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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 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!

Comments

( 33 comments — Leave a comment )
grepmaster
Dec. 26th, 2008 02:29 am (UTC)
IIRC, a human consists of 2/3 water, 10^14 human cells, and 10^15 non-human cells. And 10^11 of the human cells are brain neurons.
hkneale
Dec. 26th, 2008 02:30 am (UTC)
Have I ever told you how fond I am of DNA and the wonderous things one can do with it?

This sort of thing really fascinates me. Thanks for sharing the wiki link.
attutle
Dec. 26th, 2008 03:53 am (UTC)
typo: s/developing/detecting/
"... is a biological method for developing melamine contamination in food ..."

s/developing/detecting/
maradydd
Dec. 26th, 2008 03:45 pm (UTC)
Re: typo: s/developing/detecting/
Fixed, thanks. That's what I get for writing this stuff up while jetlagged!
mutiny
Dec. 26th, 2008 04:47 am (UTC)
I got hit with God knows what from that salad spinner when I was watching that presentation from the front row, too.

Best presentation that year, I think.
paisleychick
Dec. 26th, 2008 12:31 pm (UTC)
and to think that I was dubious about lending out my salad spinner! Glad I did.
(no subject) - mutiny - Dec. 26th, 2008 02:36 pm (UTC) - Expand
(no subject) - maradydd - Dec. 26th, 2008 03:53 pm (UTC) - Expand
(no subject) - mutiny - Dec. 27th, 2008 01:10 am (UTC) - Expand
mycroftxxx
Dec. 26th, 2008 08:27 am (UTC)
Oh thank god. Citri-lactobacillis was a _hard_ secret to keep. I've been wanting to crow from the rooftops how cool a project this since the night it was thought up.

I also really like the re-purposing of Glogurt into a self-starting melamine detector. You continue to make me sinfully proud to know you, sweetie.
ext_97806
Dec. 26th, 2008 03:54 pm (UTC)
The news release happened a bit earlier than we were planning; seems the self-organizing biohacking community that I have been waiting for for the last five years has already started attracting enough attention that reporters have come sniffing around, so we figured keeping glowgurt under wraps any longer would be silly. So yes, feel free to talk about that.

(And maradydd just spilled about our hypothetical self-sustaining cure for scurvy, so you can now tell people what really goes on on your back porch. :) We've still got a long way to go before even being ready for animal experimentation with that one, but even if we just get other people thinking along those lines, that will be awesome. The goal is to help diminish human suffering; if someone beats us to making working scurvygurt, I won't be crushed.)
3_2_1_letsdance
Dec. 26th, 2008 11:58 am (UTC)
That's incredible, and I'm frankly in awe that there are people in this world intelligent enough to actually do it.

Much smarter than me: this borders on magic in my world :D
aj_dot_com
Dec. 26th, 2008 12:50 pm (UTC)
I would give my eye teeth to hang out on your porch when you are thinking this stuff up.
Best of luck.

go go science!
vatine
Dec. 26th, 2008 12:52 pm (UTC)
I suspect you mean that you keep your notes here rather than subwossnamed on your LJ. Otherwise, interesting.
maradydd
Dec. 26th, 2008 03:45 pm (UTC)
Thanks -- yet another jetlag fail on my part.
ndgmtlcd
Dec. 26th, 2008 02:28 pm (UTC)
How many Gs do you get out of that salad spinner? How long do you have to spin?
maradydd
Dec. 26th, 2008 03:49 pm (UTC)
For the "purifying DNA with common household items" trick, a minute was more than enough, though I'm not sure how many Gs that was. For centrifuging bacteria, I use a microcentrifuge that I got secondhand off ebay for $30; you really want something that can do about 5000 RPM.
allonymist
Dec. 26th, 2008 04:00 pm (UTC)
I'm glad to see you've gone public with the Cghurt project; it's been really frustrating not being able to tell people about a project this awesome and cool.
bunnykitteh
Dec. 27th, 2008 09:56 am (UTC)
LOL I am so glad I found you... and enjoyed the pic of you in that article, even if they made you fuzzy :(

I like science quite a bit. I'm not a big fan of GMO food at all though. And I don't understand how the moral obligation isn't simply to distribute wealth and resources and access to resources fairly enough to ensure people don't die of such diseases.

I think we have a moral obligation to keep non-GMO foods safe for the people who want to eat them. I *never* want any GMO food in my body and don't think anyone else has the right to make that impossible for me. Too late, I know.

Anyway, hope I don't get dismissed as a crazed luddite. I don't think I am. :-)
ext_97806
Dec. 27th, 2008 10:10 am (UTC)
And I don't understand how the moral obligation isn't simply to distribute wealth and resources and access to resources fairly enough to ensure people don't die of such diseases.


