Rhonda Patrick· PhD
And that's something that's evolving very fast. [Rhonda]: I mean, I think that DNA damage, and that's been pretty well-shown, damaging DNA, both mitochondrial and nuclear DNA, the damage that can lead to aberrant cells metab-, like cells. [Dom]: And I think the mitochondria are more important because the mitochondria have less of a robust DNA repair mechanism. And also the DNA of the mitochondria have more coding regions. So if you bombard cells with radiation classically, radiation biologists are taught that that radiation is directly damaging nuclear DNA and then that kicks on, causes the genomic instability that causes cancers, but I think what is being more appreciated now is that the mitochondria are selectively vulnerable because their DNA repair mechanisms are far less robust. They have much greater coding regions within their DNA, and they are the ones kind of calling the shots, they're making the energy, and if the energy status of the cell goes down, that's going to trigger the nucleus, that's going to trigger an energetic crisis in the nucleus, and the nucleus is going to kick on oncogenes to transform the cell from a normal to a cancer cell. So the stability of a nuclear genome is tightly regulated to the energetic state of the cell. [Rhonda]: Yeah, so I have a little bit of a different way of thinking about it mostly because I'm also doing a lot of research on this experimentally. So I measure damaged DNA, and I measure mitochondrial function after I induce radiation in some sort of... [Dom]: In primary cells? [Rhonda]: In humans, in blood cells, yeah. But so, mitochondria, you mentioned that nuclear, they have more repair mechanisms, and that's true, but mitochondria have very elegant and beautiful way of repairing damage through fusion, right, mitochondrial fusion and fission. And this is a process, I mean, this is how we are able to repair damaged mitochondria because they're constantly fusing with healthy mitochondria changing, I mean, exchanging their DNA content, protein, things like that, and fissing back part. So, of course, when those mechanisms become impaired, then that's, we start to have more accumulation of damage more because they can't repair. [Dom]: Fission proteins, the production of the proteins that cause that are also tightly linked to oxidative stress. [Rhonda]: Yeah, so I mean there's lots of different ways to repair damaged mitochondria. I also did a lot of work in graduate school. But I don't think it's clear, I don't think that the metabolic theory of cancer... [Dom]: Far from clear. [Rhonda]: You know, when you drop the ATP status in the cell, what happens is the cell dies and apoptosis gets trigger, and that's the primary...before oncogenes are activated, the cell dies. [Dom]: Unless it's if it's more gradual, then you have the activation. And most cells die. So you have 999 cells die and then you have one that, kind of, activates the complement of genes that can, allows it to survive, gives it survival advantage. That's what you get with chemo, too, or radiation when you blast a tumor with radiation. You get, there's few that can survive. And if you do that over and over to the tumor or over the course of chemos, you're kind of making a super-cancer because you're increasingly selecting for the most aggressive, glycolytic hardy stem cell-like tumor cell by hitting it with more chemo, you're just causing more DNA damage and more transformation, mutagenicity. Do you see it like that? [Rhonda]: I don't know. [Dom]: I'm not against standard of care, but I'm in favor of. [Rhonda]: I wanted to believe, in graduate school, I wanted nothing more than to believe that mitochondrial dysfunction is the cause of cancer, but I just couldn't, just couldn't attribute to myself. You know, I kept trying and trying, it would have been easier for my graduate... My graduate career would have been shorter, for one, but I just couldn't enough evidence to convince myself of it. And that doesn't mean that it doesn't, it's not true, it just means, I just...so far don't...I don't think that's the origin of cancer. I think that metabolic dysfunction plays a very important role in causing cancer. Most primarily through inflammation through all the effects of, like the insulin signaling and the inflammation, the reactive oxygen species. All these things that are damaging the cell, but I don't necessarily see it the way that you, sort of, described it as them... [Dom]: An initiator. [Rhonda]: Yeah, them changing or activating oncogenes. I don't think that's really been shown. [Dom]: I don't think anyone's studying that because...or studying it in the way that would make it clear, and I think it may vary between cancers like leukemia and lymphoma and relative to glioblastoma. I mean, we know these are just, they have a different metabolic and a different gene signature. Glioblastoma has hundreds, if not thousands, of genetic mutations. You know, so hence the name glioblastoma multiforming, you have all these different cell types and everything. Whereas other types of, like, for leukemia, for example, Gleevec works marvelously well because it's targeting something that's very specific. So I think it will be impossible to get a clear answer to this and I don't think it's... I think maybe I'm a centrist. So I'm somewhere in between the