My mouse has two daddies

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This is awesome news. Biologists have figured out how to enable two male mice to have babies together, with no genetic contribution from a female mouse. I, for one, look forward to our future gay rodent overlords.

It was a clever piece of work. Getting progeny from two male parents has a couple of difficulties. One is that you need an oocyte, which is a large, specialized, complex cell type, and males don’t make them. Not at all. You can tear a boy mouse to pieces looking for one, and you won’t find a single example—they’re a cell found exclusively in female ovaries.

Now you might think that all we’d have to do is grab one from a female mouse, throw out its nuclear contents, and inject a male nucleus into it, but that doesn’t work, either. The second problem is that during the maturation of the oocyte, the DNA has to be imprinted, that is, given a female-specific pattern of activation and inactivation of genes. If that isn’t done, there will be a genetic imbalance at fertilization, and development will be abnormal. What we need to be able to do is grow an oocyte progenitor with male DNA in a female ovary.

So that’s what was done, and here’s how.

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Start with Father #1, whose cells all contain an X and a Y chromosome. Connective tissue cells were extracted from the mouse (in this case, an embryo), and then reprogrammed by viral transduction with modified copies of the genes Pou5f1, Sox2, Klf4, and Myc. This step produces induced pluripotent stem cells (iPS cells), or cells that have the ability to develop into all (probably) of the tissues of the body. These cells are then grown in a dish.

The next step is to give Father #1’s cells a sex change operation. This turns out to be trivial: in culture, cells can spontaneously lose a chromosome by non-disjunction, and 1-3% of the cells will lose their Y chromosome, and convert to X0. No Y chromosome means it is now a functionally female cell.

There is a significant difference between humans and mice here. Sometimes (about 1 in 5,000 births) humans are born with only one X chromosome, a condition called Turner syndrome. These individuals appear to be entirely normal females, except for some minor cosmetic differences, an unfortunate predisposition to a few problems like heart disease, and of particular relevance here, are also sterile. Mice are different: Turner syndrome mice are fertile. Apparently, mice have a god-given edge in the gay reproduction race.

Once a population of Father #1’s cells that are X0 are identified, they are then injected into a female mouse blastocyst to produce a chimera, an embryo with a mix of host cells (which are genetically XX) and donor cells (which are X0). That they’re mixed together in the resulting offspring doesn’t matter; it may be a callous way of looking at it, but the only purpose of the host XX cells is to provide a female mouse environment to house Father #1’s X0 cells that end up in the ovaries.

That’s the result of all this tinkering: a female mouse is born with a subset of Father #1’s reprogrammed cells nestled in her ovaries, where they mature in a female body and differentiate into oocytes. The oocytes divide by meiosis, producing egg cells that contain either one X chromosome, or no sex chromosome at all (0).

Finally, Father #2 comes into the picture. Father #2 is an ordinary male, with testes containing cells that go through meiosis and mature into ordinary sperm containing either one X chromosome or one Y chromosome. These sperm are used to fertilize eggs from the chimeric female, which, by all the shenanigans describe above, are derived from Father #1. Both male (XY) and female (X0) progeny ensue. That this actually occurred was thoroughly confirmed by testing the progeny for genetic markers from both fathers…and it’s true. The only genetic contributions were from the dads, and nothing from the host mother.

Now you may be sitting at home with your dearly beloved gay partner and wondering whether you will be able to have babies together someday. Or perhaps you’re a narcissistic man sitting at home alone, thinking you’d like to have babies with yourself, if only you could convince a few of your cells to make eggs (this is another possibility: there is no barrier to this technique being applied in cases where Father #1 is also Father #2, except that it is incestuous to the max). I expect it will be possible someday, but it isn’t right now. There are a few obstacles to doing this in humans.

  1. We haven’t worked out that genetic reprogramming trick for humans yet, so we don’t have a technique for producing pluripotent stem cells from your somatic cells. Give it time, though, and keep funding adult stem cell research, and it’ll happen.

    Also note the rule of unintended consequences. The fundy fanatics have been anti-embryonic stem cell research for years, and one of their tactics has been to insist that adult stem cell research is far more important. In the long run, it is…and oh, look what we’ll be able to do!

