Principal Investigator in Cancer and Autoimmune Diseases
Department of Immunology
Virginia Mason Research Center
University of Washington
One early spring day, I was on my way to work. A stranger greeted me and asked me what I did for a living. After learning that I am a cancer researcher, his eyes lit up and asked: "Are you going to find a cure for cancer?" His question plunged me deep into thought and now I would like to share some thoughts with you.
Ever since my grandmother passed away so suddenly from malignant liver cancer about twenty years ago, the word "cancer" has never left my mind and heart. It was the innocent hope from my young heart that one day I would find a cure that has led me to this stage of my career.
Since 1988, I have followed the path of the reductionism-based modern science approach to study Biology at multiple levels: from Anatomy to Histology, Cell Biology, and, finally, to Molecular Biology, using yeast as a model system to study gene regulation. After I obtained my Ph.D. degree, I felt I was ready to go face-to-face with cancer and therefore stepped into the field of cancer research. I do research in this field, like many others, via observing cells in artificial systems, specifically, what we call in vitro systems, which are cell lines grown in petri dishes.
In 1992, when I started my postdoctoral training at Massachusetts General Hospital in Boston, I "met" this powerful protein called Transforming Growth Factor-beta (TGF-beta). This molecule is a potent suppressor of cell growth. In our body, there is a large number of TGF-beta-like proteins, all of them are very powerful, in that each of them is in charge of the formation and maintenance of different major organs of our body. Most of these proteins are potent inhibitors of cell growth. In our body, there is also a large group of proteins whose functions are to actively promote cell growth. Here the ancient wisdom of China, the theory of the balance of Yin and Yang in the macrocosm, is beautifully reflected at the molecular level, in the microcosm of the cell. Research conducted over the past twenty years has led to the elucidation of the detailed molecular network in a normal cell which goes through a highly regulated life cycle of growth, specialization (what we call differentiation), aging and death. In every step of the life of a cell, we can "hear the song" and "see the dance" of the interplay of the Yin and Yang factors in great harmony. The disruption of the balance between these two factors is recognized as the foundation for uncontrolled cell behaviors, one of which manifests as cancer. How does a normal cell turn into a cancer? What went wrong? A normal cell responds to environmental cues to determine when it can enter the growth phase, called the cell cycle, which consists of several distinct stages, named G1, S, G2 and M. There are gates between each stage. The cell has to meet certain requirements before it can move on. These gates are very important, since if there is something wrong in the cell, the gates will serve to safeguard the cell by stopping it at that phase until the problem is somehow fixed. If the problem cannot be fixed, the cell would trigger an alarm system that, amazingly, leads to a well-orchestrated death program. Thus, a normal cell acts in accord with the system it belongs to. When mistakes occur, the cell has a mechanism to "sacrifice" itself for the benefit of the whole. A cancer cell somehow outsmarts the laws at each gate of the check points between the different phases of growth, thereby continuing to grow in number. The death mechanism is also abolished so that they reach "immortality." Of course, such temporary immortality is followed by the death of the whole, which reflects, interestingly, a very ignorant but totally selfish "spirit".
In the past twenty years, cancer researchers have learned that it takes many steps for a cell to accumulate the various protein mistakes that eventually wipe out all major safe-guarding mechanisms at the level of a cell. Then the cell starts to metastasize, during which it again violates multiple system laws, including the laws of the immune system. Like the policeman, the immune system normally provides constant surveys of the body systems to eliminate abnormal cells.
The real mystery is why the cell can manage to accumulate so many mistakes without being eliminated. Within the microcosm of a cell, we know that many safeguarding mechanisms are in place. Within the "midcosm" of a body, we know that there are also many safeguarding mechanisms in place. Why does every safeguarding mechanism fail in a cancer patient? Some biologists believe that cancer is due to some mistakes at the gene level, which allow the genetic material to be unstable, called genetic instability, thus leading to large scale mistakes at the gene level. However, a normal cell knows how to fix a mistake at the gene level and also knows how to initiate the death program when it fails to fix the problem.
