ome time ago I wrote about how misallocated government funding is
distorting science by placing undue emphasis on clinical trials while
ignoring basic research. What the National Institutes of Health will
fund matters not just to scientists but to the general public: the NIH
funds the vast majority of biomedical research in the United States. If
they stop funding basic research, academic researchers will have no
choice but to stop trying to understand the causes of disease.
That's especially true in Alzheimer's disease. What we're seeing, even in highly-ranked journals, is that many of the papers that are getting published in the field are seriously flawed. Oh sure, their data are solid, their methodology is state-of-the-art, and their graphics are snazzy, but their conclusions are embarrassing: almost every result is stuffed, squealing and screaming, into the misfolded protein paradigm, where it does not want to go.
Traditional grant review session at NIH. More and more often the reviews are conducted over the Internet. Contrary to appearances, the participants are not eating caviar or drinking champagne (although it sometimes seems like they're drinking something from their reviews)
That paradigm cost Big Pharma billions of wasted dollars and thousands of person-years of wasted effort, and the theory is now hanging by a thread: the NDA for the last immunotherapy standing, aducanumab, is sitting on somebody's desk at the FDA, where it will almost certainly get a REJECTED stamp on it in big red letters as the bureaucrats demand another phase three trial. The pressure on the FDA to approve something notwithstanding, it would be unimaginable for them to approve a drug on the basis of Biogen's slicing-and-dicing of their patient population. Too many smaller pharma companies are waiting in the wings to see if the FDA will open that can of worms.
Clinical research is, of course, important, but making clinical trials the principal focus for diseases for which the pathophysiology is unknown, as it is with Alzheimer's disease, is to put the cart before the horse. A clinical trial is the final test of a theory. If there is no theory to test, a clinical trial is a very expensive wild guess. But that's what NIH wants to pay for, so that's what people are doing.
In one experiment, some researchers tried blasting people with ultrasound on the theory that the blood-brain barrier, or BBB, was clogged and opening it would let the beta-amyloid out. One problem with that theory was that opening the BBB causes neurodegeneration. Another is that it's simply a variation of the misfolded protein theory.
Beta-amyloid does form clumps, called oligomers. The non-clumped monomers are harmless, so maybe you might think shaking the clumps apart with sound waves might work. Unfortunately, the frequency needed for that would be so high it would never penetrate the skull, and the energy needed would also blast apart the brain cells and the DNA, which would be very bad for the patient.
So it's pretty clear why the NIH wants to drive basic researchers out of the field. There are no satisfactory animal models for Alzheimer's, and thanks to the abysmal quality of much of the past work on that topic, nobody, not even the foundations, will fund the creation of a new one. Example: one group claimed that feeding rabbits cholesterol gave them Alzheimer's, even though it had been known for decades that cholesterol doesn't cross the BBB. When that finding bombed out, the researchers hypothesized that the finding depended on the type of water the rabbits were given.
It was not as crazy as it sounds: Koch's postulates are still the golden rule in studying disease. If Alzheimer's is a real disease, it has to be possible for some other species to get it. Maybe the cholesterol could be metabolized to something that did cross the BBB. Or maybe, as often happens, our corrupt academic system put too much pressure on the researchers to see what they wanted to see. Whatever the cause, the effect of this failure and many others like it was to discredit any future research into the topic.
Another example was the dozens of genetically modified mouse strains that produce vast quantities of beta-amyloid in their brain. Sure enough, putting huge amounts of a protein whose function is unknown into a mouse's brain produces a toxic effect. But the mouse does not have Alzheimer's disease any more than the streptozotocin-treated rat, which is given a drug that induces insulin resistance and diabetes-like symptoms, has diabetes. From time to time other species have been proposed, but they've all failed the lovability test: if a species is too much like a human or too much like somebody's pet, you can't use it. We use rats mainly because (in my view) those of our ancestors who didn't hate rats died out in the Black Death. Not fair, I guess, but hey, the rats started it.
One alternative is to use samples from brain banks. These have their own problems: transcriptomics is impossible (despite many papers claiming otherwise) because there is no way to know if the relevant RNA has degraded. Proteomics and genomics circumvent this, but both have been done many times already, so it's becoming nearly impossible to publish; and lipidomics is still in its infancy, waiting for a simple way to identify the structure of an unknown lipid by mass spec.
Another alternative is to use living human brain cells, which poses ethical problems. Maybe a person with Alzheimer's, knowing that death is inevitable, would sacrifice a few brain cells, but without control samples (which you will never get) they'd be useless. They're also very hard to grow, while fetal brain cells, which grow easily, are not only unethical to use but also irrelevant to a disease that only occurs in the aged.
A third alternative is to find ways of replacing the dying brain cells, maybe by reprogramming other cells to become neurons or by putting new cells into the brain. This may be a direction for the future, but at the moment it sounds little different from implanting nanoengineered brain cells to replace the human brain with a bionic one. That would cure a great many problems, including traumatic brain injury, but at the moment it's science fiction.
It looks, then, like an insurmountable problem: if there is no way to know if the process you're studying in the test tube or in your cultured cells has any relationship to the disease, what conclusions can you draw from it?
The answer is that you do what biologists have always done: make a hypothesis, test it in cells, then reproduce it in animals to build an animal model. But if the federal government won't pay for that, it won't happen, and our top researchers will have no choice but to retire and sit on the beach drinking piña coladas while we try not to think about the horrible things that are happening to our poor patients. And hoping we don't become one.
may 11 2021, 6:44 am
