Part I: A Brief Overview of The Study for The General Public
Guest post from Jingcheng Wu.
Cancer affects the general population in an extensive and intensive way. It accounts for 1 out of 4 deaths in the US.1 The global annual cancer cases are expected to rise to 22 million within the next two decades.2 Existing drugs used in chemotherapy on the market are not only ineffective 97% of the time,3,4 but also cause severe damage to the body as a whole due to the drugs’ high toxicity. We are all too familiar with the frightening adverse effects of chemotherapy such as hair-loss, holes in intestine, swelling of the body, feeling sick and tired, abnormal bleeding, to name a few. Many cancer patients choose death over going through the agony of chemotherapy by refusing the treatments.
The reason behind the severe toxicity of anti-cancer drugs lies in their low selectivity. Aiming at killing cancer cells, the drugs also massively destroy normal cells and impede the growth of new healthy cells. Thus come the tragic sufferings very often seen in the oncology wards. The current cancer drugs attempt to cure the patients while kill them at the same time. The solution, then, lies in finding a new way of targeting cancer cells with minimal harm to normal cells.
An ideal target for cancer treatments should be commonly found in a wide range of cancer cells and exists in far less amount in normal cells. Researchers found such a target, which is a protein called the “c-src.” Among half of the most common and most lethal human cancers, high c-src activity has been detected,5 and is found to be an essential element that causes cancer. Therefore, inhibiting c-src activity can contribute to a key breakthrough in cancer treatment, and will in turn benefit a potentially large world population that may be devastated by c-src dysfunction.
An ideal drug in this case should only inhibit c-src activity without interfering with normal cellular functions carried out by other proteins, including the ones that highly resemble c-src. As the famous quote from Art of War goes, “if you know both your enemy and yourself, you need not fear the results of a hundred battles. If you only know yourself but not the enemy, for every victory gained you will also suffer a defeat,” it is apparent that having a thorough understanding of c-src is key to designing the ideal drug, so that we can find out its potential “weak spots” and get a grip on them. It is an easy realization in theory but hard implementation in practice due to the immense computing power required to scrutinize the dynamic behavior and structure of c-src. All we had before were a few static snapshots of it. A detailed dynamic picture of c-src had not been available until Folding@Home6 came into the picture.
In order to do so, Folding@Home harness the unused computing power in personal electronic devices from volunteers worldwide. The combined computing power makes Folding@Home computing network the fastest super computer in the world.7 As a result of that collective effort, we simulated how each atom of c-src and surrounding water molecules moves, and we discovered a major “weak spot” of c-src that can be exploited to suppress c-src’s cancer-causing activities.
This weak spot exists exclusively in an intermediate stage in c-src’s transformation between inactive and active states. These details on c-src structural changes in various states are difficult to study; yet they turn out to be very important to developing a drug with the desired characteristics. (Refer to Part II for details.) The newly discovered “weak spot” is a unique structure on c-src that binds to certain drugs. It makes an ideal drug possible by allowing certain drugs to only influence c-src but nothing else, which minimizes damage to normal cells.
This study is a fantastic starting point and template for future studies to build onto. We can add more complex interactions to future simulations. Also, multiple structures on c-src can be used together for a single drug to exert high potency. In addition, the same techniques can be used to study other cancer-related proteins at atomic level, and in turn their subtle structural differences can be used for future drug design with high specificity and selectivity.
The Folding@Home mission is a beautiful example of the world uniting to combat a common enemy of humanity. The collective power of our research group and our donors push the frontiers of biotechnology to new limits and redefine the impossible.
References
- American Cancer Society. 2014 Cancer Facts and Figures.
- World Health Organization. Cancer Key Facts.
- Cairns, J. The treatment of diseases and the war against cancer. Scientific America. 253(5): 51-59 (1985).
- Morgan, G., Wardy, R. & Bartonz, M. The contribution of cytotoxic chemotherapy to 5-year survival in adult malignancies. Clinical Oncology. 16: 549-560 (2004).
- Dehm, S. & Bonham, K. SRC gene expression in human cancer: the role of transcriptional activation. Biochem. Cell Biol. 82 (2): 263–74 (2004).
- Shirts, M. & Pande, V. Screen savers of the world unite!. Science. 290, 1903-1904 (2000).
- PS3 network enters record books. BBC News. 02 Nov 2007. Web. 15 Mar 2014. <http://news.bbc.co.uk/2/hi/7074547.stm>.