BioEngineering

Molecular Bioengineering

Contents

 

Faculty

Core Faculty

James Bryers, PhD
Albert Folch, PhD
Xiaohu Gao, PhD
Ceci Giachelli, PhD
Samantha Harris, PhD
Allan Hoffman, ScD
Tom Horbett, PhD
Don Martyn, PhD
Gerald Pollack, PhD
Suzie Pun, PhD
Buddy Ratner, PhD
Mike Regnier, PhD
Marta Scatena, PhD
Pat Stayton, PhD
Pedro Verdugo, MD
Paul Yager, PhD


Other Faculty: Nelson Fausto and Chuck Murry (pathology), Paul Bornstein and Steve Hauschka (biochemistry), Ollie Press (medicine), Scott Wilbur (radiation oncology), Danny Shen (pharmacy), John Slattery, Jash Unadkat, and Ken Thumel (pharmaceutics).

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Description

The phenomenal rate of progress in the fields of molecular and cellular biology is rapidly creating new opportunities for molecular bioengineering to advance medicine and biology. Fundamental advances in our understanding of how biomolecules control healthy physiology, how cells communicate, how molecular machines are coupled to force and signal transduction, how the body protects itself against the initiation of cancer, etc. are opening many new avenues for developing medical technologies. The expansion of the Molecular Bioengineering Program to include Nanotechnology arises from the natural synergy between molecular bioengineering research and the new infusion of nanotechnology research, with several Bioengineering faculty research programs already straddling both areas. The Molecular and Nanotechnology Thrust brings some of the broader nanoengineering advances found in chemistry, physics, and biology into the bioengineering field for the advancement of medicine. This Thrust also contains strong programs in muscle contraction and engineering of biopolymer gels that complement those of the molecular bioengineering faculty.

Areas of Research in Molecular Bioengineering & Nanotechnology

The Molecular and Nanotechnology Thrust Area encompasses a broad variety of research areas. Some are directed toward more fundamental research that is tied to identifying and better understanding the barriers to medical advancement, while others are directed toward translational research and development of better medical technologies such as drug delivery and diagnostics. A unifying theme is bioinspiration and biomimicry, where nature's mechanisms for molecular interactions and medicine are both studied and tied to technology development.

Smart Delivery (Hoffman, Pun, Ratner, Stayton). The next generation of delivery systems must be quite "smart," in the sense that they must often be able to target specific cells, transverse biological transport barriers, and control release levels in response to physiological or external signals. A principal property of biological molecules and systems is their ability to change properties in response to stimuli. For example, the high gene transfection efficiency of viruses arises from their unique fusogenic proteins that sense the lowered pH of endosomes and respond by becoming membrane active to enhance transport of DNA across the membrane barrier. It is this ability to sense and respond that provides control over a wide variety of cellular processes, and this type of molecular intelligence also represents an important design goal for many drug delivery strategies. Stayton and Hoffman are developing nanoengineered polymeric materials that are bioinspired by viral/toxin strategies, and which have built-in stimuli-responsiveness to control and enhance intracellular trafficking of biomolecules such as proteins, peptides, RNA, and DNA and their targeting to specific compartments. Another example is from Ratner and Crum, where molecular self-assembly strategies are being developed to create molecularly engineered coatings that sense ultrasound signals and release controlled doses of drugs from underlying implants. The Pun group focuses on advancing macromolecule drug delivery technology by developing materials that use biomimetic approaches to overcome transport limitations in tissues and within cells.

Molecular Biomechanics of Adhesion (Bryers, Pollack, Thomas). Physical and mechanical forces regulate many of the processes of physiology and disease. Biofilms are dense microcolonies of microbial cells entrapped within a polysaccharide matrix attached to a surface. The Bryers group’s systems approach to biofilm research comprises such topics as: receptor:ligand specific adhesion, genomics/proteomics of biofilm formation, three-dimensional mass transport phenomena in thick biofilms, and gene therapy approaches to anti-sense RNA control of biofilm polysaccharide secretion -- all within a quantitative engineering framework. The Thomas group seeks to understand how mechanical force regulates individual molecules at the molecular level. In particular, the Thomas group studies a bacterial adhesion protein that only binds strongly if it is pulled apart from its target and the von Willebrand Factor protein that binds platelets together to help our blood clot at high flow to stop a bleeding injury. A combination of computation and experiments are applied to understand how these proteins work. The Pollack group is pursuing the issue of adhesion from the point of view of water structure. His group has recently found that hydrophilic surfaces acquire hydration layers much larger than generally anticipated — up to hundreds of micrometers. These hydration layers exclude solutes, and may therefore have unexpectedly profound influence on surface adherence.

