That’s really super, supergirl (part 1)

28 11 2018

“What’s so bad about superbabies?”

It’s a question I ask my 300-level bioethics students after we’ve spent 12 or so weeks discussing eugenics, genetics, stem cell technology, somatic cell nuclear transfer, and the varieties of assisted reproductive technologies. They’ve also written their first set of research papers—some of which take up the question of just how humans could be enhanced (“should” is taken up in the second paper).

Most of them tend to recoil from the question, even if they can’t exactly say why, while a few take a Hell, yeah! Why not? approach to enhancement.

And, oh yes, we spend a fair amount of time trying to figure out just what counts as “enhancement.” Therapy or treatment, I note, is generally accepted by bioethicists as Good, but enhancement is looked upon with considerably more suspicion. Normal is good, well is good; better than well? Ehhhh.

Which is a long way of saying that there are a lot of us who are primed to react to the news that germline genetic engineering has not only been attempted, but accomplished, in human beings for the first time.

Germline genetic engineering (or transfer) is distinguished from somatic-cell gene transfer in that any genetic changes will be passed down to offspring—which is to say, the germ cells (sperm & eggs) are themselves changed. The most efficient way to achieve this is to alter the cells of an early embryo (a 2-3 day-old morula or 4-6 day-old blastocyst): at this stage the cells are undifferentiated, so if you are able to insert altered (“recombinant”) genetic material (rDNA or rRNA) into all of these cells, as they divide and specialize they will carry the altered material into every cell—including, of course, the germ cells.

One of the great challenges in gene transfer of whatever sort has been getting rDNA/rRNA into enough cells to affect function; that the morula and blastocyst have so few cells bypasses this problem. Another issue has been inserting rDNA/rRNA into the correct place in the genome—and only that one place in the genome—to affect genetic expression. (There are other issues, especially regarding the vectors , or delivery vehicles for recombined sequences, but I’ll skip over these for now.)

Okay, so you’ve heard of CRISPR, yes? Clustered regularly interspersed short palindromic repeats? Why, of course, Terri; who hasn’t filled their days wondering about clustered regularly interspersed short palindromic repeats? Skipping (almost) alllllll of the technical stuff, CRISPR is a huge advance over other forms of gene transfer and gene editing: by using a guide enzyme, eg, Cas9, researchers are able precisely to target a specific sequence. . . .

Well, shit, I’m losing you, aren’t I? I start with superbabies and now I’m talking about “targeting specific sequences.” So, some basics:

Almost all of our cells (exc: red blood cells) contain a nucleus, which in turn contains chromosomes, which are histones (a protein) wrapped in a very tight spool of DNA.

DNA comprises a sugar-phosphate double-helix connected by the nucleotide base-pairs (bp) adenine (A), which is always paired with thymine (T), and guanine (G), which is always paired with cytosine (C). Determining the exact order of these base pairs on a strand of DNA is “sequencing”; a sequence will look like this: ATTCCAAGGGGTAACAATTCGACCTGAT. . . .

A strand of DNA is about 6 feet long and is mostly noncoding: it has no direct role in protein synthesis. (I should note that the non/functionality of this noncoding or junk DNA is disputed, which is neither here nor there for this discussion but thought I should mention it anyway. If you don’t understand what this means, don’t sweat it.)

A very small portion of the DNA, less than 2%, comprises genes, or coding sections of DNA. Genes are the Action Jacksons of DNA, the functional units of heredity, involved in protein synthesis, and, unlike in the noncoding sections, if something is messed up with your genes it can affect how you function. The average gene size anywhere from 10-27K bp (yes, disputed), with the largest, dystrophin, over 2.3M bp.

So: DNA is the set, genes are the (very small) subset. Most members of our species have about 19,000 genes scattered amongst 3.2 billion base-pairs and across 46 chromosomes. (Some of us have more chromosomes, some have fewer, but most of us have 46.) Some chromosomes have thousands of genes, some (well, the Y chromosome) has fewer than 100.

