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A wake up call from the Micro-Cosmo
Eden Wang, Ph.D.
12/5/2002



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One early spring morning on my way to work, a stranger greeted me. He asked me what I do for work. Upon learning that I am a cancer researcher, his eyes lit up and he asked: “Are you going to find a cure for cancer?” His question plunged me into deep thought, and now I would like to share my thoughts with you.

Ever since my grandmother passed away suddenly from malignant liver cancer about twenty years ago, the word “cancer” has never left my mind and heart. The innocent hope from my young heart that one day I would find a cure 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, to cell biology, and finally to molecular biology, using yeast as a model system to study gene regulation. After I obtained my doctorate, I felt I was ready to come face to face with cancer. And so I stepped into the field of cancer research, which took the common approach of observing cells in artificial systems (by growing cells in defined conditions outside of the body).

In 1992, when I began my postdoctoral training at Massachusetts General Hospital in Boston, I “met” this powerful protein called Transforming Growth Factor-beta (TGF-beta). Although TGF-beta does many different things in the body, three functions make it stand out. First, from studies carried out in mice, the lack of TGF-beta causes mice to die from extensive inflammation, suggesting that TGF-beta is necessary to calm down our immune system. Second, both mice studies and human studies have linked defects in cellular responsiveness to TGF-beta with cancers, suggesting that TGF-beta suppresses cancer formation. Third, in our body, besides TGF-beta, there are large numbers of TGF-beta-like proteins. These proteins are very powerful, in that each of them is in charge of the formation and maintenance of different major organs of our body; there are factors in this group that regulate bone formation, muscle size, the formation of the nervous system, kidney and eye lens. Despite the many different functions of these proteins, most of them function as potent inhibitors of cell growth.

Additionally, in our body, there is a large group of proteins whose function is to actively promote cell growth. Here the ancient wisdom of China, the theory of the balance of Yin and Yang in the Macro-Cosmo, is beautifully reflected at the molecular level, in the Micro-Cosmo of the cell. Research in the past twenty years has led to the elucidation of the detailed molecular networks in a normal cell, which goes through a highly regulated life cycle of growth, specialization (or as we call it, differentiation), aging, and death. In every stage of a cell’s life, we can “hear the song” and “see the dance” of the interplay of the Yin and Yang factors in great harmony. 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 goes wrong? A normal cell responds to environmental cues to determine when it can enter the growth cycle (what we call the cell cycle), which consists of several distinct stages (G1, S, G2, and M). Between each phase, there is an important gate that acts as a checkpoint. In order for the cell to move on to the next stage in the growth cycle, it has to meet certain requirements. If something goes wrong in the cell, the gates will serve to safeguard the cell, by stopping it at that phase of growth until the problem is somehow fixed. If the problem cannot be fixed, the cell will trigger an alarm system that, amazingly, leads to a well-orchestrated programmed death for that cell. Thus, a normal cell acts in accordance with the system it belongs to. When mistakes occur, the hurt cell has a mechanism to “sacrifice” itself for the survival of the whole. Contrary to a normal cell, a cancer cell somehow “outsmarts” the laws at each gate between the different phases of growth. Therefore, it continues to grow in number. Moreover, the programmed death mechanism is abolished so that cells reach a state of “immortality”. Of course, such immortality is temporary, and is followed by the death of the whole. Interestingly, the nature of the cancer cell reflects a very ignorant and selfish “spirit”, one that ultimately leads to the worst outcome for cell and body.

Over the past twenty years, cancer researchers have learned that it takes many “hits” before a cell accumulates enough various protein mistakes to wipe out all major safeguard mechanisms at the cellular level. Eventually, the cancer cell will metastasize (meaning, travel to and infect other parts of the body), and again violate multiple system laws. In the case of the immune system, its normal policing role of monitoring the body system in order to identify and eliminate abnormal cells is lost.

