Making blood in the lab
The volume of blood needed every day by the NHS, and around the world, is staggering. But what about growing blood in a lab, could we do that? Chris Smith was joined by Cedric Ghevaert from the department of haematology at the University of Cambridge, to find out more about lab grown blood...
Cedric - So platelets are one of the three main blood components. They’re actually the smallest cell in the body, if you look at a millimetre on a ruler you can line 250 platelets in that millimetre. The interesting thing is that some people argue they're not even a cell, because they don't contain a nucleus, they don't have DNA.
Chris - When I was learning biology at school they said platelets are bits of cells.
Cedric - That's absolutely true. They are fragments of a parent cell that lives in the bone marrow, and called a megakaryocyte, and one megakaryocyte will release about 1000 to 2000 of these little fragments called the platelets.
Chris - Every day?
Cedric - Every day we produce 10 to the 11 platelets
Chris - 100 billion Every day?
Cedric - That’s right.
Chris - And so these cells are just budding off little bits of themselves, which then go circulating around in the bloodstream.
Cedric - That's absolutely right.
Chris - And what are they doing there? What is their role?
Cedric - The main role of the platelets is to monitor your blood vessels, so they contain two things: Their outer layer, which is called the membrane. And on that membrane they have all sorts of little receptors, and these receptors will tell the platelets that the blood vessel has been damaged. When the platelet detects that it does two things, it will attach to the damaged blood vessel, and it will become activated and by that, it will then tell other platelets around, “you need to come and help.” These platelets will then stick to each other and form a plug to literally block the hole.
Chris - Do they change shape or anything? Do they become, sort of spiky or anything, to become more jagged so they jam in the hole.
Cedric - So they do become spiky, indeed you see that under the microscope when you activate the platelets. They go from a disc to this sort of spider, and that allows them to indeed interact with each other even better. The thing that they also do, is to then pull. They literally pull the wound together to try to stem the blood flow.
Chris - And they're presumably the first responders when you have a wound. They're there first because they're at the scene of the crime already because they're in the blood. And then as more come along, they're recruiting more of their mates from the numbers that come in the blood flow, and what do they provide the initial foundation of a blood thrombus or a clot.
Cedric - That's absolutely right. So once they become activated, inside the platelets there are granules, and those granules contain things that tell the blood, “you need to clot.” These things are released when the platelets become activated. And that leads to an amplification of the blood clotting that proteins are linked together, they form a polymer, and that polymer is a sort of a mesh that will capture more platelets and really plug the hole.
Chris - So the platelets are pulling more raw materials that are dissolved in the blood into that wound site, and then turning it into this dense mesh work that's gonna be a stable repair.
Cedric - That's absolutely right.
Chris - So they're really critical aren't they?
Cedric - Absolutely.
Chris - We can't do without them. And what's the problem with just growing them in a dish, because we can grow loads of things in dishes these days. We can you know, cells grow in dishes easily. So why can't you just churn out platelets in a dish?
Cedric - The main challenge with producing platelets in a dish is to do it so efficiently that actually we have a product that can be used, for example by the NHS and cost efficient. So if you look at a bag of platelets which we give for a transfusion, it contains three times ten to the eleven.
Chris - So 300 billion platelets.
Cedric - So where the platelets score as it were, is that we only need to produce one megakaryocyte, to produce a thousand platelets. And we can grow the megakaryocyte from stem cells. So the idea is that we can take stem cells, grow them into a megakaryocyte, and then right at the last stage of production, suddenly you have this massive amplification, a thousand times more platelets than you had megakaryocytes.
Chris - But if it's that easy to just grow these things in a dish, why are we not doing it? What is the what's the problem at the moment.
Cedric - The main problem is that particular last step. When the megakaryocyte is in the bone marrow it gets its cue from its environment. And it will detect the blood flow. It will be talked to by the cells that are around it, and that, it's very difficult to reproduce in the dish. If we produce megakaryocytes in liquid, in a culture dish they can produce 1 to 10 platelets, so we are at least a hundred times below what a megakaryocyte can do.
Chris - So you've got to have some way of recreating that very specialised three dimensional relationship in the bone marrow, where all these cells are in contact in a particularly special arrangement which seems to be the cue to them, to churn out platelets with the efficiency that they do when they're inside the body.
Cedric - And that's exactly the challenge that my group and several other groups across the world are trying to answer. And there are two ways to do this. First we need to tell the megakaryocyte there’s a flow. They sense the flow, and that makes them release the platelets. So we put them in a bioreactor where they're exposed to shear, which is basically fluid going along them.
Chris - That's kind of mimicking the blood flowing through the bone marrow. So that would normally be bending and distorting the cells a bit, I presume, and that's what makes them churn off or snap off bits.
Cedric - That's right. So they produce these long digits which we call proplatelets, and these long digits elongate in the bloodstream and then snap off these platelets.
Chris - And when you make them, having mimicked this as best you can, do the platelets that you produce in the dish look like, and critically work like, the ones that are made naturally in the bone marrow?
Cedric - That's the critical thing that we are trying to address at the moment. They are bigger when we produce them in the dish, and they don't seem to quite react like normal platelets. However that doesn't mean that it won’t work really well. What we need to do is to test them through a range of assays to really make the statement; these platelets are good, they will monitor your blood vessel, they will last in circulation.
Chris - Is your aim to make platelets bespoke for a patient? Or would you make off the shelf platelets, a bit like we'd currently do with transfusion medicine, where we just make a big bag of platelets collected from a range of donors?
Cedric - So at the moment we can produce platelets from either four donations, from four different donors, or we take them off a special machine where we have one pool of platelets coming from one donor, but we've talked the blood group before, one of the challenges with platelets, is that some people are immunised and they need platelets of a very specific blood type.
Chris - When you say immunisation, you mean that they've made an immune reaction to certain types in the past, so you've got to basically restrict what types you give them?
Cedric - Exactly. The beauty of working with stem cells is that we can edit the DNA somewhat, and because we can edit the DNA we can actually make platelets that don't express blood group, that are universal platelets. The one we produce in the dish can go to anyone. And that's one of the beauties of this technology.
Chris - And are you far away?
Cedric - We are not that far away. We are looking at human clinical trials in the next two to three years.