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:

DNA methylation: it's like a chastity belt for your chromosomes.
“DNA methylation: it’s like a chastity belt for your chromosomes.”

We humans have a lot of genes — twenty or thirty thousand, give or take a chromosome. But we also have a problem. All those genes are packed into the DNA of each and every one of our cells. You’ve got genes for hemoglobin next to genes for neurotransmitters next to liver enzyme genes next to the ones that tell your left foot to grow toenails. The whole caboodle, in every single cell.

You can’t have all those genes turned on at once, in all the cells. It’d be a disaster. Think of your DNA as a big walk-in closet full of clothes. Some things go together, some things clash, and other things you only wear for holidays — or when senile-assed Aunt Clara shows up to see the stupid lop-eared bunny suit she bought you. But you don’t wear everything you own all at once. That would make you a crazy person.

So it goes with your cells. Depending on where they live — in a little row house along the spinal column, maybe, or a brownstone in the colon — they want to fit in with the neighbors and express the right set of genes. When in Rome, do as the Romans. And when in the respiratory system, don’t spew out growth hormones. That’s not your job, bunnybutt.

There are several ways that cells can shut down or “silence” genes, but one of the most common is DNA methylation. It sounds complicated, but it’s actually pretty simple. To make a protein in a cell, a bunch of enzymes have to get at the bit of DNA coding for it. Those enzymes read the code into RNA, and the protein is built from that. “Methylation” means taking a methyl group, a single-carbon molecule similar to methane, and glomming it onto that DNA structure like a wad of used chewing gum.

Slap enough methyl groups onto a stretch of DNA, and those RNA-making enzymes can’t get at it. Any genes in the neighborhood get completely shut down, like a Honda running out of gas or a dudebro wearing Axe cologne. Even better, when the cell divides, the DNA methylation pattern gets passed down the line. So it’s a great way for specialized cells to shut off genes they have no business fiddling with — basically a permanent genetic cock block.

Though critical for development in mammals — pssssst, that’s us — DNA methylation isn’t used in the same way by all species. Fruit flies, for instance, apparently have better things to do with most of their DNA, and yeast haughtily looks down its nose at DNA methylation.

Or would, if yeast had a nose. Or eyes. Or the genes for being haughty.

In other organisms, DNA methylation comes up a lot. Some — humans and tomatoes, for two — use it to silence potentially harmful genes inserted by viruses into the genome. DNA methylation tends to decrease over time, so it can be used as an indicator of aging. And it’s been linked to diseases like cancer, Alzheimer’s and atherosclerosis, and could offer clues about how those conditions develop.

So DNA methylation is pretty important. Without it, all our cells would crap out all the possible human proteins and we’d be big unregulated oozing blobs of cytoplasm. Like a certain amorphously-shaped cartoon character with a distinct lack of impulse control.

And that’s not attractive. I don’t care how cute a bunny suit you slap on it.

Image sources: UIUC TCB Group (DNA methylation), The Berry (Ralphie bunny), GenTwenty (dudebro shutdown), UnderScoopFire! (Homer, unregulated)

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

Telomeres in a nutshell: the short of it is bad, and the long of it isn't great, either.
“Telomeres in a nutshell: the short of it is bad, and the long of it isn’t great, either.”

Many things tend to get shorter as we age. Patience. Hairstyles. Time between bathroom breaks.

But something else shortens when we get older, and it’s more important than all the others. Except maybe the haircuts. Nobody likes a geriatric hippie.

This “something else” is a telomere, and it’s a squiggly bit of genetic material stuck on the end of each of our chromosomes, for protection. Sort of like those fiddly plastic things on the ends of shoelaces that stop them from fraying.

(Those are called “aglets”, by the way. That’s not science. I just thought you’d want to know.)

Telomeres play a similar role in our cells — and the cells of most everything else that isn’t a bacterium. When we’re young, the telomeres on the ends of our chromosomes are long. Each time our cells divide, the telomeres get a little shorter, until they’re very small or gone completely. Cells in that state typically don’t divide any more; they’re content to put on a shawl, find a nice rocking chair and wait for the end.

It’s like the aglets on your shoelaces got shorter every time you wore your sneakers, until they finally disintegrated, the laces unraveled and your shoes fell off. Only instead of going barefoot, your hair and skin and brain cells don’t grow back any longer. Which is somewhat more inconvenient, even if you’ve already moved to that shorter hairstyle.

The other more-than-somewhat inconvenient thing about telomere-less chromosomes is that they can lead to cancer. Without those protective bits at the end, genetic material can get chewed away, which is bad. Or chromosomes can link together and loop around, which is also bad. As in, cancer bad. Much worse than frayed shoelaces.

So longer telomeres are better, right? weeeeeell — it depends. In general, yes. Antioxidants in foods like blueberries and kidney beans and artichoke hearts help to lengthen telomeres, and that’s good.

How you get your chromosomes to eat right, I don’t know. Mine are always binging on chips and deoxyribonucleic Oreos.

The thing is, our cells also make an enzyme — called telomerase — that naturally rebuilds telomeres in certain situations. Production of this enzyme is tightly regulated; it’s not normally produced very often or in large quantities. It’s like liquid gold. Or a really good gin and tonic.

In the lab, though, scientists have shown that extending telomeres can reduce signs of aging in mice and worms. Which is great for cowards and lawyers, I suppose — but someday, it could even be applied to humans. That would be sweet.

But there’s a catch. Most of our cells don’t grow constantly. Outside of skin and hair and the insides of our intestines, many cells really shouldn’t be dividing very often. You don’t want lungs the size of life rafts, or a gall bladder you could play volleyball with. Not unless you’re opening a really weird sporting goods store.

So in those cells, if telomerase was always around, the telomeres would keep getting longer. And that might signal the cells that they should divide and divide, out of control. And what are cells dividing willy-nilly, out of control? That’s right: cancer.

So telomeres are tricky. They’re like the Price Is Right showcase game of life: you want as much as you can get, without going over. Because if you do, the consolation prize might be something way worse than Rice-A-Roni.

Image Sources: The Tao of Dana (chromosome telomeres), Heavy (old hippies), Creative Homeschool (aglets), LEXpert (The Price Is Cancer)

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