This sounds like I’m going off track, but, really, there’s a point behind all of this.

I like to compare DNA to a road, genes to cities and towns, and chromosomes to different regions of the US: some chromosomes are like the northeast, packed with many genes, and others (the Y chromosome) are like South Dakota, with those city-genes few and far between.

To change gene NYC, say, you need to be able to get a package of rDNA or rRNA to the right place on the sequence, and then (to continue the analogy), you have to get that package not just to the right city (gene), but to the right borough, to the right street, the right address, the right apartment, and to the right room in that apartment.

This is “targeting.”

The other issue is to get the right package to the right city in the right borough, etc., in a sufficient number of cells, with “sufficient” often meaning “millions and millions.” (Again, with an embryo, this would appear to be less of an issue.) Oh, and once the package is delivered, it needs to be opened and turned on, i.e., integrated into the gene and made functional.

So, targeting, sufficiency, and functionality have all been obstacles to successful gene transfer. In fact, only one gene transfer product, involving immunotherapy, has been approved for use in the US, and that only happened last year.

Now CRISPR, CRISPR is highly efficient at targeting and integration, and is often referred to as a “cut-and-paste method” of gene editing: it uses an enzyme to guide the package to the targeted sequence, snip out the old sequence and insert the new. Another analogy: think of the “find and replace” function in a word processing document. You type the old word (say, “Chris”) into find, the new word (“Kris”) into replace, and hit go.

Much, much MUCH more efficient than manually looking for “Chris” and replacing it with “Kris.”

Great, yeah? Wellllll, not always. One of the problems with CRISPR is off-targeted mutations. Say you only want to replace Chris with Kris on page 1, but it find-and-replaces throughout the entire 20-page document. Or maybe it replaces “chris” in words like “Christmas” or “christen” or “christallmighty!” with “Kris”.

That would be bad for your document; it would be even worse for your genes.

Also—and here’s where the analogy to find-and-replace breaks down—the cut-and-paste doesn’t work every time. CRISPR efficiency is much higher than that for other methods, but it’s not 100 percent. This means that some cells will take up the changes and other cells won’t, resulting in mosaicism, or an organism which contains more than one genome.

Mosaicism is also a natural phenomenon, and not necessarily a dangerous one, but it could at the very least affect the efficacy of the gene transfer and the function (aka health) of the organism.

Okay, that’s enough for tonight. Next: whatsamatta with what He did?

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I got life

29 09 2015

So: “pinched nerve” might be a lay and not medical term, but it does describe a real phenomenon, in my case, an impingement upon the sciatic nerve.

No, I didn’t get this diagnosis from a doctor—there’s not much she could do, so why bother—but it’s pretty clear from my symptoms that my occasional lower back troubles can cause what is literally a pain in my ass.

If I want a more exact diagnosis than “o.l.b.t.”, then, yes, I’d need to see a doctor and undergo a variety of expensive (e.g., MRI) tests, but as a more exact diagnosis would likely lead to no greater precision in treatment—rest, time—there’s seems little point in doing so.

I am gonna have to get more ibuprofen, though.

I.

While I haven’t enjoyed in any way the pain from my grumpy sciatic nerve, I did take interest in the (non-pain) side effects of the jumped-up nerve, namely, the random twitching up and down my lower right side.

At one point early on I watched the middle toe of my right foot flutter like a drunk hummingbird. It didn’t hurt at all, and if I concentrated, I could stop the movement; in any case, after 10 or maybe 20 minutes, it stopped.

Sometimes my glutes twitched, sometimes, the muscles in my calf. It’d start, then stop, seemingly at random.

I still get the occasional muscle-shudder, but as whatever is annoying the nerve is slowly retreating, so to is the twitching.

II.

