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My Hobby: Solving public health problems
Once upon a time, there were a boy and a girl. The boy ran a tech conference, and the girl worked for a company that made DNA. She submitted a talk about DNA design software to the conference, and it got in, and she was very, very excited.
While preparing to give her talk, the girl mentioned to the boy that if she only had a salad spinner, she could kick off her talk with a cute demo. "I will find you a salad spinner," said the boy, and he did (thanks to![[livejournal.com profile]](https://www.dreamwidth.org/img/external/lj-userinfo.gif)
kragen), and the demo was very cute indeed.
After the conference, the boy and the girl got to talking about other amusing things that people could do with DNA, and somewhere in there, someone had the idea that it would be really funny to take Lactobacillus acidophilus, otherwise known as yogurt bacteria, give it the gene to produce green fluorescent protein, and make yogurt with it. Or "glowgurt", if you prefer.
They were, however, rather busy with a number of other projects, both together and separately, and along the line they fell for each other like a ton of bricks and got married.
This is where the story actually starts.
Back in August,ext_97806 and I were in Houston for my sister's wedding. Naturally, we spent a fair bit of time also hanging out at mycroftxxx's place with his housemate pturing and the other residents of the House of Discord. One evening, we were all kickin' it on the porch, shooting the shit about science (like ya do), and glowgurt came up. This led to some speculation about other things one could coerce bacteria to produce, and ext_97806 hit on a brilliant one: essential micronutrients. In particular, Vitamin C.
See, most mammals synthesize ascorbic acid (as C is also known) on their own. A few, however, have deletion mutations which prevent them from being able to: guinea pigs, some bats, all monkeys, all apes, and us. These mammals must get ascorbic acid in their diets, or else they'll end up with vitamin C deficiency, known as scurvy.
Scurvy is serious business. These days we think about it when we think of pirates or sailors, because during the seafaring days, it was really difficult to lay in enough supplies of citrus fruit and other ascorbic-acid-containing foods to last for an entire sea voyage. It's a really unpleasant disease. Sufferers lose their teeth and fingernails, bleed from the gums and mucous membranes, and experience severe joint pain, as vitamin C is necessary for collagen synthesis. Over time, healed scars can reopen and knitted fractures rebreak. Untreated, it is fatal, usually due to brain hemorrhage.
Thanks to modern food distribution, scurvy is uncommon in the industrialized world, except among one population: the homeless, typically elderly homeless men. Infants who are fed unfortified formula get it too. In the Third World, the situation is much more troubling. It's difficult to conduct studies on the prevalence of scurvy in the populations most likely to suffer from it, because those populations are hard to get to: refugees. An estimate of 100,000 cases of scurvy in East Africa alone is likely an underestimate. And most of the victims are children.
The bitter irony is that scurvy is 100% curable: all you have to do is get vitamin C to people. Of course, this is a big challenge when the population that needs it most is remote and resource-poor: if there were reliable distribution channels and money to pay for distribution, we could get supplements to them. Or citrus fruit.
We can't re-engineer living people to make their own ascorbic acid. But we can engineer bacteria to do it, rather easily in fact. How does that help scurvy sufferers, though? One word: probiotics.
Every human body is home to billions and billions of bacteria. We are their universe, and we literally could not live without them. The bacteria we house help us digest food and provide us with some of our essential micronutrients already -- poor maligned E. coli, for instance, manufactures Vitamin B12. So, pick a bacterial symbiote that lives in the gut and that people are willing to eat -- like, oh, say, yogurt bacteria -- and give it the ability to manufacture vitamin B12, or to help us manufacture it ourselves. (We're only missing one enzyme from the metabolic pathway that produces ascorbic acid.) Make yogurt with it, and just give the stuff away. Teach people how to make more yogurt from the yogurt they already have -- microbes are totally the gift that keeps on giving -- and slowly, one bite of yogurt at a time, we can do to scurvy what Salk and Sabin did to polio.
There are some challenges. (There always are.) Giving a bacterium the ability to produce a new protein has the side effect of making it less competitive: it's spending more of its energy on producing that protein, and thus less on dividing like crazy. Over time, its unaltered relatives will outnumber it, and eventually its population will dwindle to the point where it dies out. Selection is a bitch like that. However, if we can figure out some way to tweak the altered bacteria so that their rate of growth is on par with unaltered bacteria, then we can shift the balance of the game. Can we do this at all? Can we do it without affecting the existing essential roles that lactic acid bacteria play in us and in every other organism out there? I'm not sure. But that's what research is for.
