Natural Sciences > Biology > Biological Computing: At the Crossroads of Enginee

Biological Computing: At the Crossroads of Enginee posted by duggu on 12/9/2007

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Abstract/Syllabus

Courseware/Lectures

Test/Tutorials

Course Highlights

This course features a complete bibliography of readings.

Course Description

Syllabus

Summary

Imagine you are a salesman needing to visit 100 cities connected by a set of roads. Can you do it while stopping in each city only once? Even a supercomputer working at 1 trillion operations per second would take longer than the age of the universe to find a solution by considering each possibility in turn. In 1994, Leonard Adleman published a paper in which he described using the tools of molecular biology - including nucleic acids, enzymes, and affinity purification with a biotin-avidin magnetic bead system - to solve a smaller 7-city example of this problem. His paper generated enormous scientific and public interest, and kick-started the field of Biological Computing. Mathematicians, computer scientists, chemists, biologists, and engineers came together to create a new field in which contributions from each are critical for the success of the whole. Currently Biological Computing encompasses many areas of active research. For example, three-dimensional self-assembly of molecules can be used to create stereometrical shapes or to effect computation. Molecule-based string rewrite systems aim to emulate various mathematical models of computation using DNA as rewritable tape. Work in the area of exquisite detection focuses on lowering the number of solution molecules that can be detected, while whole-cell computing focuses on hijacking normal cellular processes for computation. We will discuss how the engineering point of view differs from the scientific perspective, and how each colors one's thinking and approach to research. We will analyze the Adleman paper, as well as papers that came before and after it, and critically examine them with an eye to identifying engineering and scientific aspects of each paper and the interplay between the two. Non-Biology majors welcome. Care will be taken to fill in any knowledge gaps for both scientists and engineers.

Course Format

The course is a weekly seminar based on primary literature. We will discuss two original papers each week. The papers must be read in advance of the class. Our goal will be to critically analyze these papers. To help us achieve that goal, each of you will be expected to send me via email by the morning of the class two discussion questions for the articles covered that day.

In discussing the papers, we will focus on articulating the main point of the paper, identifying whether the paper had a scientific or an engineering goal, and discussing how the various techniques were used or created to achieve that goal. We will further discuss methodology and logic of the papers with a particular focus on whether the techniques used were appropriate for the goals. For small experimental demonstrations of principle, we will also consider potential scalability of the work and its potential applications.

Each class will conclude with a short introduction to the material presented in next week's papers.

Attendance

This is a discussion class, so attendance is mandatory. You are allowed to miss one of the 12 sessions of the class, but please notify me ahead of time that you will not be there. You will also need to arrange to pick up the papers for the next week from me. If you need to miss a second class, you must talk to me ahead of time so we can arrange an appropriate make-up assignment.

Assignments

There are two writing assignments and two oral presentation assignments for this course. Written assignments include writing a sample abstract for a previously published paper and a paper which describes in detail a technique and/or method encountered in the class readings. Oral presentations include giving a short formal introduction to an assigned reading and a final presentation on a student selected published paper at the end of the term.

Grading

The course is pass/fail. Participation in class discussion, completion of the assignments above, and satisfactory attendance will result in a passing grade.

Calendar

Calendar Schedule
Lec #	Topics	key dates
1	Introduction
2	Adleman and his Techniques
3	Self-assembly for Fun and Profit	Abstract-less paper for writing assignment 1 out
4	More Self-assembly - Any Logic to it?
5	Self-assembly - The Way of a Million Wires?	Sample abstract (writing assignment 1) due
6	Nanodevices
7	Quorum Sensing - Keeping an Eye on Your Neighbor
8	The World's Smallest Biological Computational Device	Writing assignment 2 due
9	Engineered and Naturally-occurring Molecular Switches	Edited drafts for writing assignment 2 handed back to students
10	Ciliates - Do They Compute?	Final draft of writing assignment 2 due Students select papers for final oral presenation assignment
11	Molecular Gates and Circuits
12	Student Presentations
13	Bridging the Gap - From Building Networks to Deciphering Networks

