Genetic Expressions

A break from our regularly scheduled science coverage to report on an SfN social event + a slightly-bitter commentary on Yellow Cab service of San Diego….

So. Monday night finally rolled around- the night of the Lady GABA throwdown at Stingaree in downtown San Diego. The place was pretty crowded (as was anticipated) and the DJ was pretty good! A clip of some of the sing-along to the music below: ( note:it was dark, so this is more for audio than video really)

The party was slated to officially end at 2 am, so around 1:30 am, my friends and I decided we’d try to beat the rush and catch a cab back to the hotel. After waiting around a few minutes and realizing there were no cabs in sight, we decided to call one up. So, I called Yellow Cab. The representative assured me that there should be one there “soon” as there are “plenty of cabs in downtown”. Well. This statement, dear reader, was kind of… a lie.

After 10 minutes, a Yellow Cab did pull up – but another group of drunk friends flagged it down. “Wait…is that our cab?” my friend, Kira asked me. We weren’t sure, so while the group of 5-6  drunk friends battled it out over who should get in the cab we tried asking the driver if he had been called up or not (he shook his head no) – and quite unnecessarily, one of the girls in the group put up her hand to my friend’s face and said in a most condescending tone: “Honey, we got this.” We should have just gotten in the cab while their friends were arguing it out. Hindsight is a powerful thing.

So after another 10 minutes, I called up Yellow Cab again. I spoke with the same lady who assured me that our cab was on its way – “Number 63,” she said to me, “it should be there soon.” Alright, well – at least we were altogether. We waited and waited, then waited some more. Finally, after forty-five minutes of waiting, I called up, yet again.

It’s unfortunate that I didn’t get the same lady because it was really she who deserved to get a piece of my mind. Instead, someone named Robert answered the phone. I began to explain what happened and he responded unperturbed and quite matter-of-factly: “there aren’t any cabs available.” When I told him that not only were we assured at the outset that there were plenty of cabs available, we were given the specific number of a cab (63) – he said, “she lied to you.”

Indeed. Well, dear reader, you may be wondering if I tried calling up another cab company at this point. I did. I called Orange cab. No lies this time. Just someone who told me that there was no one he could send out but that we should try walking to the Mariott next to the Convention Center to see if we could find any out there. So, we begrudgingly, began ambling our way over. If a picture is worth a thousand words, then a video is surely worth a hundred thousand.

There is a happy ending to the story. About a minute after I ended the recording, Staci and Kira were finally able to hail a cab (hallelujah!) and when the driver turned up the radio and “Promiscuous Girl” started playing, we didn’t even care. We were warm, we were off our feet, and we were finally heading back to the hotel where some warm beds awaited us.

“We need to be careful in thinking it’s all about genetics – it’s not all about genetics. We need to take into account: epigenetics.”   ~ Paolo Sassone-Corsi

[photo credit: John Hersey of NYTimes]

So I think we’ve established this much: in order to understand the biological-behavioral interface, we need to better understand epigenetic processes. More specifically, we need to know: Which epigenetic marks are transmitted transgenerationally? And how are they?  Which marks are stable and which marks can be erased? What genes are susceptible to de novo methylation and what environmental factors (chemical, nutritional, hormonal, behavioral…) mediate these effects? Furthermore, how do these processes vary over space and time? [or in scientific jargon: what is the spatio-temporal specificity of these marks?]

These are just some of the questions scientists are facing as they attempt to break ground in the emerging field of epigenetics in neuroscience. Of course, this in no way implies the mechanism itself is new – to call it emerging simply means our awareness of this as a mechanism is emerging. So take any of the questions above, try to crack it open and what you’re likely to get (in addition to some hopefully useful data): even more questions.

Okay, so it’s complicated. What’s new, right? It seems obvious to state that the brain, genetic networks and the relationship between all these pieces is, well, complex – and yet, sometimes it’s the obvious truths that need to be stated. Truths that are obvious, tend over time, to be forgotten as we proceed along the investigative journey – especially when it comes to using (necessarily) reductionist methods to discover the functional components of a larger and complex, whole.

