Podcast Extra: Evidence of a ‘transmissible’ Alzheimer’s protein

Host: Benjamin Thompson

Hi, listeners – Benjamin from the Nature Podcast here. This week, we’ve got a Podcast Extra for you. We couldn’t include it in the regular show because the paper it’s based on was released on a Thursday, but we didn’t want you to miss out, so here’s reporter Ali Jennings with the story.

Interviewer: Ali Jenning

Medicine has made huge advances over the last century, but there have been times where novel treatments have done harm as well as good. One such treatment is the subject of a new paper now published in Nature. It involves giving human growth hormone to persons of short stature to help stimulate their growth. Researchers from the Prion Institute at University College London suspected that some early batches of this growth hormone might be linked to the build-up in the brain of a protein called amyloid-beta. Build-up of amyloid-beta is bad news – it’s one of the hallmarks of Alzheimer’s disease. The researchers wanted to see if these batches of growth hormone really were causing the accumulation of amyloid-beta in the brain.

Interviewee: John Collinge

So, we used genetically modified mice and we injected these mice with material from a number of these vials of growth hormone, and we found that the animals did indeed then develop amyloid-beta pathology.

Interviewer: Ali Jennings

This is John Collinge, who led the research.

Interviewee: John Collinge

So, that was a very striking finding and obviously also a very worrying one in terms of its implications.

Interviewer: Ali Jennings

But to understand the implications properly, you need to know the whole story because this paper is really the final chapter in a saga that started some years ago. Bear with me – I promise it’s worth it. Back in the 1950s, doctors found a way of producing human growth hormone to help treat persons of short stature. They harvested it from the pituitary glands of human corpses. But in 1985, the treatment had to be stopped.

Interviewee: John Collinge

What became apparent in around 1985 was that some of these batches of hormone had been accidentally contaminated with Creutzfeldt–Jakob disease prions.

Interviewer: Ali Jennings

Creutzfeldt–Jakob disease – also known as CJD – is a particularly nasty neurological disorder. Much of John’s work focuses on the proteins that cause this disease, proteins called prions.

Interviewee: John Collinge

The prion protein is a normal brain constituent but it can become misshapen and the misshapen forms stick together to form long chains of material.

Interviewer: Ali Jennings

The build-up of prion proteins progressively damages the brain. Over the years, more and more patients who had received contaminated growth hormone developed CJD. In 2015, John’s team we’re examining the brains of a group of these patients for evidence of CJD prions. But alongside the prions, they found large build-ups of amyloid-beta.

Interviewee: John Collinge

This was very surprising because this pathology, although it’s relatively common in people in their 80s for example, is exceedingly rare. You wouldn’t expect to see it in young people such as these patients who died in their 30s and 40s.

Interviewer: Ali Jennings

In 2015, John’s team published data from eight of these patients, showing this unusual amyloid-beta pathology. To explain their finding, they suggested that the growth hormone that the patients had been treated with had been contaminated not only with prions that cause CJD but also with amyloid-beta. Now they needed causal evidence to show that amyloid-beta really was in the vials of hormone and that it really could cause the brain pathology. In other words, that amyloid-beta in the growth hormone could seed more amyloid-beta in the brain.

Interviewee: John Collinge

So, what we thought it was essential to do was to see if we could find such vials, see whether they had seeding activity in them. This was a bit of a long shot given this material would have sat around for decades at room temperature, so we weren’t terribly optimistic what we were going to find in this, but we thought it important given the public health implications of what we were suggesting.

Interviewer: Ali Jennings

So how do you get your hands on decades-old growth hormone that’s been considered a public health hazard for over 30 years?

Interviewee: John Collinge

It turns out that Public Health England fortuitously kept an archive of much of that material from before 1985, and we were able to piece together particular batches that we know the patients were exposed to. A bit of sort of detective work there.

Interviewer: Ali Jennings

The team finally tracked down the elusive hormone. In their new paper, they tested it and found that it did indeed contain amyloid-beta.

