Making a human connection

As organ-on-a-chip technology advances at pace, the next step is to connect them and understand a new drug’s effects on the entire human body – without having to go to the trouble of using a real one. And, as James J. Hickman explains, we are getting close… very close.

It’s the Holy Grail of drug development, an Arthurian quest that has thwarted researchers for decades and continues to elude them today: Alzheimer’s Disease.

Despite billions of dollars poured into this quest for a cure, there have been few successful Phase III trials to date. And the cost of these trials pales in comparison to the cost of not finding a cure.  There are estimated to be 50 million people in the world with dementia – that’s more than the population of Spain. In the United States alone, there are 5.5 million people living with the disease, with an estimated cost of $277 billion annually; longer life expectancies may bring these figures to 13.3 million people, with an annual cost of more than $1 trillion, by 2050.

The problem? The current standard of preclinical drug evaluation is based on simple cell cultures and animal studies. But animal biology differs from human biology, and countless drugs have passed through animal studies with promising results, only to fail in human clinical trials.

Clearly, we need alternatives. What is needed is a better way to simulate systemic human responses to drugs and other compounds. We need a way to predict potential hurdles earlier in development, saving precious time, resources, and possibly lives.

What ails us While the push to solve the Alzheimer’s problem may be one of the biggest catalysts for the replacement of animal models, it’s far from the only ailment that would benefit from more accurate predictions based on human models. Failures in late-stage clinical trials plague every field of drug development.

Not only does this result in wasted time and money, but it compromises the success of future clinical trials as well. High failure rates in clinical trials deter many physicians and patients from choosing to participate, especially if there is already an approved drug on the market. This becomes a barrier for drugs that aim to treat diseases better than the current standard.

Conversely, diseases without therapies may have more volunteers for clinical trials, but because there are so many prospective drugs for these diseases, companies must compete for the same patients. And rare diseases, which have even fewer patients, would benefit most from an ability to prioritize which drugs enter clinical trials.

Another driver for change has been the cosmetics industry. With new “cruelty-free cosmetics” legislation passed in the European Union, and more being proposed in the U.S., cosmetic companies like L’Oreal and Lush have invested heavily in new in vitro models that more accurately replicate in vivo results.

Have A Heart… and Brain, and Liver One of the most promising new technologies to replace animal models are organs-on-a-chip. These small, microfluidic systems contain engineered microchips that simulate certain aspects of human organs. Lined with human cells and designed to mimic the chemical and mechanical characteristics of their target tissue, the microchips have tiny channels that, in the example of the lung-on-a-chip, accommodate the artificial lung and also simulate inhaling and exhaling. Microelectrode arrays and cantilever systems also allow for noninvasive electronic and mechanical readouts for chronic as well as acute drug studies.

Researchers interested in how a novel compound affects the heart, can turn to heart-on-a-chip models developed by Harvard University’s Wyss Institute or Orlando-based company Hesperos, Inc. These models recreate different functional aspects of the heart, including muscle contraction and electrochemical impulses, and detect how the cells respond to any compound introduced into the system, providing researchers with valuable insights that previously were impossible to see.

It has long stumped clinicians why probiotics work for some people and not others. A gut-on-a-chip system helped researchers from The University of Texas at Austin finally gain insight into the connections between probiotics and intestinal inflammation. By uncoupling multiple factors and reintroducing them one at a time, the researchers were able to show that a leaky intestinal wall is the deciding component of the efficacy of the probiotic.

Better together While these single organs-on-chips are excellent predictors of toxicity and efficacy, the ultimate goal is being able to understand a new drug’s effects on the entire human body. Companies such as Hesperos, Emulate and TissUse have developed systems that connect multiple organs-on-a-chip in order to study their interactions together.

For Alzheimer’s Disease in particular, Hesperos recently transitioned their Phase I grant from the National Institute on Aging to a Phase II to test a multi-organ system to realistically mimic the biology of the disease and the effects of potential new therapies under realistic human physiological conditions. The three-organ system incorporates brain cells (cortical neurons), functioning GI tract and blood-brain-barrier assemblies, in addition to recirculating blood and cerebral spinal fluid surrogates. The model will use both healthy brain cells developed from pluripotent stem cells, and cells with different mutations that are consistent with Alzheimer’s.

The company’s neuromuscular junction model, which recreates human neuronal connections to skeletal muscle, could also prove valuable in the study of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy. Nerve cells (motoneurons) cultivated from human stem cells and primary skeletal muscle cells (myoblasts) are plated on opposite sides of a thin, compartmentalised silicone membrane, creating a barrier that provides electrical and chemical isolation. Over the course of several days, the muscle cells fuse to form muscle fibers (myotubes). The motoneurons project axons through the microtunnels and form neuromuscular junctions with the myotubes. These junctions serve as conduits for communication between the two cell types, similar to what happens in the human body. The result is mini muscles that can be contracted by motoneuron activation or direct electrical stimulation.

Other examples of integrated models include those for thrombosis and immune system modulation by Boston-based Emulate, and those to explore tissue and organ repair by Berlin-based TissUse.

These human-on-a-chip models are transforming the study of how drugs get metabolised in the body and cell signaling molecules produced in response to drugs. One of the most common studies in preclinical trials, for instance, involves determining how a drug is processed in the liver, as the toxicity of drugs can change once metabolised. In some cases, they become less effective; in others, the metabolites that are produced can cause unexpected – and sometimes dangerous – effects. Current human-based in vitro toxicity studies have only limited capacity to predict such systemic heart/liver functional changes, and that has been the demise of many potential therapeutics.

Metabolism can also differ from patient to patient, significantly affecting the outcome of therapeutics. In the era of precision medicine, human-on-a-chip models could be of enormous benefit in tailoring therapies to individual patients. By being able to test therapeutics on a patient’s own cells and see the outcomes, doctors would be able to avoid many adverse drug effects, which account for 770,000 deaths and injuries annually.

Aside from the obvious benefits to the patients’ safety, adverse effects place a significant financial burden on hospitals, which ultimately are passed on to the patients. Add that to the estimated $2 billion it costs for a drug to make it to market, and the price of not putting the money spent on the 90% of drugs that ultimately fail into something that would give a more reliable return, and you have an extremely convincing case for investing in any technology that could streamline the drug discovery and clinical trials process.

Human-on-a-chip models are that technology. In the quest for cures and the battle to find cheaper, safer, more effective and ethical therapeutics, they are becoming increasingly important additions to our scientific arsenal.

Author:

James J. Hickman, Ph.D., Chief Scientist, Hesperos, Inc., Professor of NanoScience Technology Center, UCF.