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Good Science

March 2018


March 26, 2018   organ on a chip

 

The Physicians Committee is posting a series of informative articles to provide readers a more in-depth understanding of human-relevant research models. This occasional series will provide readers with more information about how new technologies promise to revolutionize scientific research, product testing, and even medical education. Scientists working on these technologies are pioneering a more ethical and effective approach—and we can’t wait to tell you more.

Microengineered Organ-Chip is made out of a flexible polymer that features tiny channels that can be lined with thousands of living human cells. Image credit: Emulate, Inc.

Microengineered Organ-Chip is made out of a flexible polymer that features tiny channels that can be lined with thousands of living human cells.

Image credit: Emulate, Inc.

Is the Pepto-Bismol theme song the anthem to your life? You aren’t alone! Digestive diseases affect 25 percent of the United States population, yet there are few treatments available to help. The human intestine-on-a-chip (Intestine-Chip) technology may help ease your gastrointestinal (GI) system by revolutionizing our understanding of digestive diseases and paving the way for future treatments.

The gastrointestinal system is responsible for the breakdown of food and liquid into nutrients for the body to absorb and use for energy, growth, and cell repair. The bacteria in the intestine—the gut microbiome—plays an important role in digestion. Microbes aid in the metabolism of food, the production of certain vitamins (like vitamin K), and are essential for immune function and overall health. Many drugs that are ingested orally can affect the delicate equilibrium of the microbiome. An Intestine-Chip model can help illuminate how to protect the microbiome.  

Scientists from Cedars-Sinai Medical Center and Emulate, Inc. have bioengineered a new Intestine-Chip. This innovative in vitro (cell culture) model combines the microfluidic organ-on-a-chip technology with organoid-based methods by incorporating human cells onto a microengineered chip about the size of a USB stick. This IntestineChip is created using blood and skin cells that are reprogrammed into induced pluripotent stem cells, which can produce any type of cell. Using special proteins and other substances, the cells are able to generate into organoids or three-dimensional mini organs.

The chips are created by casting an upper and lower layer with microfluidic channels, using a flexible polymer with a silicon membrane in between. The layers are united together using plasma bonding to form the complete chip. The cells are then seeded into the channels to form the intestinal lining. This Intestine-Chip is unique because it can replicate many anatomical functions of the human intestines. It has to ability to simulate physiological fluid flow and peristalsis-like motions, which allow scientists to analyze the intestinal physiology and pathophysiology as they would inside the human body. This chip offers insight into the biological mechanisms of the intestinal epithelium, the layer of cells that forms the lining of both the small and large intestine and which plays a major role in many GI diseases.  

The Intestine-Chip‘s ability to accurately replicate the human intestinal epithelium has the potential to drastically improve treatments for the millions of people who suffer from debilitating GI diseases such as Crohn’s Disease, inflammatory bowel disease, and ulcerative colitis. Since these chips can be developed using a person’s own tissue, they have the potential to set a new standard for personalized medicine. Rather than testing numerous drugs on animals, which may be costly and ineffective, or in a living patient, scientists could use a patient’s own cells to develop a personalized Intestine-Chip. Different drugs can then be tested in the chip to determine which treatment is best for each individual patient. This human-relevant system is a promising alternative to unsuitable methods using animals, can be used for drug discovery, and will lead to safer and improved treatments. This is a monumental technology that will improve researchers’ understanding of how medicines, diseases, and foods interact with a person’s microbiome and affect an individual’s health. 

Recent news reports indicate that at least two pharmaceutical companies, Roche and Takeda, have partnered with Emulate to use the organ chips in drug discovery and development. Roche will use the chips in place of animals to run drug safety and efficacy tests. Takeda will use the Intestine-Chip to discover and evaluate GI disease drugs and biomarkers.

Link to article: https://www.sciencedirect.com/science/article/pii/S2352345X1730187X

Workman MJ, Gleeson JP, Troisi EJ. Estrada HQ, Kerns SJ, Hinojosa CD, et al. Enhanced utilization of induced pluripotent stem cell-derived human intestinal organoids using microengineered chips. Cellular and Molecular Gastroenterology and Hepatology. 2017. https://doi.org/10.1016/j.jcmgh.2017.12.008

 

Following the news that the National Institutes of Health (NIH) budget has increased by $3 billion for fiscal year 2018, the Physicians Committee wrote to NIH director Frances Collins, urging Collins to use the additional funds to prioritize human-relevant research. Read the letter below:


Physicians Committee Letterhead

March 23, 2018 

Dr. Francis Collins
Director, National Institutes of Health 9000 Rockville Pike
Bethesda, Maryland 20892 

Dear Dr. Collins, 

I am writing on behalf of the Physicians Committee for Responsible Medicine and our membership of more than 12,000 physicians and more than 175,000 other medical professionals, scientists, educators, and supportive lay members about increased funds provided to you in the recent fiscal year 2018 (FY18) Labor, Health and Human Services, and Education funding bill. We recommend that you invest this additional $3 billion in human-relevant research, not animal research. 