  2. The reprogramming trick involves viral transfection, the insertion of mutant copies of a few specific genes. This is probably not desirable. All kids are mutant anyway, but this is adding a specific, constant kind of mutation to all of the individuals produced by this method.

  3. It still requires a woman, and a woman who has been embryonically modified as a blastocyst at that. Did you know women have rights, including the right to not be a vessel for a scientific experiment? It’s true. They also take years and years to grow to sexual maturity, so even if you got started right now it would be a dozen years before she started making oocytes for you, and by the way, she’d inform you that she only produces eggs for herself, not you.

    There may be ways around this, but the techniques aren’t here yet. To produce eggs, we really don’t need the whole woman, just the ovary: another goal of stem cell research is to regrow organs from cells in a dish, for instance to build a new heart or pancreas for transplantation. Consider ovaries on the list of organs.

  4. That difference between mice and humans, that X0 mice are fertile while X0 women are not, seems like a serious problem. We apparently need the pair of X chromosomes working together to provide the correct gene dosage for normal maturation of the egg. It just means that we need to add an extra step to the procedure for people, though: transfer by injection an extra X chromosome from a donor cell from Father #1 to the X0 cells, producing a composite XX cell derived entirely from a male.

  5. The fundies will go raving apeshit bonkers. So what else is new?

  6. OK, there are also some serious ethical concerns that would need to be worked out, independent of the Bible-thumping theocratic sex police. As you can see from the recipe above, this is a procedure that involves extensive manipulation of embryos, almost all of it experimental, and the end result is…a baby. We should be conscientious in our care in any procedure that can produce human beings, especially if there is risk of producing damaged human beings. This can also only be categorized as a kind of expensive luxury treatment, and it’s difficult to justify such elaborate work for solely egotistical gratification. Especially for you, nerd-boy masturbating alone at home. (But learning more about the mechanisms of reproduction is more than enough to justify this work in mice, at least).

Wait…all this is just for male gay couples. What about nurturing lesbians who want to have children together? That has another tricky problem: you need a Y chromosome to induce normal sperm differentiation, and lesbian couples don’t have any of those. At all. They’re going to have to go to a male donor for a genetic contribution, diluting the purity of the genetic side of the procedure. However, that has a technology in the works to help out already: see obstacle #4 above. We’ll have to isolate iPS cells from Mother #1, inject a donor Y chromosome into them, cultivate chimeric male (or chimeric testis in a dish) to produce sperm, and then fertilize eggs from Mother #2 with the Mother #1-derived sperm. Any sons produced by this procedure would have three parents, Mother #1, Mother #2, and the Male Donor who provided the Y chromosome, and only the Y chromosome. Any daughters, though, would only have two parents: Mother #1 and Mother #2.

Isn’t reproductive biology fun? It’s the combination of exciting science with terrifyingly deep social implications.

Deng JM, Satoh K, Chang H, Zhang Z, Stewart MD, Wang H, Cooney AJ, Behringer RR (2010) Generation of viable male and female mice from two fathers. Biology of Reproduction DOI:10.1095/biolreprod.110.088831.

There are people meaner than I am

I got a surprising amount of criticism of my review of the arsenic-eating bacteria paper — some people thought I was too harsh and too skeptical and too cynical. Haven’t those people ever sat through a grad school journal club? We’re trained to eviscerate even the best papers, and I actually had to restrain myself a lot.

Anyway, I’m a pussycat. You want thorough skepticism, read Rosie Redfield’s drawing and quartering of the paper, which rips into the hasty methodology of the work. Man, after that, the body ain’t even twitching any more, and they’re going to have to clean up the pieces with a wet-vac. It’s beautiful.

It’s not an arsenic-based life form

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Oh, great. I get to be the wet blanket.

There’s a lot of news going around right now about this NASA press release and paper in Science — before anyone had read the paper, there was some real crazy-eyed speculation out there. I was even sent some rather loony odds from a bookmaker that looked like this:

WHAT WILL NASA ANNOUNCE?

