Boston T-ransplant Party

Here is a nice story showing the cutting edge science you can find in the the most everyday items. You have probably made lots of sand castles in your life, but have you ever wondered why it is so easy?  It's not necessarily easy to make the fortification of your dreams, but it is very easy to make damp sand stick together, you don't have to mix sand with water in a specific recipe, it just seems to work.  In fact if you mix between about 1% and 20% water by volume with your sand the strength of the mixture is almost constant.  This is surprising because that is a huge change in the amount of water.

You may not have asked this question but Mario Scheel in the Max Plank Institute in Gottigen, Germany did.  Finding out the answer is quite difficult, because it is a three dimensional problem and sand is opaque so it is very hard to view what is going on.  He and his colleagues managed to look inside a sand pile using X-ray microtomography.  This is basically a miniature version of a CAT scanner you find in hospitals.  It takes a series of X-ray images from different directions, and then uses a computer to put them together into a 3D model of what is going on.

They took many 3D images of piles of sand with different amounts of water and measured the properties of the mixtures.

The water seems to form little bridges between the sand grains, a bit like two trumpet bells glued to one another.  The water's surface tension will then act to pull the two grains together giving the wet sand its strength.  You would have thought that the more water you add the more bridges that form and so the stronger the sand and Mario found this was true up to about 1% water.  Beyond this point bridges get close enough together that they start to merge forming bigger bridges and blobs of water.  These blobs are weaker than the small bridges, so this cancels out the increase in water and leads to no change in strength.

This may sound like just fascinating news for the under eights, but understanding how granular materials behave is very important in understanding soils, concrete and the stability of slopes, amongst many other things.

Scientists in Canada have confirmed that oestrogens from OCPs in sewage water can spill over into rivers and feminise fish. Moreover it can have previously unrecognised impacts on other parts of the food chain.

Karen Kidd is a researcher at the Uni of New Brunswick.  She added oestrogens to the water of a lake in Canada for 3 years and monitored the fish population.  The short-lived fish, like the fat head minnow, feminised and then showed dramatic reductions in population as clearly the affected males were breeding less effectively.

The populations of longer-lived fish were less impacted because they were less dependent on rapid breeding to replace their numbers.  BUT, big fish, that were not affected directly by the oestrogens, showed a very large drop in population in subsequent years - because they had lost their food source of smaller fish.

Consequently there's a twist in the tale of this fish story because oestrogens, it seems, can have indirect effects on fish populations that were previously unrecognised.  The good news is that oestrogens only last about 12 days in the environment, so if we sort out the sewage situation then the fish should bounce back, which is what happened within 3 years in the canadian lake after the oestrogen administrations were stopped.

One of the biggest breakthroughs in the transplantation field has been the discovery of immuno-suppressants.  These are drugs that can partially switch off the immune system to prevent it from rejecting what the body sees as foreign tissue or non-self in a donor organ.  But this comes at a cost because the drugs are quite toxic and immuno-suppressed patients are also quite vulnerable to infections and cancers.

Instead scientists have been searching for ways to persuade the immune system to accept the new foreign tissue in a donor organ as its own.  Harvard's professor Megan Sykes and her colleagues have now managed to do that by giving patients a partial bone marrow transplant collected from the same donor as the kidney they're receiving.  Somehow the new bone marrow re-educates the immune system so that it ignores the new kidney and the patients no longer require any kind of immuno-suppression.

Megan - Since the very first time allogeneic transplants were performed, that means transplants that were done one individual to another, we've known that there is this rejection response that will destroy the graft unless something is done to prevent it.  So the success of allogeneic transplantation in patients in the last quarter century or so has depended on the use of immuno-suppressant drugs that suppress the immune system in a way that prevents the rejection of the graft.

Chris - There are some consequences of doing that though, aren't there?

Megan - Yes.  The trouble with that is these immuno-suppressive drugs suppress all immune responses so that the immune system is very generally compromised.  What that means is that the recipient is predisposed to developing infections and also cancers, diseases because it turns out the immune system is needed to protect us from developing cancers.  These are very serious side-effects and in addition there are a number of metabolic side-effects associated with these drugs and other unpleasant side-effects that people would like to avoid.

