DNA background

Algorithm Helps Scientists Decipher How Drugs Work Inside the Body

From Drug Discovery & Development, Algorithm Helps Scientists Decipher How Drugs Work Inside the Body:

Researchers at Columbia University Medical Center (CUMC) have developed a computer algorithm that is helping scientists see how drugs produce pharmacological effects inside the body. The study, published in the journal Cell, could help researchers create drugs that are more efficient and less prone to side effects, suggest ways to regulate a drug’s activity, and identify novel therapeutic uses for new and existing compounds.

…The method involves creating a computational model of the network of protein interactions that occur in a diseased cell. Experiments are then performed to track gene expression changes in diseased cells as they are exposed to a drug of interest. The DeMAND algorithm combines data from the model with data from the experiments to identify the complement of proteins most affected by the drug. …

The study’s senior author notes that the process “could accelerate the drug discovery process and reduce the cost of drug development by unraveling how new compounds work in the body.” Read more here.

alternative toxicity testing computational toxicology databases
Photo attribution: The Wyss Institute

Alternatives going mainstream

Things are getting interesting when high-tech replacements for animal testing catch the eye of online financial publications like The Economist, Fortune Magazine, Forbes, and CNN Money

Some stories on organs-on-chips and 3D bioprinting from just the last few weeks:

The Economist: Towards body-on-a-chip

Fortune Magazine: This new technology could do away with animal testing

CNN Money: 3-D printers could soon make human skin

Forbes: L’Oreal seeks quantum leap with 3D printed skin

Congratulations to the Wyss Institute, winners of the London Design Museum’s “Design of the Year” award for their organs-on-chips.

Named Design of the Year by a jury chaired by the artist Anish Kapoor, it is the first time the award has gone to a design from the field of medicine, beating off competition from Google’s self-driving car, a project to clean up plastic from the sea and an advertising campaign to convince people to buy misshapen fruit.

3D bioprinting alternative toxicity testing organs-on-chips
Image attribution: National Center for Advancing Translational Sciences

Have you met “Chip”?

The National Center for Advancing Translational Sciences website has a new interactive feature introducing “Chip,” a handsome collection of 3-dimensional tissue chip devices scientists are working to integrate into a human-on-a-chip. The project is a collaboration between NCATS, DARPA, the FDA, and numerous academic research partners.

Screen shot from NCATS video, "Tissue Chip for Drug Screening"

Screen shot from NCATS video, “Tissue Chip for Drug Screening”

At least a dozen “chip” systems are under development, aiming to model processes in the brain, heart, lungs, kidneys, liver, intestines, muscles, skin, reproductive system, and more. As these fully functional cell, tissue, and organ models are perfected, scientists will be able to use them to test potential drugs or vaccines for their effectiveness or toxicity in humans, with much greater accuracy than animal tests can provide. Currently, over 90% of drug candidates fail in development because drugs that looked promising in pre-clinical (animal) trials turn out to be toxic or ineffective in human trials.

You can read more about tissue chip research in this article from AltTox.org. For more technical information, see the September 2014 issue of Experimental Biology and Medicine, which is devoted to the topic.

And watch this NCATS video, “Tissue Chip for Drug Screening,” for more on this exciting research.

Related posts: Advances in human relevant testing & NIH announces funding for the next phase of its tissue chip for drug screening program

3D cell & tissue culture alternative toxicity testing organs-on-chips
mtg room crop

Report on the SOT Satellite Meeting, “Updates on Activities Related to 21st Century Toxicology and Evidence-based Toxicology”

(Reprinted from the April AltTox Digest; used with permission.)

At the start of this year’s SOT satellite meeting, “Updates on Activities Related to 21st Century Toxicology and Evidence-based Toxicology” (co-sponsored by the Center for Alternatives to Animal Testing [CAAT], the Human Toxicology Project Consortium [HTPC] and the Evidence-based Toxicology Collaboration [EBTC]), co-moderator Thomas Hartung noted that the annual gathering began in 2009 with 12 people in attendance.  This year, at least 80 people attended – an impressive crowd for a meeting that takes place in the final hours of the week-long Society of Toxicology convention. The annual meeting features updates on US and EU programs and projects dedicated to advancing the toxicity-testing paradigm outlined in the NRC’s 2007 report, Toxicity Testing in the 21st Century: A Vision and a Strategy.

