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You’re supposed to celebrate the achievements of women in science, technology, engineering and math today. Some of you women out there will be doing science today, some of you will read about it, and some of you will be doing like I’m doing: teaching it to women (and men!). At the very least, try to tell a girl that she can grow up to be anything she wants — and that includes being a mathematician, an engineer, or a scientist.
This morning, in 45 minutes, I’ll be tuning in to AM950 to listen to Sean B. Carroll on Atheists Talk radio. He’s going to be talking about his new book, Brave Genius: A Scientist, a Philosopher, and Their Daring Adventures from the French Resistance to the Nobel Prize
I’ve tried. This busy little cat we’re fostering simply will not sit still for a good photograph. This week we tried torture: she was sent off to the vet for a day where they applied needles and knives to her, injecting her with vaccines and doing tests and snipping various organs. I was sure she’d come home worn out and sore and tired, but no — she’s running around the place, jumping on me, chasing dust bunnies as if she hadn’t had her belly sliced open and both forelegs shaved for the various needles she was stuck with. This was getting ridiculous.
Then, moments ago, she found a good book and curled up with it. Unbelievable.
She’s a developmental biologist. Either that or she’s a Wolpert fan.
I’m thinking of trying the ultimate test, and leaving out a copy of The Happy Atheist
You want her? Contact the Stevens Community Humane Society. Tell them you want to save Ivy. I’ll even throw in a developmental biology textbook to sweeten the deal. I wouldn’t want her to get bored.
I’m trying to raise money for the The Leukemia & Lymphoma Society, and I promised to do a few things if we reached certain goals. I said I’d write a post microRNAs and cancer if you raised $7500. And you did, so I did. I kept my clothes on this time, though, so here’s a more serious picture of yours truly: this is what my students see, which is slightly less terrifying, nicht wahr?
If you want more, go to my Light the Night fundraising page and throw money at it. If we reach our goal of $10,000, I’ll organize a Google+ Hangout to talk about cancer. Note that we’re also getting matching funds from the Todd Stiefel Foundation, so join in, it’s a good deal.
It’s all epigenetics. Now I’ve gone and done it: I’ve used the “e” word, epigenetics. Nothing seems to fire off well-meaning misconceptions from otherwise sensible pro-science folks than epigenetics — it’s a major new revolution in evolution! It changes everything! It’s a way to get inheritance of acquired characteristics!
Nope.
Epigenetics is routine and has been taken for granted by cell biologists for at least 6 decades. It is simply a principle of gene regulation — switching genes off and on — that persists over multiple cell generations. You aren’t surprised that when liver cells divide, they produce more liver cells, are you? They’ve simply inherited transcription factors and patterns of modification of DNA from their parent cell that restricts their cell fates. There are also patterns of gene expression induced in gametes within parents that modulate initial patterns of gene expression in the fertilized zygote — that is, the state of the parental cells affects the state of the embryo’s cells — which is exactly what you’d expect.
What seems to set people off is that it is an effect of the environment on the state of the genome, and there is this bizarre bias floating around that that can’t happen. Of course it can! Every summer when you get a tan, every winter when you put on another five pounds, every time stress at work makes you prone to get sick…those are environmental factors influencing your biology.
In previous installments of this series, I told you about oncogenes, genes that when over-expressed or over-active switch on cellular processes (like proliferation) that promote cancer, and tumor suppressor genes, which protect against cancer, and which in cancers, are often found to be inactivated or down-regulated. Over-expressed? Down-regulated? That sounds like the sorts of things epigenetic changes can do.
Further, here’s an interesting observation. Everyone knows the standard pathway: genes in DNA are transcribed into RNA which is then translated into protein. One might naively imagine, then, that the amount of RNA produced would be roughly correlated with the amount of protein produced. It’s not. In analyses of cancers, only 20% of the mRNAs involved showed any correlation between the quantity of mRNA and the quantity of protein — there is something else that is modulating either the amount of translation or the turnover of proteins in the cell, and the fact that 80% of the genes playing a role in cancer show such variation tells us that these kinds of regulatory effects are important.
