Note (12/2015): Hi there! I'm taking some time off here to focus on other projects for a bit. As of October 2016, those other projects include a science book series for kids titled Things That Make You Go Yuck! -- available at Barnes and Noble, Amazon and (hopefully) a bookstore near you!

Co-author Jenn Dlugos and I are also doing some extremely ridiculous things over at Drinkstorm Studios, including our award-winning webseries, Magicland.

There are also a full 100 posts right here in the archives, and feel free to drop me a line at with comments, suggestions or wacky cold fusion ideas. Cheers!

· Categories: Biology, Genetics
What I’ve Learned:

Knockout mouse: one lab animal that really goes to the mat for science.
“Knockout mouse: one lab animal that really goes to the mat for science.”

The late author Douglas Adams once said a thing about cats:

If you try and take a cat apart to see how it works, the first thing you have on your hands is a nonworking cat.

He was making a point about how living things are extraordinarily complex, even more so than things like alarm clocks and carburetors and the London Bridge — which, while also complex, can in fact be taken apart and reassembled into reasonable working order.

(By people who are not me. I struggle to reassemble a hamburger after I’ve taken the top off to adjust the pickles.)

Note that the esteemed Mr. Adams never said anything about mice.

Since 1989, scientists have been able to produce essentially the non-cat (and mostly un-messy) equivalent of what Douglas Adams described: a mouse that’s been taken apart to see how it works — and then put back together, with one of the pieces missing.

Unlike your average neighborhood mechanic or electrician, however, the missing bits of these mice are left out intentionally, to find out what they do. And before visions of Frankenmice or other murine monstrosities skitter through your head, let’s clarify that we’re talking about “pieces” at the genetic level. Nobody’s hacksawing the ears off your favorite Disney rodent.

Well. Not for science, anyway.

The term for one of these genetically-altered mice is “knockout mouse”, which sounds like someone Jessica Rabbit shares an apartment with. Or some remedial schlub you have to fight in Punchout if you get your ass kicked by Glass Joe.

Happily, it’s neither. The “knockout” part of the name refers to the knockout of a specific gene. To create a knockout mouse, scientists recreate the sequence of a mouse gene in the laboratory — but with a fatal flaw. They alter the gene sequence so that it can’t produce the functional protein it normally would. They then introduce this broken gene into stem cells collected from mice.

Because the mucked-with gene is still nearly the same sequence as the normal version, some of the stem cells will integrate the new copy into the same spot in the genome, via a process called homologous recombination. It’s a rare occurrence — the cell’s DNA has to need repair in just the right place, when the engineered gene copy happens to be handy — but researchers have designed ways to know when it happens, and to retrieve those few cells where the gene has nestled in just right.

Since each cell contains two sets of chromosomes, the engineered stem cells have one “good” copy of the target gene, in addition to the scrambled one they’ve just picked up. Those stem cells get inserted into an early-stage mouse embryo, which is then implanted into a female mouse to grow. If all goes well, the embryo grows into a baby mouse containing cells from both the original embryo and the injected-in cells. This is called a chimera. And if all goes really well, the sex organs on those baby chimeric mice will come from the injected cells, with one wonky copy of the target gene.

From there, it’s just a hop, skip and a few tiny Barry White albums to a knockout mouse. The chimeras with one wonky copy of the gene in their sperm or eggs are bred, and some of their offspring will inherit that wonky gene — along with a normal copy from the other parent. But, cross-breed a few of those single-copy mice together, and eventually you’ll come up with a mouse with a non-functional copy inherited from both parents. That’s a critter where the gene essentially doesn’t exist any more — and that’s a knockout mouse.

There are now thousands of different types of knockout mice, each demonstrating the effects a particular gene has — by its absence. Knock out one gene, and the mice without it become more susceptible to cancer. Knock out another, and they lose their hair. Another, and the mice grow huge and chubby.

Scientists use knockout mice because many of their genes are similar to ours, and often function in the same way. It’s not a perfect model, but “knockout people” are generally frowned upon in the medical community, so it’ll have to do. And knockout mouse models have been used to study everything from aging to arthritis to obesity to cancer, so they’re extremely useful as research tools.

They might also, according to Douglas Adams’ books, be hyper-intelligent pan-dimensional beings who’ve set up the Earth as a grand cosmic experiment. And he was pretty spot-on about the cat thing, so it’s worth mulling over.

