Last month I attended a presentation by a biological therapeutics Pfizer VP. While several non-scientific nuances of this talk piqued me (in particular, how 30 years ago it was relatively easy to carve out a business role for yourself if you had medical knowledge), it was the focus on neurological science that really interested me. This executive said that many large pharmaceutical companies have exited neurological drug research and development. Why? The fruitlessness of the field. The exec contended that 90% of the mental health diseases today are treated with the same medication that they would have been treated with 30 years ago. While I cannot vouch for that statement, I agree the field hasn’t seen disruptive breakthroughs. Modern big pharma was arguably defined by neurologic medications – Valium in 1978 and Prozac in the 1990s –but stagnation in breakthrough neurological science has led to the exodus of many big drug companies from the field. Although the aging population surely portends a surge in brain diseases and potential opportunities, big pharma giants such as GlaxoSmithKline, Bristol-Myers Squibb, and AstraZeneca have demurred.
While drug development has been stagnant, the research has not: I personally know scientists in Alzheimer’s whose research has shown very promising results, and moreover, there has been a spur of Alzheimer’s developments in the news lately. Nature recently published a fascinating publication from The National Hospital for Neurology and Neurosurgery in London suggesting Alzheimer’s disease could actually be transmissible. The tell-tale sign of Alzheimer’s - amyloid Beta pathology – was found in the brains of six out of eight people who had died of Creutzfeldt-Jakob disease. The shocking connection is that years before, the patients had been injected with contaminated growth hormone, suggesting that sticky amyloid-Beta seeds not only traveled along with the hormone, but actually prompted the development of disease plaques. It is believed that misfolding of amyloid-beta makes the peptide sticky, so that it forms clumps. Paired with this recent finding, the concern is that Alzheimer’s could be passed on by other routes such as blood transfusions or contaminated surgical instruments. While this research implies amyloid-plaque formation can be triggered by transmission of a seed, what of the other Alzheimer’s patients who have no history of such injections or surgeries?
A similar cadaver study implicated disparate findings, the results recently published in Scientific Reports. A lab led by Dr. Carrasco at the Autonomous University of Madrid examined the brain tissue of 25 cadavers. 14 of the subjects had Alzheimer’s when they were alive, while the other 11 were Alzheimer’s free. Surprisingly, the brains of all 14 of the Alzheimer’s patients had fungal cells in some of the neurons, while fungus was absent from the Alzheimer-free brains. While a sample size of 25 is quite small, the statistical significance of these results is nonetheless decisive. Does this mean fungi usher in the disease? Alzheimer’s progresses slowly and causes immune responses such as inflammation, and untreated fungal infections progress slowly and can trigger inflammation and blood vessel damage, which has also been observed in many Alzheimer’s patients. If fungi is responsible, this is welcome news: many medications have anti-fungal properties that could potentially be exploited to treat Alzheimer’s. However, this study highlights a common conundrum is science: are the findings causative or associative? In other words, is it the Alzheimer’s disease that is allowing fungus to take a foothold? Perhaps there is not an ultimate cause for Alzheimer’s, but instead Alzheimer’s is a general response arising from a variety of neurological insults.
While drug development has been stagnant, the research has not: I personally know scientists in Alzheimer’s whose research has shown very promising results, and moreover, there has been a spur of Alzheimer’s developments in the news lately. Nature recently published a fascinating publication from The National Hospital for Neurology and Neurosurgery in London suggesting Alzheimer’s disease could actually be transmissible. The tell-tale sign of Alzheimer’s - amyloid Beta pathology – was found in the brains of six out of eight people who had died of Creutzfeldt-Jakob disease. The shocking connection is that years before, the patients had been injected with contaminated growth hormone, suggesting that sticky amyloid-Beta seeds not only traveled along with the hormone, but actually prompted the development of disease plaques. It is believed that misfolding of amyloid-beta makes the peptide sticky, so that it forms clumps. Paired with this recent finding, the concern is that Alzheimer’s could be passed on by other routes such as blood transfusions or contaminated surgical instruments. While this research implies amyloid-plaque formation can be triggered by transmission of a seed, what of the other Alzheimer’s patients who have no history of such injections or surgeries?
A similar cadaver study implicated disparate findings, the results recently published in Scientific Reports. A lab led by Dr. Carrasco at the Autonomous University of Madrid examined the brain tissue of 25 cadavers. 14 of the subjects had Alzheimer’s when they were alive, while the other 11 were Alzheimer’s free. Surprisingly, the brains of all 14 of the Alzheimer’s patients had fungal cells in some of the neurons, while fungus was absent from the Alzheimer-free brains. While a sample size of 25 is quite small, the statistical significance of these results is nonetheless decisive. Does this mean fungi usher in the disease? Alzheimer’s progresses slowly and causes immune responses such as inflammation, and untreated fungal infections progress slowly and can trigger inflammation and blood vessel damage, which has also been observed in many Alzheimer’s patients. If fungi is responsible, this is welcome news: many medications have anti-fungal properties that could potentially be exploited to treat Alzheimer’s. However, this study highlights a common conundrum is science: are the findings causative or associative? In other words, is it the Alzheimer’s disease that is allowing fungus to take a foothold? Perhaps there is not an ultimate cause for Alzheimer’s, but instead Alzheimer’s is a general response arising from a variety of neurological insults.