So this morning, at the minisymposium “Transgenerational Inheritance and Epigenetics: Animal Models of Neuropsychiatric Disease” that’s exactly what Dr. Tracey Bale, researcher at the University of Pennysylvania and chair of panel, did. She then launched into the data her lab has begun to unearth in an attempt to answer the following question:

What is the critical window within which induced maternal stress will affect male offspring at various gestational periods?

To answer this question, her group presented various stressful stimuli to the animals, then ran behavioral assays on the male offspring during early, middle, and late gestational periods. They found that the behavioral readouts (anxiety tests, spatial learning, etc) were sex-specific (hinting at an imprinting mechanism). They followed this observation with a scan to look at genes which showed sex-specific differentiation in expression. 96 genes revealed sex-specific expression, 32 of which appeared “demasculanized” (assessed based on angio-genital distance and testes-weight measures). This observation that the up or down regulation of certain genes was sex-specific, prompted the group to look at microRNAs.

Why? MicroRNAs (miRNA) regulate about 30% of protein-coding genes and they are enriched on the x-chromosome. Also, miRNAs are present in high levels in sperm (facilitating a mechanism whereby maternal stress effects can be transmitted through the germline and result in a measurable phenotype in the male offspring as adults). What did they find? 4 out of 329 miRNAs scanned for sex-specific responses to stress showed changes in expression levels. They went on to discover that these 4 miRNAs had one major common gene target (with various other targets as well) How’s that for specificity?

So what does it all mean? miRNAs can target gene expression in the brain of males in the F2 generation – in other words: this is proof that stress-mediated epigenetic changes can be transmitted across generations. I’ll let you chew on the public health implications of that one.

Until Tomorrow!

Today’s Special Presidential Lecture was such a treat! Every once in a while, we’re lucky enough to find something which engages us such that as we listen, we find ourselves almost literally sitting at the edge of our seat… hanging on to every word in an effort not to miss anything.

[image above taken from: “The Hidden Life of our Genes” movie]

Paolo Sassone-Corsi began his lecture entitled: “Joining the dots: Epigenetics, Plasticity and the Circadian Clock” by introducing Conrad Waddington’s term “Epigenetic Landscape” The idea is that cells with the same initial genomic profile develop into distinct cellular subtypes. The metaphor is that of marbles on a hill, where the marbles are the cells and the landscape of peaks and valleys represents an added layer of regulation (in this case: epigenetics).

It’s the “path” which the marble takes down the ridges and valleys of the landscape which determine the “fate” of the marble (i.e. where it will end up = what kind of cell it finally becomes). Won’t discuss this in this post: but one can see how the marbles going “back up the hill” then corresponds to the re-programming of stem-cells back to their “pluripotent” state.

Waddington’s epigenetic landscape, from C.H. Waddington. The strategy of genes: a discussion of some aspects of theoretical biology (Allen & Unwin, 1957)

After reviewing the structure of DNA, chromatin and epigenetic marks, and the ideas of Waddington, Sassone-Corsi began to paint the audience a picture of how what we traditionally understand and refer to as epigenetics, works in concert with circadian-regulated mechanisms in the body in order to increase or decrease plasticity.

“At least 10-15% of all cellular transcripts oscillate in a circadian manner,” he noted and “most of these are CCGs.” He went on to explain that this indicates a larger mechanism of regulation at play. In other words, epigenetics had to be involved. In their investigation of how circadian rhythms and epigenomic expression were coupled, they discovered that SIRT1, a nicotinamide adenin dinucleotide (NAD(+))-dependent HDAC, functioned in a circadian manner.

If SIRT1 sounds familiar – it’s because it’s found in red wine and is known to regulate aging, inflammation and metabolic processes. “It’s the French paradox,” he said “the French eat fatty foods and are still healthy because they drink red wine.” Don’t get your hopes up, though. He was quick to say, “this doesn’t mean you should drink too much!”

