Affiliated Faculty: Arnold, Asthagiri, Doyle, Elowitz, Meyerowitz, Murray, Pierce, Smolke, Sternberg, Winfree

The SSB group in Bioengineering at Caltech is developing advanced techniques for the analysis, design, and synthesis of behavior within biological and biomolecular systems, with applications in biology, biomedicine, and biotechnology.  Research within the group focuses on biological systems ranging in scale from single molecules to whole organisms.   Design and analysis of circuit-level and systems-level behavior, from molecular switches and devices to information processing networks, is emphasized using techniques from a broad range of engineering disciplines such as control theory, chemical engineering, computer science, physics, and applied mathematics.

The following research projects illustrate current research activities:

Gene Regulatory Circuits for Differentiation
A fundamental problem for biology and bioengineering is to understand the molecular mechanisms underlying cellular differentiation programs and to develop the ability to alter or re-engineer these behaviors.  Certain types of cellular differentiation are probabilistic and transient.  In such systems individual cells can switch from an original state to an alternative state and back again.  In Bacillus subtilis, competence is such a transiently differentiated state associated with the capability for DNA uptake from the environment.  Individual genes and proteins underlying differentiation into the competent state have been identified, but it has been unclear how these genes interact dynamically in individual cells to control both spontaneous entry into competence and return to vegetative growth.   Here we show that this behavior can be understood in terms of excitability in the underlying genetic circuit.  Using quantitative fluorescence time-lapse microscopy, we directly observed the activities of multiple circuit components simultaneously in individual cells, and analyzed the resulting data in terms of a mathematical model.  We find that an excitable core module containing positive and negative feedback loops can explain both entry into, and exit from, the competent state.  We further test this model by analyzing initiation in sister cells, and by re-engineering the gene circuit to specifically block exit.  Excitable dynamics driven by noise naturally generate stochastic and transient responses, thereby providing an ideal mechanism for competence regulation. This image shows a small micro-colony of B. subtilis cells.  Some of these cells are dividing vegetatively (green fluorescent rods), while others are sporulating (white).  The red cells have spontaneously differentiated into the competent state.  Movies like these allow us to quantitatively analyze differentiation dynamics at the single-cell level.

Analysis of Developmental Patterning
The most remarkable example of multicellular structure formation is the development of an organism from a fertilized egg. Many of the molecular networks guiding the development of simple organisms, such as the worm C. elegans, also operate in human cells. Thus, these model organisms offer a powerful system to parse molecular signals involved in multicellular patterning. We have focused on an intriguing stage in C. elegans development where cell patterning depends not only on a spatial gradient in a soluble factor (a morphogen), but also on direct cell-cell interactions. In fact, these two extracellular signals are coupled by an intracellular signaling network of biochemical reactions. We have developed a mathematical model to analyze how this coupling benefits multicellular patterning. Our analysis reveals that coupling enhances cell preception of the extracellular gradient, so that a gradient in the soluble factor outside the cells produces an even steeper gradient in intracellular signals. Such gradient amplification may play a crucial role in patterning over moderate length scales, where a substantial morphogen gradient may not be established. These model predictions are being validated using a quantitative imaging platform with animals where coupling is preserved (wild-type) or ablated by molecular genetics and RNAi.

Engineering Molecular Biosensors
We are exploring the design strategies for constructing molecular switches that act in vivo as both biosensors and ligand-controlled regulators of gene expression in bacteria, yeast, and mammalian cell culture. Much of our effort is focused on the design of nucleic acid-based molecular sensors, although the design of some protein-based sensors is being explored as well. In the area of trans-acting molecular switches, we are exploring the design of sensors that act through diverse gene regulation mechanisms such as the RNA interference (RNAi) pathway, ribozyme-based cleavage, and the antisense pathway. In the area of cis-acting molecular switches, we are exploring the design of sensors that act through regulatory mechanisms such as alternative splicing, RNase III cleavage, ribozyme-based cleavage, and internal ribosome entry site (IRES) activity.

Curriculum

Students in the SSB program are expected to demonstrate proficiency in the study of biological systems at the molecular and cellular levels, and in the mathematics and engineering tools used to study and design such systems.  First-year coursework in the program is intended to build upon undergraduate training and to complement concurrent research activities. The following table lists the coursework requirements of the SSB academic program.

SSB Requirements (Year 1)

Boot Camp:
Prior to first term

Math track (3 terms):
ACM 95/100 abc

Biology track (3 terms):
Bi/Ch 110, Bi/Ch 111, Bi/Ch 113

SSB core track (3 terms):
APh/BE 161, ChE/BE 163, ChE/BE 169

Research track:
Research rotations in three labs BE250

An incoming student who demonstrates prior proficiency in any required course can obtain permission to opt out of that course. However, the student must maintain a course load of 36 units each term, and the student will be responsible for the course material during the qualifying exam. Students are expected to pursue research rotations in several labs during the first year to gain exposure to a number of different research areas before choosing an advisor and settling on a research project. 

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