News from the Front Lines

Douglas R. Green, PhD

Chair, Immunology Department; Co-Leader, Cancer Biology Program; Peter C. Doherty Endowed Chair of Immunology

St. Jude Children's Research Hospital, Memphis, TN

Why did you get involved in cancer research?

For some scientists, the quest to cure a disease is what drives us.  For others, and this includes me, it is the exploration of the unknown.  My own quest started with wanting to understand how cells in the body signal each other to coordinate the development of an organism, and in particular, how this complex interplay could have evolved.  I decided that the immune system was a good place to start since we seemed to know more about the cells, their interactions and communication, and how through these we could develop something as complex as the discrimination between "self" and "not self."  Very philosophical! I was involved in some of the early discussions on the evolution of development (40 years ago!) and thought a lot about this deep problem. This led me to try to understand how cells in the body can commit suicide, something that at the time was utterly mysterious.  We made an amazing amount of progress (by "we" I mean the scientific community, although our lab contributed what we could). But cell suicide is not only important in health, it also has important roles in cancer, and this led me into cancer research. Now, all these years later, we still "follow the trail of data" to see where it will lead.  We now study many biological phenomena that arose from our efforts leading us into other areas of cancer biology and that of other diseases. It's an adventure.

What do you think is the most exciting thing happening in the world of cancer research right now? 
 Why is this important and what implications does it have? 

Like many immunologists, the explosion of work on anti-cancer immunity is in the forefront.  I think we have a very great deal to learn, and in doing so, we can only improve on the success.  But there are other very deep questions about how certain proteins orchestrate developmental and tissue processes that dictate the process of cancer development.  This is relevant to cancer immunity, but also to other aspects of cancer. The more we learn, the more likely it is that we can disrupt the cancer process. These are aspects of "normal" biology that become abnormal in cancer, and we are learning the key "pressure points" that, if we can control them, will change the way we treat cancer.  Last year, the foundation held a small, vibrant meeting on Myc and Ras (two of these key proteins), underscoring what we know, and what we need to know.

What do you think most people get wrong about cancer? 

Most of all, we tend to blame the patient.  Did they smoke? Eat red meat? Get too much sun?  Sleep on hard pillows? This is very human: We want to know that we aren't at the same risk.  But while there are many, many benefits to a healthy lifestyle, most cancers are not "caused" by the things we do or do not do.  Cancers are caused by mutations, and while some things in our environment can increase the risk of mutation, in the end, cancer is rotten, rotten luck.  Childhood cancer, in particular, is not influenced by lifestyle choices; these poor children are innocent. As are many, many other cancer patients (and I would say, nearly all).  

There is another misconception that I regard as "stupid."  Many people I meet firmly believe that we have the "cure for cancer," but that doing so would restrict the amount of money that hospitals, companies, and others make.  Here's the thing, if I knew the cure for cancer, even if I were told this under secrecy and the risk of life imprisonment, nobody could shut me up about it--I would tell everyone.  This is, I insist, true of every cancer scientist I know. Thinking that the cure is being kept a secret is simply, well, stupid.

Are there any other promising trends in the cancer research field that we should know about? 

An emerging concept is that of persisters, cells that survive therapy without new mutations (by "persisting" the opportunity arises for such mutations to occur).  Why do some cells live and others die? Do persisters change their sensitivities to other treatments (the answer seems to be yes).

Related to this is the finding that cancer cells can engage core cell death pathways (e.g. induced by therapy) but survive.  However, such cells increase their rates of mutation as a consequence of the death pathway (at least in the case of cell death by apoptosis).  A remarkable finding is that inhibiting the apoptosis enzymes called caspases can actually eliminate this effect, improving outcomes.

Another exciting area is that of cellular competition--cells compete in cancers and in normal tissues, with "winners" and "losers".  Surprisingly, each class (winner/loser) directs the other--losers "tell" winners to win, and winners tell losers to lose. If we can understand these signals and how they are controlled, we will have learned something that could be incredibly valuable for directing cancer cells to "lose."

All of these are unexpected findings coming from the study of cell death pathways, and underscore how making discoveries at the fundamental level can redirect our efforts to treat cancer.

Where should we be focusing most of our time and effort in getting closer to a cure? 

In the last 10 years, there has been a trend that could be stated like this:  "We know enough biology, we need to direct our attention to translating findings to the clinic."  But here is the thing: We simply do not know from where the next breakthrough will come. Here's an example (there are many):  When investigators studied how bacteria combat the viruses that infect them, we could have easily said that this is useless research that does little more than satisfy the curiosity of a few scientists.  But this research gave us CRSPR, the most powerful tool for manipulating genetics that we have ever seen (and holds enormous promise for engineering cells to combat cancer).

"Basic" research (I prefer the term "discovery research") is much less expensive than translation research, but this is where we cut support when funds are restricted.  Yes, we must translate our findings, but we are exploring an entire realm with tiny flashlights--there is so much we simply do not know.