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November 08, 2005

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Closing in on the Cure: an Interview with Zheng Cui

Dr. Zheng Cui specializes in tumor biology at Wake Forest University Hospital in Winston-Salem, North Carolina. As an associate professor at the university, he teaches biochemistry, molecular biology, lipid biochemistry, cancer biology, and cancer immunology. Dr. Cui's groundbreaking research in identifying innate immunity to cancer in mice and, more recently, human beings has received significant recent media attention. At the Speculist, we have been following these developments for some time. So we were delighted when Dr. Cui agreed to take the time to chat with us about this exciting research and what it has to say about how cancer will be dealt with in the very near future.

We'll also be talking to Dr. Cui in an upcoming FastForward Radio segment, so keep watching this space.

How did you make the initial connection between cancer and the immune system?

In 1999, my lab encountered a mouse that was expected to die upon a lethal injection of cancer cells that uniformly killed all other normal mice we tested before, several dozens or even several hundreds. But he didn’t. In the following years, we came to realize that the ability of survival from lethal cancer challenges was a genetic trait that can be passed on to 40% of offspring if one parent was cancer-resistant. We also found out that the apparently innate, naturally-existing resistance was entirely mediated by the cellular immune system. One could deplete the cellular immune system and thus abolish the resistance or transfer the immune cells from the resistant donors to normal mice that would subsequently acquire similar resistance to cancer. It also became apparent that this kind of cancer resistance is very different from any previously described cancer immunity in the literature, this newly found innate cancer immunity was much stronger. We basically used the “normal mice” that were used for demonstrating immunity to cancer as our negative controls (non-resistant controls). We knew at very early stages that we were dealing with something very different, a rare display of Mother Nature’s power in a very simple form.

It appears that immunity to cancer in mice is an all-or-nothing affair, but in human beings it falls according to a normal distribution. How do you account for this difference, and does it suggest to you that -- owing to the necessarily limited sample size of human beings that you have examined for cancer immunity to date -- there may be people out there with "super" cancer immunity: not subject to change of seasons, stress, or some of the other limitations you have encountered?

The difference is based upon the fact that lab mice are most inbred and humans are outbred. The lab mice are maintained as pure strains. Within the strains, breeding is routinely done between brothers and sisters of same strain. After many generations of this kind of inbreeding, the genetic make-up of all the mice within the strains and very much homogenized. Thus, the mice within the same strains are considered as identical twins except occasional germline mutations. Most humans, on the other hand, except identical twins, are outbred populations and have distinct genetic make-up from each other.


Dr. Zheng Cui

The anticancer activity in human leukocytes is very dynamic. It suggests that it is indeed interfaced with many environmental factors, such as the changes of seasons, stress and aging. Before we have evidence showing that some humans may indeed have the “super” activity untouched by these factors, we would rather base our treatment strategies on the influence of these factors on most human donors. I do believe that there are humans out there to have such “super” activity but these individuals are rare in my opinion.

Why would cancer immunity be subject to external conditions such as stress or the seasons?

One thing we have collectively learned is that reactions of humans to things like stress is a physiological response called “fight or flight response”. The major mediator of this kind of response is the release of stress hormones such as glucocorticoids, or steroid hormones. These hormones become potent stimulators of SOME physiological functions, like heart beat, skeletal muscles contractions etc. Meanwhile, steroid hormones suppress many other physiological functions that are not immediately crucial for survival responses, or “fight or flight”. This is merely a redistribution of energy metabolism from auxiliary functions to strength-related functions. Short and not-so-frequent stress reaction is not considered harmful to humans and other animals. However, if the stress signals linger, the constitutive release of low level of stress hormones would have a lasting suppressive effects on the immune functions. It is well documented that stress suppresses immunity in many aspects.

Many biologists believe that life forms including humans began at equatorial regions where solar energy is constant year-round. As humans become civilized with tools to travel, they began to move away from the equator and into places with seasonal changes. In the early days of moving north and south from the equator, one way to confront winters when food became severely scarce was to hunker down in the caves and reduce energy-consuming activity. This kind of life pattern may have lasted for over a million years for humans to overcome the food shortage in the winter. Human activity in the winters only began after industrialization, about several hundred years or several thousands years ago at best. It is possible that the changes in our physiological strategies for overcoming winters adapted over a million years has not caught up with the only recent events of industrialization in recent centuries. The extremely cases for animal to overcome winters are the cases of hibernation, such as in the bears and ground squirrels. The metabolic rates could have easily dropped to 5-10% of their summer levels. Humans don’t go to that extreme. But many of us do feel winter lows in everything in comparison to summers. Maybe the immune reaction is just one of these things sensitive to winters when we have to confront flu and other infectious diseases. The flu season may be a good example of weakened immune system due to winters.

The next step in your research is to test a transfusion of cancer-killing granulocytes in human subjects. How will you choose your test subjects? When do you expect the trial to begin?

Our first trial for using granulocytes from cancer-resistant donors to treat cancer patients will begin, hopefully, in June of 2008, when the cancer-killing activity in leukocytes returns and after we are able to raise enough money to support the trial.

We will choose cancer patients who no longer respond to conventional cancer therapies. We prefer the patients who have what we called measurable diseases so that the outcome of the treatment can be easily monitored. Patients have to be ambulatory and have at least 4 months of life expectancy. Sometimes, even the best medicine can’t save the lives of patients if it is too late.

We will select the donors who are healthy and preferably young and have high cancer-killing activities. Of course, they should be free of infectious diseases.

How do you anticipate this research to impact the treatment of other diseases? Is there an immune component to heart disease or diabetes? It would seem that there is a straightforward (potential) application for HIV.

I would be very happy if this new treatment can bring some kind of clinical benefits to cancer patients, such as one or more extra years of good quality life without the side effects of chemo and radiation therapies. Everything more would be just bonuses. After that, I am pretty sure that there will be an army of scientists who would figure out how they can translate this new concept for treating other human conditions.