Marconi and motor neurones

Up in the hills above Trieste is the International Centre for Genetic Engineering and Biotechnology - the ICGEB. They work on a range of topics related to the life sciences, including in the case of Emanuele Buratti, motorneurone disease. So why,  I found myself wondering, is there the front end of a very large iron boat plonked in front of the building…

Chris - We're out in the car park and I couldn't help noticing you have the front end of a boat in the car park. It's huge! What is this doing here? What is this?

Emanuele - Exactly, Chris? So basically it is actually the boat that used to belong to Guglielmo Marconi, as you know, a very famous international scientist in the early 1900s, the one who basically developed the telegraph. He managed to buy this boat, he called it Elektra after his daughter and after the goddess of electricity. And basically this boat during the second World War was taken over by the Germans and it was turned into a gunboat in order to participate to the war effort.

Chris - But that was sometime after Marconi had died by the Second World War, presumably?

Emanuele - Yes. He had already died. He died quite a few years before. So the boat was requisitioned in 1943. When it was turned into a gunboat, the first thing that happened, as soon as it left the harbor for the first time was for a British plane to come along, bombed it and strafed it, and then it sunk in very shallow water <laugh>. And so after they basically managed to recover the boat, they didn't know what to do with it because it was still a famous boat. It had been owned by Guglielmo Marconi for many years. And so they decided to keep it basically in a junkyard in the harbor. And half of it, we never knew what happened. The other half ended up in a museum in Rome and then there was this front end of the boat and nobody knew what to do with it.

Emanuele - And in Trieste, when they decided to develop a synchrotron facility, they said 'Oh, but the synchrotron facility is actually going to be named "Elettra", the same name as the boat. So why don't we take the front end of the boat and we stick it right next to the synchrotron facility. And the scientists there, they all went crazy because they said, We have electrons spinning around at almost light speed right now, in our synchrotron facility, and now you're going to put 2000 tons of iron next to it. This is going to mess up all our experiments. And they had already decided to bring it up the mountain. As you said, they didn't know where to put it and they ended up replacing it here in the area Di Cerca, where everybody's working on molecular biology, neurodegeneration, that has nothing to do with it really.

Chris - I have to say though, I went on holiday to the west of England recently and I found myself in a shed at the seaside in the middle of nowhere, National Trust property. And I thought, what is this shed? And it turns out that was the building that Marconi constructed to do the initial ship-to-shore experiments to test that the concept of transmitting radio signals over water. Probably the ship that it was talking to would've been this one.

Emanuele - Yes. he must have been walking on the deck <laugh> just above us. Absolutely. Because this is from where he basically, he turned this ship into his lab.

Chris - He must have been pretty well off because this would've been a very big vessel. It's a huge great iron hole cut in half and you've got a chunk in your car park. The hole at the front end, there's a massive great dent in the front. When I saw that, I thought someone had been careless positioning it here. Is that the damage that our boys did then?

Emanuele - Exactly. That's the British bomb <laugh>. That sunk it! <laugh>.

Chris - So you ended up the beneficiary of this historical object in a molecular biology institute, doesn't really fit, bit incongruous.

Emanuele - Well, I mean, in a way, if you think about the kind of energy that is transmitted in motor neurons, it's all based on the electrons, right? So maybe there is some <laugh> sense out of this <laugh>

Chris - When it comes to motor neuron disease. What are you doing though?

Emanuele - I'm working on a protein called TDP-43, and that is the main protein that is aggregating in neurons of patients affected by ALS. And what we're doing in the lab is trying to understand why it aggregates and especially the consequences of its aggregation, trying to understand why these neurons are dying when this protein is aggregating.

Chris - Can you just describe when a person has motor neuron disease or ALS, what is happening and how do they know they've got it?

Emanuele - So normally the onset of ALS is very subtle. People realise that they have maybe some problem walking or maybe moving their arms. And what is happening is that your motor neurons are gradually dying. And so you initially start to lose all your voluntary movements, including walking, moving your arms, moving your head. Then eventually the paralysis spreads to the involuntary muscles so that most people eventually die of respiratory failure.

Chris - You talk about aggregations going on in the affected cells. What's building up?

Emanuele - Basically this is a protein that normally shuttles from the nucleus to the cytoplasm. And what it does is actually controlling the fate of many hundreds of mRNAs. So their life cycle, how long they stay in the cell, how they're translated, how they're processed in general.

Chris - These are the messages that are gonna tell the cell what to do?

Emanuele - Exactly. So what happens is that the cell gradually loses this ability to process the messengers. And once this damage becomes big enough, then of course the cell is going to die.

Chris - This stuff builds up inside the cell, robs the cell of its ability to handle these messages properly so it dies. Is the goal then to try and work out why that is happening and reverse it or to use it as an intervention? How are you trying to tackle this?

Emanuele - For a very long time it was thought that the best strategy would've been to prevent this aggregation. But now there is some evidence basically considering this aggregation as initially protective. So the cells has an excess of this protein tries to put it into the aggregate because it doesn't do any harm. But once the aggregates become very big, then of course they become toxic and the cell dies. So now most strategies mostly aim at making the cell work better.

Chris - Are you able to do that? I mean, can you see any avenues through which you might be able to intervene meaningfully to either stop these things growing any bigger or stop them having a toxic effect on the cell?

Emanuele - Some people are trying to find small molecules to stabilise the cell metabolism. In our case, what we're doing in the lab is to look for modifier genes that can allow the cell to cope much better in the presence of these aggregates. And so we're trying to find these genes. Also, there are gene therapy approaches where basically people are trying to get rid of the mutant protein to replace it with a normal gene.

Chris - Of course, one of the problems that very often happens with these sorts of diseases is that by the time you know you've got it, you've lost the vast majority of the cells that you started with and you can't put them back. And so people are saying we'd need to diagnose people early, intervene with preventative treatments early and that should stop it happening. But that means we need to be able to test people and have a meaningful test but we also need to put a whole bunch of people on treatment for many, many years potentially. Which may not be ideal.

Emanuele - Yes, exactly. So the idea is that of identifying biomarkers that will be able to tell when the disease is starting and so start the therapy long before the symptoms can arise.

Chris - Have you got any?

Emanuele - So there are several under study. We will soon hopefully be starting a project on looking at this protein in blood platelets to see if we can actually see some signs of the disease in people who are still asymptomatic.

Chris - And by looking at the blood, it's a proxy marker for what's going on in the spinal cord.

Emanuele - Yes. So basically what happens is that this protein is present in all cells of our body. And so what we think could be going on is that the same kind of insult that are occurring in the brain cells will also be present in the platelets identified there. That is a much easier source of material.