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How a New Breed of Rodents is Changing the Face of Science

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By Maggie Koerth-Baker

Need a mouse that's resistant to anthrax but will get drunk easily? There's a lab mouse designed for that. Need a mouse that can get Parkinson's disease but will never catch polio? There's a mouse for that, too. The caged rodents in today's labs aren't the guinea pigs of yesteryear. They're specifically bred and highly standardized. And credit for that goes to Clarence Cook Little, a visionary researcher who saw the potential in an overlooked rodent and revolutionized biology in the process.

Little Big Man

The son of a dog-show judge, C.C. Little arrived at Harvard in 1906, set on studying man's best friend. But one day during class, Professor William Castle gave him some career advice. He slid a mouse across his desk to Little and told him to find out everything he could about that organism. "This," he said, "will be the one to watch." Castle, a founding father of genetics in America, was not the kind of person you ignore. Fortunately, Little listened.

Between 1909 and 1914, C.C. Little toiled in the biology labs of Harvard's Bussey Institute, using mice to learn how mammals inherit traits from their parents. But when he ran his experiments, Little found that the creatures lacked the sort of standardization expected of other lab subjects. At the time, experimenting on mice usually meant catching a bunch in the basement of some campus building and carting them over to the lab. While certainly fresh and feisty, Little's test subjects were difficult to obtain and differed greatly from one another. So he began to dream of mice strains that were identical and docile, "like newly minted coins." Little's solution? Inbreeding.

Good Breeding

Take two closely related specimens, play some Barry White, and presto! You've got pure white mice. If only it were that easy.

In reality, C.C. Little's process for creating inbred mouse strains was neither quick nor exact. One of the biggest problems with inbreeding is that it can lead to rare genetic diseases. Little got around this problem, but his solution required years of trial and error. He would mate mice, then sit back and wait for something weird to happen ... or not happen. If a mouse was born with a trait that Little didn't like, he'd remove it from the gene pool. If a mouse possessed a trait that Little considered desirable, he'd launch a multi-generational inbreeding process to create a new strain. Once Little had his own lab, he employed assistants whose sole job was to check mouse litters for mutants.

Sometimes, the traits that Little and his team found most useful were the ones that produced the least healthy mice. He discovered, for instance, that you can breed strains of mice with bodies that readily accept transplanted cancer tumors. These mice provided some of the first evidence that susceptibility to cancer can be inherited, just like hair color.

In the early part of 1929, Little became the director of the American Cancer Society, and later that year, he opened a research institute in Bar Harbor, Maine, called the Jackson Memorial Laboratory. Unfortunately, the timing wasn't ideal. Within days, the stock market crashed, and Little lost nearly all of his funding. For the next three years, he struggled to keep the lab afloat. At one point, Little's researchers were actually doing their own construction work on the building and getting food from staff fishing trips.

Finally, Little made a crucial decision that would change medical and genetic research forever: He compiled a catalog of the inbred strains he'd created and used for his own research, and he offered to sell it to other institutions. In the world of research, where scientists traditionally shared their resources, Little's for-profit catalog was considered gauche. But while the move defied convention, it may also have been Little's biggest contribution to science.

Researchers quickly realized the value of using standardized mice strains, and the money began pouring in. The reliability of Little's breeding techniques, along with his lab's commitment to quality control, helped scientists reduce the number of variables in complex experiments.

Today, it's estimated that 95 percent of the world's lab mice are descended from mice born in the Jackson Laboratory.

Yet, it would be almost 40 years before mice got the public kudos they deserved. In 1978, Little received the Coley Award, created in 1975 expressly to honor lab mice and the people responsible for them. But by then, C.C. Little had already been dead for seven years. Critics believe the delayed recognition had something to do with the fact that Little had spent the last 15 years of his life tirelessly campaigning for Big Tobacco. In 1956, he'd resigned from the lab to become the scientific director for the Tobacco Industrial Research Committee, where he argued against the idea that smoking causes lung cancer. Despite this late-life misstep, Little's contributions to the scientific world are impossible to dismiss.

