News Archive - Item #20080424a

Bioengineering and Pharmaceutical Sciences Join Forces at UCSF

A new department at UCSF has been created to focus on extraordinary new ways to solve health problems. The Department of Bioengineering and Therapeutic Sciences is the first of its kind to join the academic expertise of bioengineers and pharmaceutical scientists. It was officially approved on February 25, 2009 by UCSF Chancellor J. Michael Bishop, MD.

The department is co-chaired by Kathy Giacomini, PhD (image left), an international expert in pharmacogenomics, and Sarah Nelson, Dr.rer.nat. (image right), a pioneer in developing new imaging techniques. It is a union of the former Department of Biopharmaceutical Sciences in the School of Pharmacy, led by Giacomini, and the Program in Bioengineering in the School of Medicine, led by Nelson. It is UCSF's first department across two schools.

Today's approach to developing and evaluating medical devices and potential medicines through the point that they are approved for use in patients is painfully slow, inefficient and expensive, explains Nelson. "We aim to change this through the new department by combining new biological discoveries with cutting edge technology."

"We saw a tremendous possibility to leverage our bioengineering and pharmaceutical sciences programs for the benefit of patients, and we went for it," Giacomini says. "It's a marriage of scientists who are experts in building biological tools with those who look for ways to understand and interrupt the mechanisms of disease. Our purpose is to speed the innovation of medicines and medical devices to sophisticated, effective, targeted 'intelligent' therapeutics."

According to Nelson, "We are the first department of this kind in the country. We're acting on our belief that in order to excel science has to be approached in wholly new ways through new and unexpected relationships, including those with government and industry. The department's structure is critical for recruiting faculty members who think outside the confines of traditional disciplines, and promote our PhD graduate programs."

5 Research Areas Drive Innovation

Imagine completely artificial organs made of specially engineered materials that the body does not reject. Envision tiny sensors in the blood that continuously monitor levels of drugs and key molecules, and that release precisely dosed, powerful disease treatments exactly when needed. Or consider the possibility of getting a prescription for the best possible medicine tailored to you individually, based upon your genetically determined response to drugs.

Helping patients by turning these possibilities quickly into reality is the aim of the new department.

According to Giacomini and Nelson, the innovations driving new and affordable ways to diagnose and treat disease are more likely to come from academia than from industry.

"Our science is the key to a promoting a healthier and more technology savvy world," Nelson says. "We are improving our understanding of the biological alterations associated with specific diseases. We are using computational methods to understand genomic data and to make predictions. We are engineering biological systems and devices. The end result is better, smarter therapeutics, and improved health."

The new department is organized around five research areas:

1. Drug Development Sciences
2. Pharmacogenomics
3. Therapeutic Bioengineering
4. Computational and Systems Biology
5. Cellular and Molecular Engineering

Here are just a few examples of the department research under way in these areas:

1. Drug Development Sciences: Improving the efficiency and success of drug development

Leslie Z. Benet, PhD, is developing new tools to speed drug development, including the creation of what he calls a "man on a chip." The chip is analogous to the microarray chips used to track genes and gene activation, but instead of focusing only on nucleic acid, Benet's chip permits the study of drug effects on living tissue by mimicking drug metabolism and toxicity with living cells plated onto plastic. An initial focus is on liver cells. These cells play a central role in the metabolism and elimination of most pharmaceuticals.

Benet is making strides in applying microfluidic techniques to bathe cells in a liquid growth medium that substitutes for the blood supply as a source of circulating nutrients, drugs, metabolites, and other molecules in a more natural way than can be achieved with other techniques.

By combining microfluidics, tissue culture, new generations of sensors, machines for reading the chips, and sensitive bioanalytical methods, Benet aims to make available an efficient and more accurate early screening technique for evaluating the efficacy and toxicity of new drug candidates.

Francis Szoka, PhD, is the biochemical version of an adept Eurobus driver, helping molecules get through customs and to their destinations intact. He designs nanomedicines that carry and release drugs at specific sites in the body. These containers are nanosacs, called liposomes. They are composed of two layers of phospholipids--the same molecules that make up cell membranes. Szoka's liposomes are widely used, as the product Doxil, to deliver drugs to treat cancers. He continues to develop better targeted cancer treatments and is also devising gene therapies using these and other sophisticated drug carriers.

2. Pharmacogenomics: Revealing the genetic reasons underlying why people respond differently to medications

Deanna Kroetz, PhD, explores the pharmacogenomics of the most common and deadly form of adult leukemia, called acute myelogenous leukemia. Cancers that are resistant to standard AML treatment, or that become resistant over time, often make large amounts of proteins that pump drugs out of cells. In some cases, tumors make extra-active pump proteins. Kroetz and colleagues are collecting information for comparison on AML gene variations, pump protein levels, and pumping potency, as well as information on patient survival and side effects. The work could lead to useful lab tests and better selection of patients for drug trials, according to Kroetz.

"If we have tests to avoid it, I don't think patients will be willing to take a drug that they won't respond to, that has significant toxicity, and that they will have to be taken off of in a month," Kroetz says.

Kroetz and pharmacogenetics colleague Giacomini lead a National Institutes of Health Pharmacogenomics of Membrane Transporters Project. The goal is to understand the genetic basis for variation in drug response for drugs that interact with those proteins, called membrane transporters, that actively move materials across a cell membrane.

3. Therapeutic Bioengineering: Building devices to understand biology, detect, and treat disease

Therapeutic bioengineer Shuvo Roy, PhD, is addressing the great shortage of transplantable kidneys available to the growing population of patients suffering from end-stage renal disease. "We want to build an implantable, artificial kidney to eliminate dialysis ultimately," Roy says. "It will not just be a unit to perform filtration of toxins; it will also incorporate a cell bioreactor that will perform some of the basic metabolic functions of a native kidney."

