Oly Bartley | 6 JUN 2016
Organ donation. It’s an unusual topic for neuroscience (unless you’re talking about this), but the brain might just present the biggest issue preventing the advancement of this essential field. Why? Because a recent innovation relies on growing human organs inside pigs, and the initial studies show that we risk human cells entering the pig brains. What if their brains become too human? What if they start to think like us? Could we end up with a new race of Pig-men? It’s an intriguing idea (that might make you feel a little weird inside), but before we think about the ethical implications of an interspecies brain, let’s think about how this all came about.
The ‘Organ Deficit’
Anyone who has ever tuned into a dodgy medical drama on daytime telly will know that sometimes organs need to be replaced, and without that replacement organ, the patient will die. The problem is getting hold of donor organs is difficult! You need it to be fresh, you need it to be compatible with the patient, and you need it before the patient’s time runs out. What people often forget is that you also need to hope someone else tragically died before their time, but also before you do.
If that wasn’t distressing enough, if you look at the numbers you’ll see the current system is not only morbid, but also failing us. In the USA alone twenty two people die everyday waiting for an organ (http://www.organdonor.gov/about/data.html) and those who are lucky enough to receive one often have to suffer for many years before hand (https://www.organdonation.nhs.uk/real-life-stories/people-who-are-waiting-for-a-transplant/) . We are suffering from an Organ Deficit, and this one won’t be fixed with a little austerity.
Wouldn’t it be better if a doctor could simply say “Your kidney is failing, but don’t worry, we’ll just grow you a new one and you’ll be right as rain again!”? Nobody would have to die to get that organ, or suffer for years on a waiting list. The only people who might actually suffer are the scriptwriters of those medical dramas (and mildly at that). Growing new tissue for patients is a core aim of scientists working in regenerative medicine. But there is a list of problems that have to be overcome first. Unfortunately, that ‘list of problems’ isn’t a short one, and despite decades of research, several big leaps, and even a few Nobel prizes, the end still isn’t in sight. Meanwhile, another day passes and another twenty two people have missed their window.
What we need is a temporary fix; some way to increase the number of organs available to help the people in need now, and allow scientists to continue researching in the background for the ideal solution. Something with a fancy long name (and an unnecessary number of g’s) – something like Xenogeneic Organogenesis.
Ok, I admit, I made that term up. But it makes sense! Let me translate. ‘Xenogeneic’ means working with cells of two different species, and ‘Organogenesis’ means growing organs. Simply put, we’re talking about growing new human organs inside of host animals. How? Well, in a breakthrough paper Kobayashi et al. (2010) demonstrated a way to grow fully formed rat organs inside a mouse.
This was achieved through a technique called Blastocyst Complementation; when an embryo is injected with stem cells from a second animal. The resulting animal is called a ‘chimeric animal’, because it is made of cells from the two different animals, and those cells are genetically independent of each other. This has been successfully achieved in animals of the same species before (e.g. putting mouse stem cells into a mouse embryo), but here they crossed species by creating a mouse-rat chimera and a rat-mouse chimera (See image A, below, taken from Solter, 2010). The chimeras were morphologically similar to the animal species of the host embryo (and mother), but crucially, the chimeras were composed of cells derived from both species, randomly placed across the animals. In other words, whilst the mouse-rat chimera looked like a mouse, if you looked closely at any body part then you would see it was in fact built of both mouse and rat cells. The researchers believe this happened because the stem cells don’t alter the ‘blueprints’ that the embryo already has. Instead, they grow just like other embryonic stem cells, following chemical directions given to them and gradually building the animal according to those instructions.
Satisfied they could use blastocyst complementation to create inter-species chimeric animals, the researchers went one step further. They genetically modified a mouse embryo to prevent it from growing a pancreas (in image B this is called the ‘Pdx1-/-’ strain: a name that refers to the gene that was removed) and injected unmodified rat stem cells into the embryo. They were hoping that by preventing the mouse embryo’s stem cells from being able to form a pancreas, the chemical directions to build a pancreas would only be followed by the newly introduced rat stem cells. And guess what? It worked! They reported the pancreas inside the Pdx1-/- strain was built entirely of rat cells (See image B, above, taken from Solter, 2010).
