Matthew Kaiser.
The blog recently had the opportunity to sit down with Matthew Kaiser, an Oregon State University undergraduate senior in microbiology from Salem, Oregon. Kaiser, who hopes to pursue a career as an MD/Ph.D., has led an exciting research project on the potential treatment of cancer using intravenous vitamin C. He also recently delivered a talk titled “Is Humanity Ready for an Upgrade?” at a recent TEDx symposium hosted by OSU.
What follows below is an edited excerpt of our interview with Kaiser in which he discusses the roots of his project, its potential application, and his experience of conducting and presenting high level research at a very young age.
The Roots of the Research Project
The beginnings of this research project were more or less like most undergraduate project tend to start. Not all, but some tend to be these big black box projects, we call them, in that there are a lot of unknowns. It’s almost like, “we really don’t know a lot about this but hey, we’ll give it to an undergraduate to take a stab at it. Because even that way if it doesn’t work out, if we find out that there really is no story here, they get the research experience and then we don’t necessarily waste a graduate student’s time or post-doc’s time on a project that didn’t end up being published.”
But where this project started was, of course, back in the days of Linus Pauling who was among the first to suggest that high doses of Vitamin C could have an anti-cancer effect. But following his initial studies with Vitamin C, or ascorbate, there were studies that came out by the Mayo Clinic and other labs that showed that Vitamin C did not have a protective or anticancer effect. And so it was largely abandoned by the medical community for several years but it continued to be researched in kind of an alternative medicine environment. Through that, as our understanding of how Vitamin C is metabolized by the body developed, we were able to understand that if Vitamin C was delivered orally, it was completely different than how Vitamin C could be regulated if it was administered through an IV, because if you administer it through an IV you’re able to bypass all the digestive control and renal reabsorption in your small intestine. That normally would limit the amount of Vitamin C that gets into your bloodstream and then becomes vitally available.
So this project started kind of on the cusp of these exciting studies looking at the pharmacokinetics and, again, looking at the bioavailability of Vitamin C. And just to put it in perspective: so if you go home and eat fifty oranges, like all my friends like to try and do because they know I work on Vitamin C, they’re like “oh, Vitamin C and cancer, I can eat fifty oranges, right? And I can prevent cancer or cure myself or colon cancer?” And what we’re looking at in this project are doses that can only be achieved by IV because if you eat these fifty oranges, the maximum you can saturate your blood plasma level is about 220 micromolar. To put it in perspective, so if you can saturate your blood to a level of about 200 micromolar following oral ascorbate, if you go home and had an IV or you went to a clinic and you had an infusion of IV ascorbate, you can saturate blood plasma up to 30 millimolar. And there’s a thousand micromolars in one millimolar. So, extremely different doses can be achieved by these two different routes.
Conducting the Research Project
Where my project began was there were researchers that were looking at this difference and showing that Linus Pauling was in fact correct that high doses of Vitamin C, if it’s administered through an IV, can have anticancer effects. And so there’s this rekindling of interest in the story of high dose Vitamin C, or what’s called pharmacological ascorbate, in regards to cancer treatment. Buthere was still this unknown. People could see that it had a selective effect in patients but people were still unsure what was the underlying mechanism. There was an implication for high doses of hydrogen peroxide and that’s, I guess, where my project took off. So I began my undergraduate research experience in the laboratory of Roderick Dashwood, who’s no longer here. He’s actually now a new center director at the IBT Texas A&M in Houston, Texas. But his lab focused on primarily the epigenetic and genetic defense mechanisms of colorectal cancer and looked specifically at certain derivatives and things found in diet like organoselenium compounds and things like sulforaphane which are found in cruciferous vegetables; broccoli, cauliflower, things like that.
So his lab looked at colon cancer and epigenetics, and we were able to look at the growing literature on this, again, Vitamin C story that was kind of being rekindled. And people kept pointing to hydrogen peroxide as being a big reason for Vitamin C’s ability to be toxic to any kind of cell type, let alone cancer cell types. And there’s literature that supports the idea that hydrogen peroxide actually acts as a potent enzyme inhibitor. And in particular, one group of enzymes that our lab really focuses on because of the role it plays in epigenetics, are a family of enzymes called histone deacetylases. And what these proteins do is they modify the chromotine structure of DNA to therefore change the way genes end up being expressed.