NASA HAS DISCOVERED A LIFE FORM ON MARS +200 33%
DISCOVERED EVIDENCE OF LIFE ON ONE OF SATURNS MOON +110 47%
ANNOUNCES A NEW MODEL FOR THE EXISTENCE OF LIFE -5000 98%
UNVEILS IMAGES OF A RECOVERED ALIEN SPACECRAFT +300 25%
CONFESSES THAT AREA 51 WAS USED FOR THE ALIEN STUDIES +500 16%

[The +/- Indicates the Return on the Wager. The percentage is the likelihood that response will occur. For Example: Betting on the candidate least likely to win would earn the most amount of money, should that happen.]

I think the bookie cleaned up on anyone goofy enough to make a bet on that.

Then the stories calmed down, and instead it was that they had discovered an earthly life form that used a radically different chemistry. I was dubious, even at that. And then I finally got the paper from Science, and I’m sorry to let you all down, but it’s none of the above. It’s an extremophile bacterium that can be coaxed into substiting arsenic for phosphorus in some of its basic biochemistry. It’s perfectly reasonable and interesting work in its own right, but it’s not radical, it’s not particularly surprising, and it’s especially not extraterrestrial. It’s the kind of thing that will get a sentence or three in biochemistry textbooks in the future.

Here’s the story. Life on earth uses six elements heavily in its chemistry: carbon, hydrogen, nitrogen, oxygen, phosphorus, and sulfur, also known as CHNOPS . There are other elements used in small amounts for specialized functions, too: zinc, for instance, is incorporated as a catalyst in certain enzymes. We also use significant quantities of some ions, specifically of sodium, potassium, calcium, and chloride, for osmotic balance and they also play a role in nervous system function and regulation; calcium, obviously, is heavily used in making the matrix of our skeletons. But for the most part, biochemistry is all about CHNOPS.

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Here’s part of the periodic table just to remind you of where these atoms are. You should recall from freshman chemistry that the table isn’t just an arbitrary arrangement — it actually is ordered by the properties of the elements, and, for instance, atoms in a column exhibit similar properties. There’s CHNOPS, and notice, just below phosphorous, there’s another atom, arsenic. You’d predict just from looking at the table that arsenic ought to have some chemical similarities to phosphorus, and you’d be right. Arsenic can substitute for phosphorus in many chemical reactions.

This is, in fact, one of the reasons arsenic is toxic. It’s similar, but not identical, to phosphorus, and can take its place in chemical reactions fundamental to life, for instance in the glycolytic pathway of basic metabolism. That it’s not identical, though, means that it actually gums up the process and brings it to a halt, blocking respiration and killing the cell by starving it of ATP.

Got it? Arsenic already participates in earthly chemistry, badly. It’s just off enough from phosphorus to bollix up the biology, so it’s generally bad for us to have it around.

What did the NASA paper do? Scientists started out the project with extremophile bacteria from Mono Lake in California. This is not a pleasant place for most living creatures: it’s an alkali lake with a pH of close to 10, and it also has high concentrations of arsenic (high being about 200 µM) dissolved in it. The bacteria living there were already adapted to tolerate the presence of arsenic, and the mechanism of that would be really interesting to know…but this work didn’t address that.

Next, what they did was culture the bacteria in the lab, and artificially jacked up the arsenic concentration, replacing all the phosphate (PO43-) with arsenate (AsO43-). The cells weren’t happy, growing at a much slower rate on arsenate than phosphate, but they still lived and they still grew. These are tough critters.

They also look different in these conditions. Below, the bacteria in (C) were grown on arsenate with no phosphate, while those in (D) grew on phosphate with no arsenate. The arsenate bacteria are bigger, but thin sections through them reveal that they are actually bloated with large vacuoles. What are they doing building up these fluid-filled spaces inside them? We don’t know, but it may be because some arsenate-containing molecules are less stable in water than their phosphate analogs, so they’re coping by generating internal partitions that exclude water.

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What they also found, and this is the cool part, is that they incorporated the arsenate into familiar compounds*. DNA has a backbone of sugars linked together by phosphate bonds, for instance; in these baceria, some of those phosphates were replaced by arsenate. Some amino acids, serine, tyrosine, and threonine, can be modified by phosphates, and arsenate was substituted there, too. What this tells us is that the machinery of these cells is tolerant enough of the differences between phosphate and arsenate that it can keep on working to some degree no matter which one is present.