This got a lot of people very excited! Would it be possible to do this with human organs? Could we farm human organs like we do food? Could we even use iPS technology to grow autologous patient-specific organs to improve the transplantation process? The lab has now begun tackling these sorts of questions, starting by testing the viability of pig-human chimeric embryos (pig embryos with human stem cells, to make pigs built with human cells), to see if the two cell types will contribute to the animal in the same way the mouse and rat cells did.
Freaky! Is this why we’re worried about creating a race of Pig-men?
Yep. What I didn’t explain above is that the brains of those chimeric animals, like the hearts, were also comprised of both mouse and rat cells. Considering that the scientific community generally accepts it is our incredible brain that separates us as a species, what would happen if human brain cells made their way into the pig brain? How human could they become? Would they begin to look like us? Act like us? Talk like us? Even think like us? How human would they have to become before we gave them human rights? Where is the legal, moral and ethical line between animal and human when one creature is a mixture of the two?
Most people (not all) would agree that sacrificing a farm animal’s life to save a human’s is an acceptable cause. After all, we already do that for bacon… a cause that even I (an avid carnivore) cannot claim as exactly necessary. But sacrificing a half pig, half human? That sounds like something you’d find in a horror story!
Even though many scientists believe an intelligent pig-human chimera is biologically implausible (let alone a speaking one), no-one is willing to say it’s impossible. Concerns over a potentially altered cognitive state have led to the US based NIH (a.k.a USA government funding central) to announce that they will not be supporting any research that involves introducing human cells into non-human embryos (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-158.html). The fact is we don’t know enough about how the human brain develops or works. We don’t understand how the biological structures, electronic signals, and chemical balances translate to the gestalt mind experience. We don’t have one easy answer that makes “being a human” and “being a pig” distinct enough, to know how to interact morally with a pig-human chimera. And that makes me (and probably you) rather uncomfortable.
It’s also giving me all kinds of flashbacks to my school theatre group’s rendition of Animal Farm (I played Boy. Sounds like a rubbish part right? You’re wrong. He’s the narrator!). I can’t help but wonder if Orwell ever imagined his metaphorical work could have literal connotations too…
“The creatures outside looked from pig to man, and from man to pig, and from pig to man again; but already it was impossible to say which was which.”
Fortunately, nobody wants to create pig-men (at least I don’t think there is a Dr. Moreau in the research team?), and the pig-human embryos being generated are being terminated long before they grow into anything substantial. The lab wants to be careful, to understand the potential consequences before even considering letting a pig-human foetus go to full term. Naturally this means there’s a heck of a lot of work to be done, but xenogeneic organogenesis (copyright: Me) is still decades ahead of other organ replacement models. Continued work could mean viable results a lot sooner, saving countless lives. At the very least, it would enable us to study natural organ growth directly, fast-tracking dish-driven stem cell models.
Is this really the best solution available to solve the Organ Deficit?
Good question reader! Let’s bring this discussion back to a simpler solution. Late last year (1st Dec 2015) Wales (home of The Brain Domain) became the first country in the UK to change the law to make organ donation ‘opt-out’ instead of ‘opt-in’.
This isn’t a new idea. Many other countries have implemented an opt-out system before, and generally statistics look good (http://webs.wofford.edu/pechwj/Do%20Defaults%20Save%20Lives.pdf) . Yet there is ongoing debate about whether this change will be sufficient alone (http://www.bbc.co.uk/news/uk-wales-34932951). Cultural variations and infrastructural differences in health care systems have a large impact on the effectiveness of such legislation, but generally speaking we should see some improvement. If that improvement is sufficient, then the policy will likely be rolled out across the rest of the UK (fingers crossed we beat the four years it took to get the plastic bag charge across the river Severn!). But if that is still not enough, then we’ll just have to hope those at Stanford can find a way to make xenogeneic organogenesis a real no-brainer.
- Kobayashi, T., Yamaguchi, T., Hamanaka, S., Kato-Itoh, M., Yamazaki, Y., Ibata, M., Sato, H., Lee, Y.S., Usui, J.I., Knisely, A.S. and Hirabayashi, M., 2010. Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells. Cell, 142(5), pp.787-799.
- Solter, D. (2010). Viable rat-mouse chimeras: where do we go from here?. Cell, 142(5), 676-678.