thus saying goodbye to the future Professor Tatro

I am not sure why I started doing this, I think that it started because during the first quarter, I felt like I had put a lot of effort into organizing these materials. They exist in physical form. The words, symbols, equations, and diagrams represented my newly acquired knowledge and skills … it would have felt weird or destructive to throw them away. And so I kept them from one quarter to the next. Then from freshman year to sophomore year, and so on … lugging around boxes of binders from dorm to Mom’s house to dorm to apartment to apartment from city to city and from timezone to timezone. These binders came to represent my identity as a scientist. Continue reading

Optimizing Funding Policies and Other Strategies to Improve the Impact and Sustainability of Biomedical Research

The National Institutes of Health is requesting information from the public, specifically targeting the scientific research community. They do this by issuing RFI’s (can you get what that stands for?) as “Notices.” “Notices” have an “NOT” number, and are the official communication of the NIH with the public. Most recently, they have issued NOT-OD-15-084: RFI: Optimizing Funding Policies and Other Strategies to Improve the Impact and Sustainability of Biomedical Research. I have been encouraging my friend and colleagues on Teh Facebookz, Twitz, and other social networks to provide their feedback.

I want to put my social networking where my mouth is and share with the world my own comments that I submitted last night. There is a 500 word limit for each question. I was very surprised to see the conversational tone of actual responses to a previous RFI. I had thought that these were supposed to be well thought-out, evidence-based golden nuggets of wisdom; when really they are lists of anecdotes. They range from dripping with contempt and resentment to blissful entitlement. So I assure you, whoever reads this, that your comments will be just as valuable as they are for other RFI’s1. I was really only inspired to submit my comments after reading the contents of the last RFI which I wanted to, but didn’t because I didn’t think my opinion was worthy2. If you read the other RFI comments, they are generally less structured and more stream-of-consciousness. My comments as follows: Continue reading

Know your model.

In biomedical research, we are often trying to answer questions at different levels. By “level,” I mean from molecules, cells, tissue, organ, organ system, organism, community, and ecosystem. It is rare that biomedical research gets to the community and ecosystem level. There’s also a cost / benefit consideration to what “level” your particular research question is answering. Studying a problem at the level of the organism is much more expensive than studying a problem at the level of molecule — however one might argue that studying at the level of the organism is more biologically / clinically relevant.

cells
The cell model used in my lab, SH-SY5Y cells. Left: Non-differentiated cells, neuroblastoma, continue division. Right: Differentiated cells, stopped dividing, extended axons & dendrites, secrete neurotransmitter.

At each level, you have the thing in your lab that you are actually manipulating and observing and this thing is used to represent something greater, hopefully a more general concept. That’s known as a “model.” Continue reading

UC San Diego MicroRNA Scientific Interest Group

I have started a new MicroRNA Scientific Interest Group, which I intend to be campus-wide and bring together researchers whose work touches these molecules, because they seem to be involved in nearly every pathway.

My Department has created as website and Google-calendar, which is linked to here: http://psychiatry.ucsd.edu/education/Pages/InterestGroups.aspx

I am very excited to get this started. As I mentioned to my Dept Chair: I have not organized any large events like this since I was a fearless grad student, so I am a little bit nervous. However, the first meeting was a success. Students and faculty were engaged, asked questions — and the discussion took the evening 40 minutes past the planned stop time!

For the first meeting, I gave a brief introduction, followed by a 10 minute research presentation (of our microRNA-138 in the aging mouse, published in Am. J. Geriatric Psychiatry), and Dr Maurizio Zanetti, Prof of Medicine at the Moore’s Cancer Center gave an incredibly interesting talk about some of the tools his lab has developed.

Since the research results and data that I presented were already published, I will go ahead and embed my presentation here.

Cheers.

Soma to Germline Information Transfer via MicroRNA in Sperm

A few months ago, I posted about an article which  speculated that the evolution of the modern human brain was a result of Lamarckian evolution. To recap — this means that a trait is acquired during one’s life experience, and that trait is transferred to the offspring. The classic example is that giraffes have long necks because a precursor animal stretched its neck to reach high foliage, the next generation was born with longer necks because of its parents’ reaching. The next generation reached yet higher, and the next generation had yet longer necks. In humans, the example is something like a blacksmith has big muscles from working at a forge all day, he passes on his big-muscles to his son because of the use of his arms.

For something like brain development to be influenced by life experiences, I speculated that hormonal changes (e.g., corticotropin release hormone, ACTH, cortisol, norepinephrine) as a result of psychological stress or trauma would have to induce epigenetic changes in sperm.

Imagine my surprise when I directed my web browser to Nature News where researchers at the Brain Research Institute at the University of Zurich discovered that specific microRNAs were indeed increased in the sperm of male mice exposed to psychological trauma (being forced to be away from their mother during rearing, who was undergoing stressful experiences, i.e.: cold-stress or forced swimming)…. and these microRNA increases persisted for yet one more generation, and also was increased in their hypothalamus and cortex. So this is one interesting piece of the puzzle.  The Pubmed Link.

They do not yet know the mechanism of the microRNA-induced changes. But there are several steps that need to be taken to be sure that the observed effect is real, and a few grains of salt.