So, the great mystery is this: How does a cell manage to accumulate so many mistakes without being eliminated? Some biologists believe that cancer results from just a few mistakes at the gene level, which cause the genetic material to become unstable (we call this genetic instability), which then leads to large-scale mistakes at the gene level. However, genetic instability also starts from just one or two genetic mistakes. We now know that a normal cell has sophisticated mechanisms to detect and fix genetic mistakes, and can activate programmed cell death if it fails to fix the problem. Even if a cell could not fix its own problems, the body has so many different ways to safeguard itself and eliminate a bad cell. In fact, we are immersed in an environment that can constantly introduce mutations within our genetic materials, but most of us do not develop cancer. This suggests that our body has the potential to combat the mutations. Therefore, the fact that cancer manages to grow in a body is already a sign of system failure, rather than of a simple genetic problem.

Then, what causes the system failure? Below I would like to share with you some recent observations made in my area of research.

Many labs, including my own, study how cells communicate with each other via proteins. TGF-beta is produced by almost every cell in our bodies. When it is released into the space outside of a cell, TGF-beta serves as a signal to “instruct” cells that have a unique set of proteins that can recognize and bind to it. Once these binding proteins (which we call receptors), which sit on the cell surface, bind to TGF-beta, these receptors will then “talk” to proteins inside of the cell. The detailed steps of protein-to-protein communication inside of a cell in response to an outside-of-cell protein are mapped out carefully by many labs in the research community. Such studies belong to the field that we call “the signal transduction field”. 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 is a group of proteins inside of the cell called “Smad”. These Smad proteins 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 of these Smad proteins. Just recently, we discovered that Smad carries out its “mission” through directly talking to an extremely important protein system in the cell. This protein system is called “the 26S proteasome system”. The 26S proteasome is a giant protein machine made of many proteins, and forms a cylindrical structure with a “cap” and a “base” on both sides (see Figure). In many cases, when a protein is “chosen” to be digested by the proteasome, the protein is marked by a tree-shaped structure made of a small protein called ubiquitin. Then, the marked protein is somehow recognized by the 26S proteasome and is converted from a regular global shape into a linear shape, like a noodle, to pass through the inner chamber of the proteasome cylinder, where digestion of the “noodle” occurs. In other cases, there are different ways for proteins to be shipped into the proteasome. This proteasome system is in charge of the following duties in a cell: 1) to get rid of old, abnormal, or damaged proteins by breaking down the proteins into small pieces; 2) to actively participate in almost every aspect of cellular functions via breaking down some extremely important proteins at the right time and space; 3) to present to the immune system invasion signals and damage signals, when viruses and bacteria enter the body, or when a cell behaves abnormally. We found, to our surprise, that the growth inhibition role of TGF-beta requires Smads to “talk” to the proteasome. “Talk” between proteins are via protein-to-protein interactions. That is to say that one protein binds to another protein, triggering the change in shape of both proteins, and this shape change serves as a kind of protein language meant to initiate additional interaction or a chemical reaction. Such communication between Smads and the proteasome system are highly sophisticated and extensive. The outcome of such communication leads to the Smad-dependent breakdown of some extremely important “leaders” in the cell system, thus profoundly altering the many functions of a cell, including but not limited to growth inhibition. From this perspective, the name “Transforming Growth Factor” is truly very appropriate. These observations also reveal the molecular foundation for the extremely complex biological activities of the TGF-beta protein and its related proteins.

As I was pondering the meaning of this finding in relation to cancer, my friend Dr. Lili Feng called me. 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 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 had just completed her studies on comparing the expression level of 12,000 genes in those who practice Falun Dafa to those in people who do not. To my great surprise, she mentioned some genes in the proteasome system. Therefore, 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 set of data Lili sent to me was a pile of numbers assembled randomly from the experiments. But from the pile of numbers emerged one clear message: more than ten different proteins in the proteasome system are drastically reduced in Falun Dafa practitioners’ immune cells. This indicates that the proteasome system is downsized. It would not make much sense if only this system were downsized, since lack of a sufficient proteasome system would lead to the accumulation of junk and old proteins. And sure enough, in the same set of data, more than ten different proteins that belong to another protein system called the “ribosome” are also drastically reduced. The ribosome is responsible for making new proteins. I suddenly realized that the data suggests the coordinated downsize of the entire pipeline of protein production and protein consumption.