Readings

Course readings.
Lec #	Topics	Overviews	Readings
1	Introduction	We will begin by introducing ourselves and talking about what each of us hopes to get out of the class, our backgrounds and sources of interest in the subject of the seminar. We will then examine the structure of a sample scientific paper, and discuss what one looks for in a good paper. We will conclude with a brief background necessary to understand the papers assigned for next time.
2	Adleman and his Techniques	We will look at the original paper that "shook the world" as well as a paper from a distinct area of biology that uses one of the experimental techniques used by Adleman. We will discuss and critique both papers.	Adleman, L. M. "Molecular computation of solutions to combinatorial problems." Science 266, no. 5187 (November 11, 1994): 1021-4. Arguello, R., A. L. Pay, A. McDermott, J. Ross, P. Dunn, H. Avaklan, A. M. Little, J. Goldman, and J. A. Madrigal. "Complementary strand analysis: a new approach for allelic separation in complex polyallelic genetic systems." Nucleic Acids Research 25, no. 11 (1997): 2236-2238.
3	Self-assembly for Fun and Profit	Base-pairing of DNA allows for a built-in duplication mechanism. Antiparallel nature of DNA ensures that strands of DNA can only base-pair in one orientation. Are these two features enough to assure that partially single-stranded DNA molecules with complementary regions will assemble according to "directions" programmed into their sequence? We will look at two papers today-one a proof-of-principle of DNA tile self-assembly, and one (five years later) on investigating physical properties of these tiles. We will discuss whether the proof-of-principle is indeed that, and whether knowing physical properties of the molecules makes any difference in designing the tiles for computation.	Winfree, E., F. Liu, L. A. Wenzler, and N. C. Seeman. "Design and self-assembly of two-dimensional DNA crystals." Nature 394, no. 6693 (August 6, 1998): 539-44. Sa-Ardyen, P., A. V. Vologodskii, and N. C. Seeman. "The flexibility of DNA double crossover molecules." Biophysical Journal 84 (June 2003): 3829-37.
4	More Self-assembly - Any Logic to it?	So now we know that some partially single-stranded DNA molecules can assemble in a predicted configuration. How complicated can that configuration be? Can computing by self-assembly actually take place? Can one build gates? Circuits? Computation histories? Taking a step back, we will also ask how practical such computations may be.	Mao, C., T. H. LaBean, J. H. Relf, and N. C. Seeman. "Logical computation using algorithmic self-assembly of DNA triple-crossover molecules." Nature 407, no. 6803 (September 28, 2000): 493-6.
5	Self-assembly - The Way of a Million Wires?	Continuing our discussion from the previous week, we ask whether the limitations of the self-assembly approach we discussed make the technology more immediately useful in the area of nanofabrication.	Liu, D., S. H. Park, J. H. Reif, and T. H. LaBean. "DNA nanotubes self-assembled from triple-crossover tiles as templates for conductive nanowires." Proc Natl Acad Sci U.S.A. 3, no. 101 (January 6, 2004): 717-722.
6	Nanodevices	One class of nanodevices consists of molecular level machines that operate on and with the help of DNA strands, and are, in fact, constructed of DNA. We will consider two examples of such devices, examine their construction and kinetic properties, as well as potential uses for such devices.	Yurke, B., A. J. Turberfield, A. P. Mills, F. C. Simmel, and J. L. Neumann. "A DNA-fueled molecular machine made of DNA." Nature 406 (August 10, 2000): 605-8. Simmel, F. C., B. Yurke, and R. J. Sanyal. "Operation kinetics of a DNA-based molecular switch." J Nanosci Nanotechnol 2, no. 3-4 (July 2002): 383-90.
7	Quorum Sensing - Keeping an Eye on Your Neighbor	Some bacteria, such as Vibrio fischeri, exhibit quorum sensing behavior, whereby "sensing" a certain concentration of self-secreted autoinducer in the culture is the signal to activate transcription and translation of certain genes. This mechanism is maintained through constitutive production of low levels of quorum-sensing signals that allows bacteria to sense the ambient cell density and to induce the expression of specific genes when signal level rises above threshold. We will analyze the classic paper that describes isolating and determining the roles of various genes in one of the operons responsible for bioluminescence. We will also look at how the various parts of the system can be used as components to engineer a bacterial communication system.	Weiss, Ron, and Thomas F. Knight. "Engineered Communications for Microbial Robotics." In DNA 2000, Lecture Notes in Computer Science. (DNA Computing: 6th International Workshop on DNA-Based Computers, Leiden, The Netherlands, June 13-17, 2000.) Edited by A. Condon. Vol. 2054. Berlin, Germany: Springer-Verlag GmbH, 2001, pp. 1-16. ISSN: 03029743. Engebrecht, J., K. Nealson, and M. Silverman. "Bacterial bioluminescence: isolation and genetic analysis of functions from Vibrio fischeri." Cell 32, no. 3 (March 1983): 773-81.