There must be something stepping in and interfering somewhere between transcription of the gene into messenger RNA, and translation of messenger RNA into protein. One of the somethings is microRNA.
These are tiny little snippets of RNA, typically 22 nucleotides long, that have complementary sequences to their target gene mRNA — they bind to matching RNAs and inhibit translation. Thousands of these microRNAs have been discovered in the last few years, and they’ve also been found to play important roles in regulating gene expression in blood cell lineages, brain activity, insulin secretion, and fat cell development…and in cancer.
As you might guess from the previous articles in this series, there are obvious ways microRNAs could promote cancers. A microRNA that blocks tumor suppressor genes from being expressed could be modified to be produced at a higher level, or a microRNA that would hamper an oncogene’s activity could be mutated to be unable to recognize its target. Easy! Simple! Well, except that this is biology, and nothing is simple in biology (trust me, if you don’t enjoy problems blowing up in your face and getting harder and harder, don’t become a biologist.)
One reason this is complicated is that there are so many details to be worked out — swarms of microRNAs are involved, we don’t know the majority of them, and we don’t know what we’ll learn as we discover more. As Weinberg says,
…the discovery of hundreds of distinct regulatory microRNAs has already led to profound changes in our under- standing of the genetic control mechanisms that operate in health and disease. By now dozens of microRNAs have been implicated in various tumor phenotypes, and yet these only scratch the surface of the real complexity, as the functions of hundreds of microRNAs known to be present in our cells and altered in expression in different forms of cancer remain total mysteries. Here again, we are unclear as to whether future progress will cause fundamental shifts in our understanding of the pathogenetic mechanisms of cancer or only add detail to the elaborate regulatory circuits that have already been mapped out.
But also, we’ve learned that it’s not simply a matter of a few short bits of RNA getting transcribed and dumped into the cytoplasm — there is a whole elaborate cellular apparatus dedicated to microRNA processing. Behold!
Don’t panic, I’ll hold your hand and we’ll walk through it. miRNA genes are first transcribed into RNA by RNA polymerase II; notice that the transcript, which is called a pri-miRNA (or primary microRNA) contains some long stretches of internal complementarity, and that the RNA folds into a hairpin loop. This RNA is grabbed by an RNA binding protein, Pasha, and an RNA cutting enzyme, Drosha, which snips off some excess bits to produce a smaller stem-loop structure about 70 nucleotides long, which is partially double stranded RNA. It also gets a new name: Pre-miRNA. Pre-miRNA is then exported out of the nucleus and into the cytoplasm by a channel protein, Exportin-5.
Once in the cytoplasm, another RNA cutting enzyme, aptly named Dicer, snips off a few more bits to reduce it to two very roughly complementary RNA strands, now called the miRNA:miRNA* duplex. One of these strands is then loaded into a set of proteins to form the miRNA-associated multiprotein RNA-induced silencing complex, thankfully called miRISC for short.
The short, 22-nucleotide long strand of RNA in the miRISC is what gives it specificity — the miRISC proteins carry it along as a template to match against messenger RNAs they encounter. If the miRNA makes a perfect match to some unfortunate strand of messenger RNA, the miRISC cuts up the mRNA to destroy it. If it’s an imperfect match over just some significant fraction of the 22-nucleotide sequence, it it just locks up the RNA and represses its translation.
The way these can affect cancer is illustrated below. If a microRNA that inhibits an oncogene is mutated (b), that oncogene will increase the amount of protein produced from the available RNA; the oncogene could even be normal in sequence and function, and just the boost in its signal could contribute to tumorigenesis. Alternatively, a mutation in a microRNA gene that affects a tumor suppressor could amplify its production (c), producing a greater inhibition of a healthy gene that acts to prevent tumorigenesis.