Intelligent Design

These days, when geneticists want to create a new strain of mice, they often take a more hands-on approach. In the early 1980s, researchers began genetically manipulating mice by inserting genes from other species (including humans) during the earliest stages of embryonic cell division. The result was "transgenic mice." Scientists also began turning off specific genes during early development, creating "knockout mice." Both types of mice are incredibly important in today's research. For instance, unaltered mice can't get polio, because they don't have the right cell receptors for the virus to latch onto. But transgenic mice with human genes can catch polio just like people. Thanks to transgenic poliovirus receptor mice (known to their friends as TgPVR), we have a better way to test polio vaccines, making them safer and more effective.

Knockout mice are every bit as special. In 1996, scientists created knockout mice that stopped being able to produce a protein called Nrf2. This caused the mice to have low dopamine levels, and they developed the telltale physical symptoms of Parkinson's disease. Their condition directly contributed to a February 2009 finding by researchers at the University of Wisconsin-Madison, which stated that mice that produce ultra-high levels of Nrf2 are immune to Parkinson's, even when they are injected with chemicals known to cause the disorder. Currently, there is an international effort to uncover even more breakthroughs by systematically creating a knockout mouse variety for every gene on the mouse genome. Scientists have created knockouts for about 5,000 genes, and there are only 15,000 more to go.

Although the history of lab mice began with inbreeding, their future almost certainly lies in higher technology. And this time, the innovators won't die before being properly lauded. The three scientists responsible for transgenic and knockout mice were rightly honored in 2007, when they were awarded the Nobel Prize.

This article originally appeared in the September-October 2009 issue of mental_floss magazine.

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iStock // Ekaterina Minaeva
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Man Buys Two Metric Tons of LEGO Bricks; Sorts Them Via Machine Learning
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iStock // Ekaterina Minaeva

Jacques Mattheij made a small, but awesome, mistake. He went on eBay one evening and bid on a bunch of bulk LEGO brick auctions, then went to sleep. Upon waking, he discovered that he was the high bidder on many, and was now the proud owner of two tons of LEGO bricks. (This is about 4400 pounds.) He wrote, "[L]esson 1: if you win almost all bids you are bidding too high."

Mattheij had noticed that bulk, unsorted bricks sell for something like €10/kilogram, whereas sets are roughly €40/kg and rare parts go for up to €100/kg. Much of the value of the bricks is in their sorting. If he could reduce the entropy of these bins of unsorted bricks, he could make a tidy profit. While many people do this work by hand, the problem is enormous—just the kind of challenge for a computer. Mattheij writes:

There are 38000+ shapes and there are 100+ possible shades of color (you can roughly tell how old someone is by asking them what lego colors they remember from their youth).

In the following months, Mattheij built a proof-of-concept sorting system using, of course, LEGO. He broke the problem down into a series of sub-problems (including "feeding LEGO reliably from a hopper is surprisingly hard," one of those facts of nature that will stymie even the best system design). After tinkering with the prototype at length, he expanded the system to a surprisingly complex system of conveyer belts (powered by a home treadmill), various pieces of cabinetry, and "copious quantities of crazy glue."

Here's a video showing the current system running at low speed:

The key part of the system was running the bricks past a camera paired with a computer running a neural net-based image classifier. That allows the computer (when sufficiently trained on brick images) to recognize bricks and thus categorize them by color, shape, or other parameters. Remember that as bricks pass by, they can be in any orientation, can be dirty, can even be stuck to other pieces. So having a flexible software system is key to recognizing—in a fraction of a second—what a given brick is, in order to sort it out. When a match is found, a jet of compressed air pops the piece off the conveyer belt and into a waiting bin.

