Miranda Orr, PhD, Research Health Scientist and Instructor at UT Health San Antonio talks about “zombie cells” and Alzheimer’s.
Interview conducted by Ivanhoe Broadcast News in September 2018.
I like the terminology ‘zombie cells’, or zombie-like. But what exactly do you mean by that?
Dr. Orr: It means cells that have become stressed, but did not die and are not living how other healthy cells live. It’s at an in-between state, like an undead cell. The scientific term is cellular senescence. With time senescent cells contribute to the death of healthy cells around them. For these reasons senescent cells have acquired the nickname “zombie” cells.
Explain your analogy of the skin cancer.
Dr. Orr: The senescent or zombie-like state is best studied in other tissues, not the brain. In other tissues, what happens is if, for example, a skin cell is damaged, it can either repair the damage, die or, if it doesn’t die, it can keep multiplying and become cancer. If it doesn’t do any of those, it becomes senescent or “like a zombie” and it remains alive despite the damage. These cells become very secretory, which means they “spit out” or secrete molecules into their environment. The molecules they secrete are toxic, so they end up destroying the surrounding tissue. In the brain during Alzheimer’s disease progression, and in other chronic brain diseases as well, often time normal proteins (proteins that we all have in our brains even when healthy) can begin to clump up and damage cells. One of the proteins, tau, that clumps up forms tangles. The tangles form inside neurons, your brain cells, and the tangles are the closest correlate with dementia. The more tangles there are in the brain, the worse the dementia is and the more cell loss there is. But the cells with tangles themselves don’t actually die, so the hypothesis was that maybe these tangles are causing cells to enter the “zombie-like state” called cellular senescence. In turn the neurons with tangles would be contributing to the death of surrounding healthy cells.
So in this case, the living dead might be a good thing as it relates to Alzheimer’s. What could be perceived as a bad thing?
Dr. Orr: The “zombie cells” end up destroying the tissue around them with time, so you would want to clear them. You don’t want to keep them around.
In your research, what are you trying to do in relation to those cells in the tangles?
Dr. Orr: What we did in our study first was determine whether or not this was happening in Alzheimer’s disease, so we acquired data from postmortem brain tissue from patients with Alzheimer’s disease and we looked for this phenomenon. Once we saw that it did exist in human patient tissue, we used a mouse model that develops tangles to see if tangles also caused senescent cells to form in mouse brains. Once confirmed in the mouse model, the next step was to use drugs that had been shown to clear senescent cells or the “zombie cells” in other tissues and diseases. We treated our Alzheimer’s mice with the same drugs to see if there would be any benefit.
Do you inject the drug into the mouse?
Dr. Orr: It’s oral.
It’s oral and then once it gets in there, what exactly happens? Describe the process.
Dr. Orr: To the drug?
How the drug sort of interacts with the tangles and the zombie cells.
Dr. Orr: So the zombie cells have developed an armor essentially that protects themselves from their own toxic compounds. What these drugs do is disable their own armor so they kill themselves.
And once that happens, that’s a good thing?
Dr. Orr: That’s a good thing. Once those “zombies” have actually killed themselves one source of toxicity and disease is now cleared from that tissue and the drugs are rapidly cleared from the system. Another aspect that we’re really excited about is that these drugs don’t have to be given every single day. They don’t have to remain in the system. In our study, we treated the mice for three months but the mice only received the drug six times.
And what did you see?
Dr. Orr: We saw that the drug seemed to have stopped the disease in its tracks. We treated mice that were about equivalent to a 70 year old human and these mice had really advanced disease so their brains had already started to shrink. They already had a loss of cells, they had a lot of tangles. We treated one group of these mice with the drug and another group of the mice with a placebo. The mice that got the drug, when we looked at their brains three months later, their brains looked much better than the ones that received the placebo.
So when you say they looked much better, does that mean some tangles were gone or what happened?