Richard Paules (US National Toxicology Program) started the presentations with a report on progress in the interagency Tox21 program. The program has moved into Phase III, during which they will be increasing the use of computer models for in vitro to in vivo extrapolation, adding new cell lines, expanding the pathway coverage and human relevance of assays, and developing a high-throughput (HT) transcriptomics platform.

Rusty Thomas (US Environmental Protection Agency) then described a number of initiatives underway in the ToxCast program, including research to develop the metabolic competence of existing assays, developing new assays for priority targets such as the thyroid, and exploring the use of organotypic cell cultures. ToxCast is also expanding its read-across program (and recently hired AltTox Editorial Board member Grace Patlewicz to spearhead that effort).

David Dix (US Environmental Protection Agency) gave an overview of the progress in the EPA’s Endocrine Disruptor Screening Program (EDSP), noting that improved technologies are greatly accelerating the project. The agency is concentrating on building user confidence in its screening battery and expanding the use of computational modeling. (Read an introduction to the EDSP in this two-part In the Spotlight article.)

Melvin Andersen (Hamner Institutes), a co-author of the NRC’s 2007 report, noted that considerable technical and scientific progress has been accomplished in the 8 years since publication of the NRC’s recommendations. Several key pathways have been well-described, and others are under construction. The new challenge is to determine how to communicate this progress to the public, and build their confidence in these methods.

Mark Cronin (Liverpool John Moores University) then provided an overview and update on the six components of the EU’s SEURAT-1 program. (Read more about the SEURAT-1 program in this New Perspective article.) A number of useful tools are coming out of this project, but the key outputs are proof-of-concept case studies. Level 1 studies are designed to demonstrate methods for consolidating existing knowledge to describe key adverse outcome pathways (AOPs). Level 2 studies demonstrate the integration of in vitro and in silico tools to generate predictive models. Level 3 studies, to be finalized later this year, will demonstrate how these models and knowledge bases can be used in quantitative and read-across-based risk assessment and decision-making.

Thomas Hartung reported on the activities of CAAT. Among many initiatives, CAAT is developing a read-across program that aims to facilitate 2018 REACH registrations. CAAT has also been coordinating a series of workshops in Europe and the US to advance “green toxicology” – using in silico tools to design safer chemicals. Filling in for scheduled presenter Marty Stephens, Hartung also described the work of the EBTC, which has been developing and promoting the methods and uses of systematic review in toxicology. Hartung noted that evidence-based toxicology stands to advance twenty-first century toxicology in several ways, including providing a means of assessing the quality of legacy data and new assays, providing guidance on integrating data sources, and ultimately using this information to facilitate validation procedures.

Catherine Willett updated the group on HTPC activities. Willett explained that the HTPC focuses its efforts on three areas: contributing to the advance of relevant science by sponsoring workshops and seminars, lobbying in the US and EU to increase funding for key government initiatives, and developing communication strategies to encourage regulatory and public acceptance of the NRC’s testing strategy. In the last year, the group has especially concentrated on this third area, developing an informative graphic and a series of videos that will be posted on the group’s website later this year. She noted that the HTPC also co-sponsored a seminar at SOT this year – “AOPs 201,” which covered the development and use of AOPs for regulatory purposes. Videos from the seminar will be shared on the group’s website.

The meeting closed with its traditional “open mic” segment – inviting short presentations or discussion questions from those in attendance. The update meeting will convene again at the end of next year’s SOT convention in New Orleans.

(Registered participants of the meeting will be able to access presentation slides on the EBTC website.)

alternative toxicity testing AOPs computational toxicology HTPC partners Meetings & Events Tox21 ToxCast
Crop duster (photo credit: Roger Smith/Creative Commons)

Advances in human-relevant alternatives for inhalation toxicity testing & screening

Many of the situations in which inhaled particles or substances can cause toxicity involve repeated exposures to the substance – e.g., cigarette smoking, use of inhaled medications, or on-the-job exposure to agricultural or industrial sprays and vapors.

To test for the effects of repeated inhalation exposures without using animals, scientists are developing increasingly sophisticated in vitro models of the human respiratory system. These in vitro alternatives use cultured respiratory cells and tissues that are kept alive in conditions designed to imitate the environment of the human airway. For repeat-exposure tests, it is necessary to keep these “reconstructed” cells and tissues alive and functional for extended periods of time.