After much experimentation, Mattheij rewrote the software (several times in fact) to accomplish a variety of basic tasks. At its core, the system takes images from a webcam and feeds them to a neural network to do the classification. Of course, the neural net needs to be "trained" by showing it lots of images, and telling it what those images represent. Mattheij's breakthrough was allowing the machine to effectively train itself, with guidance: Running pieces through allows the system to take its own photos, make a guess, and build on that guess. As long as Mattheij corrects the incorrect guesses, he ends up with a decent (and self-reinforcing) corpus of training data. As the machine continues running, it can rack up more training, allowing it to recognize a broad variety of pieces on the fly.

Here's another video, focusing on how the pieces move on conveyer belts (running at slow speed so puny humans can follow). You can also see the air jets in action:

In an email interview, Mattheij told Mental Floss that the system currently sorts LEGO bricks into more than 50 categories. It can also be run in a color-sorting mode to bin the parts across 12 color groups. (Thus at present you'd likely do a two-pass sort on the bricks: once for shape, then a separate pass for color.) He continues to refine the system, with a focus on making its recognition abilities faster. At some point down the line, he plans to make the software portion open source. You're on your own as far as building conveyer belts, bins, and so forth.

Check out Mattheij's writeup in two parts for more information. It starts with an overview of the story, followed up with a deep dive on the software. He's also tweeting about the project (among other things). And if you look around a bit, you'll find bulk LEGO brick auctions online—it's definitely a thing!

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Cs California, Wikimedia Commons // CC BY-SA 3.0
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How Experts Say We Should Stop a 'Zombie' Infection: Kill It With Fire
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Cs California, Wikimedia Commons // CC BY-SA 3.0

Scientists are known for being pretty cautious people. But sometimes, even the most careful of us need to burn some things to the ground. Immunologists have proposed a plan to burn large swaths of parkland in an attempt to wipe out disease, as The New York Times reports. They described the problem in the journal Microbiology and Molecular Biology Reviews.

Chronic wasting disease (CWD) is a gruesome infection that’s been destroying deer and elk herds across North America. Like bovine spongiform encephalopathy (BSE, better known as mad cow disease) and Creutzfeldt-Jakob disease, CWD is caused by damaged, contagious little proteins called prions. Although it's been half a century since CWD was first discovered, scientists are still scratching their heads about how it works, how it spreads, and if, like BSE, it could someday infect humans.

Paper co-author Mark Zabel, of the Prion Research Center at Colorado State University, says animals with CWD fade away slowly at first, losing weight and starting to act kind of spacey. But "they’re not hard to pick out at the end stage," he told The New York Times. "They have a vacant stare, they have a stumbling gait, their heads are drooping, their ears are down, you can see thick saliva dripping from their mouths. It’s like a true zombie disease."

CWD has already been spotted in 24 U.S. states. Some herds are already 50 percent infected, and that number is only growing.

Prion illnesses often travel from one infected individual to another, but CWD’s expansion was so rapid that scientists began to suspect it had more than one way of finding new animals to attack.

Sure enough, it did. As it turns out, the CWD prion doesn’t go down with its host-animal ship. Infected animals shed the prion in their urine, feces, and drool. Long after the sick deer has died, others can still contract CWD from the leaves they eat and the grass in which they stand.

As if that’s not bad enough, CWD has another trick up its sleeve: spontaneous generation. That is, it doesn’t take much damage to twist a healthy prion into a zombifying pathogen. The illness just pops up.

There are some treatments, including immersing infected tissue in an ozone bath. But that won't help when the problem is literally smeared across the landscape. "You cannot treat half of the continental United States with ozone," Zabel said.

And so, to combat this many-pronged assault on our wildlife, Zabel and his colleagues are getting aggressive. They recommend a controlled burn of infected areas of national parks in Colorado and Arkansas—a pilot study to determine if fire will be enough.

"If you eliminate the plants that have prions on the surface, that would be a huge step forward," he said. "I really don’t think it’s that crazy."

[h/t The New York Times]

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