AI Helps Unravel a Cause of Alzheimer's Disease and Identify a Therapeutic Candidate (ucsd.edu) 39
"A new study found that a gene recently recognized as a biomarker for Alzheimer's disease is actually a cause of it," announced the University of California, San Diego, "due to its previously unknown secondary function."
"Researchers at the University of California San Diego used artificial intelligence to help both unravel this mystery of Alzheimer's disease and discover a potential treatment that obstructs the gene's moonlighting role."
A team led by Sheng Zhong, a professor in the university's bioengineering department, had previously discovered a potential blood biomarker for early detection of Alzheimer's disease (called PHGDH). But now they've discovered a correlation: the more protein and RNA that it produces, the more advanced the disease. And after more research they ended up with "a therapeutic candidate with demonstrated efficacy that has the potential of being further developed into clinical tests..." That correlation has since been verified in multiple cohorts from different medical centers, according to Zhong... [T]he researchers established that PHGDH is indeed a causal gene to spontaneous Alzheimer's disease. In further support of that finding, the researchers determined — with the help of AI — that PHGDH plays a previously undiscovered role: it triggers a pathway that disrupts how cells in the brain turn genes on and off. And such a disturbance can cause issues, like the development of Alzheimer's disease....
With AI, they could visualize the three-dimensional structure of the PHGDH protein. Within that structure, they discovered that the protein has a substructure... Zhong said, "It really demanded modern AI to formulate the three-dimensional structure very precisely to make this discovery." After discovering the substructure, the team then demonstrated that with it, the protein can activate two critical target genes. That throws off the delicate balance, leading to several problems and eventually the early stages of Alzheimer's disease. In other words, PHGDH has a previously unknown role, independent of its enzymatic function, that through a novel pathway leads to spontaneous Alzheimer's disease...
Now that the researchers uncovered the mechanism, they wanted to figure out how to intervene and thus possibly identify a therapeutic candidate, which could help target the disease.... Given that PHGDH is such an important enzyme, there are past studies on its possible inhibitors. One small molecule, known as NCT-503, stood out to the researchers because it is not quite effective at impeding PHGDH's enzymatic activity (the production of serine), which they did not want to change. NCT-503 is also able to penetrate the blood-brain-barrier, which is a desirable characteristic. They turned to AI again for three-dimensional visualization and modeling. They found that NCT-503 can access that DNA-binding substructure of PHGDH, thanks to a binding pocket. With more testing, they saw that NCT-503 does indeed inhibit PHGDH's regulatory role.
When the researchers tested NCT-503 in two mouse models of Alzheimer's disease, they saw that it significantly alleviated Alzheimer's progression. The treated mice demonstrated substantial improvement in their memory and anxiety tests...
The next steps will be to optimize the compound and subject it to FDA IND-enabling studies.
The research team published their results on April 23 in the journal Cell.
"Researchers at the University of California San Diego used artificial intelligence to help both unravel this mystery of Alzheimer's disease and discover a potential treatment that obstructs the gene's moonlighting role."
A team led by Sheng Zhong, a professor in the university's bioengineering department, had previously discovered a potential blood biomarker for early detection of Alzheimer's disease (called PHGDH). But now they've discovered a correlation: the more protein and RNA that it produces, the more advanced the disease. And after more research they ended up with "a therapeutic candidate with demonstrated efficacy that has the potential of being further developed into clinical tests..." That correlation has since been verified in multiple cohorts from different medical centers, according to Zhong... [T]he researchers established that PHGDH is indeed a causal gene to spontaneous Alzheimer's disease. In further support of that finding, the researchers determined — with the help of AI — that PHGDH plays a previously undiscovered role: it triggers a pathway that disrupts how cells in the brain turn genes on and off. And such a disturbance can cause issues, like the development of Alzheimer's disease....
With AI, they could visualize the three-dimensional structure of the PHGDH protein. Within that structure, they discovered that the protein has a substructure... Zhong said, "It really demanded modern AI to formulate the three-dimensional structure very precisely to make this discovery." After discovering the substructure, the team then demonstrated that with it, the protein can activate two critical target genes. That throws off the delicate balance, leading to several problems and eventually the early stages of Alzheimer's disease. In other words, PHGDH has a previously unknown role, independent of its enzymatic function, that through a novel pathway leads to spontaneous Alzheimer's disease...
