Brain scan of an Alzheimer’s patient.
Photo: BSIP/UIG via Getty Images
Almost two weeks ago, a scandal broke out in the otherwise staid world of Alzheimer’s research. An investigation report below Science revealed that a Vanderbilt University researcher, Matthew Schrag, had found that slides were included in a highly influential 2006 article about the disease that was published in the journal Nature were invented. The revelation has cast doubt on a popular, if increasingly controversial, theory about how Alzheimer’s causes its severe damage. I spoke to Nobel laureate Thomas C. Südhof, a Stanford professor of molecular and cellular physiology and an expert on the disease, about the impact of the news and how our ideas about Alzheimer’s are changing.
Are you fully convinced that this has a future Nature Paper contain fabricated images?
I have to answer that cautiously. I would say that the data resulting from the forensic analysis that I have seen of the images strongly supports the idea that there is a fake. What worries me more is that there are multiple allegations of forgery of images against the author. I don’t really know it happened. But if I were to see that in a review process using modern image analysis technology – which is not standard in journals and was not standard before – it would certainly lead to the rejection of the work.
I’m obviously a layman on this subject. But as far as I know, the allegedly fraudulent data has bolstered the already widely held theory that plaques of beta amyloid proteins — I don’t know if “cause” is the right word here — are a key marker for Alzheimer’s.
Yes, they are not just a key marker. They are also likely a causative agent of the disease. The question here is not whether they are important – I think everyone would agree that they are important. The question is whether they alone drive the disease process or whether they are part of a larger ensemble of events that cause the disease. They used to be thought to be the main drivers, but that has changed in the last decade. I think most people in this field would now say that they are a facet of the disease process. Still, I don’t think the importance of beta amyloid has been questioned.
It seems to me that there are two separate stories going on here. One concerns the alleged falsification itself, why anyone could do it, the pressure of science and so on. The other is a much broader story about Alzheimer’s research and where it ends. If the data shows the alleged problems, what do you see as the broader implications?
To be honest, I don’t think there are – or not many. Let me explain why. In science, falsification usually occurs when people publish high-quality papers that nonetheless pretty much confirm what everyone else is thinking. That is why most counterfeits go undetected. In this case, there was a strong community belief that amyloid beta proteins, which accumulate in the brains of Alzheimer’s patients, play a central role in the pathogenesis of the disease. And I think that belief will remain because that data was confirmatory to some extent, but it didn’t really add anything significantly new.
I think the problem we have in science isn’t necessarily fake or people faking things. The problem is the fact that as scientists we are human and as human beings we tend to agree with each other and try to find further supporting evidence for something that is believed to be correct. And the peer review process that leads to the publication of papers has become very problematic in recent years, which has exacerbated this problem.
Have there been promising avenues in Alzheimer’s research that have been marginalized, at least in part, over the past 20 years due to preoccupations with amyloid beta proteins and plaque formation?
Absolutely. And I think that’s still the case today because the field moves pretty much in step with certain ideas in mind that are at the heart of all research. It used to be beta amyloid, and now it’s largely another component of the disease, the inflammatory component, which I think is undoubtedly very important as well. In Alzheimer’s, you have inflammation of the brain, and that inflammation is mainly caused by a type of cell called microglia, which is involved in immune responses and which is clearly very important to the disease. And so, rightly so, a lot of resources are now flowing into the microglia.
But what I think we’re missing in Alzheimer’s research in general is a broader view of the entire landscape. Not just microglia, not just beta amyloid. If you look at these genes that are associated with Alzheimer’s disease, they likely have a wide range of functions. For many of them we don’t really know the functions. The most important gene associated with Alzheimer’s disease is the APOE gene, a lipoprotein that transports lipids. And it’s also a signaling molecule that sends signals between cells, but we don’t know exactly what it’s doing in the brain.
So I think there is more to the disease and as a discipline we need to be open minded and look at all the components of the disease process, especially the cellular biology of the nerve cells because they die.
That this disease has so many components, as opposed to some others that may have a more specific cause and effect – is that why finding a treatment for it is so difficult?
No, no – consider this: Do you think the brain is simpler than a cancer cell? And we’ve put 50 times as much money into cancer research as into brain research? And we still can’t cure most cancers. Why should we expect Alzheimer’s disease to be easier than cancer? It is not.
Biology is inherently complex – that’s the nature of the animal. Every cell is complex. We haven’t really put a lot of effort and time into brain disease as a community because there hasn’t been that much funding. There’s been tons of money for cancer, and there’s been some success, but let’s face it, despite the success, we can’t cure most cancers—the most common types of cancer that kill people. It’s a fact. So we shouldn’t expect brain researchers to be that much smarter than cancer researchers. You are not.
I didn’t realize it was so underfunded.
It’s much better now than before. But it’s still much, much less than cancer. If you look at biotechnology, I would say that more than 90 percent of biotechnology is dedicated to cancer. You can probably count on one hand those researching Alzheimer’s disease or Alzheimer’s drugs. So there are big differences in effort. And that has structural reasons. Because if you have cancer and you know that you will die in a year or two, you are much more motivated to do something about it than with a disease like Alzheimer’s, which is very chronic and lasts much longer.
Are there any signs that new avenues of research could lead to something even incrementally better than current Alzheimer’s treatments?
I think it will. I am an eternal optimist. And the reason isn’t that there are little advances here and there that are there. The way science works, you can’t plan scientific discoveries. You don’t know when they will happen. Otherwise you’d already have the discovery, wouldn’t you? Basic curiosity means that a scientist is trying to solve a problem. They are curious about a problem because they don’t know the solution and in trying to find it they discover things that have the potential to open up a whole new perspective on an illness at any time.
And so it’s very, very important to support a science that is purposeful in the sense that it solves a problem of a disease, a problem of a biological process, but not purposeful in the sense that it develops a drug.
In science, when you have a lot of good minds working on a scientific problem, and there’s an open mindset in the community that’s willing to consider not just one hypothesis and one direction, but many different ones, then things become happen. Discoveries are made. Funding for Alzheimer’s disease is much better than it was a few years ago. And I think we’re going to see a lot of progress.
Genetics are leading the way, and we now have a better understanding of genetics than ever before. This is crucial because it gives us the clues to the biology. It doesn’t explain the biology of the disease. It doesn’t tell us how the disease happens, but it’s kind of a clue in a crime thriller where you try to identify the culprit. We will make it, and when we do, we will know how to better target our medicines. Until then, the community will try to find some shortcuts, some ways to get to the point faster. But the best and safest way is to do curiosity-driven research that solves the problem of what actually happens in the disease.
This interview has been edited for length and clarity.