Today and Tomorrow in Tissue Engineering

In this post, find some thoughts on costs and risks in the future of regenerative medicine and organ engineering, as well as a pointer to a recent Nature article on the field of tissue engineering. By all accounts researchers have come a long way in the past decade towards the goals of new organs on demand, perfect healing of any injury, and restoration of age-damaged tissues. The reward for all that has been achieved to date is a clear view ahead to show that a great deal more is left to be accomplished. Progress continues, however, and the regenerative treatments and transplants of the next decade will look like the science fiction of past generations - as is only right.

Consider that the shape of the technology landscape is at root determined by costs. After scientists in any given field are far enough beyond fundamental research to understand the bounds of the possible for the next twenty years, research programs then tend to aim downhill at the implementations and outcomes that cost less, are more efficient, and cause less trouble. Why aim to build something that will be an expensive source of problems and few benefits when you don't have to? Of course no group of humans are completely rational, but over the long term economic incentives usually win out.

This is just as true for tissue engineering as for any other field of research and development. A great deal of effort is presently going towards the ability to create organs on demand, with the primary focus neing on decellularization: not growing organs from scratch, but taking a donor organ, possibly not even human, clearing out its cells, and replacing them with new cells derived from a patient. As an implementation this will be a great improvement over the present state of organ transplantation. Yet in the grand scheme of things this is all still a highly expensive, risky, and traumatic set of medical procedures. Organ replacement is major surgery, and major surgeries require highly trained medical teams, extended hospitalization, and an attendant risk of death. This is the standard because there is no better alternative today.

So consider this picture of cost and risk for a moment. It really doesn't seem likely that the advances in tissue engineering needed to be able to grow patient-matched organs from a small skin sample, taking place between now and the 2030s, will then be coupled with extensive transplant surgeries. It's a viable approach in the case of the comparatively rare traumatic accidents suffered by young and robust people, but just won't work as a way to address the consequences of degenerative aging across the entire population. You won't see organ factories churning away to support the old, while everyone undergoes many complex surgeries in their 60s and 70s. It is impractical: excessive cost, excessive risk. We can think about the outer limits of the possible given the ability to regrow any organ, but it seems unlikely that full body replacement or other science-fiction staples will actually happen as a matter of course, rather than being a rare and risky attempt at saving a life when nothing else can possibly work.

Much more likely is that the very same progress in biotechnology that allows for the construction of patient-matched organs from scratch will also allow for considerable regeneration of age-damaged organs in situ. It is all a matter of control over cells, their states, and their signaling to produce a coordinated reconstruction of tissues. This would have to be coupled with other rejuvenation treatments to clear out accumulated metabolic waste in tissues, such as cross-links, lipofusin, and amyloid, and repair other forms of damage in long-lived cells that remain in place throughout the treatment. The business of repairing organs in place, especially those that do not naturally regenerate all that well such as the heart, is probably going to be more complex to achieve than clearance of waste, however. If there is anything that today's investigations into regeneration can teach us, it is that all cellular activities are exceedingly complicated.

The cost in the case of in situ regeneration is a very different picture from that of transplantation. In place of surgeries, hospitalization, and exceedingly expensive medical teams you have mass-produced infusions carried out in out-patient clinics, coupled with diagnostic tests to monitor progress. This is more than an order of magnitude less expensive if you look at today's medical costs for similar treatments, and further the risk of death and complication is far less pronounced. So bear this all in mind when looking at the state of tissue engineering today:

Tissue engineering: Organs from the lab

In their quest to create organs in the laboratory, researchers have come a long way. Engineered tissues are already used in medical research and have even entered clinical trials. But they are much simpler than the real thing. To make a stomach, a lab might use 3D printing to create a mould that could be seeded with the appropriate cells. But without cues provided by blood flow and interactions with other tissues, the result would be simply a stomach-shaped statue, unable to digest or growl. An organ is much more than a mass of cells arranged in a particular configuration: it also has support scaffolds, blood vessels to deliver nutrients and signal molecules, and a hierarchy of intricate control functions that can respond to internal and external cues.

All this makes it tough to build a functional, physiologically relevant organ in the lab. But tissue engineers are making inroads into the problem. To try to tackle the biological complexity of organs, they can choose from various fabrication approaches. One method is to place cells into elaborate, but still simplified models of an organ the size of a microscope slide, which can then be connected together to probe how organs interact. These miniature 'organs-on-chips' provide a unique vantage into organ function and disease, and for applications such as toxicity tests of drug candidates. An alternative approach is to foster the ability of cells to self-assemble, in the hope that they will recapitulate actual organ development and reveal insights into the process.

Whatever the strategy, researchers can start with biologically simple approaches, and then add complexity to the model a little at a time. Just how similar an artificial version of an organ needs to be to its original depends on the questions that are being asked of it. Artificial organs may look very different from their in vivo counterparts but nonetheless be useful for drug testing and basic research. Whether the goal is to understand an organ or to replace it, the eventual aim is an engineered system that functions as reliably as the real thing. Researchers across the world are using these systems to address a wealth of important questions. They can, for example, help to reveal how cancer cells detach from a tumour to invade other tissues, and allow scientists to recapitulate processes in disease and development, such as what might go awry in neurodevelopmental disorders.

Ultimately, the usefulness of the tool is what is important, not the specific approach that is chosen. Engineered tissues are starting to allow incisive experiments and even replacement therapies. And perfectly mirroring nature may not, in all cases, be what is needed. What is critical is that the organ has enough complexity to accomplish its function. Whether it be a patch for damaged hearts, a better toxicity test or an insight into a devastating brain disease, tissue engineering delivers what scientists crave: more understanding, and the potential to help people.


Excellent post.

For one thing, even if one could afford multiple transplants, and even if the risk of death is low... it would still be an ordeal. Who wants that? And then you get to redo it 10 or 20 years later? I do not care how much money you have... I do not think you want to become Frankenstein's monster...

And let us not forget that you cannot very well transplant a new brain... There are other organs where transplantation is likely very difficult. For example, a heart transplant can never be a trivial matter...

So the real goal has to be in situ regeneration. And we already know that stem cells are the key.

Vaguely related: Looks like one can grow a thymus gland inside a mouse...

Posted by: Daniel Lemire at June 24th, 2015 7:02 PM

Would doing this (in situ regeneration of organs and tissues) make a person look physically younger? What about other physical cosmetic changes? How would, say, plastic surgery be altered by this technology, if at all?

Posted by: APersonOnline at June 25th, 2015 9:32 AM

@Daniel: if you had to redo the transplant a decade or two later, its cost would likely be much cheaper than what you had to pay for the first transplant.
So it's not actually a problem in itself.

The real issue is that one simply cannot transplant every single damaged cell of one's body... so it is clear that transplants will never be a long term solution.

@APersonOnline: my *layman* understanding is that if the underlying mechanisms ruling over one's body can be restored to their optimum, youthful functioning, those inner changes should be reflected outside. I.e. one would indeed look younger.

Thus, plastic surgery would be must less invasive if useful at all. Anti-age procedures such as peeling would be completely abandonned and shape-shifting procedures (nose shortening, etc.) could perhaps be done through gene editing (if that makes any sense, and if it does, it would be far far away).

Posted by: Nico at June 25th, 2015 2:44 PM

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