Another challenge is making sure that we don't overdo it. It's pretty hard to overdose on Vitamin C; the LD-50 in humans is unknown, but in rats it's about 12 grams per kilogram, so if the numbers are similar for people, I'd have to choke down nearly two pounds of Vitamin C at one sitting to have a 50% chance of dying from it. Doses on the order of six grams per day over the course of many months can cause diarrhea, headache and other uncomfortable side effects, and people with iron overload disorders (wherein the body is too good at utilising dietary iron) can have their problems exacerbated by too much vitamin C. But there are two pieces of good news here. First, it's much easier to limit the rate of bacterial growth than it is to increase it, and second, there's a lot of wiggle room. 40 milligrams per day is probably adequate, 90 milligrams per day is enough for anyone, and the maximum recommended daily dose is 2,000 milligrams. So if we produce a population density that will provide people with about 40mg/day, it's unlikely that we'll fuck anyone up.
It's gonna take a lot of work. I won't pretend otherwise. We're talking about making major changes to the way humans everywhere interact with an organism that is vital to our existence, and that's a sobering thought. But so is the fact that hundreds of thousands of people suffer from a disease that can be eradicated.
To me, that means we're morally obligated to try. We're also obligated to be damn careful. But we have to try. So we are.
Another project I'm working on, along with engineer Jonathan Cline and a research team at National Yang-Ming University in Taiwan, is a biological method for detecting melamine contamination in food, which we've dubbed the "melaminometer". You might remember how last fall, there was a huge panic about contaminated pet food that was causing cats and dogs to die of kidney failure. This was traced to melamine, a triazine molecule which is 66% nitrogen by mass and can be used to make food products look like they contain more protein than they actually do. Unfortunately, not only is melamine not a dietary protein, it also pairs up with cyanuric acid to form insoluble crystals which accrete in the kidneys and cause irreversible, fatal kidney failure.
Oh, and the stuff has started showing up in milk products, including baby food, in China. The FDA has already banned all imports of Chinese dairy products out of fear for people's safety, and with good reason.
So why a biological detector? Well, as you might have guessed, with simple detection methods, melamine can masquerade as protein, and that's no good. The FDA uses chromatography and mass spectrometry, both of which are time-consuming and require a lot of equipment, plus someone who's trained to use it. A number of labs produce ELISA kits that can detect melamine very accurately and rather quickly (each test only takes about half an hour), but the kits aren't cheap and the cost adds up. We're aiming to produce a bacterium that lights up in the presence of melamine, in order to make available a test that is inexpensive, portable, and accurate.
You can read more about the work we're doing here -- that's right, we're keeping our notes on a wiki. Yeah, open science!
While preparing to give her talk, the girl mentioned to the boy that if she only had a salad spinner, she could kick off her talk with a cute demo. "I will find you a salad spinner," said the boy, and he did (thanks to
kragen), and the demo was very cute indeed.After the conference, the boy and the girl got to talking about other amusing things that people could do with DNA, and somewhere in there, someone had the idea that it would be really funny to take Lactobacillus acidophilus, otherwise known as yogurt bacteria, give it the gene to produce green fluorescent protein, and make yogurt with it. Or "glowgurt", if you prefer.
They were, however, rather busy with a number of other projects, both together and separately, and along the line they fell for each other like a ton of bricks and got married.
This is where the story actually starts.
Back in August,
ext_97806 and I were in Houston for my sister's wedding. Naturally, we spent a fair bit of time also hanging out at mycroftxxx's place with his housemate pturing and the other residents of the House of Discord. One evening, we were all kickin' it on the porch, shooting the shit about science (like ya do), and glowgurt came up. This led to some speculation about other things one could coerce bacteria to produce, and ext_97806 hit on a brilliant one: essential micronutrients. In particular, Vitamin C.See, most mammals synthesize ascorbic acid (as C is also known) on their own. A few, however, have deletion mutations which prevent them from being able to: guinea pigs, some bats, all monkeys, all apes, and us. These mammals must get ascorbic acid in their diets, or else they'll end up with vitamin C deficiency, known as scurvy.
Scurvy is serious business. These days we think about it when we think of pirates or sailors, because during the seafaring days, it was really difficult to lay in enough supplies of citrus fruit and other ascorbic-acid-containing foods to last for an entire sea voyage. It's a really unpleasant disease. Sufferers lose their teeth and fingernails, bleed from the gums and mucous membranes, and experience severe joint pain, as vitamin C is necessary for collagen synthesis. Over time, healed scars can reopen and knitted fractures rebreak. Untreated, it is fatal, usually due to brain hemorrhage.