The National Institutes of Health (NIH) is the nation’s leader in biomedical research and has the potential to fund groundbreaking discoveries to improve health and save lives. As you are aware, animal studies are costly, time-consuming, and often poorly predictive of human health. With a continuously growing population in the United States and new and emerging health issues always on the horizon, changes in our approach to research funding are urgently needed. 

Currently, thousands of diseases affect humans that do not have effective treatments. Yet, new drugs take over 10 years to develop, typically cost more than $2 billion, and have a 95 percent failure rate in human clinical trials. Animals will always have physiological, anatomical, and genetic differences from humans that will impede the translation of research findings derived from animal biology. It is time to invest more in the development and application of human-based methods. We recognize that NIH is beginning to invest more in human-relevant models via the National Center for Advancing Translational Sciences and other initiatives; however this investment pales in comparison to the amount put towards animal research. We must shift this balance. 

This bill allocates $1.8 billion for Alzheimer’s disease research, which is the only top-ten chronic disease without an effective intervention for treatment or prevention. Today, 5.3 million Americans suffer from Alzheimer’s, and this number is expected to triple by 2050. At present, Alzheimer’s research relies on animal models, despite the fact that 99.6 percent of Alzheimer’s drugs that appear successful in animals fail in human trials, and it is known to scientists that animals do not develop the disease to the same capacity as humans. Rather than misusing the supplementary $414 million that is being allocated to Alzheimer’s research for FY18 on ineffective animal research, it should be devoted to efficient, human- relevant research. 

There are many humane and reliable human-relevant methods that are already being used to conduct scientific research and regulatory testing. Organs-on-chips and the multi-organ body-on-a-chip are cutting edge platforms that can significantly advance drug and toxicology screening and open the door for personalized medicine. Human-derived stem cells are redefining research by improving scientists’ understanding of how diseases progress and allowing the development of therapies for regenerative medicine. Three-dimensional bioprinting has made enormous advances, allowing the expansion of new therapies and diagnostics. This technology has the potential to one day manufacture custom-made organs. 

Adequate funding and support is severely needed to increase the development and application of these technologies. Investment in human-relevant methods should be prioritized over unhelpful and ethically questionable “humanized” mice and animal-human chimeras. In addition to funding extramural investigative research using human-relevant models, we suggest NIH consider other strategies to support a transition away from animal research. For example, increased resources and incentives could be provided to allow easier access to human tissues for research, grant applications featuring human- relevant models could be “fast-tracked” for approval, and specific calls for proposals could specify human-relevant models. 

We urge NIH to take this opportunity to increase its funding of groundbreaking human-relevant research, making research more ethical and effective and improving public health. Thank you for your attention to this urgent and important matter. 

Sincerely, 

Janine McCarthy, MPH Research Policy Specialist 

Kristie Sullivan, MPH Vice President for Research Policy

March 1, 2018   animal testing

 

It’s that time of year again! The Society of Toxicology (SOT) annual meeting—the world’s largest gathering of toxicologists—is taking place March 11-15 in San Antonio, Texas. Just like last year, Physicians Committee scientists are actively participating in sessions throughout the conference to advance their work in promoting more effective, nonanimal toxicological test methods. 

We are again sponsoring events to engage and train toxicologists and regulatory scientists with scientific and policy initiatives to replace animal tests with more human-relevant methods, including our Adverse Outcome Pathway seminar. We are also participating in multiple poster sessions to inform attendees of current topics in predictive toxicology and alternative test methods. 

Here is a select list of Physicians Committee-sponsored sessions or events. If you are attending SOT, we invite you to attend these sessions. Please contact Kristie Sullivan (ksullivan@pcrm.org) for more information. 

You can also download a curated list of other SOT scientific sessions and events of interest to scientists working with in vitro and computational methods. 

Monday, March 12

Poster Session:  Regulatory Policy and Policy Evaluation

The Preclinical Innovation and Patient Safety Initiative: Recommendations for Modernizing Preclinical Testing

Presenting Author: Elizabeth Baker

9:15 a.m. – 4:30 p.m. (Author Attended: 10:45 a.m. – 12:15 p.m.)

