We Could Regrow Livers

There are currently 16,000 Americans on the waiting list for a liver transplant, but there are only enough livers for 6000 transplants a year.  Every year, more than 1500 people die waiting for a liver transplant.

One commonly mentioned idea to close the organ donor gap is to pay people for their organs to incentivize more donation.

New science may open other possibilities as well. Eric Lagasse’s lab at the University of Pittsburgh’s McGowan Center for Regenerative Medicine has been experimenting with lymph nodes as a transplantation site.  Simply put, if you put hepatocytes (liver cells) into a lymph node, the node will grow into a functioning mini-liver.  This rescues mice from lethal liver failure.

Injecting cells into lymph nodes also works with thymus cells, which can give athymic mice a functioning immune system.  And it works with pancreas cells, which, when injected into lymph nodes, can rescue mice from diabetes.

The procedure only partially works with kidneys, which are much more structurally complex — the cells implanted into lymph nodes show some signs of growing into nephrons, but aren’t completely functional.

Interestingly enough, this effect was documented in 1963 by immunologist Ira Green. If you remove the spleen or thymus from a mouse, and replace it with ectopically transplanted spleen or thymus tissue, the tissue grows into a functioning, structurally normal, miniature thymus or spleen.

In 1979, researchers found that hepatocytes injected into the rat spleen (which is part of the lymphatic system and analogous to a large lymph node) functioned normally and grew to take up 40% of the spleen.

There have been clinical studies in humans of hepatocyte  transplantation, generally with less than impressive results, but generally these hepatocytes are infused through the portal vein or renal artery, whence a small fraction of the cells reach the liver and spleen. It’s still possible that injection into lymph nodes would be more effective. As the above article states,

One possible explanation for the discrepancy between the laboratory and clinical outcomes may relate to the route of hepatocyte delivery. Following infusion using direct splenic puncture, dramatic corrections in liver function have accompanied hepatocyte transplantation in laboratory animals. In patients with cirrhosis, however, allogeneic hepatocytes have been delivered to the spleen exclusively through the splenic artery.

A natural question to ask is: why isn’t more being done with this?  “Inject liver cells into lymph nodes” is not a particularly high-tech idea (as far as my layman’s understanding goes.)  Nor is it a completely new idea; researchers have known for decades that hepatocytes grow into functioning liver tissue, particularly when injected into the lymphatic system.  You’d think that a procedure that could replace liver transplants would be profitable and that founding a biotech company to do human trials would be a tremendous opportunity, especially since there is less scientific risk than there often is with other early-stage biomedical research (e.g. preclinical drugs).

Part of the problem is that the business model in such cases is unclear.  This has been a pattern we noticed several times at MetaMed; often a medical breakthrough is not a new drug or device, but a novel medical procedure.  It is not permissible to enforce a patent (e.g. to sue someone for infringement) on a medical or surgical procedure.  Medical ethics (for instance, see this statement from the American Academy of Orthopedic Surgeons) generally holds that it’s unethical to patent a surgical procedure.  This means that it’s difficult to profitoff the invention of a medical or surgical procedure.  The total value of being able to offer a liver transplant to anyone who wants one would be billions of dollars a year– but it’s not clear how anybody can capture that value, so there’s less incentive (apart from humanitarian motives) to develop and implement such a procedure.

It also means that it’s difficult to disseminate information about new medical or surgical procedures. Learning to perform procedures is an apprenticeship process; one doctor has to teach another. This, combined with natural risk aversion, means the spread of new procedures is slow. If a new surgery had been shown conclusively, by excellent experimental evidence, to be better than the old one, it still would not necessarily sweep the nation; if the clinician who pioneered the new surgery isn’t a natural evangelist, it may never be performed in more than one hospital.

This seems to be an opportunity in search of a viable strategy. There are spectacular results in regenerative medicine (frequently coming out of the McGowan Institute — see Stephen Badylak’s work in tissue regeneration).  It’s not clear to me how one would make those results “scale” in the sense that we’re used to in tech companies.  But if you could figure out a model, the market size is mind-boggling.

If you had a way to regrow organs, how would you validate it experimentally?And how would you get it to patients?  And how would you do it fast enough not to lose tens of thousands of lives from delay?