  1. The study used high-throughput analysis, and screening-type methodologies. These should always be followed up with low-throughput analyses because the reliability of any one target in a high throughput screen of RNA quantity is low. We did this with our PLOS One study. We used a different methodology to quantitate a panel of several microRNAs from our high throughput screen which quantitated 380. We chose some that were up, some that were down and some that were not different. We plotted the signal in the single-target method vs. the high-throughput method to validate that they matched. This, in my opinion, is a must-do, if you plan to make a claim about any one transcript.
  2. The mechanism is not understood. How do the microRNA’s change in the sperm? One good place to start would be to look at the promoter region for the candidate microRNAs that were altered — are these transcription factor sites or hormone response elements (e.g., that would respond to cortisol)?  Are there methylation sites?
  3. The next additional step is to show that changing the concentrations of those microRNAs has some effect on prenatal CNS development.
There are several variable sequences located the the 3` untranslated region (3`UTR) .... which is where the microRNA action takes place. We don't know yet if there are functional microRNA response elements here, but several are "predicted" by the power of having sequenced the human genome. One function of this gene is to feedback-inhibit signaling of hormones, including those responding to stress, but also involved in development & metabolism.
There are several variable sequences located the the 3` untranslated region (3`UTR) …. which is where the microRNA action takes place. We don’t know yet if there are functional microRNA response elements here, but several are “predicted” by the power of having sequenced the human genome. One function of this gene is to feedback-inhibit signaling of hormones, including those responding to stress, but also involved in development & metabolism.

This topic is very near and dear to my own research plans and goals. I’m going to recreate here a figure that I used to illustrate the point of the FKBP5 gene. This protein’s function is to modulate the glucocorticoid receptor nuclear translocation, it essentially inhibits it; so it serves as a feedback mechanism for particular cells to “turn off” cortisol signaling very quickly after it starts. But if FKBP5 is too high … no cortisol signaling was allowed in the first place. There are gene polymorphism in FKBP5 associated with major depression … and one of my future research plans is to determine the big how and why.  One potential way is by altering microRNA response element sequences.   …. aaaand it comes full circle. I would be interested to know of any of the microRNAs discovered to be changed in the sperm of traumatized male mice might also bind to FKBP5.  Cool stuff, huh?

 

Politics, Budgets, and NIH Funding for New Investigators

This post gets into the weeds discussing funding for biomedical research in the US. I want to discuss historical funding trends, changes in NIH policy, the relationship between politics and funding research, and ask whether “peer review” is truly unbiased.

Image
New R01s for Established (blue) and New (yellow) Investigators (top) over time. Fitted linear lines with 95% confident intervals are also plotted. Proportion of new R01 applications that are awarded to New Investigators (blue, bottom). Noted on the timeline are Government Shutdowns (green dashed), NIH New Investigator Policy changes (solid), NIH budget doubling period (magenta dashed), and the Budget Control Act (Sequestration).

Continue reading

The Mysterious “Shin Splint”

When I first started running about 7 years ago, I experienced pain in my right shin, which got worse with use and exercise. Specifically, this is pain in the medial tibia, exacerbated by stress and use (running). I asked around about it, and it was explained to me like this: these are “shin splints,” which are tears in the tendon which connects the muscle to the bone, specifically the calf muscle to the bone around that area. I was told that it was caused because the tendons are not strong enough to support the stress put on by the new exercise of the muscle pushing and pulling on it. The only thing to do is to rest and let it heal. So that’s what I was told. I let it heal by doing alternative cardio exercises like elliptical machine (which uses way fewer calories than running and doesn’t strengthen many muscles, but if you employ techniques to make it more difficult, you can strengthen the gluts & thighs) and rowing machine. After the pain went  away, I incorporated calf muscle-building exercise into my routine and never had a problem since. So that’s my anecdote.

What does the research say?

First of all the etiology (root biological cause) behind “medial tibial stress syndrome” is not known. So the story I was told, believed, and repeated, might not necessarily be true, but it is plausible. I found a pretty good review of risk factors (here). Continue reading

Do microRNA cause Lamarckian evolution?

I was perusing Pubmed Centeral to look for something interesting to read while waiting in between interviews yesterday and I came across this article titled, “Lamarckian evolution explains human brain evolution and psychiatric disorders.” Intriguing concept. Fun illustrative example and thought exercise. My short answer is: Only by an extraordinarily loose interpretation of Lamarckian evolution and by narrowing the scope of natural selection unnecessarily, and if a just-so set of experimental observations proves that brain plasticity leads to epigenetic or RNA changes in testes and ovaries. So I think the arguments of the paper are weak, but still worth thinking about for anyone interested in evolution of the human brain and its quirks. To look at this, let’s review the basics.

Mechanism for transmitting acquired traits. Activity and experience-dependent changes to brain cause exosomes containing microRNA released into the circulation; which is then passed on to offspring, influencing brain development and behavior/cognition. In my opinion, implausible mechanism of evolution.
Mechanism for transmitting acquired traits. Activity and experience-dependent changes to brain cause exosomes containing microRNA released into the circulation; which is then passed on to offspring, influencing brain development and behavior/cognition. In my opinion, this is an implausible mechanism of evolution of the human brain.

Continue reading

Snakes on a Brain

In October, 2013 ScienceNews put out a press release describing an article published by researchers from UC Davis and U Toyama (Japan) advancing the “Snake Detection Theory.” They measured the responses of pulvinar neurons to visual stimuli, including a hand, face, geometric shape, and a snake. They report that they found a specific response to the snake as a visual stimulus, and that it supports the notion that the primate brain evolved under evolutionary pressure from living alongside snakes as competitors and predators.

The pulvinar neurons are located in the thalamus (in humans, the pulvinar nucleus, or cluster or neurons, is the largest in this structure). The thalamus is a structure that is deep in the vertebrate brain and it relays sensory and motor signals to the cerebral cortex, it regulates consciousness, sleep, alertness. This group of neurons receives input from crossed optic fibers (that is, the right part receives input from the left eye), which then relays information to the cortex of the occipital lobe. They also communicate with other regions, but that is the path of visual stimuli. Continue reading