Cancer – The Whole is Greater Than the Sum of its Parts
Cancer is a complex and adaptive disease with roots in normal developmental biology (ie, embryogenesis and morphogenesis). Consequently, cancer’s mysteries can’t be solved by reducing it to genetic mutations and aberrant signaling pathways.
BRIAN PICCOLO’S EXPERIENCE
In late 1969, Brian Piccolo, a young professional football player, discovered he had embryonal cell carcinoma. The tumor was growing deep in his chest. He underwent radical surgery and chemotherapy in November, when treatment was declared a success.
Brian Piccolo’s cancer returned rapidly, and in the spring of 1970, he endured two additional surgeries and more chemotherapy; nevertheless, the cancer could not be slashed away or poisoned. Treatment had been physically and emotionally catastrophic. In the end, his doctors turned to radiotherapy—radiation—in an attempt to burn out the cancer. All to no avail: Brian Piccolo died in June; he was 26 years of age.
Slash-poison-burn
Half a century after the National Cancer Act of 1971 (also known as the “War on Cancer”) began to pour billions of dollars into cancer research, not much has changed. Surgery, chemotherapy, and radiotherapy continue to be the mainstays of treatment for most cancers and the unlucky patients so afflicted.
Progress through prevention and early detection
Progress in increasing life expectancy, or survival, for patients who have cancer has been made. Increases in survival have been due largely to cancer prevention (eg, a large reduction in cigarette smoking) and early detection through routine cancer screening. Overall, cancer treatment has had only a modest impact on survival.
Although some advances in cancer treatment have led to clinical success, notably for melanoma, prostate cancer, and myeloma, too many other cancers continue to be deadly. A recent report on survival from a European cancer registry reveals this truth: over the past decade, patients who had advanced solid tumors experienced a limited survival increase of little more than a month. Generally, expectations for survival are low. Consider that the inclusion of new cancer drugs on the World Health Organization’s Model List of Essential Medicines requires that a cancer treatment increase overall survival by only 4 to 6 months over the standard of care.
Another way to look at improvements in cancer treatment is through the lens of regulatory approvals. A review of nearly 300 randomized clinical trials of systemic treatment in breast, colorectal, and non–small cell lung cancer published in leading biomedical journals during the last decade (in trials with a “positive” outcome), found that the median increase in overall survival amounted to just 3.5 months.
WHY AREN’T WE DOING BETTER?
Science has been driven forward for hundreds of years by a reductionist approach, in which phenomena are reduced to their simplest parts. Once teased apart and examined, the parts are reconstructed step-by-step to recreate an in-depth knowledge of the whole. This approach, which works well in physics, has not been very effective in unravelling complex adaptive biological systems such as cancer, in which the constituent parts are interdependent, interact and influence one another, and evolve to adapt to changing conditions.
“The paradox of studying phenomena at a microscopic level when many of the drivers are operating at a much larger scale may partially explain the general lack of therapeutic improvement made for most cancers.”
Brent A. Reynolds, et al
Innovations in molecular biology and genomics have focused the application of reductionist research on cancer. This approach has produced the widely accepted notion that carcinogenesis results from genetic mutations (oncogenes) and has led researchers to create cancer models in which cancer is induced in mice, but these studies have little relevance to human disease and its treatment.
SHIFTING AWAY FROM THE CURRENT PARADIGM
The somatic mutation theory of cancer has dominated cancer research for a hundred years. It is a molecular theory that reduces carcinogenesis to molecular events, explaining most cancer at the level of genetic mutations and the signaling pathways that they modulate within cells. Consequently, cancer is regarded in terms of mutations that drive carcinogenesis (so-called driver mutations).
Has our focus on mutations led us astray?
The incompatibilities between the somatic mutation theory and clinical experience were recognized a decade before President Nixon’s War on Cancer. Since then, accumulating evidence of theoretical anomalies has established that driver mutations occur in healthy cells with no ill effect, whereas malignant tumors can and do develop in the absence of driver mutations. Accordingly, “somatic mutations are neither necessary nor sufficient for cancer to develop.” These anomalies (and others) that are not accounted for by the somatic mutation theory have led to a scientific crisis in cancer treatment and the research that supports it.
“It is no accident that mutations are increasingly being questioned as the causal event in the origin of the vast majority of cancers, as clinical data show little support for this theory when compared against the metrics of patient outcomes.”
Bjorn L.D.M. Brucher and Ijaz S. Jamall
ONLY A CRISIS CAN POINT THE WAY FORWARD
The failure of the somatic mutation theory to advance cancer treatment opens the door for fresh thinking and the adoption of a new theory of cancer. Two prominent theories have emerged: the tissue organization field theory and the theory known as epistemology of the origin of cancer. These theories posit that cancer begins in the body’s tissues rather than in DNA and, importantly, consider genetic mutations as epiphenomena that occur late in cancer development.
Science advances when unexplained anomalies lead to a crisis that shifts the attention of the scientific community to a new theory. A new theory of cancer may point us to novel approaches to cancer prevention and treatment. A half century after the War on Cancer began, it’s time to shift the paradigm.
Written by Gene Lysko, Medical Writer
Gene Lysko is a senior medical writer at Artcraft Health. He has helped create content for diverse clients in the pharmaceutical, medical device, and medical screening and diagnostic industries. Gene is passionate about the philosophy of science, cancer biology, clinical trials, and Mother Nature. He has been a valued contributor at Artcraft Health since 2012.
Further reading
Barron H. Lerner. ‘Brian’s Song’ at 50 still offers lessons about cancer for today. https://www.statnews.com/2022/02/13/brians-song-at-50-still-offers-lessons-about-cancer-for-today/
Brücher BL, Jamall IS. Epistemology of the origin of cancer: a new paradigm. BMC Cancer. 2014;14:331.
Brücher BL, Jamall IS. Somatic mutation theory—why it's wrong for most cancers. Cell Physiol Biochem. 2016;38:1663-1680.
Raza A. Cancer is still beating us—we need a new start. 3 Quarks Daily website. https://3quarksdaily.com/3quarksdaily/2019/10/cancer-is-still-beating-us-we-need-a-new-start.html
Reynolds BA, Oli MW, Oli MK. Eco-oncology: Applying ecological principles to understand and manage cancer. Ecol Evol. 2020;10:8538-8553.
Schnog JB, Samson MJ, Gans ROB, Duits AJ. An urgent call to raise the bar in oncology. Br J Cancer. 2021;125:1477-1485.
Sonnenschein C, Soto AM. Over a century of cancer research: Inconvenient truths and promising leads. PLoS Biol. 2020;18:e3000670.
Soto AM, Sonnenschein C. The cancer puzzle: Welcome to organicism. Prog Biophys Mol Biol. 2021;165:114-119.
The structure of scientific revolutions. Thomas S. Kuhn. University of Chicago Press. Chicago; 1962.
Zhang J, Lou X, Zellmer L, Liu S, Xu N, Liao DJ. Just like the rest of evolution in Mother Nature, the evolution of cancers may be driven by natural selection, and not by haphazard mutations. Oncoscience. 2014;1:580-590.
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