There are many reasons to go to Pathology Grand Rounds talks in my school (Thursdays 12:30 @ Fitkin auditorium). Food has always been one of them, as evidenced by a growing number of individuals who will show up (usually 10-15 minutes earlier) take a COUPLE of sandwiches (that’s FOUR halves) eat them and leave within the first 5 minutes of the lecture. That’s a story for a whole another post…

I usually go there to see breath-taking pictures of spectacular tumors (yes, while eating lunch, call  me sick) or learn something new about methods of diagnostics, treatment options, or admire our astounding lack of understanding of tumorigenesis, etc… Generally the talks can get very technical (too technical? Zzzz Zzzz), today, however, it was one of those rare cases when we had an engaging and interactive speaker with a very refreshing set of ideas to present. It was  Dr. Bevin Engelward from MIT. The ideas presented were somewhat ground-breaking and provocative, questioning the relative importance of cell’s exposure to stress (UV, oxygen, radiation) to formation of cancer.

It has been established by numerous groups (Weinberg’s text book on cancer summarizes the current knowledge)  that targeted mutations in certain genes provide a cancer with an arsenal of tools to immortalize and mobilize itself, break out of the tissue of its origin and travel invading other sites. The process of how that emerges is still somewhat murky. Many believe that genome acquires random point-mutations, via cell’s exposure to stress like inflammation, drinking too much, smoking, living next to cell phone towers, BREATHING…

One idea is that, first, randomly, a gene that, say, limits cell’s ability to control its duplications is turned off by a disruptive mutation. Then, again, randomly the same cell succumbs to another mutation that prevents itself from a graceful death when its natural time comes… That’s two points for the cancer (it only needs five). Then things can get only worse. The source of these mutations? stresses to the cells. Dr. Engelward showed however that way before we get exposed to stresses our genome ages and destabilizes or re-shuffles itself!

Imagine 23 neat stacks of lego blocks, and then having someone randomly pick a block from a stack and insert it into another stack. If I watched my 23 stacks carefully, I could probably undo the damage so that everything is neat again. Similarly, the cell watches its own stacks of block (chromosomes, full of genes and other neat things) and if something goes wrong, generally the cell knows how to undo the mess and return the pieces back to their original place (each stack is redundant). If this repair mechanism fails or is somehow overwhelmed by the number of tricksters trying to shuffle the blocks, at some point the cell gives up, and cannot cope with all the chaos that ensues. Normally the cell then decides that it’s time to kick the bucket, unless of course the self-destruct button is broken (i.e. a self-destruct-gene has acquired a mutation) and the shuffled-up cell continues on with the chaos instead of a neat arrangement of genes on chromosomes… not good. What if another, legitimate cell detected its own troubles, died (Poof!), and left empty space in tissue?  That space could then be taken up by a daughter of the broken cell! Now we will have two broken cells that cannot die, but can continue with broken genome. In any case, according to the data shown in the lecture, the exposure to stress only accelerates what is inevitably happening due to shuffling, or recombination events.

It is all a part of an ongoing chicken-and-an-egg debate and, personally, it seems to me that both components (random mutations AND chromosome rearrangements) provide tissue mosaicism needed by the selective forces to choose the fittest of the cells to survive. Further studies will show whether one of the two (or maybe more) aspects is a more important a factor than the other(s). BTW, What lies at the junctions of the “blocks”, why some of them are more fragile and susceptible to breaks and rearrangements is a topic for a whole another lecture…

So, this was the first 15 minutes of the talk.

If I haven’t lost you, the second part was even more exciting.

The speaker explained another, somewhat unrelated experiment they did. In essence, they took blood serum from Hiroshima A-bomb victims (it’s important to mention that the samples were taken quite a while after the exposure to radiation). Then normal, healthy cells were subjected to the collected serum. And this is the interesting thing: the radiation did horrible things to the genomes of original cells. The serum applied to the new cells somehow transmitted the information about exposure of the original cells, and the healthy cells started to show the same signs of exposure to radiation, even though, technically, they never were irradiated !

On the same note, to verify this finding, the speaker showed another, similar experiment. Healthy cells were irradiated a little bit, just to cause some DNA damage, and then left to proliferate for 30 or so generations. After 30 generations or so, the cells accumulated quite a lot of damage in their genetic material – chaos. Again the cells were disposed of, and only the “soup” in which the cells lived for 30 generations was harvested and given to another batch of healthy cells. The healthy cells remembered the original exposure  to radiation. After 30 generations there was quite a lot of damage visible. Repeat, dispose the cells, harvest the “soup”, apply to yet another batch of healthy cells, allow them to grow and… the memory of radiation exposure  for the original cells got transmitted again.

This is extremely counter-intuitive, why would a cell want to remember and then pass on such a BAD memory, which in the end leads to accumulation of a lot of dangerous damage? Well, something similar has been studied in plants, where some crop which name escapes me at the moment is able to determine whether a condition of draught is occuring, and it can the pass that memory to its offspring via seeds. The offspring then, right of the bat when it germinates, knows to conserve resources and generally tighten the belt. The memory of “bad condition” is passed on from generation to generation to give a plant an advantage over other plants that may not know how to budget their need for resources. A few generations later rain season comes around, and the plants can switch back to the gluttonous mode of existence and pass that knowledge to their offspring. The cool thing though is that both the drought plant and the rain season plant have the same set of genes, and there are no mutations involved in passing the memory… What changes is the EPIgenome, or additional layer of information stored in cells’ nuclei. The cells have genes, which generally don’t change, but in addition the cell store information about which genes needs to be on or off.

The epigenome is extremely important. In human for example, the liver, kidney, brain, they all have the same DNA, yet the cells in each organ perform different functions, they have different morphologies, heck, liver cells are even allowed to regenerate! This is controlled by the epigenome, which is tissue specific, and masks irrelevant genes enabling only the important ones for cell function.

In case of my plants the memory of draught is useful and so it is passed on. There is also a draught-on and draught-off switch. The epigenome can easily change between two states.  So then, how is the memory of exposure to radiation useful? and why is is passed on? Exposure of genome to radiation is a very dangerous and destructive one, it is my own speculation that our cells haven’t evolved an appropriate response capable of dealing with this kind of an insult and as a result there is no way for cells to resist and repair the effects of radiation… In other words the cell detected radiation, but died before it was able to deal with the exposure and hopes that its copies will be able to fix it… Maybe in a few million years a cell’s great-great-great-(…)-grand daughter will find a way to deal with radiation and an appropriate exposure-off-switch will emerge? At this point however we are stuck with the genomes we have…

Unfortunately this “memory of exposure” has tremendously severe implications for chemotherapy patients for example. The irradiated or poisoned tumor cells die but their surrounding tissue remembers the exposure !!! The serum, remains and is potentially capable of causing recurrence of secondary tumors because the memory of exposure remains in the microenvironment. Dr. Engelward suggested another potential solution: what if we could prevent a cell from remembering about the exposure? Without going into too much details, the idea was right on the money. By turning of the cell’s mechanism to modify the epigenome, the transmissibility of exposure memory via the “soup” diminished significantly !

The epigenome is still quite mysterious, although it give us hope of understanding the mechanisms of assigning and mis-assigning functions to cells. Correcting inappropriate epigenetic patterns is slowly becoming a promising therapeutic force in our battle against cancer – there is still a loooong way ahead though. And what on earth is in that memory-of-exposure “soup” ???