Now that the researchers uncovered the mechanism, they wanted to figure out how to intervene and thus possibly identify a therapeutic candidate, which could help target the disease.... Given that PHGDH is such an important enzyme, there are past studies on its possible inhibitors. One small molecule, known as NCT-503, stood out to the researchers because it is not quite effective at impeding PHGDH's enzymatic activity (the production of serine), which they did not want to change. NCT-503 is also able to penetrate the blood-brain-barrier, which is a desirable characteristic. They turned to AI again for three-dimensional visualization and modeling. They found that NCT-503 can access that DNA-binding substructure of PHGDH, thanks to a binding pocket. With more testing, they saw that NCT-503 does indeed inhibit PHGDH's regulatory role.
When the researchers tested NCT-503 in two mouse models of Alzheimer's disease, they saw that it significantly alleviated Alzheimer's progression. The treated mice demonstrated substantial improvement in their memory and anxiety tests...
The next steps will be to optimize the compound and subject it to FDA IND-enabling studies.
The research team published their results on April 23 in the journal Cell.
Those models are known (Score:4, Informative)
Re: Those models are known (Score:2)
What if instead of AI you used "the Attention mechanism" which is what made ChatGPT able to generate perfect grammar when all the previous AI machine learning techniques (neural networks, decision trees, markov models, what-have-you) failed?
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Proteins are so a complex that machine learning model is the best approach
Definitely...since so many projects have done exactly that already. AlphaFold, ESMFold, Metagenomic Atlas, RoseTTAFold, etc. I'm pretty sure the technique is at the point these days that just about any protein structure of any interest can just be handed over to "AI" and it's as good as modeled.
Re:Those models are known (Score:5, Informative)
This is relatively new in the space. AlphaFold by DeepMind. The architecture is a variant of the transformer architecture that LLMs use.
This isn't the small statistical models that were used for this kind of stuff a decade and a half ago. It's fair to call this AI.
Sounds cool (Score:5, Interesting)
When they combine this with gene editing to introduce the Christchurch mutation ( https://www.alzforum.org/mutat... [alzforum.org] ) into many of the brain's cells, that's strong a path to cure.
Great news, I hope (Score:3)
As someone whose mother and grandmother both had serious Alzheimer's, I've got a personal interest. But in terms of the benefits to society of not having this major problem it's a great prospect. Let's hope this doesn't prove to be a false dawn.
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My Mom too. You lose them day by day and year by year, and it's excruciating.
False starts are the norm in this kind of research, and this may well be another one, but that's how you get to success in science, by scaling a mountain of errors.
Hopefully this research won't be affected by cuts to NIH, but it probably will be.
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My Mom too. You lose them day by day and year by year, and it's excruciating.
My dad passed from cancer and my mom from Alzheimer's. Dad was in the hospital for a couple weeks at the end. Mom was in long term care for 2 1/2 years before the end. No idea what my own fate will be, but given a choice I'd take the cancer over the Alzheimer's any day.
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Both my uncles on my mom's side (her two siblings) died from Alzheimer's, both within 3 to 4 three years of onset. And two years ago my mom was diagnosed with it and has been going downhill. It is a horrible disease that puts the inflicted and the family through hell for years. My mom is quite healthy, physically, but she still has to be supervised and so had to move into an expensive healthcare facility about 8 months ago. I believe the med they put her on pre-diagnosis and meds post-diagnosis haven't
Remarkably complicated for a side effect (Score:3)
Is triggering gene acttion a side effect or is it an evolved process that actually does something important that they haven't discovered yet? It wouldn't be the first time that pulling on one metaphorical piece of bilogical string unwittingly unravelled something else.
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Is triggering gene acttion a side effect or is it an evolved process that actually does something important that they haven't discovered yet? It wouldn't be the first time that pulling on one metaphorical piece of bilogical string unwittingly unravelled something else.
A good example is how some groups have evolved malaria resistance, and that made them vulnerable to sickle cell anemia.
