Mike Levin is a professor of biology at Tufts University near Boston. He aims to control cancer by using electrical gradients across the cell membranes of cells and tissue.
Mike Levin: That’s correct, yes. For many years people have studied electrical fields that are generated by epithelia and this is quite different. What we are looking at is the encoded information that is mediated by gradients of different resting potential amongst all cells and tissues. Of course neurobiologists are very comfortable with this and the nervous system, we are basically studying how non-neural cells are able to use similar types of slowly changing electrical signals to store memories and mediate decision making during pattern formation.
It turns out that these voltage gradients are very important, instructive mediators that keep the activity of the individual cells orchestrated towards the anatomical needs of the body. So to the extent that cancer is a disturbance in cells’ ability to participate in normal pattern information, these cues become very important to look at in cancer as one of the things that goes wrong when cells sort of defect from the overall pattern forming and pattern maintaining progression of the adult body. So what we’ve been doing since the last time we spoke, is to apply some of our new molecular genetic technologies for manipulating these voltage gradients and apply them to the problem of cancer. And in 2008 and 2010, we showed that disturbance of voltage gradients in specific cells of the body can actually underlie transformation towards metastasis of a different cell type. So we showed that normal melanocytes, or pigment cells, undergo a metastatic-like conversion towards, basically, a melanoma in a frog system when other cells in the body are electrically depolarized using various genetic or pharmacological means. Now this was sort of the identification of the electrical properties of the microenvironment as a new aspect that controls the cancer transformation. So what we’ve done since then, is to look at the role of voltage gradients in mediating tumorigenesis that is initiated by canonical oncogenes. So what we’ve been doing, and this is two papers that have just come out this year, is misexpressing oncogenes that come from normal human tumors; things like dominant negative P-53, rel, ras and so on, and misexpressing them in a frog model. This makes tumor like structures, and we have shown several things. First of all we have shown that the prospective tumor sites and their margins can be detected early, before the tumors become anatomically or morphologically discernable by their aberrant voltage potential. So what we have are these voltage sensitive fluorescent dyes, where you basically soak the animals in these dyes and then you observe through microscopy, the dye lights up abnormal areas of depolarized cells and these areas are the ones that are going to go on to make tumors. So this is the beginning of, I hope, a new non-invasive diagnostic modality for determining where cells with abnormal bioelectrical properties are, because these are likely to form tumors. We then went on to actually look at the functional relevance of this voltage gradient and what we did was to, once again, inject these oncogenes into our frog model and show that by artificially hyperpolarizing these cells, that is by preventing the oncogene from depolarizing the cells, we can actually significantly reduce the incidence of tumors. Not only is voltage an indicator of tumorigenic transformation, it is actually crucial to that process and we show that cells could have very high levels of oncogenes present and still fail to make tumors if we artificially hyperpolarized the cells. So that has been developing that technology and sort of dissecting the mechanism of how this happens. We basically show that the way that voltage controls tumorigenesis in this case has to do with the SLC5A8 transporter. This is a sodium butyrate transporter that has already been linked to a colon cancer and other cancers from the human literature and basically what it does is link membrane voltage level to transportive butyrate. Butyrate is an important inhibitor of histone deacetylase so we have dissected the pathway and shown that voltage controls the epigenetic state of downstream transcriptional responses through the movements of butyrate and histone deacetylase. So that basically fills in some of the molecular details of how the voltage controls this process.
Pauline Davies: Have you tried this on other creatures than amphibians?
Mike Levin: No, not yet. We have a collaboration with someone looking at the similar phenomena in the mammalian system, but we would love to have more partners to do this work in mammalian or even human tissues whether in vitro or more complex in vivo types of setups.
Pauline Davies: Well it sounds like such exciting research that surely you won’t lack people willing to come forward and participate and help you.
Mike Levin: Yes. I think that lots of people have expressed interest, and there is room for a lot more. These reagents are not difficult to apply. We have set up “gift baskets” of reagents and protocols, which makes it very easy for collaborators to do this with their own favorite system. So absolutely, anyone that is interested or able to test this with us in a mammalian system, please contact me.
Pauline Davies: I can see that your system would be very useful, If it works in humans, to enable surgeons to see the boundaries of tumors. Is that correct?
Mike Levin: That’s correct. These dyes are very easy to apply and visualize and I do think that in real time in surgery, it is quite possible that this could be used to visualize the borders of the transformed cells.
Pauline Davies: What made you decide to work with cancer?
Mike Levin: Well basically, my group is fundamentally interested in the information processing that goes on during pattern formation and pattern maintenance. The question of how embryogenesis sets up a complex anatomy and how this anatomy is maintained through many years of adulthood despite the aging of individual cells is really important. Cancer is a very crucial example of when this information goes wrong. Tumors are structures that have basically either not received or fail to obey the normal patterning cues of the body and this makes it very interesting to us. Also there are long-standing data showing that regenerative and embryonic environments, like the regenerative limb in the salamander or pretty much any embryo, including mouse embryos, are able to reprogram tumor cells with extensive genetic and genomic deformations into perfectly normal tissue. This suggests to me that the primary factor is not necessarily any intrinsic sort of irrevocable defect in the cells, but the improper communication with the environment, and this for us, because we are interested in large scale pattern information, makes it a perfect case in which to look for the roles of bioelectrical signals in this process as we do in development and regeneration.
Pauline Davies: So you started off as a theoretician, and now you have to do the practical wet lab stuff; was that a difficult transition?
Mike Levin: It was very difficult. My original training was in computer science. I was a software engineer for years, and worked in areas like artificial intelligence and so on. Transitioning to biology was very difficult. I got a PhD in Molecular Genetics; it was very hard. At that time, it was not very obvious that people with a different background should be working in this field, now people are very supportive of these interdisciplinary collaborations and so on. But at that time, I was specifically told by well known people in the molecular genetics field that this was a big mistake and I wouldn’t be able to contribute anything useful and so on. But yes, picking up all of those skills was quite difficult, but I’m glad I did it. I think living tissues are a very exciting medium in which to understand computation and memory and things like this.
Pauline Davies: What do you think about the PS-OC initiative, because you’re approaching your work from the physical sciences perspective?
Mike Levin: Yes, this is an extremely exciting set of meetings. I’ve been to several and I always learn a lot. I find that we have very productive discussions because I come from a computer science background looking at the role of computation in living tissues and I find the concepts that I deal with, are readily understood and discussed at these meeting, which is not the case at standard molecular genetics conferences. So I find this very exciting and I hope in the future to have a bigger role because we are not actually officially a part of any of the centers. I would love to collaborate more with groups here.
Pauline Davies: Thank you very much.
Mike Levin: Thank you.