virtual embryo

Organs-on-a-Chip: The Future of Chemical Toxicity Testing

By Tom Knudsen, Ph.D.

Illustration of a human brain on a computer chipLast week, my colleague Jim Johnson shared a blog post (Exciting Times for Toxicology: Creating New Predictive Models) about EPA’s leadership role to advance chemical toxicity research, including news that the Agency’s Science to Achieve Results (STAR) grant program will provide research institutions with up to $6 million each to further develop organotypic culture models (OCMs)—“organ-on-a-chip” microsystems. The grants support innovative research that will eventually model complex functions of the human system like metabolism, multicellular communication within a tissue or target organ, and how these multiscale systems change over time.

Today, I am excited to share the three institutions that will receive EPA support to advance this innovative work. The institutions and their work are highlighted below.

  • University of Wisconsin, Madison – Human Model Analysis of Pathways Center:
    The Center will research innovative cellular modeling methods to develop a broadly applicable set of tools for toxicity screening. Researchers will develop OCMs for functions within the liver, central nervous system and mammary gland with invasive carcinoma.
  • Vanderbilt University Resource for Organotypic Models for Predictive Toxicology:
    The Center will advance alternative methods of chemical toxicity testing using 3D cultures of tissues to reduce uncertainties regarding specific chemical exposures. The models will simulate a more accurate response in the liver, mammary gland, limb/joint formation, and placental tissues under different conditions and stressors.
  • University of Washington – Predictive Toxicology Center for Organotypic Cultures and Assessment of AOPs for Engineered Nanomaterials:
    The Center will develop innovative OCMs to evaluate potential toxicity in cells and organs following exposure to metal-based engineered nanomaterials within an adverse outcome pathway (AOP) model. The research will target airway tissues, kidney, liver, and testis. Models will also factor in lifestage and genetic background.

We believe that the “organ-on-a-chip” microsystems and models the centers develop will provide vital information to predict toxicity and chemical exposure within the human body and at different lifestages and provide data that further minimizes the lengthy testing involved with animal studies. Organotypic culture models have the potential to improve, evaluate, and extend computational models that are currently under development by our own scientists.

Research data will not only help explain how organs and tissues respond to various chemicals, but these models will ultimately be used to validate other predictive models such as EPA’s virtual embryo models which will advance our understanding of the potential links between chemical exposure and development, disease, or other responses.

For more information on OCM Research and our STAR grants, please see our fact sheet.

About the Author: Tom Knudsen, Ph.D. is a developmental systems biologist at EPA’s Center for Computational Toxicology. His research focuses on predictive models of developmental toxicity—building and testing sophisticated computer models. In addition to his research at EPA, Dr. Knudsen is an Adjunct Professor at the University of Louisville, Editor-in-Chief of the scientific journal Reproductive Toxicology, and Past-President of the Teratology Society. Read more about him and his work.

 

 

 

Editor's Note: The opinions expressed here are those of the author. They do not reflect EPA policy, endorsement, or action.

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Exciting Times for Toxicology: Creating New Predictive Models

By Dr. James H. Johnson, Jr.

image of a computer chip with wires coming offNext week, a number of my EPA colleagues will join toxicologists from across the world in San Diego, CA for the Society of Toxicology’s 54th Annual Meeting and “ToxExpo.” The gathering will feature more than 160 scientific sessions and 2,400 poster presentations, providing important insights into how the study of chemical toxicity can better protect public health and the environment.

Although this particular conference has been going on for more than half a century, these are exciting times for toxicologists. And I’m proud to say that EPA is helping lead the way.

Our researchers and their partners are ushering in a new generation of chemical testing and screening methods, developing “virtual embryos” and other complex models that use scientific data, computer power, and sophisticated calculations to mimic the potential effects of toxins on actual tissues and organs. With other federal partners, they are using robots to advance fast and efficient high-throughput-screening assays, greatly accelerating the pace of chemical screening while dramatically reducing the use of laboratory animals—and costs.

We are also supporting innovative, world-class research through our Science to Achieve Results (STAR) grant program. New STAR grants will be announced at the Society of Toxicology’s Annual Meeting (March 25 from 5:00 p.m. to 7:00 p.m.) when we will hold a kickoff meeting of our newly established Organotypic Cell Models for Predictive Toxicology Centers. This research is part of EPA’s Chemical Safety for Sustainability research program.

The research Centers are being established to develop three-dimensional models, sometimes called “organs-on-a-chip,” which can be used to replicate human biological interactions within tissues and organs. When developed and evaluated, these models known as Organotypic Culture Models (hence the name of the Centers) will help investigate the toxic effects of chemical substances. Such models are established from isolated cells or from tissue fragments, bridging the gap between conventional, single-layered cell cultures and whole-animal systems.

What the Centers learn will be used to develop computational models that can help predict responses and outcomes from chemical exposures, such as human disease and long-term effects on tissue and organ growth. The models they develop will also mimic biological functions such as a metabolic process.

If you are attending the Society of Toxicology’s 54th Annual Meeting and “ToxExpo” this year, you are welcome to come to the March 25th grantee kick-off meeting.

