Kidneys and Livers, Made to Order?

By Seán Finan

Last week, Organovo might just have revolutionised the pharmaceutical industry. The San Diego-based company specialises in producing structures that mimic the behaviours and functions of human tissue, using 3D bioprinting. They announced last week that they were beginning the commercial manufacture and sale of their ExVive Kidney. The product models the proximal tubule of the human kidney and holds significant promise for clinical trials of new drugs. The commercialization of the ExVive Kidney follows the release of ExVive Human Liver Tissue in 2014.

In essence, Organovo is using 3D printing technology to produce samples of “human” tissue that can be used to test the toxicity of new drugs. The printing process, known as 3D bioprinting, involves extracting human cells, culturing them and suspending them in a solution. The resulting “bioink” is fed through a modified 3D printer. Layer by layer, the printer deposits cells, producing a mass with a similar structure and density to a sample of, for example, human liver. Just like “organ on a chip” technology, these synthetic liver and kidney samples present significant advantages over traditional clinical testing.

Traditionally, new drugs have to go through extended periods of testing on animal subjects before they can be tested on humans. However, the animal models used are not always comparable to humans. Significant differences in human/animal physiology may mean that a compound that appears totally safe in mice might be toxic to humans, or visa versa. 3D printed tissue could eliminate thousands of rounds of possibly useless and definitely expensive animal testing. In addition, the technology could save a significant portion of the animals sacrificed each year to the advancement of medical science.

Another typical step in drug development that could be improved by 3D printed tissue is the testing of the new compound on a cultured dish of human cells. The dish usually contains a 2D layer of cells from the relevant organ (kidney, liver, etc). Such a model, however, is often too simple to be an accurate predictor of how a drug will interact within a human body.The 3D structure of printed tissue provides a more realistic testing environment.

Both of these advantages were illustrated in a study carried out by Organovo and Roche on their liver tissue. They set out to test a drug called Trovafloxacin. Originally, the compound had gone through the standard clinical testing process and had been approved for use. However, it was withdrawn after a year on the market when a small number of patients exhibited liver failure and died. The clinical testing, done on animal models and 2D cell cultures, had not shown any such effects at standard doses. The Organovo/Roche study was carried out after the drug had been withdrawn, using Organovo’s 3D printed liver tissue. The toxic effects of the drug were immediately apparent in the 3D tissue, compared to a 2D cultured control. The study asserts that the discrepancy is due to 2D cultures being much less able to model the complexities of cell interaction in a 3D structure.

Two further issues often come with drug development: time and money. On average, a new drug will take 12 years and hundreds of millions of dollars before being granted FDA approval. These costs would be problematic in and of themselves. However, they are compounded by the enormous attrition rate: only one in every ten drugs that begin clinical trials will be eventually granted FDA approval. Many drugs will only be abandoned at very late stages of testing. Advances in 3D bioprinting will likely allow for faster, cheaper testing and a filtering of unsuitable development paths at an earlier stage.

From an industrial point of view, these developments are exciting. However, the predicted next steps are much more thought provoking from the point of view of public policy and medical ethics.

The most immediate next step for the technology is the production of organ “cassettes”. In the US, one is name added to the organ transplant waiting list every fifteen minutes but the list of donors remains small and insufficient. Cassettes have the potential to ameliorate the problem. An organ cassette is a small section of artificially created organ tissue that could potentially be implanted in a failing organ. Often, the patient does not suffer the ill effects of organ failure until the organ has almost completely failed. A cassette implant could be a cost-effective way to bring a patient back into a functional range without a full transplant. Even a finger-sized cassette of kidney tissue could be enough to get a patient off dialysis.

The next logical step for the technology, once cassette technology has been developed, is the production of fully functioning replacement human organs for transplant. Ideally, the cells used could be cultured from the patient’s own cells, to reduce the chances of rejection. It is easy to imagine a Utopian scenario emerging with the advent of the technology. Organ transplant waiting lists would be eliminated: patients approaching organ failure could place an order for a new model as easily as they might get a prosthesis for a missing limb today. Initially, the technology would be beyond the financial means of many but costs would likely come down as time goes on. Quality control and regulatory oversight is obviously important, but there is no reason to believe that the current mechanisms surrounding medical devices could not be updated. A more interesting question is the potential impact of the technology on human longevity. In addition, given the fixation of some with the “natural”, the disappearance of the organ black market is not guaranteed.

The third step, to my mind, is the most interesting: what about better organs? Commentators have long pointed to the potential for modified human organs, enhanced human organs and even supplemental organs. If we can produce an artificial heart that mirrors human function, why not create one that can beat faster? An ear that can pick up quieter sounds? A liver that can happily process more and varied toxins? An Italian research studio, MHOX, hopes to offer replacement eyes by 2027. Users would be able to choose from a range of “enhancements”, including color accentuations. It appears that, sometime soon, biomedical technologies might allow us to see the world through an Instagram filter.

As trite as that may sound, these technologies present pressing ethical questions. What kinds of enhancements do we want to permit? Will all possible enhancements be available to everyone? Will parents be permitted to modify their children? How will these technologies impact society? What about issues of social justice and distribution? Enhancements will undoubtedly begin as luxury goods. However, it seems unlikely that health insurance will stretch to cover enhanced functionality. Those of greater means already have far greater access to established “enhancements” like education, technology, nutrition, etc. Enhanced organs will give those in positions of economic dominance a firm grip on the steering wheel of their own evolution.

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