Inverse Metabolic Engineering of Synechocystis PCC 6803 for Improved Growth Rate and Poly-3-hydroxybutyrate Production

Synechocystis PCC 6803 is a photosynthetic bacterium that has the potential to make bioproducts from carbon dioxide and light. Biochemical production from photosynthetic organisms is attractive because it replaces the typical bioprocessing steps of crop growth, milling, and fermentation, with a one-step photosynthetic process. However, low yields and slow growth rates limit the economic potential of such endeavors. Rational metabolic engineering methods are hindered by limited cellular knowledge and inadequate models of Synechocystis. Instead, inverse metabolic engineering, a scheme based on combinatorial gene searches which does not require detailed cellular models, but can exploit sequence data and existing molecular biological techniques, was used to find genes that (1) improve the production of the biopolymer poly-3-hydroxybutyrate (PHB) and (2) increase the growth rate. A fluorescence activated cell sorting assay was developed to screen for high PHB producing clones. Separately, serial sub-culturing was used to select clones that improve growth rate. Novel gene knock-outs were identified that increase PHB production and others that increase the specific growth rate. These improvements make this system more attractive for industrial use and demonstrate the power of inverse metabolic engineering to identify novel phenotype-associated genes in poorly understood systems.

Explorations of the Practical Issues of Learning Prediction-Control Tasks Using Temporal Difference Learning Methods

There has been recent interest in using temporal difference learning methods to attack problems of prediction and control. While these algorithms have been brought to bear on many problems, they remain poorly understood. It is the purpose of this thesis to further explore these algorithms, presenting a framework for viewing them and raising a number of practical issues and exploring those issues in the context of several case studies. This includes applying the TD(lambda) algorithm to: 1) learning to play tic-tac-toe from the outcome of self-play and of play against a perfectly-playing opponent and 2) learning simple one-dimensional segmentation tasks.

Learning from Ambiguity

There are many learning problems for which the examples given by the teacher are ambiguously labeled. In this thesis, we will examine one framework of learning from ambiguous examples known as Multiple-Instance learning. Each example is a bag, consisting of any number of instances. A bag is labeled negative if all instances in it are negative. A bag is labeled positive if at least one instance in it is positive. Because the instances themselves are not labeled, each positive bag is an ambiguous example. We would like to learn a concept which will correctly classify unseen bags. We have developed a measure called Diverse Density and algorithms for learning from multiple-instance examples. We have applied these techniques to problems in drug design, stock prediction, and image database retrieval. These serve as examples of how to translate the ambiguity in the application domain into bags, as well as successful examples of applying Diverse Density techniques.

Reinforcement Learning by Policy Search

One objective of artificial intelligence is to model the behavior of an intelligent agent interacting with its environment. The environment's transformations can be modeled as a Markov chain, whose state is partially observable to the agent and affected by its actions; such processes are known as partially observable Markov decision processes (POMDPs). While the environment's dynamics are assumed to obey certain rules, the agent does not know them and must learn. In this dissertation we focus on the agent's adaptation as captured by the reinforcement learning framework. This means learning a policy---a mapping of observations into actions---based on feedback from the environment. The learning can be viewed as browsing a set of policies while evaluating them by trial through interaction with the environment. The set of policies is constrained by the architecture of the agent's controller. POMDPs require a controller to have a memory. We investigate controllers with memory, including controllers with external memory, finite state controllers and distributed controllers for multi-agent systems. For these various controllers we work out the details of the algorithms which learn by ascending the gradient of expected cumulative reinforcement. Building on statistical learning theory and experiment design theory, a policy evaluation algorithm is developed for the case of experience re-use. We address the question of sufficient experience for uniform convergence of policy evaluation and obtain sample complexity bounds for various estimators. Finally, we demonstrate the performance of the proposed algorithms on several domains, the most complex of which is simulated adaptive packet routing in a telecommunication network.

Learning Commonsense Categorical Knowledge in a Thread Memory System

If we are to understand how we can build machines capable of broad purpose learning and reasoning, we must first aim to build systems that can represent, acquire, and reason about the kinds of commonsense knowledge that we humans have about the world. This endeavor suggests steps such as identifying the kinds of knowledge people commonly have about the world, constructing suitable knowledge representations, and exploring the mechanisms that people use to make judgments about the everyday world. In this work, I contribute to these goals by proposing an architecture for a system that can learn commonsense knowledge about the properties and behavior of objects in the world. The architecture described here augments previous machine learning systems in four ways: (1) it relies on a seven dimensional notion of context, built from information recently given to the system, to learn and reason about objects' properties; (2) it has multiple methods that it can use to reason about objects, so that when one method fails, it can fall back on others; (3) it illustrates the usefulness of reasoning about objects by thinking about their similarity to other, better known objects, and by inferring properties of objects from the categories that they belong to; and (4) it represents an attempt to build an autonomous learner and reasoner, that sets its own goals for learning about the world and deduces new facts by reflecting on its acquired knowledge. This thesis describes this architecture, as well as a first implementation, that can learn from sentences such as ``A blue bird flew to the tree'' and ``The small bird flew to the cage'' that birds can fly. One of the main contributions of this work lies in suggesting a further set of salient ideas about how we can build broader purpose commonsense artificial learners and reasoners.

Fast Learning by Bounding Likelihoods in Sigmoid Type Belief Networks

Sigmoid type belief networks, a class of probabilistic neural networks, provide a natural framework for compactly representing probabilistic information in a variety of unsupervised and supervised learning problems. Often the parameters used in these networks need to be learned from examples. Unfortunately, estimating the parameters via exact probabilistic calculations (i.e, the EM-algorithm) is intractable even for networks with fairly small numbers of hidden units. We propose to avoid the infeasibility of the E step by bounding likelihoods instead of computing them exactly. We introduce extended and complementary representations for these networks and show that the estimation of the network parameters can be made fast (reduced to quadratic optimization) by performing the estimation in either of the alternative domains. The complementary networks can be used for continuous density estimation as well.

Active Learning with Statistical Models

For many types of learners one can compute the statistically 'optimal' way to select data. We review how these techniques have been used with feedforward neural networks. We then show how the same principles may be used to select data for two alternative, statistically-based learning architectures: mixtures of Gaussians and locally weighted regression. While the techniques for neural networks are expensive and approximate, the techniques for mixtures of Gaussians and locally weighted regression are both efficient and accurate.

People Recognition in Image Sequences by Supervised Learning

We describe a system that learns from examples to recognize people in images taken indoors. Images of people are represented by color-based and shape-based features. Recognition is carried out through combinations of Support Vector Machine classifiers (SVMs). Different types of multiclass strategies based on SVMs are explored and compared to k-Nearest Neighbors classifiers (kNNs). The system works in real time and shows high performance rates for people recognition throughout one day.