PET(positron emission tomography) scan of three different brains. Left: Alzheimer's patient with amyloid plaques, which are colored in orange and yellow. Middle: a person with amyloid plaques but not showing cognitive signs of the disease. Right: a brain free of amyloid plaques. Lifelong brain-stimulating habits linked to lower Alzheimer’s protein levels
And herein lies one of the complexities of neuroscience: the intricacies of the brain and the diseases that affect it mean there is rarely just one cause of a disease. For example, a single genetic mutation called 22q11 greatly increases the odds of an individual developing schizophrenia. However, even without that mutation, a series of small, disparate mutations can also lead to a high propensity of developing the disease. To even further complicate matters, the same small mutations that can lead to schizophrenia can lead to autism, attention deficit hyperactive disorder, or bipolar disorder in others.
Arguably, breakthroughs in neuroscience haven’t followed a deep understanding of causation. Instead, many of the field’s most important treatments have been discovered by accident. Thorazine, the first antipsychotic, was found to stop hallucinations when it had originally been intended as a sedative. Imipramine was a failed antipsychotic but became an important antidepressant when its mood improving properties were discovered. More recent drugs such as Prozac, Celexa, Abilify, and Zoloft use the same basic mechanisms as older drugs: antidepressants boost neurotransmitters such as serotonin, and antipsychotics block the dopamine receptor D2.
However, recent scientific advancements in science could begin to convert to translational results in the mental health field. Advanced techniques such as genetic sequencing and DNA editing techniques could soon revolutionalize the field. And what that means is big drug companies are getting back in. Johnson & Johnson, Roche, and Novartis are reinvigorating their efforts into neurologics, and Forbes reports that last year, $3.3 billion was invested into companies that are developing treatments for the brain, a figure that dominates any in the past 10 years. And while treatments for Alzheimer’s and schizophrenia may be more elusive, developments in the treatment of depression, post-traumatic stress disorder, multiple sclerosis, and Parkinson’s Disease may be forthcoming. While I’d love to wax on, read here for more detail. While Pfizer may conjure up disillusionment in some, I do commend the effort to push developments in neurological treatments.
Arguably, breakthroughs in neuroscience haven’t followed a deep understanding of causation. Instead, many of the field’s most important treatments have been discovered by accident. Thorazine, the first antipsychotic, was found to stop hallucinations when it had originally been intended as a sedative. Imipramine was a failed antipsychotic but became an important antidepressant when its mood improving properties were discovered. More recent drugs such as Prozac, Celexa, Abilify, and Zoloft use the same basic mechanisms as older drugs: antidepressants boost neurotransmitters such as serotonin, and antipsychotics block the dopamine receptor D2.
However, recent scientific advancements in science could begin to convert to translational results in the mental health field. Advanced techniques such as genetic sequencing and DNA editing techniques could soon revolutionalize the field. And what that means is big drug companies are getting back in. Johnson & Johnson, Roche, and Novartis are reinvigorating their efforts into neurologics, and Forbes reports that last year, $3.3 billion was invested into companies that are developing treatments for the brain, a figure that dominates any in the past 10 years. And while treatments for Alzheimer’s and schizophrenia may be more elusive, developments in the treatment of depression, post-traumatic stress disorder, multiple sclerosis, and Parkinson’s Disease may be forthcoming. While I’d love to wax on, read here for more detail. While Pfizer may conjure up disillusionment in some, I do commend the effort to push developments in neurological treatments.
Sources: (because if you cite a "scientific" development you should be able to show a credible scientific journal, people.... this bacon causes cancer nonsense is particularly irksome to me):
1. Forbes: The Coming Boom in Brain Medicines
2. Nature Letter: Evidence for human transmission of amyloid-beta pathology and cerebral amyloid angiopathy
Nature News: Autopsies reveal signs of Alzheimer's in growth hormone patients
3. Nature Scientific Reports: Different brain regions are affected with fungi in Alzheimer's Disease
4. The Economist: Fungi, the bogey man
5. Bacon Causes Cancer? Sort of. Not really. Ish.
1. Forbes: The Coming Boom in Brain Medicines
2. Nature Letter: Evidence for human transmission of amyloid-beta pathology and cerebral amyloid angiopathy
Nature News: Autopsies reveal signs of Alzheimer's in growth hormone patients
3. Nature Scientific Reports: Different brain regions are affected with fungi in Alzheimer's Disease
4. The Economist: Fungi, the bogey man
5. Bacon Causes Cancer? Sort of. Not really. Ish.
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