Lili then mentioned to me that she has read papers on mice studies regarding the correlation of proteasome system size and activity with longevity. Dr. Allen Taylor from Boston University reported that when the food supply was restricted, mice lived longer and their proteasome system was downsized (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 was beginning to surface (see below). This paper (ref 5) reported that quantitative studies of protein metabolism of a cell type grown in a petri dish revealed that a third group of new proteins are immediately destroyed upon being made. Thus, even a “normal” cell grown in a petri dish works in a very busy and wasteful state.

LiLi’s data of the greatly downsized proteasome system in the immune cells of those who practice Falun Dafa suggests that even the “normal” cells from non-practitioners are operating in a “wasteful” state. There are more economical ways for the cells to carry out their normal functions. Such an economical way at the cellular level is experienced by a practitioner at the level of the physical body, manifesting as increased physical energy and resistance to infection. Every practitioner I know in Seattle and Boston (over one hundred) has been medication-free for years.

At this point, in my mind came a response to my initial question, “What causes cancer cells to accumulate so many mistakes and allows them to violate so many safeguard mechanisms?” If a cell is instructed to make more proteins, there should be a linear increase in the workload of proteasome to break down bad proteins. To meet such an elevated workload, the cell will increase its amount of proteasome, by way of elegant feedback mechanisms. However, if the demand to break down proteins is to increase without end, a point will come at which the increased proteasome level will no longer meet the needs of the cell. Here is a critical link. Since the TGF-beta proteins and their related proteins are key growth inhibitors that are dependent upon the normal functioning of the proteasome system, an overloaded proteasome would directly affect the normal growth control by this family of growth inhibitors. In fact, due to the critical role of proteasome in the regulation of protein levels for many key “leaders” in the cell, the functional state of the proteasome is linked closely to the overall functional state of the cell. When the cell reaches a threshold at which the proteasome can no longer break down the products of “mass production”, protein “junk” will begin to accumulate and pollute the environment of the cell. After all, the proteasome system is a safeguard system for getting rid of old and bad proteins. If one cell has such a proteosome-overloading problem, then the system can help rectify it, via laws at the system level. However, if most of the cells in multiple systems were under similar crisis, then all these cells would make mistakes and could no longer function as a healthy system. The increased proteasome level observed in cancer cells likely reflects the last struggle of the cells to regain their balance.

I cannot help but wonder how many of the diseases modern people experience result from their hectic lifestyles, the mental stress they are under, and the endless pursuits they go after. All these can, through the unique human pyscho-neuro-endocrine system, transmit to the cell level a message to increase the cellular metabolism of multiple systems; this, when overwhelming the proteasome system, leads to the accumulation of cellular mistakes and the ultimate downfall of the body system.

Every morning when I take the bus to work, I sit next to a Chinese lady named Mrs. Bao, who came recently to Seattle from Shanghai to visit her daughter. She worked as a nurse-in-chief in a big hospital in Shanghai for more than 20 years. Since she worked with many cancer patients, I asked her whether she could share any insight into cancer from her clinical experience. She shared three interesting perspectives: 1) many cancer patients experienced major stress prior to diagnosis, such as divorce, loss of loved ones, and loss of job; 2) ten years ago, most of the cancer patients were elderly, but now, most patients are young; 3) the young cancer patients die more quickly than the elderly. I asked her why. “I think it is because the young people have higher metabolic rates than the elderly,” she said with confidence. She then told me how hot a cancer area feels from her experiences in changing the dressings for breast cancer patients. I looked at her and realized that we need not always rely on sophisticated technology to come in touch with the truth.

So, what is the cure for cancer? Many biologists, including myself, no longer have the confidence to claim that we will find the “magic bullets” to cure cancer. In the expert review article in the Journal of Molecular Medicine (1999), Drs. Paul Pharoah and Carlos Caldas stated: “In the world, 10 million new cases of cancer will be diagnosed during the year 2000; unfortunately, the overall survival rate for such patients has changed very little during the past 20 years, despite rapid advances in the understanding of the biology of human cancer.” This year’s Nature Magazine made a similar point: “With more than $46 billion spent on cancer research by the US federal government alone… a minority of experts has even begun to suggest that cancer has become science's Vietnam.” (Nature 416, p470, 2002). Fundamentally, cancer is not a simple gene disease, but rather is a system failure. Since any drug targets a specific protein alone, a system failure that involves the malfunctions of many different proteins in many different systems can never be adjusted by one simple drug, or by even several drugs in combination.

