A team led by Massachusetts General Hospital (MGH) researchers has developed an innovative way to culture liver cells for drug toxicity screening. In a report to be published in Proceedings of the National Academy of Sciences that has been released online, the investigators describe how liver cells grown in a high-oxygen environment and in a culture medium free of animal-derived serum quickly begin to function as they do within the liver.
Better and faster ways to screen drugs for toxic side effects could significantly reduce the cost and expense of bringing new drugs to market, along with reducing unexpected adverse events that can occur when new agents move from the clinical trial stage into wider use, the authors note. Since the liver plays a key role in the metabolism and clearance of drugs, screening for liver toxicity is an essential step in assuring the safety of new agents. But studies in animals are not always successful in predicting toxic liver effects, and freshly cultured liver cells quickly lose their metabolic competence under standard culture methods.
"Finding a better way to culture liver cells has been a major stumbling block in the development of predictive drug-discovery tools," says Yaakov Nahmias, PhD, of the MGH Center for Engineering in Medicine (CEM), the paper's senior author. "We needed to develop an environment in which liver cells behave as they do in the body."
Earlier studies by the CEM team and others suggested that animal-derived serum, commonly used in cell cultures, may interfere with the metabolism of cultured liver cells. Since one of the key stresses involved in moving cells from an in vivo environment into culture is a tenfold drop in oxygen levels, the researchers theorized that a high-oxygen, serum-free culture environment might be the answer.
Their experiments first confirmed that serum interferes with the metabolism of cultured rat and human liver cells. They then found that liver cells grown with endothelial cells in a serum-free culture with 95 percent oxygen quickly resume normal metabolic activity, including gene expression and cell function. These cultured cells successfully predicted the clearance rates for both rapid- and slow-acting drugs and maintained a high level of metabolic activity for several weeks.
"This is a significant achievement," says Martin Yarmush, MD, PhD, director of the MGH Center for Engineering in Medicine and a co-author of the PNAS study. "Oxygen had been thought to affect cell survival but not gene expression or the function of cultured liver cells. This all changed when we started looking at new formations of culture media." Yarmush is the Helen Andrus Benedict Professor of Surgery at Harvard Medical School, where Nahmias is an instructor in Bioengineering.
The new culture system is being licensed to HìREL Corporation of Beverly Hills, Calif., a company developing human-relevant models of drug metabolism. Future work will explore extending these results to other cell systems and clinical applications, such as transplantation of liver cells.
Srivatsan Kidambi, PhD, of the MGH Center for Engineering Medicine (MGH-CEM) is the lead author of the PNAS paper. Additional co-authors are Rubin Yarmush, MGH-CEM; and Eric Novik, PhD, and Piyun Chao, PhD, HìREL Corporation. The study was partially supported by grants from the National Institutes of Health and Shriners Hospitals for Children.
Massachusetts General Hospital (www.massgeneral.org), established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of almost $550 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.
Sue McGreevey | EurekAlert!
Diagnoses: When Are Several Opinions Better Than One?
19.07.2016 | Max-Planck-Institut für Bildungsforschung
High in calories and low in nutrients when adolescents share pictures of food online
07.04.2016 | University of Gothenburg
Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.
This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...
Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion
Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
27.10.2016 | Materials Sciences
27.10.2016 | Physics and Astronomy
27.10.2016 | Life Sciences