So what does it all mean? It means that researchers have found that some earthly bacteria that live in literally poisonous environments are adapted to find the presence of arsenic dramatically less lethal, and that they can even incorporate arsenic into their routine, familiar chemistry.

It doesn’t say a lot about evolutionary history, I’m afraid. These are derived forms of bacteria that are adapting to artificially stringent environmental conditions, and they were found in a geologically young lake — so no, this is not the bacterium primeval. This lake also happens to be on Earth, not Saturn, although maybe being in California gives them extra weirdness points, so I don’t know that it can even say much about extraterrestrial life. It does say that life can survive in a surprisingly broad range of conditions, but we already knew that.

So it’s nice work, a small piece of the story of life, but not quite the earthshaking news the bookmakers were predicting.

*I’ve had it pointed out to me that they actually didn’t fully demonstrate even this. What they showed was that, in the bacteria raised in arsenates, the proportion of arsenic rose and the proportion of phosphorus fell, which suggests indirectly that there could have been a replacement of the phosphorus by arsenic.

Wolfe-Simon F,
Blum JS,
Kulp TR,
Gordon GW,
Hoeft SE,
Pett-Ridge J,
Stolz JF,
Webb SM,
Weber PK,
Davies PCW,
Anbar AD, Oremland RS (2010) A Bacterium That Can Grow by Using Arsenic Instead of Phosphorus. Science DOI: 10.1126/science.1197258.

The Bible is not a medical text

Although citing the Bible seems to be a way to fast-track bad science papers to publication. In yet another example of a journal letting bad Bible interpretations pass for science, a paper titled “Newer insights to the neurological diseases among biblical characters of old testament has been published in the Annals of the Indian Academy of Neurology. It isn’t new or newer, it doesn’t offer any insights, and the title isn’t even grammatical. Among its inventions is the idea that Sampson was autistic because he was violent and had odd dietary habits, that Isaac was diabetic, and that Ezekiel had a stroke.

Could someone explain to me how dubious diagnoses based on vague descriptions of serially translated myths can actually advance our understanding of disease, other than by promoting the publication careers of scientists happy to pander to superstition? I suppose one use for these things is enhancing the jocularity of interactions between neuroscientists at the lab bench, since laughing at religious idiots could be a productive bonding experience between the grad students and post-docs.

(via Neuroskeptic and Autism Blog)

Wanna go to a science workshop?

But you can’t afford the expensive registration and travel costs? Here’s the deal for you: a workshop without walls that you attend and participate in over the internet. The subject of this one is Molecular Paleontology and Resurrection: Rewinding the Tape of Life, a discussion of origins of life research. It should be cool; set aside your afternoons on 8-10 November.

Islamic apologetics in the International Journal of Cardiology

I’ve run into this particular phenomenon many times: the True Believer in some musty ancient mythology tells me that his superstition is true, because it accurately described some relatively modern discovery in science long before secular scientists worked it out. It’s always some appallingly stupid interpretation of a vaguely useless piece of text that wouldn’t have made any sense until it was retrofitted to modern science. My particular field of developmental biology has been particularly afflicted with this nonsense, thanks to one man, Dr. Keith L. Moore, of the University of Toronto. He’s the author or co-author on several widely used textbooks in anatomy and embryology — and they are good and useful books! — but he’s also an idiot. He has published ridiculous claims that the Qur’an contains inexplicably detailed descriptions of the stages of human development, implying some sort of divine source of information.

I’ve mentioned this before. For instance, the old book claims that at one point the embryo looks like a piece of chewed gum, or mudghah, and Moore announces, “by golly, it does, sorta”, throwing away all the knowledge we have about the structure and appearance of the actual embryo, which is not a chewed lump. I’ve actually seen these kooks show pictures of a piece of gum and an embryo and declare that they are similar. It’s insane. It’s pareidolia run amuck and swamping out actual scientific information for the sake of propping up useless superstitions.

Here’s Moore himself, endorsing the divinity of Allah on the basis of mudghah.