Chris - Why can't we re-programme the immune system to try to ignore what we're putting into the body and say 'this kidney I'm putting in is friend, not foe, don't attack it?'

Megan - Well, that's exactly what we have been attempting to do for quite a long time now and that we seem to have achieved in a small group of patients in a pilot study.  The approach that we have used involves use of bone marrow which contains cells that can form all of the blood-forming cells in the body.  It's been known for quite some years now that if bone marrow of two different individuals exists in one recipient that the donor bone marrow will educate the immune system in a way that allows the immune system to regard the donor as self and so the situation that you just described is created.  Any graft from that same donor is ignored because it looks like self.  The immune system has been educated to think that graft is self.

Chris - So what you're saying is that if you gave someone a kidney transplant, if you gave them a bone marrow transplant at the same time you can change what the immune system recognises as friend and foe.

Megan - That's right.  That's the idea.  Now what I've just described has been well-established in animal models for a while now and we have a pretty good understanding of how it works in the animal models.  The problem is, how do you go to an animal model from patients?  Patients who get organ transplants in general do quite well early on, especially in the first two years.  Another problem that I haven't mentioned yet with organs transplants that are performed is that despite all the chronic non-specific immuno-suppressive therapy there's a late phase of graft rejection called chronic rejection that really hasn't been improved by all this immuno-suppressive therapy so many grafts are lost in the 5, 10, 15 year period.  If we had this state where the immune system is re-educated as we've described, not only would we not need immuno-suppressive drugs but this more chronic type of rejection would also be prevented.

Chris - Could you talk us through, step-by-step, what you did in the pilot study with these patients?

Megan - Yes.  What it involves is giving the recipient some chemotherapy but at a dose that that is well below the dose that is used in a conventional bone marrow transplant and giving the drug that is the antibody that causes depletion of the rejecting lymphocytes, the T cells in the recipient and also affects the T cells in the donor bone marrow graft.

Chris - So you end up with a patient who, for a while at least has got 2 types of bone marrow.  They've got the donor who's going to give them, say the kidney, and they've got their own bone marrow as well.

Megan - Right, that's exactly right.

Chris - Then you put in the donor organ and at that time the immune system now is being told because the bone marrow is the same, don't reject this organ.

Megan - Right, so the kidney and the bone marrow are given at the same time and the bone marrow is present in the circulation for a period of just a few weeks.  Together the bone marrow derived cells in the kidney itself are doing some complex things that we're still trying to understand to re-educate the immune system and allow it to regard the kidney as self.

Chris - In the patients that you've tested this on so far what's been the outcome and are things still working for them now?

Megan - We've done five patients in this pilot study and four of them are currently doing very well.  They've been off immuno-suppression for a number of years.  One is approaching five years.  Their kidneys are being accepted despite the lack of any immuno-suppressant drugs.

Chris - So you've proved that this can work, at least on a small scale, with kidney transplants.  What about other organs, livers, hearts, lungs things like that.

Megan - The timing of the protocol is such that the organs and the bone marrow need to be transplanted at exactly the same time.  Yet the preparation of the recipient has to begin five or six days beforehand.  You need to know ahead of time that you're going to do the transplant.  At the moment this protocol limits us to live donors and the types of organs that are transplanted from living donors right now include kidneys, partial livers and sometimes lungs but hearts at the moment would not be relevant with this protocol.  However, the overall idea does work in animal models for any type of graft from the donor.  One of the things that we're working on in our animal models is modifying the regiment so that it will be possible to time it in a way that any organ can be transplanted.

A few weeks ago, we reported on the breakthrough where scientists in America had been able to
build a beating heart in the lab.  We invited Dr Steffen Kren, from the University of Minnesota, to join us on the show.

Helen - I wonder if you could first of all tell us a little bit about your beating heart and what's been going on in your laboratory.

Steffen - Sure. This is usually regarded as what's thought of as tissue engineering. The elements to create a tissue are typically cells which we can get from a variety or sources and a scaffold. In this case, we've devised a process whereby with diffusion profusion we can remove all the cells from a solid organ leaving the extra-cellular matrix, the protein that the cells excrete. This forms a remarkably detailed scaffold that represents the organ in three dimensions but it's completely a-cellular. Then using three-dimensional tissue culture techniques we can add cells back and create a new tissue that hangs on that scaffold.

