From Stuart Buck (subscribe to the newsletter):
Rachael Neve is a neuroscientist perhaps best known for being one of the first to clone the Alzheimer’s precursor protein (APP) gene back in 1987.
Instead of the typical interview questions, Neve sent a thoughtful essay full of provocative thoughts about neuroscience, NIH, and academia. Enjoy!
What do I do now?
I am a neuroscientist at Harvard Medical School. I have spent my career trying to find out what causes Alzheimer’s disease and creating new viral vectors for gene delivery into the brain.
My funding story is quite different from the norm, so I shall narrate it chronologically.
I did my Ph.D. work in genetics at UC Davis, starting in 1976, in a small lab. I was the first graduate student of Raymond Rodriguez, who had just developed the first multicopy cloning vector, pBR322, so I was one of the original group of scientists involved in “recombinant DNA” technology.
I submitted my first paper to Nature and it was immediately accepted. I wanted to do research on learning and memory and specifically on Alzheimer’s disease, so I joined a trisomy 21 genetics lab at Children’s Hospital in Boston.
By that time, it was known that virtually every Down Syndrome patient who reached the age of 50 developed Alzheimer’s disease. I readily received funding from the Down Syndrome Society to find the connection between trisomy 21 and Alzheimer’s disease.
The decade that followed was a glorious time to be doing academic research. I had told my Ph.D. advisor in 1980 that I wanted to use my molecular biology expertise to study the brain. He said, “not in your lifetime”; at that time recombinant DNA technology had just transitioned to yeast from bacteria.
He was wrong. By 1983 I had made a highly complex cDNA library from the human brain.
Boston was a hub of academic research, with new discoveries in molecular biology happening almost daily by scientists at such places as MIT, Harvard Medical School, and the Whitehead Institute. We all shared our knowledge with each other; I remember it as a collegial and almost intoxicating time during which I interacted daily with multiple labs at Children’s Hospital and other institutions in Boston. Principal investigators joined their postdocs and graduate students at the bench. Funding from NIH was at its zenith, with the cut-off at 35-40 percent.
I thought that this was what academic research would always be like.
My lab was one of the first four labs to clone simultaneously the cDNA for the Alzheimer’s amyloid precursor protein (APP) gene, in 1987, and yes, it was on chromosome 21.
Not long after I published the cloning of the APP cDNA 35 years ago, I was told that a very prominent AD scientist at Harvard Medical School “hated” me. Why? He thought that I should have collaborated with him to clone the gene, rather than cloning it independently.
I was dumbfounded to hear this. It was my first taste of what it would be like to work in this field.
Nevertheless, the next two years were productive. We published several high-profile papers. I wrote a grant application in which I proposed that determination of the normal function of APP had the best chance of helping us figure out how it went awry in AD; it was funded with a high score.
In the meantime, familial AD mutants of APP had been cloned. They caused dementia and Alois Alzheimer’s famous “plaques and tangles” in patients. Studies showed that the FAD mutants of APP were processed abnormally to produce amyloid in the brains of mice and humans, and that in humans this was accompanied by dementia. Game, set, match. Clear the amyloid from the brain and cognitive function would be restored. This hypothesis quickly gathered momentum because it was so “obvious.”
Then came my downfall: I and Bruce Yankner published a 1989 paper in Science in which we showed that when we expressed the C-terminal 99 amino acids of APP (C99) in PC12 cells, differentiation of those cells into a neuronal phenotype with NGF caused the cells to die. Moreover, C99 killed cells in primary hippocampal neurons.
This might not have been quite the downfall that it turned out to be if we had not also shown that the amyloid peptide failed to kill neurons in the same context. A little later, we expressed FAD mutants of APP in primary neurons and showed that the predominant peptide produced by them was not amyloid but C99. Even worse for my standing in the amyloid field, I showed that gamma-secretase inhibitors did not rescue neurons from C99 toxicity.
By the time I tried to renew my grant application in which I sought to elucidate the normal function of APP, the amyloid hypothesis had a steely grip on the field.
I was more productive than ever, but I had to fight to get NIH funding or publish in the highest level journals.
Shockingly, NIH bought into the amyloid hypothesis.
My program officer at NIH recommended that I include a “pro-amyloid collaborator” in my grant application.
It took me three years to get it renewed, and then only because he “specialed” it despite the fact that I didn’t get a score high enough to put it into the fundable range.
I was fortunate to receive sizeable grants in the late 90s from private donors who had no stake in the amyloid hypothesis. Without that funding I would have had to shut my lab down.