There’s a lot more detail and ground I’m not covering here – but I’m pretty sure I hit the main points. Here’s an excerpt from one of his abstracts: “Accumulating data show that chromatin remodeling events may be critical for providing specificity and plasticity in circadian regulation, and metabolic cues may be involved in directing such epigenetic events.”

I’m going to have to sit down and read his actual papers after the SfN meeting rush is over, to fully appreciate and grasp the implications of these findings. I encourage you to do the same! More blog posts on this topic are sure to be upcoming…

So it turns out: Cruella DeVille…isn’t all that cruel. I know, I know… it’s hard to believe. It’s even harder to believe that now when I look at pictures of her, or even clips of her (such as the scary one linked above) … I feel an immense swell of respect and love for the woman who is actually Glenn Close – and not just Cruella (tell your inner six-year old to stay with me here).

Every year, the SfN meeting is kicked-off by a “Dialogues with Society” section. This event is as described by the Society itself an event which: “features a luminary speaker whose work touches on brain function and the diversity of human experience.”

This year’s topic? Mental Illness – and the stigma associated with it. Glenn Close opened this year’s meeting by sharing the story of how one day, she was stopped by a woman off the street who asked her: “Are you…who I think you are?” Close, unsure of how to respond asked the woman: “I don’t know…who do you think I am?” The woman apparently paused and said “I don’t…remember your name – but I loved you in Mammia!” Glenn Close is laughing now, as she recounts this – and we are laughing along with her. “Why yes, I am Meryl Streep thank you!” she responds good-humouredly.

She then follows the question more deeply with us, her audience. Am I who you think I am? She flashes her genes up on a slide, telling us they make her “fabulous and divinely complex” Close explains she had her genome sequenced because, “mental illness runs in [her] family” and she wanted to glean a deeper understanding of her own biological makeup.

Following her introduction, Close’s nephew, Calen Pick, and her sister, Jessie Close, both shared their experiences of living with mental illness. Calen (a painter) has schizophrenia and Jessie has Bipolar disorder. It was with their blessing and courage, Glenn Close explains, that she decided to start a non-profit organization “Bring Change 2 Mind”.

“We aimed high,” said Close, “and we filmed the PSA at Grand Central Station” 

Not only were the speeches given by her Jessie and Calen moving in their courage and  honesty, but as Thomas Insel pointed out on stage after their speeches, the love that kept their family together was palpable. It was clear that they supported each other unconditionally – and perhaps more notably: it was clear that they saw each other as more than the disease that afflicted them.

“All of you can help in this new struggle. As you continue to make such astounding strides finding the sources of disease and disorder it will take consumers who have the courage to talk about their illnesses, without fear or shame. And it will take a public who will respect and support them without judgment or censure,” Close said.

Without judgment? Clearly this requires a vigilant self-awareness that is operating to continually monitor our knee-jerk responses and our gut-level reactions to those people in our environment that are different from us, that make us uncomfortable, that we don’t understand.

It requires courage on our part not to take the easy way out and to simply label someone as crazy or schizo or depressed (as though it’s their fault). It requires courage on our part to grow deeply aware of our reflex to disconnect from such individuals, forgetting our shared humanity, forgetting that the other person is a person. It requires us to ask ourselves: is that person…who we think they are?

[Update 11/19: The video is now posted on the SfN 2010 Annual Meeting website. Click here for a link to the page]

Apologies for the delays in posting. Those of you who saw my post late last night (now deleted) know that it was largely due to an unfortunate incident with a cab driver, a GPS and several lost-in-translation moments (i.e. really long story short: didn’t make it back to the hotel until past midnight). So, today I’m doubling up. Going to blog about Glenn Close’s talk yesterday morning as well as some of the interesting epigenetics talks I went to today. Stay tuned!

You may have noticed: This blog is still working its way towards completion! Thanks for bearing with me as I put the pieces together!