Molecular Motion (Pollack, Regnier). The Pollack group studies the molecular mechanism of biological motion. Their most recent work uses specially fabricated nano-levers to measure molecular scale forces and nanoscale displacements. This unique, high-resolution technology is being applied to track the translation of single isolated actin filaments over single isolated myosin filaments. The results are showing quantal step-like translations. Translation steps are integer multiples of the actin monomer spacing along the filament — a finding with important implications for the mechanism of biological motion. The Regnier group studies conversion of chemical energy into mechanical work by myosin motors and its regulation by accessory proteins. A major area of interest in this research group is how different myosin isoforms and myosin mutants alter this chemo-mechanical transduction process, and how this results in different motor behavior that can have profound physiological consequences. Understanding this energetic process also provides valuable clues to how protein motors can be best utilized to develop micro- and nano-scale devices.

Gels and Mucus (Pollack and Verdugo). Life takes place in a polymer gel phase that operates at nanoscale dimensions. In this environment, cell functions have evolved through millions of years of optimization. The application of polymer gel theory has fueled a remarkable progress in the understanding of fundamental cellular processes, including secretion, contraction, signal transduction, etc. The application and validation of these principles have the potential not only to advance the understanding of cell biology, but also to allow the development of systems that mimic what nature has learned through selection and evolution.

Microfluidics (Folch, Hoffman, Stayton, Yager). Both the Folch and Yager laboratories are developing advanced microfluidic technologies. The Folch lab’s mission is to develop miniature cell culture tools for quantitative neurobiology studies, with a focus on axon guidance and synaptogenesis. Micro- and nanotechnology are applied to control the microfluidic environment and the underlying substrate of muscle and nerve cells. The Folch lab is also developing single-cell nanoprobes and computer algorithms for high-throughput recognition of sub-cellular morphology. The Yager Lab main focus is the design and development of microfluidic devices and systems for chemical and biochemical measurement, particularly those needed for point-of-care biomedical diagnostics. Chemical fluidic dynamic modeling is an important tool in that work. In addition, the Yager lab develops microfluidic-specific optical methods of analysis of biological samples. The Hoffman and Stayton labs are utilizing smart polymer-coated nanobeads combined with smart polymer-coated microfluidic channels to develop microfluidic applications that include point of care diagnostics, affinity separations and enzyme bioprocesses.

Surface Plasmon Resonance Imaging (Yager). Surface plasmon resonance (SPR) is an optical effect that allows measurement of the concentrations of molecules in the first few hundred nanometers above a metal film. It is an alternative to fluorescence as a detection method that requires no labels. SPR has been used for a decade to measure concentrations of analytes in solution, slowly and one at a time. The Yager laboratory has developed a simple SPR imaging system for rapidly measuring the concentrations of tens to hundreds of analytes in parallel. The primary approach is based on immunoassays, but other analytical methods are being adapted as well.

Regulation of Muscle Contraction (Harris, Martyn, Regnier). Muscle contraction, including contraction of the heart, occurs as the result of cyclic interactions between myosin and actin, which is regulated by several associated proteins. The Harris, Martyn and Regnier labs use a variety of transgenic, molecular biology, cellular & protein mechanics, and computational approaches to understand the protein-protein interactions involved in the strong coupling of myosin motor function during contraction. The Harris lab focuses on understanding the molecular mechanisms of cardiac contraction and the role contractile proteins play in inherited cardiomyopathies and heart failure. Results from these studies provide a better understanding of the molecular mechanisms of muscle contraction and how defects in contractile proteins can cause altered heart function and ultimately lead to disease. The Martyn lab seeks to understand the mechanisms by which muscle length has a profound effect on contractile output, particularly in cardiac muscle. Ongoing work involves study of the protein interactions invovled in determining the length dependence of contractile properties in mammalian cardiac muscle. The long-term objective of the Regnier group’s research is to understand the detailed mechanisms of calcium mediated regulation of contraction in striated muscle for use in assessment of cardiac myopathies and development of therapeutic interventions. Collaborative projects include 1) development of a spatially explicit, stochastic kinetic model of the 3 dimensional myofilament half-sarcomere that explains differences in regulation of cardiac vs. skeletal muscle contraction, and 2) development of therapeutic approaches such as viral transfection strategies and cardiomyoplasty to improve cardiac performance following dysfunction that occurs with myocardial infarct or chronic ischemia.

