The Peptoids are Coming

It’s too bad we’ve abused the word “innovative” so horribly, because every now and then I come across a bit of new research that really deserves the title. This week it happened again, with a paper that’s scheduled to appear in Cell right about now. On its surface, it doesn’t sound especially promising: the researchers, led by Muralidhar Reddy and Thomas Kodadek at Scripps Florida, claim to have found some potential biomarkers for Alzheimer’s disease. Announcements like that flood my inbox, and seldom amount to much. I think this one is a bit different.

There are three amazing things about the new study, but before I explain them I’ll put the finding into context. A “biomarker” is anything we can measure that distinguishes people with a disease from people without a disease. If you’ve ever been tested for a viral infection, such as HIV, hepatitis B, or H1N1 influenza, you’ve experienced a biomarker assay. The first-line tests for those and many more viruses are actually looking for antiviral antibodies in your blood. Because they’re so easily accessible and detectable, antibodies are the markers of choice in biomedicine, and antibodies against a virus are a pretty strong indicator that you’ve either been exposed to it or vaccinated against it.

For many diseases, though, scientists have had a very hard time finding biomarkers. Pathologies such as Alzheimer’s disease and cancer certainly change the mixture of antigens in the body, and everything we know about immunity says that there should be corresponding changes in antibodies. In theory, we should be able to detect those changes and use them as biomarkers.

Unfortunately, there’s a chicken-and-egg problem. If you don’t know what the antigen is, it’s tough to fish out antibodies against it. Viruses are the low-hanging fruit, because all we have to do is isolate the viral capsid and use it as a probe for the antibodies we want. Researchers have also had some success with autoimmune diseases, such as lupus, where the pathology of the disease provided some hints about what antigens the immune system might be attacking. For many other non-infectious diseases, including Alzheimer’s, we’re groping in the dark.

Reddy et al. decided to use an entirely novel approach to this problem. They started by using a technique called combinatorial chemistry, which allows them to synthesize a huge number of different molecules from common building blocks. It’s a standard strategy in the drug industry, but the Scripps team’s approach had a twist: instead of conventional drug structures, they built their molecules from artificial amino acid-like building blocks, yielding short sequences called peptoids. That produced a library of thousands of structures that look more or less like small protein fragments, but that aren’t quite the same as regular biological proteins. In essence, it’s a library of different shapes representing the universe of possible antigens, without bias.

Next, the investigators sampled blood from mice with or without an experimentally-induced autoimmune disease called EAE. The peptoids identified a few antibodies that differed between the diseased and control animals, and those antibodies held up very well as biomarkers in a subsequent test on blinded samples. Apparently, peptoid libraries can be used to discover novel, reliable diagnostic assays for a disease without being given any initial information about what the antigens are. It paves the way for a whole new approach to hunting biomarkers. That’s the first amazing thing.

Having proved the concept, Reddy and his colleagues moved to testing blood from Alzheimer’s disease patients and healthy controls. Again, they found some antibodies that can distinguish the two groups reliably. So this brand-new approach has immediately provided a set of promising leads for Alzheimer’s biomarkers, a field that has been struggling for years. That’s the second amazing thing.

The third amazing thing was the press release Cell put out to accompany this new paper. It would have been easy, and almost standard procedure, to hype these findings through the roof: “Researchers develop reliable blood test for Alzheimer’s disease,” or “New method is a game-changer for diagnosis.” Instead, I got the barely-worth-a-click headline “A blood test for Alzheimer’s disease?” Yes, with a question mark*.

Under the headline, the text is just as cautious:

Kodadek says they have since extended the test to more patients and it appears to be holding up well. Nevertheless, development of a clinically useful test will depend on further validation. It’s possible that the test might not work as reliably well in a collection of patients representing different ethnic groups or different forms of dementia, he cautions. They’ll also need to transition their peptoid technology to a simpler platform better suited for use outside of a research laboratory.

It’s not entirely clear whether an early test for Alzheimer’s disease would be broadly useful today given that there aren’t any real treatment options, he added. Such a test might initially be most useful to pharmaceutical companies, by allowing them to better identify patients with early Alzheimer’s for enrollment into clinical trials.

I’ll add one more cautionary note. We don’t know whether the Kodadek lab is detecting a useful early biomarker for Alzheimer’s disease. They might just be seeing the antigen changes that occur later in the disease, when physicians could just diagnose it from the symptoms. Nonetheless, it’s the coolest new technique I’ve seen from the biomarker field in a long time.

* Of course, I also received a somewhat more hype-enriched press release from Scripps, but even it isn’t so bad once you get past the headline.

Reddy, M. M. et al., Cell 144, 132-142, January 7, 2011, DOI 10.1016/j.cell.2010.11.054.