One major reason is "lack of an efficient transportation infrastructure". Getting yogurt cultures to local villagers who can pass them amongst each other in a self-sustaining, self-sufficient fashion is a far more reasonable approach than expecting that vitamin C supplements will be, and continue to be, available for distribution to remote communities not easily accessible due to bad roads political turmoil, etc. This is not an argument against distributing essential vitamins and health care to those who need it, but more a practical recognition of the fact that we're talking about a part of the world where leadership roles change on a monthly basis, internal politics are complex and often bloody, and making regular shipments of large amounts of pills or food items may be impractical or infeasible. We're hoping to lower the barrier of delivery for these nutrients in the face of external forces that are not easy to change. If you can find a way to get vitamin C to all the people who are currently suffering from or dying from scurvy, that would be awesome -- but we'd still go ahead with this project, under the assumption that whatever supply and distribution techniques that existed tomorrow might not exist the week after that.

As for never wanting GMO food in your body, I'm in general agreement that people should have choices as to what they consume in their food, but on the GMO issue, if you eat things like cows or wheat or corn, you're eating food that would never have existed if it weren't for a rudimentary form of genetic modification. There's a lot of general misunderstanding of what GMO foods are, and what genetic manipulation of food involves, and that's part of what we're trying to help fix.

Bigger problems with food in America at least, in my opinion, have to do with the amount of high-fructose corn syrup (a chemical produced by a not-entirely-simple process that arguably has a detrimental effect on humans who consume it) and the level of hormones found in various meat products. I.e., the stuff Americans do to their food between harvesting it and selling it is on the whole far scarier and more concerning than food that is improved due to genetic modification.
(no subject) - bunnykitteh - Dec. 27th, 2008 11:11 am (UTC) - Expand
(no subject) - maradydd - Jan. 27th, 2009 06:49 am (UTC) - Expand
(no subject) - bunnykitteh - Jan. 27th, 2009 08:45 am (UTC) - Expand
(no subject) - maradydd - Jan. 27th, 2009 09:15 am (UTC) - Expand
(no subject) - maradydd - Jan. 27th, 2009 09:49 am (UTC) - Expand
(no subject) - maradydd - Jan. 27th, 2009 09:56 am (UTC) - Expand
(no subject) - bunnykitteh - Jan. 27th, 2009 10:30 am (UTC) - Expand
jozafiend
Dec. 27th, 2008 04:58 pm (UTC)
Very cool, congrats on getting this off the ground!
radven
Dec. 28th, 2008 10:12 am (UTC)
BTW - you rock.

I was thrilled to see your picture show up in the AP News app on my iPhone. Coolness!
cthulu_for_pm
Dec. 31st, 2008 01:58 am (UTC)
People like you are sixteen kinds of awesome.

Keep up the good work!
davidsarah
Jan. 14th, 2009 05:51 am (UTC)
That's an amazing idea. As others have correctly pointed out, you rock.

Any other vitamins besides C and B12 that could be produced in the same way?
maradydd
Jan. 27th, 2009 07:02 am (UTC)
In theory, any small molecule can be produced through the action of enzymes. The hard part is figuring out which enzymes; some, such as melamine deaminase, are specifically targeted to just one molecule. (As one example, melamine deaminase will not deaminate atrazine, which is chemically quite similar to melamine [they're both aminated triazides], and the enzyme which breaks down atrazine won't touch melamine.) Custom protein design will be the real biology revolution, and there's a lot of work in biology, chemistry, and CS that will need to be done in order to make these kinds of predictions.

But as far as vitamins go -- any vitamin we eat is already produced by some living organism, so it's a matter of finding the appropriate pathway and transfecting it into a symbiotic organism. This is likely to be challenging for vitamins which are the result of a lengthy metabolic pathway, because the more novel proteins you want your synthetic organism to produce, the less fit the organism becomes overall. I'm not sure why E. coli produce B12; that symbiotic relationship is one of those great happy accidents which has us where we are today.

What we're hoping to exploit with C is slightly different: the fact that humans already have every step of the ascorbate synthesis pathway except the last one. We're hoping that if we can create L-gulonolactone-oxidase-producing bacteria that are symbiotic with C-deficient animals, the animals will be able to utilise the L-gulonolactone to produce their own ascorbic acid. I do not know if this will actually work, but it just seems morally wrong not to find out.

As for whether there are other essential micronutrients for which humans are simply missing a step in the pathway -- I don't know, as I haven't researched that far. We were initially looking into putting the entire ascorbate synthesis pathway into bacteria, then I started reading about L-gulonolactone oxidase and went "WAIT YOU'RE FUCKING KIDDING ME." Again, happy accident.
(no subject) - aliothsan - Jul. 30th, 2009 06:41 pm (UTC) - Expand
( 33 comments — Leave a comment )

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