The results Lili obtained suggest that Falun Dafa, a mind-body cultivation practice, can downsize, in a coordinated way, the protein production and protein degradation systems. So here are the data to suggest that there is a way to regulate systems, though such a way is not via the application of an external chemical compound, but via some self-work. The potent healing effects of the Falun Gong are striking and demand serious attention by the medical field. How does it work? What is so unique about Falun Gong? In my limited understanding, one of the most unique features of Falun Dafa, which makes it stand out from all other mind-body practices, is that it is a complete system of cultivation, which guides a person to look within himself in every situation in life, instead of looking outward. Under the guidance of higher principles, a person gradually can take a positive perspective on every tribulation. Instead of worrying for self-loss and self-gain, one gradually steps out of this little self and uses compassion to embrace the world. This provides one with the inner strength to face all tribulations with peace and harmony. Such peace and harmony is manifested directly at the level of the cell, by the reduced metabolic state of the cell. If the cell makes fewer proteins, the proteasome is fully functional in safeguarding the cell in degrading old and damaged proteins and in fine-tuning the levels of each important regulatory protein in the cell.

Upon sharing some of my thoughts with my high school friend, who is a physicist from Caltech and now working for IBM, he made the following comments: “This down-sizing effect seems to agree with the physical law which states that the minimum energy state is the most stable state. Meditation provides a way of returning to a stable point. The world needs a stabilizing mechanism as well.” What is the purpose of science? My answer to this has always been very simple: “Science is a path to find truth.” This is the reason I wished to be a scientist when I was young and the reason why I continue to be a scientist, although in the field of science, the search for truth is frequently challenged by the drive for profit. As a human being first and a scientist second, we are also held accountable by all universal laws. So, it is only the most natural thing for me, as a scientist, to be outspoken about the truth, regardless of how we label it within the field of biology, spirituality, and society.

Lili has a wonderful sense of humor and a wild imagination. One day she asked me: “If the micro-Cosmo and macro-Cosmo have a correspondence, what would be the counterpart of the proteasome in the macro-Cosmo of the universe?” Her answer was “the black hole.” “You see,” she continued, “the proteasomes are very busy when cells are sick, and what does it mean when the black hole is very busy in the universe?” When I heard that, I thought of the vast social problems and their connection with our lifestyle; it is truly a case of mass production and mass consumption. Isn’t it amazing that the different cosmic systems of the cell, body, society, and the entire universe, from micro to macro, exhibit such striking similarities and correspondence?

Honestly, how many of us will remember to take a look at ourselves during our lives? When we have problems, we look at everything outside, everything except ourselves. When we experience birth, disease, aging, and death, we all look for answers from outside. We use up so many resources to find the cure for diseases. Now, we are hoping that a day will come when a super-computer will enlighten us with the mysteries of life. But, what if this entire physical world is a reflection of a deeper reality? A long time ago, the ancient sages and spiritual enlightened beings spoke of a reality that transcends this physical world. Now, modern physics has revealed the multi-dimensional nature of the universe (ref 6). Moreover, modern philosophy has come to the conclusion of the holographic nature of the physical world, including the human brain (ref 7). Biology is in a unique position among all sciences, since it directly studies life’s phenomena. The knowledge we have gathered at the level of molecules within the cell has now also revealed the amazing correspondence between the micro-Cosmo of the cell and the macro-Cosmo of human society and the universe. Everything in the physical world seems to share a holographic nature that resides beyond this physical world. The understanding and cure of diseases, therefore, may only come from a new understanding of this ultimate nature of the universe, which also might be the core of our true selves. Modern people are focusing all their attention on the colorful physical world, pursuing material gains. Have we stared into our own image for too long?

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.
6. Pease R. News Feature “Brane New World”. Nature 411:986-988.
7. David J. Bohm, “A new theory of the relationship of Mind and Matter”. Journal of the American Society for Psychical Research 80, No.2 . April, 1986.


*Dr. Eden Wang is Principal Investigator in Cancer and Autoimmune Diseases at Virginia Mason Research Center, University of Washington.

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