MicroRNAs can function as tumour suppressors and oncogenes. a | In normal tissues, proper microRNA (miRNA) transcription, processing and binding to complementary sequences on the target mRNA results in the repression of target-gene expression through a block in protein translation or altered mRNA stability (not shown). The overall result is normal rates of cellular growth, proliferation, differentiation and cell death. b | The reduction or deletion of a miRNA that functions as a tumour suppressor leads to tumour formation. A reduction in or elimination of mature miRNA levels can occur because of defects at any stage of miRNA biogenesis (indicated by question marks) and ultimately leads to the inappropriate expression of the miRNA-target oncoprotein (purple squares). The overall outcome might involve increased proliferation, invasiveness or angiogenesis, decreased levels of apoptosis, or undifferentiated or de-differentiated tissue, ultimately leading to tumour formation. c | The amplification or overexpression of a miRNA that has an oncogenic role would also result in tumour formation. In this situation, increased amounts of a miRNA, which might be produced at inappropriate times or in the wrong tissues, would eliminate the expression of a miRNA-target tumour-suppressor gene (pink) and lead to cancer progression. Increased levels of mature miRNA might occur because of amplification of the miRNA gene, a constitutively active promoter, increased efficiency in miRNA processing or increased stability of the miRNA (indicated by question marks). ORF, open reading frame.
This is not simply a hypothetical possibility, either. Dozens of miRNA genes have been implicated in human cancers — they show abnormal variations in expression in specific cancers and also have known oncogene/tumor suppressor targets.
These microRNAs are a relatively new scientific phenomenon — they weren’t even a blip on the radar when I was a graduate student, and when I did start hearing about them in the 1990s, they were thought of as a weird mechanism found in highly derived nematodes. Now we’re seeing them everywhere, and beginning to recognize their importance in controlling all kinds of genes. The process of developing tools to control miRNAs is underway in the laboratory, but it has a long way to go before we have effective clinical tools to combat cancer with miRNAs or antagonists to miRNAs. At the very least, it’ll be another tool we can use.
Calin GA, Croce CM (2006) MicroRNA-cancer connection: the beginning of a new tale. Cancer Res. 66(15):7390-4.
Esquela-Kerscher A, Slack FJ (2006) Oncomirs – microRNAs with a role in cancer. Nat Rev Cancer 6(4):259-69.
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646-74.
You may have heard that men and women have some subtle differences in morphology — there is considerable variation and overlap, of course, but there are discernable patterns. It’s not just the obvious breasts and shoulders and hips, either, but, for instance, slight differences in the hands. Men tend to have ring fingers that are longer than their index fingers, while those two fingers in women are of approximately equal length. Which makes it interesting that many Paleolithic cave paintings include tracings of the artists’ hands.
You can see where this is going. We should measure digit lengths in these stencils!
Archaeologist Dean Snow of Pennsylvania State University analyzed hand stencils found in eight cave sites in France and Spain. By comparing the relative lengths of certain fingers, Snow determined that three-quarters of the handprints were female.
"There has been a male bias in the literature for a long time," said Snow, whose research was supported by the National Geographic Society’s Committee for Research and Exploration. "People have made a lot of unwarranted assumptions about who made these things, and why."
There need to be massive caveats to the interpretation of the data. In modern populations, variation and overlap means that assessments of sex from digit lengths only has 60% accuracy, which is terrible — I checked out my own hands with a crude visual inspection, and by my right I’m a woman, by my left I’m a man, and both have very slight differences. Their sample size is also very small: 32 hands that were clear and sharp enough to measure. But at the same time, they report that the degree of sexual dimorphism in the hands was much greater than is seen in modern populations Well, maybe: I’d like to see the dimorphism data for modern hunter-gatherer populations, in particular from African populations with their greater genetic diversity. Also, you can’t call it sexual dimorphism if you don’t have an independent measure of the sex of the handprints. Maybe there was greater non-sexual variation in hand shape and, for instance, women made all of the stencils, but 15,000 years ago 25% of women had “man hands”.
Still, at least the data says that the cave painters were more diverse than expected, which fits better with a hypothesis that both men and women were active participants in these surviving, visible aspects of Paleolithic culture.