One of the reasons I love teaching my bioethics course is that I get to talk about human biology, which is so astonishingly jerry-rigged that I can’t help crowing “biology is so cool!”

Most of us Homo sapiens sapiens have 46 chromosomes occupying the nuclei of our somatic cells, but some of us have 45 and some have 47, 48, or even 49 (that’d be one of the varieties of Klinefelter’s).

A woman with Turner syndrome is missing a second sex chromosome (45,XO), and while she’s infertile and may experience some developmental delays, she likely will have normal intelligence and may live out a normal life span. On the other hand, a child born with a deficiency in the short arm of the 5th chromosome will be born with Cri-du-chat syndrome, which affects both her physical and intellectual development, and may leave her unable to communicate.

So, missing an entire chromosome might have fewer effects than missing a portion of an arm of chromosome. A man who is 47,XYY is likely to experience no effects whatsoever, 47,XXY will have Klinefelter’s (and thus be infertile), and 21,XXX (Trisomy 21 or Down syndrome) will experience profound physical and intellectual effects.

Oh, and some women are 46,XY.

Now, one of the things that can be inferred from this little recitation of chromosomal abnormalities is that the genes on these chromosomes are tremendously important, such that the genes on the short arm of the 5th chromosome are involved in aspects of our development that genes on the sex chromosomes are not; similarly, the Y chromosome is so gene-poor (~350) that doubling up on the Y has no discernible effect.

Then again, the few genes—most importantly, the SRY gene—that do remain on the Y are clearly important: their dysfunction, after all, can result in an XY woman.

The second thing that can be inferred from all of this is that biology is messy—I haven’t even discussed mosaicism or chimerism, or situs inversus or any of the other kinds of weirdnesses within us—and that the messes themselves are messy: sometimes they matter a whole lot, and sometimes not at all.

III.

So the first day my sciatic nerve commenced its protest it hurt to stand, was uncomfortable to walk, and running felt fine.

The second and third day, it hurt so much in the morning that shortly after rising I would sit down, gasping, from the screaming in my leg; after moving around a bit, however, the pain receded.

A couple of days I limped. Some days it hurt to put pressure on my right leg, some days it hurt not to put pressure on it. If I positioned my foot this way I was fine, that way, not; later, the fines were reversed.

I can walk quickly, but for the past 4 or 5 days, can’t run. Going up and down stairs was initially problem-free; now I grasp the railing.

Slowly, slowly, I am getting better: while the troubles migrate, they also abate. I was hoping they’d be gone by now, but I expect by next week, they will be.

IV.

Aging sucks.

V.

I’d rather not have gone through this and will do my damnedest to forestall a recurrence, but it does make me wonder what is going on beneath my skin.

Yes, I pay attention to my body, but usually when something is wrong I can trace it back to its source: I ate too much, didn’t stretch after a workout, wiped out on an icy sidewalk;  thus having linked effect to cause, I lose interest.

)And with migraines, well, they’re just SO irritating that I become preoccupied with the pain itself; the rare occasions when I get auras I am less fascinated than, well, irritated. Knock it off, shimmering lights, you’re blocking my view.)

In this case, I’m pretty sure I know what set off the latest back pain, but how that migrated down into the sciatic nerve, and how that nerve proceeded to respond to this trespass hopscotched around predictability. Why is my toe shaking? Why is my calf muscle clenching and unclenching?

What the hell is going on?

Oh, I know: what’s happening is that my body is now more assertive in letting me know it is unhappy with my treatment of it, i.e., that I’m getting old.

It’s not that when younger I thought I was in charge of my body, but, yeah, I thought I was in charge of my body.

I’m not humbled, but bothered, to learn otherwise, and I will not be gracious in relinquishing control.

It will be a fight to the death.





Lions and tigers and bears, oh my!

5 10 2013

So it turns out domestic cats share over 95 percent of their genomes with tigers.

Of course they do.





And I said “nothing”

7 02 2013

Was I gaslighting myself?

