Environmental Factor

August 2011


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Symposium highlights emerging role of 3D tissue modeling in EHS

By Ernie Hood
August 2011

Donald Ingber, M.D., Ph.D.

Ingber described his group's work at the Wyss Institute and provided an overview of the many exciting developments in the field, as well as an encouraging look at the future potential of 3D tissue modeling. (Photo courtesy of Steve McCaw)

Donald Ingber, M.D., Ph.D, at the podium

Ingber discussed the importance of 3D model systems taking biological forces, such as shear and flow, into account in order to effectively recreate physical conditions in the cell. (Photo courtesy of Steve McCaw)

Richard Superfine, Ph.D.

Superfine described his group's Virtual Lung Project, which is designed to provide in vitro and in silico modeling of mucus clearance. (Photo courtesy of Steve McCaw)

Raymond Tice, Ph.D.

Tice communicated Tox21's enthusiasm for 3D tissue modeling approaches to help transform toxicology from an observational to a predictive science, but noted that there is still much research to be conducted before it can reach its full potential. (Photo courtesy of Steve McCaw)

Judging from the presentations at the June 27-28 NIEHS workshop, “Engineered Tissue Models for Environmental Health Sciences Research” (see text box), it won't be long before 3D tissue models are essential tools in risk assessment and environmental health. After decades of basic research, the science and technology underlying these “organs-on-a-chip” are developing rapidly, and the field appears to be poised for translation and commercialization into a variety of applications in toxicology, pharmacology, and medicine.

“We think that this is the future,” said keynote speaker Donald Ingber, M.D., Ph.D.(http://www.childrenshospital.org/cfapps/research/data_admin/Site97/mainpageS97P0.html) Exit NIEHS, founding director of the Wyss Institute for Biologically Inspired Engineering(http://wyss.harvard.edu/) Exit NIEHS at Harvard University and a pioneer in the field. “I think it can be integrated and have impact quickly… It's of a scale that it can be manufactured with microchip technologies that are cheap and robust, and the response that we're getting from the chemical industry, as well as pharma, has been amazing.

Highlighting new opportunities in biomedical research

The meeting was organized by NIEHS Program Administrator David Balshaw, Ph.D., who said that the gathering had two main goals - to provide a series of presentations to the NIEHS community to showcase leading-edge engineered tissue systems as research tools and to hold an expert discussion panel to provide feedback to NIEHS on how to develop a portfolio in the field.

“It was a fantastic day and a half of science,” said Balshaw. “We heard about a variety of models, from well-established tissues like lung and skin to more developmental systems like breast cells, neuronal tissues, and capillary beds. We also talked about the development of computational models and the integration of both wet and computational models into high-throughput screens.”

Reality check - making models better mimic organisms

Although numerous 2D cell-based systems have traditionally been used to gain information about potential hazards, often findings do not translate well to human biology, because cell culture does not accurately represent many of the structures and functions of normal tissue. The potentially huge advantage of the 3D systems is their power to provide responses that more closely reflect what happens in vivo. They incorporate multiple cell types and, in many cases, reflect the fundamental anatomy found in native tissue. They even include cell-cell signaling and biological forces such as stress, strain, and flow as critical aspects of the physiological response to environmental factors.

As NIEHS/NTP Director Linda Birnbaum, Ph.D., explained in her opening comments to attendees, to achieve the desired “biological reality,” several other components are necessary to reflect the complex structures, functions, and even spatial and temporal elements that all combine in a working tissue or organ (see figure below). Although many of the needed building blocks already exist, some are still in development, and one of the objectives of the meeting was to assess the current state of the science and identify the engineering, experimental and computational work needed to accelerate progress in the field. As Balshaw put it, “There's a lot that can be done now, but a lot left to do. Throughput is still moderately low, and many systems still need to be validated. Moving this forward will rely on interdisciplinary teams.”