You may not have heard of him before, but I regularly get email from Muslims telling me that as a developmental biologist, I ought to follow Islam because of its insights into embryology, which don’t exist. Thanks, Dr Moore, you dumbass.

Well, now the Muslim cranks have another coup, having persuaded some other dumbasses to publish an appallingly bad paper in the International Journal of Cardiology, a credible peer-reviewed journal. Or, at least, formerly credible.

The paper is disgracefully bad. It’s basically a compendium of an assortment of references to anatomy and health from the Qur’an, endorsing them as accurate sources of information. For instance, the Qur’an prescribes three techniques for healing, “honey, cupping, and cauterization,” and gosh, we now know that “Honey contains the therapeutic contents sugars, vitamins, anti-microbials, among other things”!

Are you impressed yet?

Since this is a cardiology journal, the article also finds it necessary to waste the readers’ time with blather about blood and arteries. Here’s an example of the Prophet’s profound knowledge of the circulatory system.

Another great vessel mentioned in the Qur’an is the Al-Aatín or aorta “We would certainly have seized his right hand and cut off his Al-Watín,” [20]. Al-Watín has been translated into different, yet similar words, including “aorta”, “life-artery”, and simply “artery”. This verse is taken to mean that if the Prophet Mohammed was lying about the teachings of God, then God would have grabbed the Prophet Mohammad’s arm and cut a vital artery, certainly killing Mohammad. This verse confirms that 1. Blood was indeed viewed as a vehicle for life and 2. The artery directly leading from the heart is vital to survival. By analyzing the different translations and exegesis of Al-Watín, it can be safely assumed that it is the aorta that the author of the Qur’an is referring to in this verse.

Hmmm. So a warlike society that had many soldiers running about chopping into people with swords was aware that cutting major arteries would lead to rapid blood loss and death. I have no idea how they could have figured that out without an omniscient god whispering the explanation into the ears of priests.

The holy book also talks about heart disease, something else a readership of cardiologists would find interesting. Does this sound like well-informed medicine to you?

The Qur’an shares with the Hadeeth a metaphorical description of the heart as a possessor of emotional faculties, thus giving the heart many characteristics that modern science attributes to the brain. As is popularly stated in Islamic culture, every action is dependent upon intentions, and “…what counts is [to God] the intention of your hearts…”. These actions, whether “good” or “bad” determine the health of the heart, namely if it is a sound or diseased heart. A diseased heart is one filled with qualities such as doubt, hypocrisy, and ignorance among many others. Possessors of such qualities have a “hardened,” diseased heart. Other malaise qualities contributing to a diseased heart includes blasphemy, rejection of truth, deviation, sin, corruption, aggressiveness, negligence, fear, anger, and jealousy, among others.

The authors of the Qur’an and of this paper seem to have confused poetic metaphor with science.

Yeah, the article also repeats Moore’s nonsense about embryology. There’s much, much more: read the original paper for yourself, or this excellent critique that also points out all the conveniently omitted parts where the Qur’an gets everything completely wrong.

How did this crap manage to get published? Once again, we have a disgraceful failure of peer-review to weed out obvious religious propaganda, allowing an Islamic tract to appear under the guise of a scientific article. Just the fact that the references consist almost entirely of citations to pages of the Qur’an ought to have triggered some concern. I’d like to know what went wrong in the reviewing process that allowed garbage like this to make it onto the pages of the International Journal of Cardiology. Write to the editor and demand an accounting; also make them squirm in embarrassment and appreciate the damage that has been done to their credibility.

And remember: ancient holy books are sources of lies and misinformation, not science.

Loukas M, et al, The heart and cardiovascular system in the Qur’an and Hadeeth, Int J Cardiol (2009), doi:10.1016/j. ijcard.2009.05.011

Fancy that, a fabulous map

This is beautiful, I’d hang it on my wall. It’s a genetic map of the first synthetic organism, and it and many others will be on display in the Serpentine Gallery in London this weekend.

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And gosh, what do you know, I am going to be in London this weekend! I may have to sneak out of The Amazing Meeting a bit, which is going to be hard to do since it’s so jam-packed with cool people and cool stuff, but some of them might want to join me in a little extracurricular travel as well.