So yeah, I've a strong suspicion that a gene that actually causes a major problem has some other effect that might be positive in earlier life.
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Everything in biology is a remarkably complicated side effect. All aspects of biology are a horrendous mess and hey worse the deeper you look into them. Everything interacts work everything and anything can go wrong at any stage and there are probably yet more interacting mechanisms to deal work some of the wrongness.
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He's saying something of which "engineering involves tradeoffs" is a subset. Biology is often(usually?) much messier than anything engineering would create, because the changes are made without intention, and random changes are filtered by "what survived".
E.g., no engineer would ever place the neural bodies between the light source and the photo-receptor. It's a random chance made by a primitive chordate, which was "good enough to work". (IIUC, octopus ancestors made the opposite choice, and that also wo
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Successful genes are those that return progeny, and since Alzheimers takes effect long after producing progeny, then it does not negate their being passed on
One should be concerned that a genetic treatment to prevent Alzheimers _could_ effect other processes related to producing offspring, and that should be a concern before changing DNA
Beyond that, the treatment discussed in this article is related to treating the proteins produced by those genes, and would most likely not affect progeny
The potential here
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. A wealth of literature supports the role of serine-derived one-carbon in methionine re-methylation through the synthesis of 5-methyl THF, and polymorphisms in one-carbon metabolism enzymes can influence chromatin methylation and ultimately disease risk (Stover, 2011). However, we did not observe the expected serine-dependent re-methylation in cancer cell lines when methionine was present. We show that non-energetic metabolic stress can have a dramatic and rapid effect on total ATP levels, causing an even greater decrease than glucose starvation. However, this drop in ATP is not clearly detected by the classic energetic stress sensor AMPK, likely because lower de novo ATP synthesis is accompanied by lower levels of AMP. We see that despite dramatic decreases in ATP levels, cells survive and maintain proliferative potential. These are important observations given the widely held belief—based on studies involving energetic stress—that cells maintain constant ATP levels at all costs and that ATP concentration is “universally homeostatic” (Hochachka and McClelland, 1997). The term “ATP synthesis” is very commonly used (Pubmed returns over 600 papers with this term in the title) to describe the generation of ATP by adding phosphate(s) to AMP or ADP. However, this form of ATP generation can more accurately be referred to as ATP turnover or regeneration, as the adenosine nucleotide is conserved during such reactions. As the present study demonstrates, true (i.e., de novo) ATP synthesis—achieved by the assembly of glucose and amino acids through multi-step de novo purine synthesis—is also a major contributor to the functional ATP pool in cancer cells. https://pmc.ncbi.nlm.nih.gov/a... [nih.gov]
It appears as though the serine pathway is needed for creation of part of the mitochondria
Breakdown of serine by the enzyme serine hydroxymethyltransferase (SHMT) produces glycine and one-carbon (1C) units. These serine catabolites provide important metabolic intermediates for the synthesis of nucleotides, as well as methyl groups for biosynthetic and regulatory methylation reactions. Recently, it has been shown that serine catabolism is required for efficient cellular respiration. Using CRISPR-Cas9 gene editing, we demonstrate that the mitochondrial SHMT enzyme, SHMT2, is essential to maintain cellular respiration, the main process through which mammalian cells acquire energy. We show that SHMT2 is required for the assembly of Complex I of the respiratory chain. Furthermore, supplementation of formate, a bona fide 1C donor, restores Complex I assembly in the absence of SHMT2. Thus, provision of 1C units by mitochondrial serine catabolism is critical for cellular respiration, at least in part by influencing the assembly of the respiratory apparatus. https://pmc.ncbi.nlm.nih.gov/a... [nih.gov]
And used when a cell experiences hypoxia.