Dr. Orr: We saw a significant reduction in the number of tangles and when we looked at their brains on MRI scans, we saw that their brains were larger and they didn’t have as much other pathologies that are typically seen in brain scans in Alzheimer’s patients. For example, the regions of the brain where the cerebral spinal fluid is held actually swell or grow in Alzheimer’s disease and the same is true in our mice. The mice that got the drug, their ventricles, or those areas that keep the cerebral spinal fluid, were actually smaller, which is a good thing.
Is all of this research, and eventually when you start your trials, directed at getting rid of the tangles? Is that sort of the key?
Dr. Orr: You are correct; however, we didn’t know if we would get rid of tangles. How we actually interpreted the data is that we prevented more from developing. We’re not sure with this exact study if we removed any or if we just kept them from increasing. We can say, with certainty, that mice that received the drug had fewer tangles in their brain at the end of the study than the mice that received the placebo.
This is early stage that you’re looking at, right? Catching it soon?
Dr. Orr: In our mouse study, it would not be considered an early stage disease. They were pretty advanced. That’s why we’re really excited because most of the other treatments, to work, have to be administered either before the mice get sick or at very early stages. In this study, we started treating the mice when they already were sick.
So they’re already sick and old and they get better. How do they get better? Does it halt the process of the tangles?
Dr. Orr: That’s how we are interpreting the data. We stopped the disease from progressing.
Are you going to do the late stage and the early stage when you get to the human trials?
Dr. Orr: We’re going to start early, as early as we can – the strategy being to try to stop the disease from progressing.
As a scientist and a doctor, how do you see this problem with Alzheimer’s? It seems like everybody has it.
Dr. Orr: It’s a huge problem. It’s the most common neurodegenerative disease. One in nine people over the age of 65 has it (currently this number is 5.5 million Americans over the age of 65 with Alzheimer’s disease) and the risk of getting it continues to increase as you grow older. It’s a very big problem and we don’t have any good disease modifying therapies.
So you’re not looking at the basis or the foundation of what’s causing it, but you’re looking at stopping it in its tracks?
Dr. Orr: We are looking at all aspects, but this happened to be one that we seemed to have stopped in its tracks. With further studies, we will be able to determine whether or not this treatment strategy can reverse or prevent the disease as well.
I want to ask you from start to finish because what people are thinking is, when can I get my hands on this? And I know it’s a really long process that we’re talking about.
Dr. Orr: For moving it to trials?
People who have Alzheimer’s actually taking the drug— how far away is that if the clinical trials go as expected? Does it take a long time?
Dr. Orr: It does. The good news is that one drug is FDA approved already. It’s used to treat Leukemia. We used a drug combination of two drugs. One is the cancer drug and another is a natural compound. Since one is FDA approved, and the other a natural compound, they can more quickly move to trial. And there are already trials looking at this drug combination for other diseases and so far it looks like they are well tolerated, which means moving it to another disease such as Alzheimer’s disease will hopefully happen quickly. The other aspect that we’re really excited about is that this drug does not have to be given every single day. Even though there are toxic side effects with the cancer drug, it might only have to be given maybe four days every few months or four days every year. Those kinds of details will have to be determined in clinical studies.
What are the names of the drug and the natural?
Dr. Orr: Dasatinib and Quercetin is the natural.
What did you refer to that as, a natural compound?
Dr. Orr: Yes. It’s found in foods (examples: capers, berries, onions, peppers).
Again with the diet. Is there anything I missed?
Dr. Orr: We also acquired postmortem brain tissue from patients that had a diagnosis of progressive supranuclear palsy (PSP). That’s another disease that develops these tangles of pathogenic tau. We all have tau protein in our brain, even as healthy individuals. However, tau protein is sensitive to a variety of stressors, and these stressors can change the normal shape and function of tau protein. Altered forms of tau protein are the most common pathology that occurs among brain diseases. So we started with Alzheimer’s disease and PSP, but we’re hoping that it could apply to many other diseases including Parkinson’s, traumatic brain injury, and the list just goes on.
END OF INTERVIEW
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