IGEM:Harvard/2007/Brainstorming/miscpre59

Some great ideas here. I wanted to follow-up on some discussions of gut flora. I recently learned that E.coli is actually not one of the dominant inhabitants of the gut --- just one of the most easily cultured (see http://en.wikipedia.org/wiki/Gut_flora and references therein). I'm not usually a big wikipedia citer, but in this case is does an excellent job of summarizing and referencing specific citations.

Re a suicide program. A number of groups have developed methods for this. Check out work by Arnold and colleagues on "population control". Death genes abound, so putting them under the control of some external "switch" could be one possible course of action. See: You L, Cox RS 3rd, Weiss R, Arnold FH. Programmed population control by cell-cell communication and regulated killing. Nature. 2004 Apr 22;428(6985):868-71.

Great work, Jagesh

Also regarding gut flora: our friendly laboratory E. coli is apparently at a great competitive disadvantage vis-a-vis wildtype E. coli (wildtype E. coli secrete biofilms that protect themselves from our immune system). So, anything we do along the lines of vitamin biosynthesis is only a proof of concept. Alexander

After thinking about the legal and practical implications of using bacteria for jobs such as detoxification, biosynthesis of drugs, and detection of toxins, I realized that it might be useful to have some sort of "off" switch - a way to quickly and efficiently kill the engineered bacteria without using antibiotics or anti-septics. It might not be useful in the strict sense since engineered bacteria are likely to be maladapted for natural environments, but it might put people at ease.

There are any number of methods of doing this, but the easiest is probably adapting a bacteriophage that integrates its genome into the E. coli genome - perhaps the lamba phage. From there, we would need to play with the promoters so that we are able to switch the virus to the lytic part of its life cycle at will. We could either switch out the wildtype promoters and install an entirely new promoter, or we could tamper with the lambda promoters. More on this later

Alexander

I hope you'll consider presenting more on this on Monday. Even if not, the thought is intriguing. I understand the hesitation to use antibiotics (presumably, resistance?), but my presentation on adaptamers tomorrow might have lightly-related ideas - since the potential uses of adaptamers are quite broad, we could potentially target drugs or bacteria-killing substrates to the cells. As you said, the legal and practical implications would probably cause me to discard the idea, but at least it's tangentially related.

Stephanie

I wanted to put forth an idea -- vitamin production & microbial therapy. The idea comes from the fact that vit B producing microbes inhabit the ruminant gut so these animals almost never have B-deficiency. But for humans, without a proper diet, we end up getting diseases like Beriberi.

the other thing is the bioavailability of these vitamins whether we ingest them as food or as pills -- 'microbial therapy' could solve this by coupling these production loops in our engineered bacteria One way to put an end to this could be synthesizing bacteria that can inhabit the human stomach and produce vitamins of all kinds. ...that's the idea

Response (Stephanie): I really like this idea. I wonder what potential limitations there are, etc. Did you find any interesting readings on this?

Response (Alex): The great convenience of this is that E. Coli is not only a well-understood model organism, but also one of the most abundant gut flora. If we can actually introduce genes for vitamin synthesis, this is actually feasible. The only problem is that the genes which would do our vitamin synthesis would leach energy from the bacteria and make them less competitive than the native E. coli. Hence the native bacteria would eventually crowd out the modified ones.h