NADH provides electrons for aerobic ATP production. In cells deprived of oxygen or with impaired electron transport chain activity, NADH accumulation can be toxic. To minimize such toxicity, elevated NADH inhibits the classical NADH-producing pathways: glucose, glutamine, and fat oxidation. Here, through deuterium-tracing studies in cultured cells and mice, we show that folate-dependent serine catabolism also produces substantial NADH. Strikingly, when respiration is impaired, serine catabolism through methylene tetrahydrofolate dehydrogenase (MTHFD2) becomes a major NADH source. In cells whose respiration is slowed by hypoxia, metformin, or genetic lesions, mitochondrial serine catabolism inhibition partially normalizes NADH levels and facilitates cell growth. In mice with engineered mitochondrial complex I deficiency (NDUSF4-/-), serine's contribution to NADH is elevated, and progression of spasticity is modestly slowed by pharmacological blockade of serine degradation. Thus, when respiration is impaired, serine catabolism contributes to toxic NADH accumulation. https://pubmed.ncbi.nlm.nih.go... [nih.gov]
Serine pathway looks like it is fed during autophagy.
"Autophagy promotes mitochondrial respiration by providing serine for one-carbon-metabolism" May et al. (2020. Nat Commun) report that bulk autophagy provides serine as a one-carbon (1C) metabolite that controls respiratory growth onset by initiating mitochondrial initiator tRNAMet modification and mitochondrial translation linking autophagy mechanistically to mitochondrial function.
Autophagy is an evolutionarily conserved multi-step process that allows eukaryotic cells to recycle cellular components in response to nutrient limitation or various stress conditions.The PAS expands for de novo biogenesis of the double-membrane phagophore that sequesters autophagy substrates and matures into an autophagosome. The autophagosome’s outer membrane subsequently fuses with the vacuole (lysosome in mammals) and releases an autophagic body (inner autophagosomal membrane) into the vacuolar lumen for substrate degradation [1,2]. Autophagy is induced by nutrient depletion or cellular stress and provides new metabolites (e.g. amino acids) as building blocks to fuel cellular energy and metabolic pathways https://pmc.ncbi.nlm.nih.gov/a... [nih.gov]
Speculating but maybe Alzheimer's root cause is a virus? The autophagy equipment, that's supposed to break down dysfunctional organelle and viruses, gets taken over in some viral
Funny and sad (Score:5, Insightful)
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It's a buzzword for sure, but there is no denying that AI has, even before it became the latest buzzwords, been used in scientific research to great effect, distilling raw data into information that can be used for breakthroughs.
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Alphafold (Score:5, Informative)
From the article published in Cell [cell.com] it seems to be Alphafold and the structure it reveals seems vital to being able understand how PHGDH could be interacting biologically and therefore be a critical part of the discovery, so a shame the uscd.edu article doesn't mention it by name.
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Note that scientific papers have always have had to do some marketing. You don't get those grants to do the science without generally engaging in some fluff marketing along the way.
Re:Funny and sad (Score:5, Informative)
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Even LLMs are better than many people are willing to admit. But that's what you expect when people feel threatened.
Irritating (Score:4, Informative)
Turns out it was AlphaFold to determine the structure of the folded protein, and ChatGPT was used to grammar check the paper. https://www.cell.com/cell/full... [cell.com]
Re: Irritating (Score:4, Interesting)
Did you know that AlphaFold uses the Attention mechanism, which is the breakthrough that allowed ChatGPT to solve context-sensitive grammar, thereby supporting the idea that natural language processing is AI-complete: once you solve NLP, you can solve every other AI problem?
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OK. But a Turing machine is Turing complete. It's just a horrible way to program. Even assembler (think MIXX or I6502 assembler) is easier.
Similarly, for many problems that can technically be solved by AI, some other approach is better. It's NORMAL for the more generalized approach to be clumsier and more expensive.
Saying "you can use this approach to solve every AI problem" is not equivalent to saying "this is a good approach to use in solving every AI problem".
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which is the breakthrough that allowed ChatGPT to solve context-sensitive grammar,
No LOL. What youtube video gave you these ideas?
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You're right that they could have explicitly said that, but really there's no other game in town.
Don't let genetics be your full stop. (Score:1)
Too often genetics and a hand wave away.
But genetics doesn't operate in a vacuum, always interacting with the environment.
It's just a matter of scale and perspective.
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AI will remove medical care for millions of people (Score:1)
https://developers.slashdot.or... [slashdot.org]
Re: AI will remove medical care for millions of pe (Score:2)
This is true only if we continue to tie health care to employment. It doesnâ(TM)t have to work that way!