8	The World's Smallest Biological Computational Device	Guiness book of world records says that the device described in the first paper for today is the world's smallest biological computational device. Do you agree? What is it useful for? What kind of problems can it solve? How fast? We will also try to figure out just how novel the idea of this machine is.	Benenson, Y., R. Adar, T. Paz-Elizur, Z. Livneh, and E. Shapiro. "DNA molecule provides a computing machine with both data and fuel." Proc Natl Acad Sci U.S.A. 100, no. 5 (March 4, 2003): 2191-6. Szybalski, W. "Universal restriction endonucleases: designing novel cleavage specificities by combining adapter oligodeoxynucleotide and enzyme moieties." Gene 40, no. 2-3 (1985): 169-73.
9	Engineered and Naturally-occurring Molecular Switches	In a rare example of basic science following the engineering, scientists in the Breaker lab at Yale engineered molecular switches first, and found them in nature second. What are the features that the natural and man-made (evolved) switches share? What is different? How abundant do you think these naturally-occuring switches are?	Mandal, Maumita, Benjamin Boese, Jeffrey E. Barrick, Wade C. Winkler, and Ronald R. Breaker. "Riboswitches Control Fundamental Biochemical Pathways in Bacillus subtilis and Other Bacteria." Cell 113 (2003): 577-586. Tang, J., and R. R. Breaker. "Rational Design of allosteric ribozymes." Chemistry and Biology 4 (June 1997): 453-9.
10	Ciliates - Do They Compute?	Ciliates are protozoa with two nuclei-micronucleus that stores chromosomal DNA, and macronucleus in which the genes are spliced and rearranged into a large number of gene-size chromosomes. The process by which macronucleus is created from a micronucleus is a complicated multi-stepped process. Many researchers argue that this process has considerable computational power. The exact molecular mechanism has not been worked out, but many conjectures have been made. We will consider one such scrambled gene across a number of species and will consider the implications for one of the popular computational models of gene unscrambling mechanism.	Landweber, L. F., T. C. Kuo, and E. A. Curtis. "Evolution and assembly of an extremely scrambled gene." Proc Natl Acad Sci U.S.A. 97, no. 7 (March 28, 2000): 3298-303. Prescott, D. M., A. Ehrenfeucht, and G. Rozenberg. "Template-guided recombination for IES elimination and unscrambling of genes in stichotrichous ciliates." J Theor Biol 3, no. 222 (June 7, 2003): 323-30.
11	Molecular Gates and Circuits	Computer scientists who begin to learn biology often think of gene regulatory networks in terms of gates and circuits. Two papers assigned for today deal with constructing and evolving molecular circuits. In what ways are these circuits like the electronic ones? In what ways are they different? Is it still fair to call these "circuits?" What are the potential uses of this technology?	Yokobayashi, Y., R. Weiss, and F. H. Arnold. "Directed evolution of a genetic circuit." Proc Natl Acad Sci U.S.A. 99, no. 26 (December 24, 2002): 16587-91. Noireaux, V., R. Bar-Ziv, and A. Libchaber. "Principles of cell-free genetic circuit assembly." Proc Natl Acad Sci U.S.A. 100, no. 22 (October 28, 2003): 12672-7.
12	Student Presentations
13	Bridging the Gap - From Building Networks to Deciphering Networks	A group of researchers at Boston University has recently gone from engineering genetic network components to analyzing networks occurring in nature to elucidate how they operate. We will look at two of their papers to see how these two approaches complement each other and how advances in one help advance the other.	Gardner, T. S., C. R. Cantor, and J. J. Collins. "Construction of a genetic toggle switch in Escherichia coli." Nature 403, no. 6767 (January 20, 2000): 339-42. Gardner, T. S., D. di Bernardo, D. Lorenz, and J. J. Collins. "Inferring genetic networks and identifying compound mode of action via expression profiling." Science 301, no. 5629 (July 4, 2003): 102-5.

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