A perpetual shortage of organ donors has left medical science struggling for ways to combat the rising demand for human organs. Scientists at the University of Pittsburgh, though, may have finally found a solution. After successfully implanting tiny human livers in rats, the team has added weight to the idea that the future of organ transplants may be cultivation, not donation.
Rats Provide the Template
The procedure the researchers developed, began with human skin cells, obtained from donors. These cells were then reverse engineered into stem cells, which were then programmed to grow into the different cells needed to form a human liver. From there, the scientists seeded a “liver scaffold” – a rat-based extracellular matrix (ECM) structure – removing the rat cells and replacing them with human cells. Just perfecting these stages took the research team a decade but once they had mastered these complex steps, it only took them a month to grow the mini livers in vitro.
The team then implanted the livers into five rats, who had been immunosuppressed so that they would not reject the livers. The livers they implanted remained functional for just four days but exhibited traits of human livers – such as secreting bile, urea and other proteins not found in rats.
The researchers note that: “The regenerated human iPSC-derived mini liver containing multiple cell types was tested in vivo and remained functional for 4 days after auxiliary liver transplantation in rats.”
After four days, the team dissected the five rats to see the results of the experiment. Co-author Alejandro Soto-Gutiérrez, a regenerative medicine researcher at the University of Pittsburgh told Genetic Engineering and Biotechnology News: “Seeing that little human organ there inside the animal—brown, looking like a liver—that was pretty cool.”
Despite their initial joy, the team noted that blood flow problems had developed in and around the livers in all five rats. However, they consider their experiment to be a success since blood tests showed traces of human liver proteins in the rat. For the researchers, the next step is to try and make the implanted livers function for longer, and the rats live longer.
The researchers are fully aware that implantation and testing the livers in rats is just the first step in a long road to creating fully-functional organs for humans. If and when Soto-Gutierrez’s team manages to demonstrate fully functional livers, they face another problem and that is based on the issue of getting medical certification for the process they have developed.
Livers are one of the most in-demand organs in the United States. Data from the US Health Resources and Service Administration show that 11,514 adults were on the waiting list for a liver in 2017. Mayo Clinic data notes that only 8,000 transplants were done in 2017. The United Network for Organ Sharing found that 1,184 people died in 2018 waiting for a liver transplant. The reality is that there is just too little supply, while demand is constantly rising.
Even if a person can get a liver, the cost of a transplant is hugely prohibitive. Kaiser Health News found that the average cost of a liver transplant is $812,500 in the USA. That includes pre and post-op care as well as immunosuppressant drugs that must be taken for life to keep people’s bodies from rejecting the transplanted organ.
Soto-Gutierrez is hopeful that his team’s research is a stepping stone towards overcoming these challenges. He believes that the Biofabrication of organs can help close the gap between the supply and demand, as well as reduce costs. There is an added benefit to his approach in that it is also possible to use the method to provide a functional boost to failing livers, giving people crucial extra time while waiting for a transplant.
“What we are planning to do is to start making mini human organs that are universal,” Soto-Gutiérrez told Inverse. This means scientists can bio-fabricate liver grafts that are universally accepted. “That would change the paradigm of transplants.”
Soto-Gutierrez’s team isn’t the only one working on organ cultivation. All over the world, there is currently a huge rush to bioengineer entire organs. Researchers from the Human Genome and Stem Cell Research Center (HUG-CELL) at the University of São Paulo in Brazil successfully managed to 3D bio-print a functional mini-liver in 2019. Made from human blood cells, the mini-liver was able to secrete bile and produce proteins.
One of the key proponents of organ cultivation is the Bioengineered Organs Initiative, a multi-disciplinary research team at Carnegie Mellon University. According to their website, the initiative is “focused on developing a host of technologies that enable fully-functioning long-term replacement organs and ensure their safety and reliability.” A key area of research is 3D bioprinting, which the team is currently working on with lungs and hearts. Right now, researchers can only print small components of an organ, but with advancing technology, entire organs could one day be printed in the lab.
Adam Feinberg, a Professor of Biomedical Engineering and Materials Science said in a press release “It is important to understand that there are many years of research yet to be done. But there should still be excitement that we’re making real progress towards engineering functional human tissues and organs.”
Just creating human organs in the lab is not the end of the road. For bioengineered or 3D printed organs to become widely available, scientists will not only have to overcome lots of scientific hurdles but also have to deal with a lot of red tape.
On the scientific front, the five rats are just a tiny sample. Soto-Gutierrez and his team still have to test their livers in at least a few thousand rat samples before they even get the green light for human experimentation. Assuming they managed to achieve this, the team will have to ensure that their engineered livers are able to function for years, not days.
When it comes to bureaucratic barriers, there are a number of challenges to overcome. Currently, in the US, the Food and Drug Administration (FDA) does not regulate new surgical procedures. Jonathan J. Darrow outlined the bureaucratic mess in his paper for Cornell Law School titled “Explaining the Absence of Surgical Procedure Regulation”. He noted that issues like the structure of the surgical marketplace, the US Constitution’s Commerce Clause and perceived sufficiency of existing regulations all led to the current system.
Organ transplants fall under the Health and Human Services department, not the FDA, but bioengineered organs cannot be classified as regular organs, since they do not come from a donor. As a new medical ‘tool’, they might need certification from the FDA before becoming legal. There is currently no clear instruction on who regulates genetically engineered organs, making it nearly impossible to regulate if something goes wrong.
The ethics of such procedures are also very murky, as noted by Doris Taylor in her paper “Ethics of bioengineering organs and tissues”. One of the key issues she notes is that “the target population for tissue-engineered products primarily comprises patients with serious end-stage diseases, for whom there is rarely any conventional therapy available. These patients are particularly vulnerable to the ‘therapeutic misconception’ (i.e. situations where participants believe they are going to receive therapy and do not recognize that they are enrolled in a clinical study) and are more likely to consent to participate in research studies without fully understanding all the potential outcomes.”
So while the road to successful organ cultivation looks like it will be a long one if regulated and done right, these new methods offer the promise of revolutionising healthcare for millions, not just in the USA but around the world.
Sources: Cell Reports, Bioengineered Organs Initiative, Carnegie Mellon University, Cornell Law School, Expert Opinion on Biological Therapy, Genetic Engineering and Biotechnology News, Inverse, Mayo Clinic, Nature.com, Kaiser Health News, Popular Mechanics, US Health Resources and Services Administration, United Network for Organ Sharing, 3D Printing Industry