I was sure I had seen this book review at one of the places I frequent online, and I didn’t write it down or bookmark it, so that meant I’d be able to find it easily when I decided to go back and use it as a springboard for a post.

Except I couldn’t find the damned thing.

Slate? Nope. HuffPo? Nope. I knew it wasn’t Sully (who’s being a real prick about the whole retail servitude thing, by the way), wasn’t TNC. Someplace on the Atlantic site? Books? Health & Medicine? Tech? Nope nope nope. Didn’t think it was ThinkProgess or CrookedTimber, but checked anyway—nada. Christianity Today? Fred Clark? Nuh-uh. Really hoped it wasn’t Brad DeLong or Marginal Revolution or Pharyngula because it would be a total pain in the ass to try to dig it out.

It didn’t help that I didn’t know the title and I didn’t know the authors—although I did know there were two authors.

And I did know the topic: something about genetics and society. So, off to Amazon to try to track down the book. “Human genetics” didn’t get me there; neither did “genes” or “genetics” or these subjects coupled with “2013” (I knew the book was new). Nothin’. Same at Barnes & Noble.

What gives?! Did I NOT see a review of a recent book on genes and society? Was I imagining all of this? Jay-zeus Christie.

So: onward to the Giant Omnivorous Omniscient Grabbing of Life and Everything search, with different terms. At some point I plugged in “genetics ethics” and there on the top of the third page, a piece from the Guardian:

Genetics | Science | The Guardian

Video (5min 28sec), 30 Jan 2013: Hilary Rose, co-author of Genes, Cells and Brains, argues that we should treat the medical claims made for genetic research

Bingo! Hilary Rose! So back to the aforementioned sites and plug in Hilary Rose and. . . NOTHING! DAMMIT.

And then I thought: What about The Daily Beast? They do books, don’t they? And lo! There it was:

The Selfish Gene: The Broken Promises of the Human Genome Project

Jan 29, 2013 2:39 PM EST

What did the Human Genome Project give us? Better shampoo and billions of dollars’ worth of economic projects, but what happened to improving our lives? By Michael Thomsen.

There is a point to all of this, I promise you, but since it’s really just another way for me to lash myself over the stupid, stupid decisions I’ve made regarding my dissertation and career, I think I’ll save that for another post.

For this one, let’s end on the happy thought that I am not, in fact, crazy. At least on this.





Dumb and dumber

30 11 2011

Complete and utter blog theft from Henry Farrell at Crooked Timber, but so nicely done, I couldn’t pass it up:

Gedankenexperiment

by Henry on November 29, 2011

Let’s imagine that we lived in an alternative universe where some of the more noxious nineteenth century pseudo-science regarding ‘inverts’ and same-sex attraction had survived into the late twentieth and early twenty-first centuries. Let us further stipulate that the editor of a nominally liberal opinion magazine had published one purported effort to ‘prove’ via statistics that same-sex attraction was a form of communicable psychosis, which invariably resulted in national degeneracy when it was allowed to persist. One of this essay’s co-authors had chased sissies in his youth, but claimed he had not realized that this was homophobic; he also had occasion to observe the lack of real men on the streets of Paris, and to deplore the resulting sapping of virility in the French national character. His efforts, and the efforts of fellow researchers (all of the latter funded by and/or directly involved with the Institute for the Suppression of Homosexual Filth) succeeded in creating a significant public controversy. Some public commentators embraced the same-sex-attraction-as-psychosis argument because they were, themselves, homophobes, others more plausibly because they were incompetent, or because they enjoyed being contrarians, or both. This, despite the fact that the statistical arguments on which these extreme claims depended were demonstrably incompetent.

Now, let us suppose that the same editor who helped release this tide of noxious homophobia in the first place still played a significant role in American public debate, and still refused to recognize that he might, actually, be wrong on the facts.  . . .

