“No one wanted to believe it,” said molecular geneticist Hans Clevers.
In 2009, Clevers and his team had demonstrated an unusual new method of creating tiny, out-of-the-body replicas of human organs that could be used to study disease. These replicas were 3-dimensional organoids generated from human cells that perfectly replicated the structure of cells lining the intestine, and therefore could be studied and tested without using human volunteers.
(While it might seem as if this was a guaranteed winner in the books in terms of science innovation, Clevers and his team were rejected by several publications, before Nature finally published the report.)
Organoids could be a genius scientific workaround on a basic problem: How do we effectively, scientifically, but safely run experiments about humans? The little organs are poised to be a gamechanger in figuring out how cures to diseases could be derived. In fact, volunteers’ organoids can act as proxies that will stand in for them.
Testing new drugs and medical treatments is perilous, cumbersome, and time-consuming. More than 80 percent of new drugs tested in the U.S. to determine if they are safe for patient use fail during clinical trials because they prove to be ineffective. More than 30 percent are found to be toxic. “There is an urgent need for improved systems to accurately predict the effects of drugs, chemicals, and biological agents on the human body,” Anthony Atala, director of the Wake Forest Institute for Regenerative Medicine, said.
Which makes organoids seem like a lifesaver that can speed up and ensure the safety of the drug testing process. Innovations that generate organoids, in addition to bioprinting, include organ-on-a-chip technology and tissue-chips, which situate the organoid on a microchip.
In addition to generating organoids using bioprinters, other methods of creating organoids are being researched. Some organoids are created in lab dishes. Others use stem cells and other cellular materials to create organoids include placing tiny, testable organs on a microchip. These are called tissue-chips, which are not to be confused with organ-on-a-chip technology—both use different combinations of humans cells and materials to create either miniature organs or tissues.
One limitation of testing drugs on organoids alone is that they are isolated from the nervous system and blood system, whereas the drug could impact the related processes. To address this, scientists are linking organs-on-a-chip together, so that they form a “body-on-a-chip.” In this way, they are joined together on chips just as they are joined together inside the human body.
The U.S. Food and Drug Administration has not yet approved any of these methods, but is reviewing them. The FDA partners with the National Center for Translational Sciences (NCATS), part of the National Institutes of Health, via NCATS’ Tissue Chip for Drug Screening program. “Tissue chips are poised to deliver a paradigm shift in drug discovery,” Dr. Danilo Tagle, associate director of Special Initiatives at NCATS/NIH explained in an email.
As organoid research moves ahead on many fronts, including stem cells, 3D bioprinting has proven to be cost-efficient. A pioneer in the field, Dr. Aleksander Skardal of the Wake Forest School of Medicine’s Institute for Regenerative Medicine, has observed, “The liver and cardiac organoids that we bioprinted into tissue-on-a-chip constructs far surpassed the functionality” of alternatives.
That 80 percent fail-rate of current testing demands something new. For one thing, animal rights’ proponents would welcome the end of clinical trials that don’t involve running experiments on mammals.
Dr. Todd Evans is a professor of surgery and associate dean for research at New York’s Weill Cornell Medicine. Evans and his colleagues have generated stem-cell-derived organoids from colon cancer, and a platform for testing drugs that block disease caused by patient-specific mutations.
“Organoids represent a very important advance for modeling human disease, since they recapitulate at least to some extent the 3D architecture of an organ and thereby much better represent a tissue compared to standard 2D cell culture systems,” Evans wrote to The Daily Beast in an email.
Evans has observed how it’s possible to screen pharmaceutical compounds for effectiveness as candidates for drugs, because organoids can mimic some aspects of cell biology. “However, there are clearly limitations and these approaches will never replace clinical trials,” Evans wrote. “They are still an in vitro (in a laboratory) approach and do not take into account cross-organ communication or a multitude of human physiological and metabolic parameters. This might in the future be somewhat better achieved by ‘organ-on-a-chip’ method.”
Despite limitations, any method that ferrets out weaker drug candidates could save pharmaceutical companies, as well as taxpayers who fund the FDA, millions of dollars. Allevi, one of the pioneer research firms that developed bioprinters, designed a “desktop” bioprinter that measures 12 inches cubed and costs $10,000.
Other companies are jumping in. Pfizer Inc. is collaborating with Cambridge-based research firm Draper to develop liver, gastrointestinal, and other organ models. Colgate-Palmolive is another Draper partner, researching models of gum tissue for testing oral care products.
Use of organ models is “much more predictive” than using animals, Dr. Joseph Charest, Draper’s Biomedical Solutions program manager and director of the Human Organ Initiative, told The Daily Beast in a phone interview.
“What these models are able to do is recreate a disease state,” Charest said. “We can screen a lot of different drugs and compounds, in varying amounts, and we can do this fairly early in the pipeline, which allows you to rule out the bad ones and continue testing the good ones.”
Draper develops multiple organs-on-chips. “We’ve been able to recreate the various organs that form the female reproductive system, and put them on chips. That is one example of how we connect organs,” Charest said. “The system has various pieces of tissue that communicate with each other.
“Shortening the time required to get a drug to the clinic is really the point of all this science and research.”
“Heart-on-a-chip” causes most live hearts to skip a beat. People are “not going to get upset about making a pancreas,” Stanford University’s Bioethics Law professor Henry Greely told The Scientist in 2016. “But the closer you come to making a human brain, the more issues get raised.” Bodies-on-a-chip seem too Frankenstein-esque for some.
Nonetheless, plans include using “human cells from several hundred, if not thousands of individuals, that represent the diverse demographics of the general population for use as surrogate clinical trials on chips,” according to Tagle. “Such platforms hold promise to reduce the cost and time it takes to bring drugs into market but also to minimize risk to patients.”