I was exhilarated about the data I was generating that were consistent with that of others in the field who hypothesized that AD might be a cell cycle disease. I had shown that FAD mutants of APP caused aberrant cell cycle entry and subsequent apoptosis in neurons. I had isolated two intracellular APP binding proteins; we showed that one of them, APP-BP1, was a cell cycle protein that drives the S to M transition and was required for the neurotoxicity of FAD APPs.
Again, I had produced data consistent with the hypothesis that the FAD APPs caused neurodegeneration by pushing neurons into the cell cycle, and again I had shown that amyloid was not involved in that neurotoxicity. Karl Herrup had shown chromosomal tetraploidy in affected regions of AD brains.
It was a very exciting time. But I continued to have a hard time getting funding or publishing in the top journals.
One of the traits of proponents of the amyloid hypothesis that I don’t understand to this day, is that it was and continues to be important to some people to suffocate non-amyloid research. For a period of time, I was reviewing grant applications for the Alzheimer’s Association. I gave high scores to some very original research plans, but the Alzheimer’s Association wanted the two reviewers of each application to come to a compromise score. I would give a non-amyloid application a 9, and the other reviewer, if an amyloid proponent, would give it a 1. We would be instructed to discuss it and come up with a score that we could both agree on. What blew my mind was that the amyloidophile reviewers were actually angry at applicants who did not adhere to the amyloid hypothesis, and were determined to make sure that these applicants did not receive funding.
Today, although there a significant number of AD researchers who do not subscribe to the amyloid hypothesis and who have proposed other strong hypotheses that are consistent with the data that they have generated, they just don’t get heard. In the end, I didn’t get to publish the paper I hoped to write eventually: a definitive review of the mechanisms by which the cell cycle is activated and causes neurodegeneration in Alzheimer’s disease.
So, what has happened to the amyloid hypothesis?
It retains its grip on the field.
For decades, the amyloid proponents have said that they would be vindicated by human trials in which clearing the amyloid from the brain would slow or prevent cognitive loss in patients with AD. At least two dozen such trials so far have cleared amyloid from the brains of patients with AD, with no commensurate improvement in cognition.
The proponents of the amyloid hypothesis refuse to be deterred by data. Their excuse is always the same: intervene earlier in the progression of the disease and/or give a higher dose of the amyloid-clearing drug.
Recently the results of a trial that was to produce definitive results were announced. It was a 10-year clinical trial of several thousand people in Colombia, about 20% of whom have a genetic mutation that virtually guarantees that they will have early onset Alzheimer’s disease. People who were genetically destined to develop the disease, but who did not yet have any symptoms, were given ten years of an anti-amyloid drug intended to stop or delay cognitive decline. Once again, clearing the amyloid did not improve cognition.
The amyloid fiasco has been one of the greatest tragedies of modern biomedical research. My mother was diagnosed with Alzheimer’s disease four years ago. There is nothing that can be done to ease her emotional pain. She is in a nursing home, something that she had dreaded her entire adult life. My siblings and I make sure that at least one of us calls her every day. She has become aphasic, so we no longer expect any response from her as we relate to her the news of the day over the phone. When one of us visits, she used to be joyful; now she is suspicious that we are masquerading as her children.
“In the 30 (now 35) years that biomedical researchers have worked determinedly to find a cure for Alzheimer’s disease, their counterparts have developed drugs that helped cut deaths from cardiovascular disease by more than half, and cancer drugs able to eliminate tumors that had been incurable. But for Alzheimer’s, not only is there no cure, there is not even a disease-slowing treatment.”
I fault first of all NIA and NINDS for uncritically swallowing the amyloid hypothesis. Program officers can try to get additional funding from Congress for their programs, and it’s far easier for them to cite prominent scientists who subscribe to popular hypotheses when they make their case to Congress. I fault the editors of the highest-level journals, who allow the most famous of their reviewers to have an outsize influence on their acceptance of manuscripts.
And I fault biotech companies for their unwillingness to fund any but pro-amyloid research. Multiple amyloid-clearing drugs are still in the clinical trial pipeline; others that didn’t show clinical improvement are actually being resurrected because the FDA allowed Biogen to include a surrogate feature of AD (i.e., amyloid clearance) as a sign that the drugs are working.
Several years ago, I shifted my primary research focus to the optimization of viral vectors that I had made for gene transfer into the brain. MIT recruited me to set up a virus core in Building 46, which houses the Picower Institute for Learning and Memory and the McGovern Institute for Brain Research (I later moved my core to Massachusetts General Hospital). I collaborate with scientists all over the world, none of whom cares about the amyloid hypothesis.
Academic research is challenging and fun again.