And so what I tell my friends is to imagine a shoelace—this is a very simplistic model but it helps, I think, people visualize a little bit about what epigenetics is, because epigenetics involves changes in gene expression that are not associated with changes in the underlying DNA sequence. So, we know that DNA is made up of four base pairs: your As, your Gs, your Ts and your Cs. And you can obviously change gene expression if you change the lettering of those. You actually change the A to a T or vice versa, something like that. But epigenetics, instead of changing the language, it changes whether or not that G will be expressed or not. So, imagine your shoelace again, being knotted in different regions. So, that’s why your skin cell has the same genetic material as your heart cells, as your lung cells, as your eye cells, because all of these different cell types all have the same amount of DNA. But why are they so different? It’s because of these epigenetic mechanisms that bundled that stream or that shoelace in different areas and therefore control gene expression. And so we know that cancer cells are largely these very mutated, genetically mutated cells that have gone through successive mutations and have knotted and bundled that shoelace in different areas and then through a bunch of different enzymes and, in particular, these histone deacetylase enzymes.
So, our group wanted to see if Vitamin C – which is a pro drug for the delivery of hydrogen peroxide, which is a reported histone deacetylase inhibitor, an inhibitor of these enzymes that can control, again, the bundling and the shape of chromosomes, or your chromotine. We wanted to see if there was an effect and that was why there was a selective response between normal and cancer cells.
And so it really just started out as like well, we really don’t know but here, we’ll let the undergrad start. And I actually didn’t work under a post-doc or a graduate student, which is usually is what happens, but they let me really work very independently from an early time. Not that I necessarily led all the experiments at the beginning. But then we just started very simply, just looking at, does high-dose Vitamin C kill cancer cells in our assays. And we were able to show that yes, it does. And then the next question is, “okay, great we can kill cancer cells, but what about normal cells or non-transformed colon cells?” And so we had to do side-by-side viability assays and we were able to see, in fact, that there was a very significant difference in response and sensitivity between those two cell lines. So we were like, “fantastic, that’s great, but that’s already been published.” We already know that there is this selective response and so we wanted to dive into this big question mark or this big area of underdeveloped research, which was kind of these epigenetics, or genetic or molecular targets.
And so we began by looking at changes in protein expression within cancer cells that had been treated with high dose Vitamin C. We saw that HDAC were actually being changed. HDAC levels were going down or were changing in cancer cells, which had never been recorded before. And we know, for instance, that over expression of HDAC is a very big hallmark for cancer. It’s one of the major signals that this cell could be or is cancerous, or that it has carcinogenic behavior. And so we were able to dive right in looking at protein expression within cancer cells. And we were seeing that high-dose Vitamin C was modulating some of these very crucial HDAC, and we were like “wow, okay, no one showed any of this before.”
Again, there’s a lot of clinical data out there showing the chemistry of how Vitamin C generates hydrogen peroxide and how hydrogen peroxide get into cells, but no one had been looking at what is it about Vitamin C or hydrogen peroxide that’s actually allowing it to change gene expression or be selectively detrimental to these cancer cells but not normal cells.
And so, to be able to see these changes and these really important enzymes in this group of enzymes and then – although the name is histone deacetylase, which refers to the histone protein around which DNA is wound— there’s subtle groups that are on that which change the structure of it. And so these enzymes remove that, and so deacetylase. We know that these enzymes also have non-histone targets, so they can actually interact with other proteins. And we were really excited to find that a loss of some of these HDACs, so if you take down some of these HDACs, you would see a change in acetylation of not just the histone proteins but also their non-histone protein targets, which had not been shown in the Vitamin C literature as well.
Reporting the Findings
This led me to go on and give a talk, an invited talk at the Experimental Biology Conference in 2013. And that was my first conference I had ever attended and I ended up being selected to give an oral presentation. And I don’t think I was ever more nervous in my entire life, just because here I was standing on stage with tenured professors, post-docs, and the closest co-presenter in my session was a graduate student who was was about to defend their PhD thesis in a couple months. And here I was in my second year of research; I’d had one year under my belt. So, I felt very junior in both age and rank to be able to stand up there. But it was very exciting to know that our project was captivating enough to be selected for an oral presentation. And at that conference I was able to show that not only are we seeing these very interesting epigenetic responses in cancer cells, but then we were able to again, look back to normal cells and make a side by side comparison.