We’re doomed. Evolution is an ineluctable process; once it gets started, it’s not just an optional alternative, it becomes unstoppable, short of nuking the planet from orbit (and even then, all it takes is one surviving bacterium for it to begin again). Charlie Stross has noticed that books have crossed the threshold and are now poised for an adaptive radiation.
An epub ebook file is essentially an HTML5 file, encapsulated with descriptive metadata and an optional DRM layer. The latest draft standard includes support for all aspects of HTML5 including JavaScript. Code implodes into text, and it is only a matter of time before we see books that incorporate software for collaborative reading. Not only will your ebook save your bookmarks and annotations; it’ll let you share bookmarks and annotations with other readers. It’s only logical, no? And the next step is to let readers start discussions with one another, with some sort of tagging mechanism to link the discussions to books, or chapters, or individual scenes, or a named character or footnote.
We already share highlighting — I get a little annoyed when I’m reading on my kindle and suddenly there’s a block of text with a dotted underline — other people thought that section worthy of notice and have shared their emphasis with the world.
I’ve also noticed that the books I’ve bought through Amazon suddenly pop up with a ranking and suggestions page when I reach the end. It used to be you’d finish a book and close it satisfyingly and put it back on the shelf…but no, now it yells at you “Did you like me? Buy more of me!”
As Stross points out, the next dreadful steps, since a book has become code, will be the incorporation of malware and agents to sabotage competing books in your library and insert new ads around the place, or even replicate more of the authors’ works. I’ve downloaded some of those cheap or even free books into my epub library, and some of them are so bad that I suspect they are already intrinsically malware.
Our future:
Books are going to be like cockroaches, hiding and breeding in dark corners and keeping you awake at night with their chittering. There’s no need for you to go in search of them: rather, the problem will be how to keep them from overwhelming you.
Doomed, I tells you. I am squinting at my iPad right now. I think it’s plotting to get me.
Unfortunately. What that means is that an endeavor that ought to be impartial and based on reasoned evaluation of the evidence is tainted by bias and unavoidable cultural preconceptions. We’ve got religion turning some people into credulous twits, but just as poisonous, we have sexism skewing our analyses.
The first thing we did was look at more than 3,000 articles published between 1980 and 2006 in 12 leading peer-reviewed international relations journals. We then controlled for every possible factor that could contribute to one’s citation count including the quality of the publication, its venue, methodology, the subject matter, and the researcher’s home institution (to name a few). We suspected that an article written by a tenured professor from an elite university, published in a top journal and written on a popular topic would get more citations than an article written by an untenured professor at a liberal arts college on an esoteric topic in a second-tier journal. What we didn’t know was whether gender would matter once you held all of these factors constant. Did knowing the gender of the author make other scholars cite an article more or less?
The results were striking. Even when we controlled for an enormous range of factors, gender remained one of the best predictors of how often an article would be cited. If you were female, your article would get about 0.7 cites for every 1 cite that a male author would receive.
This paper has garnered a lot of press here, here, and here, not because it’s telling us something we hadn’t already suspected but because the data are incontrovertible. Crunch the numbers in different ways and the results are always the same: articles written by women in IR are cited less than men, all else equal.
The authors of that study have some productive suggestions. One is anonymous review: publishers should mask out the authorship and affiliations when sending papers out for review. You’re judging the work on its own quality, right, so who wrote it shouldn’t matter. I do something similar when I’m grading papers — I refuse to look at the students’ names until I’ve evaluated the whole thing.
This would also diminish that other unfortunate bias, judging papers by what institution they came out of, rather than their content.
Another suggestion is simply to have first and middle names always reduced to initials. That’s not a perfect solution, but it helps. (It doesn’t help if you’re already known by your initials, but that’s a different problem.)
I have another suggestion: maybe graduate students should all get some kind of education in equality as part of their training, so they don’t go on to be bigoted asshats when they go on to full science careers. I’ve heard it all: prejudice against women, against blacks, against Asians, against historically black colleges, against liberal arts institutions. Maybe scientists should learn not to pay only lip service to that scientific virtue of objectivity.