Thanks to modern food distribution, scurvy is uncommon in the industrialized world, except among one population: the homeless, typically elderly homeless men. Infants who are fed unfortified formula get it too. In the Third World, the situation is much more troubling. It's difficult to conduct studies on the prevalence of scurvy in the populations most likely to suffer from it, because those populations are hard to get to: refugees. An estimate of 100,000 cases of scurvy in East Africa alone is likely an underestimate. And most of the victims are children.
The bitter irony is that scurvy is 100% curable: all you have to do is get vitamin C to people. Of course, this is a big challenge when the population that needs it most is remote and resource-poor: if there were reliable distribution channels and money to pay for distribution, we could get supplements to them. Or citrus fruit.
We can't re-engineer living people to make their own ascorbic acid. But we can engineer bacteria to do it, rather easily in fact. How does that help scurvy sufferers, though? One word: probiotics.
Every human body is home to billions and billions of bacteria. We are their universe, and we literally could not live without them. The bacteria we house help us digest food and provide us with some of our essential micronutrients already -- poor maligned E. coli, for instance, manufactures Vitamin B12. So, pick a bacterial symbiote that lives in the gut and that people are willing to eat -- like, oh, say, yogurt bacteria -- and give it the ability to manufacture vitamin B12, or to help us manufacture it ourselves. (We're only missing one enzyme from the metabolic pathway that produces ascorbic acid.) Make yogurt with it, and just give the stuff away. Teach people how to make more yogurt from the yogurt they already have -- microbes are totally the gift that keeps on giving -- and slowly, one bite of yogurt at a time, we can do to scurvy what Salk and Sabin did to polio.
There are some challenges. (There always are.) Giving a bacterium the ability to produce a new protein has the side effect of making it less competitive: it's spending more of its energy on producing that protein, and thus less on dividing like crazy. Over time, its unaltered relatives will outnumber it, and eventually its population will dwindle to the point where it dies out. Selection is a bitch like that. However, if we can figure out some way to tweak the altered bacteria so that their rate of growth is on par with unaltered bacteria, then we can shift the balance of the game. Can we do this at all? Can we do it without affecting the existing essential roles that lactic acid bacteria play in us and in every other organism out there? I'm not sure. But that's what research is for.
Another challenge is making sure that we don't overdo it. It's pretty hard to overdose on Vitamin C; the LD-50 in humans is unknown, but in rats it's about 12 grams per kilogram, so if the numbers are similar for people, I'd have to choke down nearly two pounds of Vitamin C at one sitting to have a 50% chance of dying from it. Doses on the order of six grams per day over the course of many months can cause diarrhea, headache and other uncomfortable side effects, and people with iron overload disorders (wherein the body is too good at utilising dietary iron) can have their problems exacerbated by too much vitamin C. But there are two pieces of good news here. First, it's much easier to limit the rate of bacterial growth than it is to increase it, and second, there's a lot of wiggle room. 40 milligrams per day is probably adequate, 90 milligrams per day is enough for anyone, and the maximum recommended daily dose is 2,000 milligrams. So if we produce a population density that will provide people with about 40mg/day, it's unlikely that we'll fuck anyone up.
It's gonna take a lot of work. I won't pretend otherwise. We're talking about making major changes to the way humans everywhere interact with an organism that is vital to our existence, and that's a sobering thought. But so is the fact that hundreds of thousands of people suffer from a disease that can be eradicated.
To me, that means we're morally obligated to try. We're also obligated to be damn careful. But we have to try. So we are.
Another project I'm working on, along with engineer Jonathan Cline and a research team at National Yang-Ming University in Taiwan, is a biological method for detecting melamine contamination in food, which we've dubbed the "melaminometer". You might remember how last fall, there was a huge panic about contaminated pet food that was causing cats and dogs to die of kidney failure. This was traced to melamine, a triazine molecule which is 66% nitrogen by mass and can be used to make food products look like they contain more protein than they actually do. Unfortunately, not only is melamine not a dietary protein, it also pairs up with cyanuric acid to form insoluble crystals which accrete in the kidneys and cause irreversible, fatal kidney failure.
Oh, and the stuff has started showing up in milk products, including baby food, in China. The FDA has already banned all imports of Chinese dairy products out of fear for people's safety, and with good reason.
So why a biological detector? Well, as you might have guessed, with simple detection methods, melamine can masquerade as protein, and that's no good. The FDA uses chromatography and mass spectrometry, both of which are time-consuming and require a lot of equipment, plus someone who's trained to use it. A number of labs produce ELISA kits that can detect melamine very accurately and rather quickly (each test only takes about half an hour), but the kits aren't cheap and the cost adds up. We're aiming to produce a bacterium that lights up in the presence of melamine, in order to make available a test that is inexpensive, portable, and accurate.
You can read more about the work we're doing here -- that's right, we're keeping our notes on a wiki. Yeah, open science!