The impact of all this activity is a new wave of toxicology testing that is faster, more efficient, and far less costly. This will help us at EPA with our number one priority: protecting human health and the environment. That’s some pretty exciting news.

About the Author: Dr. James H. Johnson Jr. is the Director of EPA’s National Center for Environmental Research, which runs the Agency’s Science to Achieve Results (STAR) program as well as other grant, fellowship, and awards programs that support high quality research by many of our nation’s leading scientists and engineers.

Please note: We’ll be sharing more about EPA participation at the annual Society of Toxicology Meeting throughout next week, so please check back to learn more.

Editor's Note: The opinions expressed here are those of the author. They do not reflect EPA policy, endorsement, or action.

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Science Matters: Predicting the Future of Children’s Health

Children's Health MonthTo observe October as Children’s Health Month, we will periodically post Science Matters feature articles about EPA’s children’s health research here on the blog.  Learn more about EPA’s efforts to protect children’s health by going to www.epa.gov/ochp.


According to the Centers for Disease Control and Prevention, approximately one in every 33 babies born in the United States is born with a birth defect. Birth defects can heighten the risk of long-term disability as well as increase the risk of illness, potentially impacting a child for the rest of his or her life. Unfortunately, the causes of most birth defects are unknown.

EPA researchers are tapping powerful, high-tech computer systems and models to better determine how prenatal exposure to environmental factors might impact embryo and fetal development. Working on EPA’s Virtual Embryo (v-Embryo™) project, they create computer models of developing body systems and combine them with data from a number of EPA studies and toxicity databases to “virtually” examine the effects of a variety of prenatal exposures.

Virtual Embryo simulates how chemicals and pesticides, including those that disrupt the endocrine system, interact with important biological processes that could disrupt fetal development.  The chemicals used in simulations are identified by EPA’s Toxicity Forecaster as having the potential to affect development.

The predictions from the computer simulations need to be further tested against non-virtual observations. However, the models provide scientists with a powerful tool for screening and prioritizing the chemicals that need to be more closely examined, greatly reducing the cost and number of targeted studies needed.

“We’ve built small prototype systems, now what we want to do is move into complex systems models that will be more relevant to environmental predictions,” said Thomas B. Knudsen, Ph.D., an EPA systems biologist who is leading the project.

Virtual Embryo models have focused on blood vessel development and limb development, but are being expanded to include early development of the male reproductive system, which is known to be particularly sensitive to endocrine disrupting chemicals.

Knudsen says that having more models is important because different chemicals can affect biological systems in various ways. Luckily, the time it takes to develop new models decreases as researchers’ model-developing knowledge grows.

“The important challenge for us is to try to integrate some of this work with other issues of broad importance to children’s health,” said Knudsen. “We’re focused primarily on embryonic development, but a person doesn’t stop developing at birth. We have to take what we are learning from the embryo and extend that information into life stages beyond birth.”

Editor's Note: The opinions expressed here are those of the author. They do not reflect EPA policy, endorsement, or action.

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Scientist at Work: Interview with Thomas Knudsen

Dr. Tom Knudsen is a developmental systems biologist at EPA’s Center for Computational Toxicology. His research focuses on developing predictive models of developmental toxicity, building and testing sophisticated computer models such as the Virtual Embryo Project. This effort explores the potential for chemicals to disrupt prenatal development—one of the most important lifestages.

In addition to his research at EPA, Dr. Knudsen is an Adjunct Professor at the University of Louisville, Editor-in-Chief of the scientific journal Reproductive Toxicology, and Past-President of the Teratology Society.

Before joining EPA, he was Professor at the University of Louisville.

How does your science matter?

I am part of an exciting effort to develop new ways to explore development toxicology and prioritize the testing of chemicals using vast amounts of data and biological knowledge, powerful computers, sophisticated computer models and very large databases. Instead of the conventional approach to developmental toxicology, which over the past 50 years or so has relied on tests conducted on pregnant lab animals, we are developing virtual models that are both faster and less expensive.

For example, in the Virtual Embryo project we are using a suite of screening models that look at the interactions of various chemicals with the complex biology of a developing embryo. We think that these models and tools will be a new way of asking questions about how a pregnant woman’s exposure to chemicals in the environment might result in a risk to development.

Our work will help protect human health, greatly increase the number of chemicals we can screen quickly, and reduce costs all at the same time. So I guess it really does matter.

What do you like most about your research?

Most days I feel like I have the best job in the country!

The team that I work with consists of bright and exceptionally talented scientists, among them more than a half dozen outstanding young scientists and post-doctoral fellows. As a like-minded team, we strive to unravel complexity in a biological system such as the embryo.

I really enjoy the many opportunities for productive collaboration here at EPA. The opportunity to conceptualize the Virtual Embryo Project and see it grow and evolve has been most gratifying, not only because of the innovative science that it allows, but also because of the opportunities that it presents for professional development of young scientists.

Click here to keep reading Thomas’s interview.

To read more Scientists at Work interviews, click here.

Editor's Note: The opinions expressed here are those of the author. They do not reflect EPA policy, endorsement, or action.

Please share this post. However, please don't change the title or the content. If you do make changes, don't attribute the edited title or content to EPA or the author.