Helen - So you basically make a mould, if you like, in the shape of the organ you want and then fill it in will cells. Is that right?

Steffen - Yes, that's right. It's even better, in a sense, than a mould because our process retains proteins that we believe guide cells to do what we need to do; that cue cells to - in the case of undifferentiated cells, perhaps - cue them to what they should turn into for that particular spot in the tissue.

Dave - Almost like an instruction manual inside the structure which you've got left which tells the stem cell, 'you should be part of a blood vessel?'

Steffen - That's right. We're hoping to (a) understand that cell signalling phenomenon and (b) use it to our advantage to create details in a tissue that we wouldn't be able to do just by providing cells alone.

Dave - So you've taken a heart. What kind of heart were you using?

Steffen - In this case, rat.

Dave -   So you've taken a heart and in this case, cleaned it out of all the cells. Then you've just injected some stem cells and it suddenly grows back into a working heart?

Steffen - In this report, in Nature, we used neonatal cardiomyocytes. They're not stem cells, they're differentiated. They're young rat heart muscle cells. We sort of short-circuited the whole differential issue for this particular experiment. Are you following me?

Dave - Yes, that makes sense.

Steffen - Now the way we view this going forward in a transplant context, we would like the cells that we use to be autologous, to come from the patient.

Helen - How do you mean? Are you extracting the stem cells from the bone marrow, for example?

Steffen - Could be. Our laboratory has also found progenitor cells in adult cardiac tissue.

Helen - So actually from the heart that you're going to replace?

Steffen - This could end up a possible source. The way we see this as superior to cadaveric organ donation is that, in theory, grown from your own tissue the entire construct would be autologous save for the matrix itself. Worst case scenario the matrix is immunogenic that's rapidly turned over by smooth muscle cells. Perhaps over a relatively short course of immuno-suppression the autologous cells that we create turn over that protein matrix and it would become you in totality.

Dave - So the idea is you take someone else's heart, it doesn't have to be very good or it isn't working any more and then inject it with your own cells. Then it would grow into a heart and you could transplant that into you and it should start working. Is there any reason a human heart should be more difficult than a rat heart?

Steffen - Well, there's certainly a matter of scale and as a substitute we've used porcine tissue, cadaveric porcine hearts to be a point of principle in scaling this process to human-sized organs. Now at this point we've successfully de-cellulised a variety of porcine organs, not just the heart also kidney, liver, gall bladder - a variety of tissues. The scaling issue as far as the recent experiment is sort of beyond our mainly economic capabilities.

Dave - You need many more cells.

Steffen - Exactly. We would have to donate every square inch of tissue culture that we have to create the cells. At this point I don't really see that being a big issue.

Helen - How do you see the way forward in terms of, are we going to see the technology developed - actually used in clinical situations?

Steffen - Well, I think that even before that we're going to learn a tremendous amount of basic science about cell signalling. There may even be medical products along the way that are not entire replacement hearts. For instance, it may be that our tissue is a successful left ventricular patch in the case of an infarcted heart, for instance. So there may be steps along the way where this is useful technology, but stops short of a complete replacement heart.

Most of the plastics that we use at the moment are manufactured from oil. You break up long chains, and you tend to get small gases, things like ethane. Out of an oil refinery you can cook up crude oil very hot and get some useful gases. You can then react them together and then stick them together and the little units stick together. They form long polymers which is what pretty all plastics are made of.

There has been a lot of research recently into other ways of making plastics in case we do run out of oil: using biological foodstuffs mostly and also so you can make plastics which are more biodegradable because we're making plastics from oil in a way very alien to organic processes. Organic things can't break them down very well. There have been various things including genetically engineering bacteria to produce precursors to making plastics or even whole plastics themselves. If you mash up a bacteria extracts with plastic you can get a beautiful plastic out. These plastics are doing the same job if not slightly better because they aren't going to persist in the environment and cause huge pollution like normal plastics do.