Image sources: Science Alert (leptin KO mouse), S M Ong (D.N.A., looking devious), Carton-Online (Mickey, missing something), One Gamer’s Thoughts (Monsieur Joe, mid-taunt)

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· Categories: Biology, Genetics
What I’ve Learned:

X-linked inheritance: sometimes chromosomes aren't X-actly as they should be.
“X-linked inheritance: sometimes chromosomes aren’t X-actly as they should be.”

We humans have a bunch of chromosomes — balled-up tangles of DNA — lying around our cells. Forty-six of them, in fact, in twenty-three pairs. We get one chromosome of each pair comes from our mother and one from our father — though they may smush together and intermingle during the fertilization process.

(That’s the chromosomes, not our parents. They smushed and intermingled right before the fertilization process, obviously. Also, Barry White was probably involved, which you don’t typically find at the chromosomal level.

Most DNA strands are more into Marvin Gaye.)

The last chromosome pair — the “sex chromosomes” — is special. Males get one copy each of an “X” chromosome and a “Y” chromosome. And females double up on “X” chromosomes, leaving out “Y” altogether.

(The chromosomes get those names because under a microscope, they look a little like the alphabet letters.

To whom, I don’t know. Maybe Elmo from Sesame Street is in charge of naming biological structures.)

Put another way, if a fertilized egg gets the “Y” chromosome from the father (and one of the mother’s “X” chromosomes), the child will be male. If it gets the father’s “X” (and a second “X” from the mother), it’ll be female. Genes on these chromosomes will kick in during development, to determine the sex of the child.

(That’s how it works in humans, anyway, and most other mammals. Some animals have different sex chromosomes — like chickens, where hens have ZW and roosters are ZZ. Or grasshoppers, where females get XX and males get one X, nothing else, and are told to suck it up and stop whining.

Or platypuses, which have ten sex chromosomes, because of course they do. Platypuses are freaking weird.)

The XX versus XY choice has consequences down the line. Many genetic traits are “recessive”, meaning if just one of your two chromosomal copies is defective, you’re fine. Only if both are screwy will you have the trait or disease. For genes on, say, chromosome 3 or 12, that’s okay — everyone’s got two copies, so it’s rare to get both mucked up at once.

But X chromosome genes are trickier. Males only get one copy of X — from their mothers, remember, because to even be male, they had to get a Y from their fathers. If a gene on that lonely X chromosome happens to be horked up, they’re out of luck. There’s no backup, no “chromosome on the cloud” or flash-drive file to recover. One X chromosome, one chance to get all of “X-linked inheritance” right.

Sometimes, it doesn’t happen. If a recessive trait is X-linked and the father has a wonky copy, his daughters will all inherit it — but one bad copy doesn’t hurt. They’ll still get a “normal” X from Mom, and hopscotch happily away. If the mother is affected, all her kids have a 50% chance of catching the bad copy — but again, in girls, it’s covered by a healthy X (this time, from Dad). Only the sons, with mother’s lone mangled chromosome, get dinged by recessive X-linked inheritance.

(Daughters can also get the diseases. But it takes both an affected father and mother — and a bit of bad luck — to be so dinged. It’s like the sperm and egg walked a black cat under a ladder or something.

There’s also “dominant” X-linked inheritance, where even a single defective copy of a gene causes a disease. Females are more likely than males to inherit these conditions, but they’re pretty rare. Overall, X-linked torpedoes still sink males more often.)

So what issues can X-linked inheritance cause? Common recessive disorders include hemophilia, color blindness and certain types of muscular dystrophy. And the rarer stuff includes even nastier syndromes and diseases you wouldn’t wish on your worst newly-fertilized enemy.

So however many X’s you happen to have, be happy that the dice of X-linked inheritance probability didn’t roll snake eyes for you. Unless they did, and then curse the cocked-up chromosomes that combined to mark the mutant-X spot. If only you’d been a platypus, this might not have happened.

Something much weirder, probably. But not this.

Actual Science:
Medline PlusSex-linked recessive
NCBIAn introduction to genetic analysis / human genetics
Science PrimerX-linked inheritance
NHS UKX-linked conditions
Wellcome TrustX-linked diseases

Image sources: Madical School (X-linked inheritance), AllMusic (White ‘n’ Gaye), Aussie Pete II (Elmo [and Norah Jones!] and Y), Try Nerdy (platypus sex [chromosome] appeal)

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