NTP Biomolecular Screening Branch Chief and Tox21 liaison Raymond Tice, Ph.D.(http://www.niehs.nih.gov/research/atniehs/labs/bmsb), told participants there were many potential applications of 3D tissue modeling systems to efforts by Tox21, a unique collaboration between several federal agencies to research and test chemicals in a new way.

Not only would it be very useful for 3D systems to test compounds for their effects on organ function, Tice explained, but assessing effects on organ development would also be of great interest. He also said he hopes the models can be used to evaluate gene and compound interactions within and across species, so as to understand differential sensitivity to toxicants and what's happening at the cell pathway level. “That's where I think we can make some really great strides,” said Tice.

(Ernie Hood is a contract writer with the NIEHS Office of Communications and Public Liaison.)

figure, Generalized Components of a 3-D Tissue Model
According to Birnbaum, the combination of these elements is what gives 3D tissue models the power to mimic biological systems more closely than 2D cell cultures. All are not yet perfected, but progress has been swift in recent years. (Slide courtesy of Linda Birnbaum)

from left to right, Superfine, Fritsche, George, Takashima, Herlyn, Balshaw, Sonnenschein, Tice, Ingber, and Wambaugh
Speakers at the conference gathered in front of the Rall Building for a group shot. Shown, left to right, are Superfine, Fritsche, George, Takashima, Herlyn, conference organizer Balshaw, Sonnenschein, Tice, Ingber, and Wambaugh. (Photo courtesy of Steve McCaw)

Tissue Models on Parade

In addition to Ingber and Tice, each of the speakers at the 3D Tissue Modeling symposium presented science at the very forefront of the field:

  • Richard Superfine, Ph.D.(http://www.cs.unc.edu/People/Faculty/Bios/superfine.html) Exit NIEHS, from the University of North Carolina at Chapel Hill presented the Virtual Lung Project, which is a combined experimental and computational modeling exercise. A particular focus is on models of mucociliary clearance that can be used to assess transport and clearance of exposures in the lung.
  • Ellen Fritsche, M.D.(http://www.cefic-lri.org/about-lri/programme-management/ellen-fritsche) Exit NIEHS, of Heinrich-Heine Universität Düsseldorf in Germany works with neurospheres made of human neuroprogenitor cells, which are being used to assess toxicity through AhR, Nrf2 and Thr pathways.
  • Carlos Sonnenschein, M.D.(http://sackler.tufts.edu/Faculty-and-Research/Find-People-and-Research/Faculty-Profile.aspx?id=134) Exit NIEHS, of Tufts University, focuses on modeling the developmental basis of breast cancer. He also spoke to some of the fundamental issues relating to scaffolding and computational analysis of the complex dynamics of systems.
  • John Wambaugh, Ph.D. (http://www.epa.gov/ncct/bios/John_Wambaugh_Short_Bio.pdf)  Download Adobe ReaderExit NIEHS (25 KB) , from the U.S. Environmental Protection Agency National Center for Computational Toxicology spoke about the virtual liver and virtual embryo computational modeling projects being developed within EPA. These computational screens are a powerful supplement to the Tox21 screening effort.
  • Steven George, M.D., Ph.D.(http://www.eng.uci.edu/users/steven-george) Exit NIEHS, from the University of California, Irvine spoke about his microtissue vascularization effort, which is developing a system to form capillary beds within tissue arrays, adding an additional level of physiological relevance to engineered tissue models.
  • Meenhard Herlyn, D.V.M., D.Sc.(http://www.wistar.org/research_facilities/mherlyn/research.cfm) Exit NIEHS, from the Wistar Cancer Institute spoke about the multi-cellular skin model that is being used to examine cellular transformation in skin cancer and in efforts to derive the model from induced pluripotent stem (iPS) cells.
  • Akira Takashima, M.D., Ph.D.(http://www.utoledo.edu/med/depts/micro/faculty/Takashima.html) Exit NIEHS, from the University of Toledo, spoke about his group's multi-cellular skin model for assessing irritant and allergic dermatitis as a moderate- to high-throughput screen for potential toxicants.


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