Convention Center Exhibit Hall

Abstract: Preclinical drug testing is critical to understanding the toxicity, pharmacology, and pharmacokinetics of candidate drugs. The Preclinical Innovation and Patient Safety (PIPS) Initiative fosters collaboration among drug development stakeholders—including federal agencies, patient, research and health organizations, academia, technology companies, and the pharmaceutical industry—to implement modern human-focused preclinical approaches. Participants recognize that more predictive approaches are fundamental to the timelier delivery of safe and effective medicines. This presentation highlights the scientific, regulatory, policy, training and educational recommendations made by a group of stakeholders during the kick-off roundtable in January 2017, and explores three projects identified by PIPS participants as likely to provide high impact on the field of toxicology. First, modern approaches to validation should incorporate human data. This is the only way to overcome the challenge of comparing human in vitro approaches to currently available animal safety data. The legislation 21st Century Cures and the Prescription Drug User Fee Act mandate that FDA make real world human data/evidence more accessible. PIPS identified that implementation of the mandates should include making real world evidence available to method developers for validation purposes in order to better understand a method’s predictive ability. Second, researchers must have access to human cells and high-quality tissues in order to use human-focused approaches. Currently, there are no guidelines for collection and care of human cells and tissues intended to be used for research. PIPS is coordinating efforts to develop guidelines to ensure the increasing demand is met. Third, despite significant private and public investment in the development of human-focused approaches, many FDA regulations require animal data. While industry may use modern approaches for internal decision-making, the regulatory requirements prioritize animal data and dis-incentivize use of modern approaches. PIPS has identified the regulations and coordinated multiple projects to push the agency to update the regulations to reflect flexibility that allows for evolving science. 

Tuesday, March 13

Hands-On Seminar: Creating an Adverse Outcome Pathway in the AOP Wiki

5 – 7 p.m.

Grand Hyatt Rooms Bowie A – B 

The Human Toxicology Project Consortium and the Physicians Committee for Responsible Medicine invite you to deepen your understanding of the AOP Wiki and gain experience entering an Adverse Outcome Pathway in a structured, hands-on seminar Tuesday evening. 

Version 2.2 of the AOP Wiki was released in January 2018.  This seminar will be ideal for those wishing to gain some hands-on experience with the new version as well as those who are new to the AOP concept. We will also present an available online course on AOPs, and course attendees will work through a case example in small groups

See full agenda and please register in advance to ksullivan@pcrm.org. Registration is appreciated, but not required. Please indicate whether you will bring a laptop.

Thursday, March 15

Poster Session:  Late-Breaking 01: Model Systems

Title: Towards an IATA for Chemical Respiratory Sensitization: Establishment of Reference Chemicals to Evaluate In Vitro and In Silico Approaches

Presenting Author: Kristie Sullivan

8:30 – 11:30 a.m.

Convention Center Hall 1

Abstract: Public health and regulatory needs require approaches to detect and discriminate respiratory sensitizers from dermal sensitizers; however no single method or strategy is generally accepted. An Adverse Outcome Pathway (AOP) for respiratory tract sensitization by low molecular weight organic chemicals identifies several promising in vitro methods. Most of these methods have only been assessed with a few well-known respiratory sensitizers (e.g., toluene diisocyanate or trimellitic anhydride). To further evaluate the utility of these in vitro methods, we have set out to build a more comprehensive list of reference chemicals, including known respiratory irritants, non-sensitizers, and dermal sensitizers. The ideal list of respiratory sensitizers should cover a range of chemical classes and include “challenging” chemicals, such as respiratory sensitizers thought to elicit effects through dermal exposure and those for which specific-IgE has not been detected in humans. To build the list, we are conducting a review of established structure-based profilers, recent literature, and human clinical reports, focusing on data verified in humans for translatability to human health outcomes. We are also making use of the Abstract Sifter literature review tool (Baker et al., (2007)) to identify additional potential respiratory sensitizers. Briefly, a set of PubMed MeSH terms describing adverse effects (AEs) for 92 known sensitizers was used to query a large database of chemicals and AEs, yielding over 7000 chemicals of potential interest. The top 500 ranked chemicals (based on article counts) are currently undergoing manual review. This reference chemical list is an important step towards an assessment of potential test methods and creation of internationally-harmonized integrated approaches for the detection of chemical respiratory sensitizers.