Sugar Metabolite Bypasses Genetics in Cancer

I'm going to get to cancer metabolism in a moment, but I want to start off with a light analogy that I promise will become relevant later. Imagine you're driving a car on the highway and suddenly your steering wheel disappears. What will happen? Well, you're gonna crash, obviously, and it's going to be pretty obvious when looking at the wreckage why you crashed— there was no steering wheel. Now imagine that scenario with a tweak. You're driving on the highway, but instead of having your steering wheel disappear, there's some evil magical force. Imagine like an evil Dobby the house-elf from Harry Potter. Why? Because I like Harry Potter and everybody says I look like Daniel Radcliffe. I I don't really see it. You can tell me in the comments if you see it. But anyway, if this magical evil Dobby that can snap his fingers and temporarily, episodically, and pseudo-randomly disable the steering wheel, what will happen? Well, eventually the car will crash, but when you look at the wreckage, the signature won't be as obvious because there will be a fully functional steering wheel there in the wreckage. Okay, so I want you to contrast those two scenarios. Hold that in your mind, and that will help you understand what we're now gonna talk about, which is cancer, sugar metabolism, methylglyoxal, and diabetes. Let's dig into it. Welcome to my channel, stay curious. The paper of relevance today is entitled A Glycolytic Metabolite Bypasses Two-Hit Tumor Suppression by BRCA2. It's a new paper published in Cell, very cool paper, very dense. I'm going to kind of take the 50,000-foot view in this video, and here's the background you need to know for this video. Cancer cells arise from the accumulation accumulation of genetic insults to those cells. Once you have enough genetic defects, a cell will be able to escape normal growth regulatory processes and grow out of control. But our cells have tumor suppressors that keep this process in check. It's like many backup brakes, if you will, and you have to break a lot of the brakes before you develop a cancer cell. And breaking those tumor suppressors is thought to require breaks in DNA, DNA dysfunctions. And because you have 2 copies of every gene— thanks, Mom and Dad— you need to lose 2 copies of the tumor suppressor in order to fully break the break. This is known as Knudsen's two-hit hypothesis. So for example, you can be born with a break in one copy of the gene, say BRCA2, BRCA2, which is a tumor suppressor gene. But then sometime later in life, it's thought that you have to lose the other copy, and this is called loss of heterozygosity if you want the scientific terminology. And that's when the break is fully broken and you develop more mutagenesis and cancer. And crash the car. That's the analogy there. This is similar to like ripping away the steering wheel entirely, erasing the steering wheel. That's loss of heterozygosity. That's Knudsen's two-hit hypothesis. But scientists just discovered how a metabolite, methylglyoxal, abbreviated MGO in the paper, can operate like the evil Dobby and episodically disable BRCA2 without actually breaking the second copy of the tumor suppressor and thereby bypass Knudsen's two-hit paradigm and promote cancer, but in a kind of metabolically surreptitious way. So what is methylglyoxal? Methylglyoxal is a byproduct of glucose or fructose metabolism that can covalently attach to DNA, RNA, and proteins, and in the case of proteins, disable their function and cause metabolic derangements. And methylglyoxal is increased in states of metabolic dysfunction like diabetes, thereby creating a link between states of metabolic dysfunction and potentially mutagenesis, cancer. Now, to reinforce and double down on everything I just tried to explain, I want to read two sections from the paper in which I thought the authors did a great job articulating the core message. Now, I did modify these slightly, and to demonstrate where I modified it, you'll see the quote and you'll see a slight font color change. I did so just to make the message a little bit more clear in layman's terms, just get rid of a little bit of jargon. They write, "They discovered a mechanism underlying the mutagenic potential of glucose and fructose metabolism via bypass of the two-hit requirement for the BRCA2 tumor suppressor. Our findings identify a previously unrecognized impact of metabolism on the initiation and progression of cancer cell formation." They also write, we speculate that periodic episodes of induced tumor suppression activation triggered by intermittent metabolic stress could spark events that contribute to the patterns of genome evolution recently identified during early steps in cancer formation. In other words, our findings raise the possibility that metabolic bypass of the two-hit requirement for tumor suppression demonstrated in this paper may be an unrecognized yet widespread mechanism that connects metabolic alterations and sugar metabolism with cancer initiation. With that, I would close, but I've decided I want to actually reveal why I did this video specifically, and it derives from a comment I got from one of you, and I want to read it to you just because it was so touching to me. Nick, I'm an 84-year-old granny and I really love your content. It's inspired me to read more of the literature myself. I know, can't teach an old dog new tricks. We'll find out. Well, I was trying to decode this paper and wanted to get your thoughts about its relevance. Is it saying that eating too much sugar can promote breast cancer and prostate cancer? Does this mean that eliminating sugar may help protect me from cancer? I recently started using allulose from RxSugar after I watched your Healthiest Sugar video and really love it and want to know if it's helping protect me from cancer. That's not a plug for me, that's just a comment. Thanks for all you do. Anyway, I want to thank this person for leaving that comment. Comments like this really not only make my day, make my week, but really inspire me to do more of this scientific education. I think something I'm good at. I really appreciate the feedback and all of you being here with me to help me grow, um, but comments like this really are quite touching. Now, to address the actual question, I think it's stepping a little bit beyond this basic science paper to say that eating fructose will cause cancer. However, there are literature showing that, say, eating high fructose foods, at least animal model literature, will increase methylglyoxal levels. And it's consistent with what we see with human studies in which there is metabolic dysfunction in these pathways and there are increased methylglyoxal levels that are causing damaging effects, including complications of, say, diabetes. So for example, here's a graph from an animal model study showing that feeding fructose boosts methylglyoxal levels in fat tissue, adipose tissue. So do I think it is potentially helpful to reduce your sugar intake? Well, it's not going to hurt you, and yeah, it potentially could help you. So, you know, if you want to go bake dulce de leche cheesecake, here's a recipe from my friend Martina Slaryova— now I am plugging my friend— with some allulose, then go ahead and go for it. Again, it's not going to hurt you, and it potentially could help you. But I hope you you enjoyed the science here. And yeah, if you want to go bake cheesecake with some allulose and no fructose or sugar, then go ahead and have fun with that. I quite like baking. Actually, in another disclosure, one of my summer projects with my girlfriend is to learn to make a bunch of different cheesecakes for entertainment purposes. So between our medical school and residency demands, we're going to be baking cheesecake and maybe using some, some allulose or maybe even a little bit of honeycomb along the way. Totsumi.