Host responses to biomedical implants (Bryers, Giachelli, Horbett, Ratner, Scatena). The interaction of host tissue with biomedical implants is a critical area of research in bioengineering. The Horbett lab studies the interactions of cells and proteins at solid surfaces. Recent work on protein adsorption include the study of the expression of the cell binding domains of adsorbed cell adhesion proteins on polymers, passivation of glucose sensors with adsorbed proteins to improve their longevity in vivo, and prevention of protein uptake with ultralow adsorption non-fouling surfaces. The Giachelli lab seeks to understand cell-material interactions and molecular responses to foreign implants. Current projects include identifying and applying biomimetic strategies to cell-substrate interactions in the context of biomaterial healing, 2) biomolecular control of the foreign body reaction, mechanistic studies aimed at developing novel therapeutic targets and approaches for preventing ectopic calcification in disease and medical devices and cardiac valve and esophageal tissue engineering. The Scatena lab is interested in understanding how the extracellular matrix controls the angiogenesis process and macrophage functions. Current projects include: 1) extracellular matrix-initiated intracellular signaling events in vascular cells and macrophages; 2) novel delivery methodologies to improve blood vessel growth and stability; and 3) extracellular matrix control of macrophage function. Research in the Bryers lab has focused on the pro-inflammatory response of macrophage to various signal-presenting surfaces, both in the absence and presence of surface-colonizing bacteria. Projects include indentifying those signals that promote macrophage adhesion while moderating any inflammatory response to the material, thus allowing macrophage to better defend against infections. Outcomes of this work will support others in the development of biomaterials that “vaccinate” against biofilms. The Ratner lab and the University of Washington’s Engineered Biomaterials ERC (UWEB) is committed to precision molecular engineering of implant surfaces ("engineered biomaterials") to deliver precise signals and control healing. This engineering consists of biospecific immobilization of proteins and other biomolecules taking into account surface orientation, concentration, surface density, and identity.

Multifunctional Nanoparticles for Molecular Imaging and Drug Delivery (Gao). The Gao research group is interested in nanomedicine, which is the use of engineered nanostructures for detection, analysis, and treatment of human diseases such as cancer, cardiovascular diseases, infectious diseases, and neurological diseases. For example, advances in semiconductor quantum dots (Qdots) have produced a new class of fluorescent labels for ultrasensitive and multiplexed molecular imaging. These quantum-confined nanoparticles provide unique optical and structural properties that are not available from either traditional single molecules or bulk solids. Valuable Qdot properties include size-tunable emission, large absorption coefficient, narrow emission peak, broad absorption profile, photostability, and very high brightness, which render Qdots the best molecular probe for imaging and detection. Besides Qdots, we are also interested in other types of nanoparticles such as magnetic nanoparticles, metallic nanoparticles, and polymeric nanoparticles. These nanostructures are designed for MR imaging and targeted drug delivery, and have applications in materials sciences.

 

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 Career Opportunities

Students and postdocs trained in the Molecular Bioengineering program have found great success in a wide variety of academic careers and industry careers that range across the bioengineering, biotechnology, pharmaceutical, medical device, and biomaterials fields, as well as at the NIH. Some examples include Dr. Ashutosh Chilkoti, faculty at Duke University in Biomedical Engineering, Dr. Yuguang Wu at Becton Dickinson, Dr. Zhongli Ding at Alza Corporation, Dr. Sandy Koppenol at Icos Corporation, and Dr. Bishow Adhikari in the Division of Heart and Vascular Diseases, NHLBI, NIH.

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Degree Programs

The degree programs in this Thrust Area are the Bioengineering MS and PhD degrees. There is a new Nanotechnology degree program that is connected to the Center for Nanotechnology.

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Subspecialty Areas & Suggested Coursework

Molecular Drug Delivery
The biological barriers to controlling the spatial and temporal delivery of pharmaceutics can best be addressed by an encompassing engineering approach that takes a biosystem viewpoint. Bioengineering thus lies at the center of the Smart Drug Delivery initiative, and will draw together expertise and coursework in biomaterials/ nanomaterials, molecular bioengineering, pharmaceutics, and medicine, while maintaining an engineering-based biosystems framework. In addition to the core requirements that provide necessary content in Bioen Principles of Physiology, Transport, and molecular/cellular biology, the students will gain depth through taking most or all of the following electives:

Molecular Biomechanics

 

Muscle and Molecular Motors

Host Response to Biomedical Implants

Engineering of Biopolymer Gels

Students interested in this thrust will greatly benefit by taking most or all of the following electives:

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Summary

The Department of Bioengineering at University of Washington offers a broad curriculum and research program in Molecular Bioengineering and Nanotechnology.

Page last updated January 4, 2006

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