Date: Sep 15, 2011 Author: Kathy Liszewski Source: Genetic Engineering News (
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Late-Stage Drug Failures Prompt Push for More Effective Approaches to Designing Therapies
Kathy Liszewski
Executable Cell Biology
Are living processes logical and predictable? Can we develop biological models to more fully understand the complexities of biological systems?
Yes, says Jasmin Fisher, Ph.D., researcher, executable biology, Microsoft Research Cambridge. "Over the past decade, we have generated and accumulated so much data that it exceeds the human capacity to analyze it. Data from microarrays, genome sequencing, and other large-scale technologies requires sophisticated analysis by computational methods."
According to Dr. Fisher, "Executable cell biology is a concept gaining momentum that suggests we can develop techniques for creating dynamic models that capture time- and space-dependent processes and can automate reasoning and analysis. Such large-scale models, based on formal methods from engineering and computer science, could revolutionize biology and medicine and enable the design of new therapies."
Dr. Fisher's group is studying how cells make decisions, with a particular focus on the process where stem cells commit to a single lineage (leading to a single-cell type) while having the ability to undergo multilineage differentiation.
"The elucidation of intricate mechanisms that govern stem cell decisions is essential for understanding normal development. Moreover, defects in these mechanisms play an important role in diseases such as cancer."
"We first generate a detailed map of different interactions that increase or inhibit different cellular processes. We then add dynamicity by inducing from these interactions ‘state transitions'—when a specific signal or a gene gets turned on or off. This allows us to test the translated program to determine if it correlates with cell behavior. This also can allow us to capture dynamically such processes and find out what happens first, second, etc., and how feedback comes into play."
For example, Dr. Fisher and colleagues adapted software originally designed to find errors in microcircuitry, only they used it to study C. elegans. They found a similar warning in a simulation of signaling pathways in the worm. They predicted and later experimentally verified the existence of a specific mutation that produced a functional defect in cell growth.
"One of the ultimate goals of executable biology is to simplify model building so that any scientist can use it. My personal vision is that within five years this will become a mainstream technique in biology."
Stem Cell Advances
The use of stem cells for drug screening and predictive toxicology is a field that has begun to mature, according to Stephen Minger, Ph.D., global head of R&D, cellular technologies, GE Healthcare Life Sciences.
But, he points out, there is room for much-needed improvement. "Some of the drug discovery industry has an ingrained approach that hasn't really changed much for more than 50 years. Yet traditional technologies remain poorly predictive.
"There are still many compounds that are pulled at late stages of clinical trials, or even after reaching the market, due to previously undetected toxicity issues. Vioxx is an example."
GE Healthcare has worked with Genentech to assess Cytiva™ Cardiomyocytes, developed from human embryonic stem cells (hESCs), for use in cardiotoxicity testing. "We performed a retrospective blinded dose- and time-dependent study of more than 26 compounds with known preclinical and clinical cardiotoxic effects.
"We found that Cytiva cardiomyocytes showed a good correlation with previously reported clinical cardiotoxicity. Another advantage of using hESC-derived cells is that sometimes you can gain a greater understanding of the underlying mechanism of toxicity—for example detecting mitochondrial involvement."
Dr. Minger sees the field continuing to progress both in the use of hESCs in drug discovery and also as a direct therapy.
"Already," he says, "a variety of stem cells are being used therapeutically in more than 300 clinical trials worldwide, with hESCs currently being trialed for such indications as spinal cord injury and age-related macular degeneration. I feel that there will be many more applications on the horizon."
Creating a Natural Environment
Tissue engineers have been defining new principles for developing functional substitutes for tissues that have been damaged, according to Tetsuro Wakatsuki, Ph.D., co-founder and CSO of InvivoSciences. He says his company applied those principles to develop 3-D tissue constructs for which drug developers can perform functional assays of cells grown in an arguably more natural 3-D environment.
Generally, he adds, stiff surfaces are used for 2-D cell culture. "The extracellular matrix (ECM) in which native cells reside, however, can be deformed, stiffened, or degraded to adjust their mechanical environment. The ECM stiffness can even specify stem cell lineages, suggesting the importance of the mechanical environment in development.
"In many diseases, including skin and cardiac fibrosis, mechanical properties of tissues are damaged," he continues. "Cells in those diseased tissues lose their mechanical homeostasis. Therefore, candidate compounds for reconstituting mechanical homeostasis can be identified through the mechanical measurements of cells and ECMs and monitoring physiological changes. Cell and tissue mechanics are also responsible for regulating cancer metastasis, wound healing, and embryonic development."
To achieve high-throughput profiling of cells and tissue mechanics, the company developed miniature hydrogel tissue constructs and an automatic device, the Palpator™, to quantify the resulting mechanical properties after exposure to compounds.
"The Palpator automatically inserts a probe into each well to assess and quantify tissue mechanics. Additionally, a conventional microplate reader measures intra- and extracellular biochemical activities using optical biological probes such as dyes that report mitochondrial membrane potential.
"Thus, we combine biomechanical and biochemical assays of cells and ECMs to comprehensively analyze the biological benefits of treatments. We are envisioning that this system will be a useful technology to evaluate efficacy, toxicity, and mechanism of action for early stages of drug development."