Bioengineers in the department also are developing biosensors, which are intricate devices that detect biological reactions and translate them into readable electrical signals. "The 'lab on a chip' is not quite a reality yet," explains bioengineer Tejal Desai, PhD, "but people know it's going to be an astounding tool and one that will revolutionize patient care."

The biosensors being developed at UCSF could be used at every major stage of drug research, to:

• make basic biochemical discoveries
• develop strategies for drug design
• test drug designs pre-clinically and clinically
• evaluate the individuals who are most likely to benefit from a particular drug.

To complement the new technologies that her colleagues are developing, Nelson uses the intangible principles of mathematics to acquire, reconstruct, and then analyze magnetic resonance and spectroscopic images. Her research has applications to patients with brain tumors, prostate cancer, and neurological diseases. Her goal is to develop new biomarkers that can improve human health through a sophisticated understanding of the underlying biological processes that impact disease progression and response to therapy.

4. Computational and Systems Biology: Making sense of massive amounts of information about proteins and creating models of biological systems

The department's systems biologists such as Chao Tang, PhD, are uncovering important relationships and interactions within biological systems, including metabolic pathways. Tang is combining mathematical modeling with high-precision experiments in which his lab team monitors levels of proteins and gene activation in cells. His current focus is on the cell cycle, which governs cell growth and replication. The organisms in which the cell cycle is best studied are yeasts. The molecules governing the yeast cell cycle are fundamentally similar to those found in humans. Tang manipulates yeast to test mathematical models, and then revises the models according to what he learns. Ultimately, he aims to identify new strategies for targeting cell cycle abnormalities that drive the growth of human cancers. The goal is to find new ways to stop the growth of many types of tumor cells without harming normal cells.

Andrej Sali, PhD, is a computational biologist who is developing methods for determining the structures of proteins and assemblies of proteins that are involved in all processes within living cells. This goal is being achieved through the tight integration of different types of experimental data, physical theories, and statistical inferences--spanning all relevant size and time scales--to achieve maximum accuracy, precision, completeness, and efficiency. The corresponding software, Integrative Modeling Platform, has already been applied to determine the structures of several assemblies, including the nuclear pore complex, which is the major gateway for molecular traffic in and out of a cell's nucleus.

Michael Fischbach, PhD, who will join the department faculty in summer 2009, is studying clusters of genes in soil bacteria and is developing computational methods to predict the structures and functions of small molecules produced by the enzymes that these genes encode. Small molecules made by soil bacteria include important antibiotics, anticancer agents, immunosuppressants, and cholesterol-lowering drugs, but many small molecules made by bacteria remain undetected. Fischbach is devising novel genetic and chemical approaches to detect and isolate these molecules for further study.

Researchers are developing new techniques in computational biology to use in investigating basic biological questions, as well as in drug design. For example, department faculty member Nadav Ahituv, PhD, is using computational biology and genetic engineering explore gene regulatory elements, which are DNA sequences that instruct genes when and where to turn on or off. These include the switches for genes with known drug targets.

"Computational technology is trying to catch up with the vast amount of information that is available--using state of the art technologies," says Nelson. "The problem is in extracting information that is relevant for making fundamental decisions from the vast quantities of existing data. The use of prior knowledge and the implementation of intelligent search algorithms are critical."

Computational biology will be a key to predicting drug effects among individuals within diverse populations, Giacomini suggests. Many of the genetic variations that are detected by genomic analysis are quite rare, and computational methods will be needed to predict beneficial drug effects. As the power of computational methods increases, physicians will be able to use these predictions in making treatment decisions for individual patients.

5.Cellular and Molecular Engineering: Applying engineering principles to health sciences research

Getting a drug to its target within the body is a complicated task. The current small molecules that pharmaceutical companies often envision as drugs are difficult to get into the brain or across the intestines and into the bloodstream. Then there are the many physical and chemical barriers encountered, within our tissues and cells, to bringing together the active drug component of a pill and a molecule in the body involved in a specific disease. Tejal Desai, PhD, director of the therapeutic micro and nanotechnology laboratory at UCSF, addresses these problems from the perspective of cellular and molecular engineering.

"We are thinking of new vehicles for delivering drugs to specific places in the body," Desai says. "We think about the size of the device needed to target a cell, or to target a protein within that cell, or to get through tight junctions formed by cells within tissues."

Professional and Graduate Education

In addition to the science agendas of its faculty members, the department educates a new generation of scientists and health care providers by giving doctor of pharmacy (PharmD) and doctor of medicine (MD) degree professional students the foundation in science they need to deliver increasingly complicated therapeutics to their patients, and by training PhD graduate students. The department houses and manages the:

• UCSF Graduate Program in Biological and Medical Informatics
• UCSF Graduate Program in Pharmaceutical Sciences and Pharmacogenomics
• UCSF/University of California, Berkeley Joint Graduate Group in Bioengineering.

"Many of the best young engineering students have no problem imaging artificial organs, sensors that regulate the amount of a medication in your blood, and how our genetic structure can affect our drug response," Giacomini says. "Many are excited and driven by the thought of working on solutions for medicine, and they're flocking to bioengineering graduate education programs in unprecedented numbers."

Contributed by Jeff Norris and Susan Levings

Image credit: all images © majedphoto.com except 3-panel cells: Tejal Desai, 3-panel crowd blur: Flickr/David Sim, victoriapeckham, pharmacogenomics: Crowd down Stockton street: niallkennedy, therapeutic bioengineering: Shuvo Roy, cellular and molecular engineering: Tejal Desai, lab coat: © majedphoto.com