Many labs, including my own, study how cells communicate with each other via proteins (www.vmresearch.org, "laboratory research"). TGF-beta is produced by almost every cell in our body. When it is released outside of a cell, TGF-beta serves as a signal to "instruct" surrounding cells that have a unique set of proteins that can recognize and bind to it. Once these binding proteins, "receptors", which are sitting on the cell surface, bind to TGF-beta, these receptors will then "talk" to proteins inside of the cell. The detailed steps of protein-protein communication inside of a cell in response to an outside-of-cell protein are mapped out carefully by many labs in the signal transduction research community. After six years of intensive and expensive studies, we have now identified an interesting functional mechanism for TGF-beta. It is known to everyone in this field that there are a group of proteins inside of the cell, "Smad", that are critical for carrying out the instructions of TGF-beta to suppress cell growth. In fact, many cancers, such as colon cancer, pancreatic cancer, and head and neck cancer, are all associated with defects in these Smad proteins. Only recently have we found that Smad carry out their mission through directly talking to an extremely important protein system inside the cell. This protein system consists of a large number of proteins that work together to do the following jobs: 1) mark old, aged, or dysfunctional proteins for destruction; and 2) help almost every aspect of cellular function via orderly breaking down proteins to fine-tune the levels of each protein that works as a regulator in the cell. This system also is essential for the immune system to find what is wrong when virus and bacteria enter the body, or when a cell behaves abnormally. This protein system is called "the proteasome system". The malfunction of this system also blocks the function of TGF-beta as a suppressor of cell growth.
When I was pondering the meaning of this finding, my friend Dr. Lili Feng called me one day. Lili is an Associate Professor at Baylor College of Medicine. Both Lili and I practice Falun Dafa, an ancient mind-body practice now broadly known to the public largely due to the recent persecution of Falun Dafa in China (www.falundafa.org). I knew Lili was carrying out a project to examine the effect of practicing Falun Dafa on cells of the immune system. Lili told me that she has completed her studies on comparing the level of 12,000 genes in Falun Dafa practitioners and non-practitioners. To my great surprise, she mentioned some genes in the proteasome system. So I asked her to send me the original data and decided to take a careful look. From that point on, an amazing stream of enlightening information flowed into my research system. The data Lili sent to me was a pile of numbers assembled randomly from the experiments. But from the pile of the numbers, one clear image came out: more than 10 different proteins in the proteasome system are drastically down-regulated in Falun Dafa practitioners' immune cells. This would indicate that the proteasome system is down-sized. It would not make much sense if only this system is down-sized, since the lack of sufficient proteasome system would lead to the accumulation of junk and old proteins. But in the same set of data, more than 10 different proteins that belong to another protein system called "ribosome" are also drastically reduced. Ribosomes are responsible for making new proteins. I suddenly realized that the data is suggesting the coordinated down-sizing of the entire pipe-line of proteins production and protein consumption.
Lili then mentioned to me that she has read papers regarding correlations between proteasome system size and activity with longevity, in mouse experiments. Dr. Allen Taylor from Boston University reported that when the food supply was restricted, mice live longer and their proteasome system is down-sized (ref 1-3). I then found a paper that reported the correlation of increased proteasome system activity with many different diseases. In this paper, it was reported that the highest proteasome system activity was found in cancer cells (ref 4). A third paper from Lili added the final touch to an idea that started to surface (see below). In this paper (ref 5) it is reported that, from careful studies of protein metabolism in a cell, it seems that 1/3 of new proteins are immediately destroyed after they are made. Thus, the cell is working in a very busy and wasteful state.
Lili and I started to send emails back and forth. Lili has a wonderful sense of humor and a vivid imagination. One day she asked me, "Do you know what the proteasome is in the microcosm?" Then she answered for me, "The black hole." Then she sent me a set of reports on how active the black holes are now in the Universe. "You see", she said, "the proteasomes are very busy when cells are sick, and what does it mean when the black holes are very busy?" When I heard that, I thought of the phenomenon of our modern life style: mass production and mass consumption. Isn't it amazing that the different cosmic systems of cell, body, society and the entire Universe, from micro to macro, exhibit such striking similarities and correspondence?
At this point, when I went back to think about the question, "What makes the cancer cells accumulate so many mistakes and allow it to violate so many different safeguarding mechanisms," a simple but clear answer came to my mind, "It is the hyper-metabolism rate of the proteins!" If all cells in a body are in the state of mass-production, the proteasome system is likely to be overloaded and unable to break down old and broken proteins, which then carry out wrong things, which further disrupt the balance. Since the proteins are the real players in all of the functions of a cell, when bad proteins can not be eliminated, they will continue to do bad things till the entire system is out of control. No matter how hard the cell tries to increase the amount of proteasome production, if the metabolism continues to increase, the cell will eventually fail to manage. The increased proteasome level seen in cancer cells likely reflects such a last struggle the cell trying to regain the balance.
