User:Reshma P. Shetty

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Ph.D. Candidate in Biological Engineering at MIT. I am advised by Tom Knight and Drew Endy.

B.S. in Computer Science from the University of Utah, 2002

Thesis project

My goal is to engineer transcription-based combinational digital logic in Escherichia coli cells.

Synthetic Biology seeks to intentionally design, fabricate and operate biological systems. There are three primary areas in which synthetic biological systems are of immediate utility: chemical energy, materials and information. To harness these systems to either generate new energy sources or synthesize new materials, it is necessary to develop the necessary infrastructure such that cells can be engineered to sense information, process that information using some form of logic and effect a response. Ideally, the parts and devices used to carry out information processing in vivo would have the following characteristics:

  1. Well-characterized: Device behavior should be quantitatively measured under standard operating conditions.
  2. Composable: Devices should be designed such that the output of one device can drive the input of another device. In other words, devices should be well-matched.
  3. Engineerable: It is difficult to imagine every context in which a device might be used. Therefore it is helpful if devices can be tuned such that they work well in larger systems.
  4. Numerous: Currently the size of the systems we can construct is severely limited by the lack of well-characterized devices. Therefore, it will be important to develop libraries of devices such that more complicated systems can be assembled.

My thesis work seeks to address these goals by developing a new type of transcription-based logic that uses modular, synthetic transcription factors. I derive the DNA binding domains of these transcription factors from zinc finger domains so that arbitrary DNA recognition sites may be used. I use leucine zippers as the dimerization domain so that these repressors are also capable of heterodimerizing increasing both the number and functionality of available dimerization domains. This implementation change adds modularity to the repressors so that domains are interchangeable and may be fine-tuned independently. Also, since there are large sets of both of these domains kinds available, this design enhances the scalability of transcription-based logic. Another key benefit of my proposed transcription-based logic is that by changing the fundamental event that occurs in the device from a single protein dimerizing on the DNA and repressing transcription to two proteins heterodimerizing on the DNA and repressing transcription, faster and more compact logic may be developed.

Open questions

Some of the questions that I am interested in addressing as a part of my thesis work include the following.

  1. How do you evaluate device performance? When is the performance of a device good enough? What does good enough mean?
  2. How do you engineer a device to deliver good performance?
  3. How should device behavior be characterized and quantified? How little work can we get away with and call a device characterized?

and more.

But life isn't digital!

The most common question I receive when talking about my work with others is "Biology isn't digital, so why concentrate on digital logic"? There's an answer on the Synthetic Biology FAQ but I'll give my own two cents here. In my mind, there are two valid responses to this question.

Maybe not, but we are better at thinking digitally.

This is the answer I usually give. After thinking about this question a fair amount and talking with others in the MIT Synthetic Biology Working Group (especially Tom Knight), I came to the conclusion that the first "digital" devices in electrical engineering probably weren't very digital either. In fact, even today's devices aren't 100% digital. Calling a device "digital" is really an abstraction we place upon a physical object that behaves according to certain specifications. By carefully determining those behavior requirements and carefully engineering the device, the digital abstraction holds up sufficiently well for the device to work as desired. A lot of work has already been done in electrical engineering in terms of engineering digital circuits from analog electrical components. We should be able to leverage this expertise to design digital devices from analog, biological components.

Sure it is.

Information in biology is encoded by DNA which consists of strings of 4 kinds of nucleotides. Therefore life is fundamentally digital. I first heard this argument in a talk given by Leroy Hood at MIT in 2003 but I am sure that others use it as well. If biology at its core is digital, then it is no longer so unreasonable to design digital devices from biological parts.

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