I wonder, if we lived in such a world, what Andrew Sullivan would think of that editor?

(Go read the whole thing—and definitely click through the embedded links.)

A fine response to Sully’s inability not only to wipe the shit from his shoes, but even to admit he stepped in it.

There are, of course, substantive responses to Mr. Sullivan’s flogging the pc-egalitarianism-is-killing-research-into-racial-differences-in-IQ-and-I-am-brave-for-pointing-the-way-to-truth-justice-and-the-American-way line he periodically burps up, even while admitting that “I certainly don’t have profound knowledge of the deep research of experts in the field.”

Or, you know, any knowledge, beyond that of an editor publishing the execrable Murray-Herrnstein “bell curve” thesis that blacks are dumber than whites (even as he complains that “No one is arguing that ‘that black people are dumber than white,’ “—oh yes, Mr. Andrew,  these two ‘no ones’ did exactly that).

Anyway, here’s the entire stupid thread thus far (original, response, responseresponse, response), as well as smart rebuttals by TNC here and here (read especially the comments for links to research from people who do have “profound knowledge” of the field).

In any case anyone is listening, yes, I believe that intelligence has a biological substrate, that evidence points to a multifactorial construction of intelligence, and that as a general matter there are genetic differences across populations, differences worth studying.

But that’s a damn sight away from sloppily heated declamations on race and IQ, refusal to consider the definitional (and thus methodological) problems with the terms “race” and “intelligence”, or, for that matter, on the role of “truth” in the research enterprise.

Pfft. Platonists.





Yesterday’s a day away

7 09 2009

It’s about time.

All those boxes of files, the folders full of print outs of journal articles, cut-outs from newspapers, clippings from The New Yorker and The Nation, transcripts from The NewsHour (and before, the MacNeill/Lehrer NewsHour), Gina Kolata and Elizabeth Farnsworth and Lawrence Wright. Time to go.

Start easy: start with the ‘Media/Polls’ box. There’s only one of those, and you know you want to get rid of those, right? You haven’t looked at its contents in six years, not since you left Montreal, not since you threw a shovelful of dirt over the remains of your academic career and lit out for your life.

One box, shouldn’t take long. One less to cart to wherever it is you’ll go next. And it’s on your list.

The first folder: ‘Media–to be filed’. What? I thought these were mostly polls, old and outdated and easily disposed of, save for pulling out the staples or off the binder clips and reshuffling the paper for reuse as the back end of lecture notes. Gallup and Roper and whatnot.

But here’s a piece by Sallie Tisdale, and another by Annie Dillard and another by an old colleague, Carl Elliott. Carefully annotated with publication date, volume, number. Haven’t read any of these likely since I yanked them out of Harper’s and The Atlantic 7, 8, 12 years ago.

Next up: Cloning. All the Times‘ pieces, the television transcripts. Here are a few pieces by Leon Kass, my Pilot-penned scrawls arguing with him in the margins.

Here is the stillborn promise of books never to be written, articles never to be submitted. Here is my dead career, never carefully tended, finally abandoned to die, mummified in filed slices.

And my career as an academic is dead, no question about it. Oh, I stroll through the cemetery regularly as an adjunct, but ‘adjunct’ is just another term for dead-end job.

I know this. I know this. I knew what I was doing six years ago, even if I didn’t know the consequences of what I was doing, even if I had no idea what I was doing. Still, I knew that the slow climb from assistant to associate to full professor was not for me, that I would not end an emeritus.

Even now that I know the consequences, I can’t say I was wrong to have dropped off the tenure track. Sure, I might even have managed the climb, secured myself in some out-of-the-way department somewhere, but it wouldn’t have been my life. A role, only.

It will be good for me, finally, to have finished with these files, to have disarticulated the stories and narratives within. But I know they meant something, once, that they mattered, once, and it grieves me to put it all behind me.

I will feel lighter, when I am done, however heavy I feel now.

Lighter, yes.