Interviewee: John Collinge

However, that didn’t prove that that material was seed-competent, that it actually contained the material in a form that actually could transmit the pathology, so the only way to find out whether there were seeds present was to do a biological assay and inject it into suitable animals.

Interviewer: Ali Jennings

The animals they chose were mice that can express the human amyloid-beta protein. Sure enough, the hormone produced the same amyloid-beta pathology that John’s team had seen in the eight patients from their first study. I asked John how it felt to have finally achieved this result after so much work.

Interviewee: John Collinge

It’s been very exciting to see these results and sort of surprising that it worked as easily as it did, you know, with this material that’s been sat around on shelves for decades.

Interviewer: Ali Jennings

So how important is this finding? I asked someone who wasn’t involved in the work, Lary Walker, an Alzheimer’s researcher from Emory University.

Interviewee: Lary Walker

Well, this paper is essentially a proof of concept paper. The authors wanted simply to show that there are biologically active Aβ seeds in the growth hormone preparations, and I think that’s very important.

Interviewer: Ali Jennings

So, John’s team have shown they can transfer amyloid-beta pathology into the brain of a mouse. But how relevant is that to humans? Remember that amyloid-beta is a hallmark of Alzheimer’s disease.

Interviewee: Lary Walker

Mice do not develop Alzheimer’s disease. In fact, as far as we now know, Alzheimer’s disease is a uniquely human disorder. But they do allow us to test hypotheses about the molecular mechanisms that underlie the development of Alzheimer’s disease.

Interviewer: Ali Jennings

So, the mice can show us what’s happening at a molecular scale, but they can’t tell us about how that adds up to the disease as a whole. Nevertheless, John is mindful that that message isn’t always clear.

Interviewee: John Collinge

There’s always concern that there’ll be people assuming that this means you can somehow catch Alzheimer’s disease. This is not at all what we’re saying. This is about people being seeded with material as a result of some very unusual medical procedures, indeed medical procedures that are no longer used.

Interviewer: Ali Jennings

But when they published the study in 2015, it still sparked some eye-catching headlines in the British press – ‘Alzheimer's bombshell’ was a particularly lurid example. I wondered, what was it like to be under such intense press scrutiny?

Interviewee: John Collinge

Yes, it was an interesting time, and I’m not sure the extent of coverage was particularly helpful.

Interviewer: Ali Jennings

And yet, John does think there was some cause for concern. In particular, regarding the metal instruments that are used during brain surgery.

Interviewee: John Collinge

These amyloid-beta seeds, rather like the prions, can stick to metal surfaces and the condition can be passed on by metal implants, so that was a concern that we still have, as to whether we need to be better at cleaning surgical instruments and remove any possibility of protein seeds being transmitted from one patient to another.

Interviewer: Ali Jennings

This kind of cleaning would be a big task. I asked Larry what he thought about the need for tighter medical instrument sterilisation.

Interviewee: Lary WalkerThe currently used procedures for sterilising surgical equipment really are effective, and since I believe 1976 there’s not been a case of surgically transmitted prion disease, so I think we’re doing it right.

Interviewer: Ali Jennings

John and his team have provided the first causal evidence that amyloid-beta pathology is transferable. So, does this finally feel like an end to the story?

Interviewee: John Collinge

Yeah, I don’t think the paper is a full stop. I think it’s opening up a whole range of further experimental studies in terms of looking at the transmissible characteristics of Alzheimer's pathology, and if we have the right sort of animal models, whether these sort of seeds could reproduce the full pathology of Alzheimer's disease, and not just the beta pathology.

Interviewer: Ali Jennings

In this paper, John and his team have shown that you can seed amyloid-beta pathology in the brains of mice. But whether this could lead to Alzheimer’s in people or other amyloid-related disease, is still unknown. If you’re interested in finding out more, you can find the original paper in the current issue of Nature, alongside a News and Views article by David Holtzman.