Rats in inhalation exposure chamber

Rats in inhalation exposure chamber – a standard apparatus for testing inhalation toxicity on animals

Scientists with British American Tobacco (BAT) recently demonstrated that a commercially-available reconstructed human airway tissue called MucilAir™ would remain fully responsive for at least six months in their experimental conditions, making it one of a growing number of viable and more human-relevant alternatives to testing inhalation toxicity on animals.

(Image credit: British American Tobacco)

(Image credit: British American Tobacco; click to enlarge)

The scientists monitored such regular lung tissue activities as cilia beat frequency, mucous secretion, enzyme activity and gene expression, and found that the MucilAir tissue showed normal responses throughout the test period.

According to the company press release, BAT will use the tissue model to “compare the toxicological effect of repeated exposures to aerosols generated from conventional and next-generation tobacco and nicotine products.”

image of iPSC-derived branching mini-lung

Branching mini-lung. Credit: Nick Hannan, University of Cambridge

Cultured and engineered respiratory tissues with extended lifespans can also be used to test drugs intended to treat chronic lung diseases such as cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), and asthma. Scientists at Cambridge University recently created a “mini-lung” model of cystic fibrosis by reprogramming skin cells from patients whose CF was caused by a particular genetic mutation (one that affects 3 out of every 4 CF patients). The skin cells were reprogrammed into an induced pluripotent state, from which they can develop into any kind of cell in the body. The researchers then guided the cells to develop into the distal airway lung tissue most affected by diseases such as CF, certain lung cancers, and emphysema, and demonstrated that the tissue – which the team refers to as “mini-lungs” – was functional. Said lead author Nick Hannan: “We’re confident this process could be scaled up to enable us to screen tens of thousands of compounds and develop mini-lungs with other diseases such as lung cancer and idiopathic pulmonary fibrosis… This is far more practical, should provide more reliable data and is also more ethical than using large numbers of mice for such research.”

3D cell & tissue culture alternative toxicity testing
vascular photo

New non-animal methods for predicting cardiotoxicity

Cardiotoxicity is defined as damage or dysfunction occurring in the heart as a result of exposure to a chemical substance.  Cardiotoxicity is one of the major reasons given when the development of a drug fails or a drug is withdrawn from the market.  With the cost of bringing a new drug to market averaging $2.6 billion USD, there are pressing ethical and economic reasons to find a faster, more accurate way to predict cardiotoxicity.

Developments announced in the last few weeks are encouraging.  UC Berkeley researchers led by Professor Kevin Healy published a study of their functional “heart-on-a-chip:” a 3-dimensional network of adult stem cell-derived heart muscle cells linked together on a microfluidic platform that reproduces blood flow.  The cells beat normally, and responded appropriately to the effects of four well-described heart drugs (isoproterenol, E-4031, verapamil and metoprolol).  According to Healy, “Ultimately, these chips could replace the use of animals to screen drugs for safety and efficacy.” (See the open-access paper here.)

In addition, NC3Rs recently awarded its 2014 3Rs prize to Oliver Britton, a PhD student who created an innovative computational model of cardiac electrophysiology. Because the model incorporates within-species variations in heart properties (which are usually averaged in more simplistic models), it has the potential to more accurately identify potentially toxic drug compounds – allowing them to be pulled from development before animal studies begin.  Quoted in the NC3Rs press release, Professor Ian Kimber said of the model: “Mr Britton’s paper really stood out to the panel because of (its) potential as a replacement for early-stage animal tests in drug safety studies, across a broad range of disciplines. The model has also been developed into a piece of user-friendly software, encouraging uptake and use by industry, which could have an important impact on the reduction of animals in research.”

Human-relevant alternative models such as these have the potential to reduce the cost, time, and numbers of animals expended in drug development, while increasing human safety.

Watch video of the beating UC Berkeley “heart-on-a-chip”:

alternative toxicity testing computational toxicology drug discovery organs-on-chips
Screen Shot 2015-03-08 at 9.46.56 PM

A step closer to 3D-printing organs to replace animal testing

The inventors of a 3D bioprinter capable of printing human stem cells have now developed a synthetic DNA gel that allows them to print a three dimensional scaffold containing live cells. The process brings the Heriot-Watt University team closer to their ultimate aim of 3D-printing organs for transplant or drug-testing.

Read more about the invention in R&D Mag online.

This video from 2013 explains the team’s stem cell-printing process:

3D cell & tissue culture alternative toxicity testing