“I study how peptides and proteins aggregate in a set of diseases called amyloid diseases, the most well known of which is Alzheimer’s. But the category includes Parkinson’s, type 2 diabetes, mad cow disease, and various dementias. My research focuses on how beta-amyloid forms aggregates that are damaging to neurons in Alzheimer’s.”
“Do amyloid plaques cause Alzheimer’s? Or are the plaques and the disease both products of a deeper cause? From my understanding, the scientific community is divided on this question.”
“I would tend to agree that the plaques themselves are not the causative factor. I often make an analogy to bullets and bullet casings at a crime scene. If somebody came down from Mars and wanted to understand how people die in the crime of murder, they would go to a crime scene and they would see a dead body and some bullet casings on the ground. Then, they would go to another crime scene and see the same thing. And they would say, ‘Well, the bullet casings must be causing the dead bodies,’ but correlation is not causation. That’s kind of where we are with the plaques. They seem to be the bullet casings, byproducts of the degeneration process.
We’re looking for the bullets and the bullets seem to be oligomers, assemblies of peptides that are fractions of a micron in length. We’ve put together many pieces of the puzzle. The amyloid peptide aggregates to form oligomers, which eventually aggregate to form fibrils that make up the plaques. But the oligomers are more toxic than the plaques when exposed to neurons in vitro (in test tubes). So we’ve established, shall we say, method and motive.”
“Research universities are great places to work on complex problems. The private sector is generally interested in short timelines of a few years, and all research must lead to a product. They need to develop drugs quickly to pay off investments, but it can take decades of research to reach the required levels of understanding. Companies don’t like to be told, ‘You’re going to start working on this, but you won’t have any medicine for 10 years,’ and that’s why we need university settings where the generation of knowledge can occur and knowledge can beget more knowledge and ultimately, application.
There’s a science component, understanding, and an engineering component, drug development. And I’ve always felt that organic chemistry is a dynamic balance between the understanding of pure science and the application of molecular engineering.”
“On a completely different note, what are prions and how do they cause mad cow disease?”
“Prions are infectious protein particles. They’re often referred to as misfolded proteins that infect other proteins in your body and cause them to misfold, to come together in a faulty fashion. In the case of mad cow disease, this leads to neurodegeneration. The discovery of prions was extremely controversial because people believed that you could only get sick from bacteria and viruses, and that was it. The notion that proteins could infect, the notion that proteins could be a self-propagating species, was very upsetting to much of the biomedical community. Prusiner, who won the Nobel Prize for this discovery, faced a lot of controversy. People said ‘No, that can’t be. This shakes up the paradigms!’ But this is the case and has been proven to be the case.
The bottom line is don’t eat beef tainted with prions. This goes back to our crazy agricultural practices. We grind up dead cows and feed them to other cows, bad idea for an herbivore, and then make crappy bulk hamburgers by crushing up more cows and getting every last ounce of meat off the spinal cord, which contaminates the beef with spinal cord matter."
“I got hooked onto chemistry as a kid at the age of 8 and became absolutely fascinated by matter and its transformations. It was captivating to see how something as simple as electroplating occurred. You can take a copper penny, connect it to wires, put it in a solution with electrodes attached, and pull out a silver nickel-coated penny. I thought, 'Wow, this is magical!' And I was fortunate enough to have a lab in my basement.”
“You had a lab in your basement?!”
“Yeah! Well, my parents were very indulgent and my chemistry teachers were very indulgent. They gave me keys to the high school lab and let me stay after hours, after they went home. So basically, I had access to a variety of chemicals and I did lots of experiments. After school, I loved going down to my lab for hours every day to work on something or another, from electroplating to analyzing chemicals to synthesizing various compounds to extracting gold from seawater. And there was a fair share of pyrotechnics as well, so we always had a good 4th of July show. I also built my own fume hood by putting a vacuum cleaner motor in the window to suck out the exhaust.”
“We 3D-printed the X-ray crystallographic structure of a peptide we created (X-ray crystallography was used to elucidate the double helix structure of DNA). Here we have 3 different colors –- magenta, green, and cyan –- representing 3 different amino acids coming together. At each vertex of the triangle are epicenters of genetic mutation. About half a dozen familial mutations associated with these 3 amino acids at this junction are known to be linked to Alzheimer’s.”
“Once you fully understand the mechanism by which this molecule assembles, how will you use this information to treat the disease?”
“Let’s suppose -- and we do not yet know -- that this is a bullet in Alzheimer’s. Now, we can start designing molecules that interact with or bind to these bullets to neutralize their toxicity. We’re not that far along yet, but that’s something we’d like to do several years from now. “
“The problem of Alzheimer’s disease has been with us for a long time, even as a research topic. There is still no standard treatment or effective therapy, and the one or two drugs out there are essentially ineffectual for preventing the progress of the disease. So the timescale, guaranteed long. The cost of caring for patients, huge, $200 billion a year. The impact, also huge in terms of human suffering, 5.4 million Americans affected, growing numbers. We’ve got economic drivers, but this research requires a tremendously long investment. The hope is that by the time the next generation ages, there will be ways of preventing or treating Alzheimer’s. There’s some promising work now, so it’s possible that there will be widely-used drugs in 5 years, but the very beginnings will not be the very ends.“
“It’s very hard to develop a drug when you don’t have a good understanding of the disease. Right now, most of the low-lying fruit –- diseases of which we have limited understanding but can still treat –- have been harvested. Ironically, with regard to one of the easiest areas of drug development, vaccinations, we’ve lost our minds as a society. There are parents refusing to vaccinate their children and this is nuts. The measles outbreak at Disneyland, which affected about 150 people, is the tip of the iceberg if we don’t use this relatively simple approach to disease prevention.”