We know we can kill cancer cells, but what makes them sensitive to high dose Vitamin C as opposed to normal cells? And what we were able to see is that these normal non-transform colon cells didn’t undergo the same loss of certain histone deacetylase enzymes. We looked at different repair enzymes and things that might mediate hydrogen peroxide, responses to hydrogen peroxide such as catalase or DNA repair enzymes – it’s called CtIP – and we saw that in normal cells, after being treated with hydrogen peroxide or being treated with high dose Vitamin C, we would see that normal cells had the ability to up-regulate these defense enzymes and therefore protect themselves and repair themselves if they were damaged, whereas the cancer cells were not. And again, this type of molecular data hadn’t been shown in the whole Vitamin C cancer and literature.
From there, every year I’ve been able to attend a different conference being able to share this story and so it’s really come to define my time here at Oregon State and has just been something that I’ve really fallen in love with. I never would have imagined being at this point in my life. If you would have asked me two years ago or four years ago, when I came to OSU, if I was going to ever be in science, let alone leading a project in the molecular cancer lab, I would have laughed at you. I mean it just, it’s absurd. But I think the Institute and the mentorship that I had and the excitement that came along with this project, it was very enticing and very encouraging and very captivating.
Now I’m preparing my thesis defense for here in June and am detailing more specific questions that I can dive into. What we’ve been able to show is that normal cells are very different and very distinct in regards to how they respond to Vitamin C, and by tapping into that selectivity – normal cells react this way and cancer cells react in this way – we can develop more fine-tuned treatments, either involving Vitamin C or pharmaceutical drugs that can mimic some of the behavior of Vitamin C to therefore provide better therapy for patients living with advanced cancer. And so it’s tremendously exciting and I know for me personally, I’ve devoted a ton of time and a ton of effort to this, but when I think about going in or staying a little bit later on a Friday evening or waking up a little bit earlier on a Saturday to go in to do work or to finish an essay or finish going through some data, I like to think that if I was in the patient’s position, if I was someone who was suffering from this deadly disease – I mean colorectal cancer is the second leading cause of cancer related death in the United States among men and women – I would like to think that if I was in that patient’s shoes that there would be someone out there, maybe a student, that would be willing to sacrifice a little bit of their time and energy to help me and help further this story. Because it’s very real that this disease impacts thousands and thousands of people and millions of families are indirectly impacted by that. And so yeah, it’s great to be a small drop in this big pool of science.
The Next Step
The next step will be detailing more and more about how Vitamin C gets into the cell. Right now, we’re doing studies looking at how much Vitamin C gets into the cancer cells versus normal cells, and if it does, what does the hydrogen peroxide do. And so we’re working with different DNA constructs that allow us to measure intracellular hydrogen peroxide, which is really difficult to measure because the second hydrogen peroxide usually just mutates into a variety of different radical chemical species. So it’s really hard to measure how much hydrogen peroxides form. So we’re working with different experiments to try and fine tune that and then, again, trying to answer that question: why are normal cells more susceptible or less susceptible than cancer cells? So, that will be the next step. And then obviously moving into animal models and then looking at, can we potentiate the effectiveness of high dose Vitamin C using different adjuvents?
[LPI researcher Joe Beckman’s] laboratory has worked a lot with the disease ALS and they’ve worked a lot with copper ATSM. And we know just based off the chemistry of Vitamin C that in the presence of certain metals, that it can generate even more hydrogen peroxide. And so, we’re actually doing studies right now to see if we can use a product like copper ATSM, to potentiate the effectiveness of high dose Vitamin C. So that’s the next step, is how do we fine tune the effectiveness of high dose Vitamin C as well as elucidate more than molecular things that make it unique. And so those projects can go in maybe two different directions, one going into animal models and hopefully getting into patients and another still, again, looking at the rudimentary or reductionist view of what’s going on with high dose Vitamin C.
