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:

Optogenetics: science--invented, laser doge-approved
“With optogenetics, you won’t just ‘see the light’. You’ll feel it.”

The brain is a pain in the ass, scientifically speaking. And scientific-researchly speaking, which is probably a real thing.

Studying the brain is unusually tricky. It’s a complicated organ with billions of cells, electrical signals whizzing everywhere and neurotransmitters getting passed back and forth like the last beer at a tailgate. You want “simple”, go study an appendix. The brain is not for you.

Also, the brain comes not-so-conveniently wrapped in a hard candy shell called a skull. To reach it, you’ve got to drill through bone — and then dig through brain, if the bit you’re after is in the middle. For decades, brain science was like trying to yank grapes out of Grandma’s Jell-O without breaking the mold. As any eight-year-old can tell you, that’s damned near impossible.

Then there’s the scale. Most organs you study with a microscope, or even a camera. Drop a miniature Nikon down (or up) someone’s gut and watch a day in the life of a colon unfold in real time.

Or slower, if your test subject is a big fan of fiber.

But the brain operates at millisecond speed. Blink, and you miss a million firing synapses, lighting up the cerebellum. And the cerebrum. And that other bit — the one for remembering numbers and science facts and what parts of brains are called. Mine doesn’t work, apparently.

How can scientists possibly get around all these problems? Enter optogenetics, which allows neurocowboys a new way to put eyes on the brain. Literally. (Almost.)

The ‘opto-‘ part of the name suggests light (or eye doctors), and refers to light-sensitive proteins — like those in our eyes’ rod and cone cells — found in species like fruit flies, algae and bacteria. These proteins react to specific wavelengths of light; by snipping out the DNA sequences coding them (hence the “-genetics”) and linking them to genes in test animals, scientists can set off signals in those animals’ brains — just by turning on a flashlight.

A very special kind of laboratory flashlight. Very wavelength. Much science. Wow.

Now researchers can trigger — and measure — brain events at the speed of light. They’ve even developed wireless versions of their flashy-light and brain-detect-o-matic devices, allowing them to study animals running free in the lab. Or “free” in a cage. But not attached by the forehead to an industrial science laser. Which is nice.

The techniques are fairly new, but have already changed the neurobiology game. Among other things, scientists have used optogenetic methods to implant false memories (and sexy thoughts) in fruit flies, flip-flop social behavior in mice, relax muscles in worms, break habits in rats and kill pain (again in mice) with a flash of light. Creepy Island of Doctor Moreau vibe aside, this research could someday have important applications in human medicine. Also, with all the flashing lights and artificial mind altering, the lab animals just think they’re at tiny adorable raves.

One final measure of the impact of optogenetics: In 2010, it was named scientific “Method of the Year”. Presumably, it beat out “stash your samples on ice overnight so you can duck out for Happy Hour”. For scientists, that’s a huge upset.

Image Sources: ExtremeTech (lab mouse), Jello Mold Mistress (Jell-O mold), NoodlyTime (laser doge), Redshirt Knitting (mouse rave)

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