I cannot help wondering how many of the diseases modern people are experiencing are the result of the hectic lifestyle they have, the mental stress they are under, and the endless pursuits in which their minds and hearts engage. All these can, through the unique human pyschoneuroendocrine system, transmit to the cell level orders to increase the cellular metabolism, which, when it overwhelms the proteasome system, leads to the accumulation of cellular mistakes, and, finally, to the downfall of the body system. To take a step further, is the endless desire for more money, more goods, more recognition and more power also closely linked to many of society's diseases?
So what is the cure for cancer? What is the cure for all of society's problems? What can slow down the activities of the black hole in the Universe? The problem of curing cancer is as gigantic as the latter two problems. But is there a common cause for all three? Is there a Universal Law, violation of which will lead to the manifestation of all cosmic problems, from small to big? Is it possible that everything we can see in this physical world, is a mere manifestation of a something we vaguely call consciousness?
Here comes this forbidden gray area for modern science: the realm of spirit and consciousness. Modern science locks it outside and believes that we can only understand nature by cleanly separating out matter from spirit. But what is the nature of spirit? What is its connection with matter? Without knowing the answers for these questions, can we truly be so comfortable and so confident that we can understand the laws of our body and the laws of this Universe at this physical level?
Prior to my trip to Boston, I was reading a new issue of Science, which had on its cover a famous painting by Michelangelo Merisi da Caravaggio (1573-1610), of the Greek myth of Narcissus. Narcissus, upon looking into the water, saw his own reflection, and then fell deeply in love with his own image. He could not let go of his fascination with this image but, instead, poured in all of his attention, let it consume all of his energy, and finally, he died. At the very beginning, I thought, "Why couldn't Narcissus tell that that was his own image?" Of course, at that time, I guess, they did not have mirrors. But then I asked, "Why didn't he take a careful look at himself? If he had done that, he would have found out that there were lots of similarities between his own hands and clothes and those in the image". Then I smiled, "Actually, how many of us remember to take a look at ourselves in our lives? When we have problems, we look at everything outside, except ourselves. Birth, disease, aging and death, we all look for answers from outside. We have spent so much of our resources to find the cures for diseases. We are now hoping that someday there will be a super-computer that will enlighten us with respect to the mysteries of life. But what if this entire physical world is a delusional world like what has been taught since a long time ago by ancient sages? Have we seen enough correspondence between the Universe, the human society, the human body and the cell? Is it possible that we have stared into our own image for too long? Is it time to find our true self and go home?
(Notes: After my talk, several Falun Dafa practitioners came to me and told me their personal experiences of how they or other practitioners recovered from various "incurable" diseases such as systemic sclerosis and various cancers through their cultivation practice.)
References:
1. Scrofano MM, Jahngen-Hodge J, Nowell TR Jr, Gong X, Smith DE, Perrone G, Asmundsson G, Dallal G, Gindlesky B, Mura CV, Taylor A. The effects of aging and calorie restriction on plasma nutrient levels in male and female Emory mice. Mech Ageing Dev. 1998 Sep 15;105(1-2):31-44.
2. Scrofano MM, Shang F, Nowell TR Jr, Gong X, Smith DE, Kelliher M, Dunning J, Mura CV, Taylor A. Calorie restriction, stress and the ubiquitin-dependent pathway in mouse livers. Mech Ageing Dev. 1998 Nov 16;105(3):273-90.
3. Scrofano MM, Shang F, Nowell TR Jr, Gong X, Smith DE, Kelliher M, Dunning J, Mura CV, Taylor A. Aging, calorie restriction and ubiquitin-dependent proteolysis in the livers of Emory mice. Mech Ageing Dev. 1998 Apr 1;101(3):277-96.
4. Dutaud D, Aubry L, Henry L, Levieux D, Hendi KB, Kuehn L, Bureau JP, and Ouali A. Development and evaluation of a sandwich ELISA for quantification of the 20S proteasome in human plasma. J. of Immuno. Meth. 2002; 260:183-193.
5. Yewdell JW. Not such a dismal science: the economics of protein synthesis, folding, degradation and antigen processing. Trends in Cell Bio. 2001; 11 (7):294-297.
Presented at the Boston Future Science Forum in April 2002.
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Category: Perspectives
