14 June 2020, Cancer and complexity science, Essay #1

Cancer and complexity science
Essay #1
14 June 2020

My research focuses on how cancer arises based on complexity theory. I find it helpful to write and talk about it, not just to physicians and scientists but to my friends, family and neighbors. In these essays, I will cover the highlights of my work. I welcome your comments or questions by replying below or emailing me at NatPernick@gmail.com.

What is complexity science, and why is it important in understanding cancer?

1. The war on cancer has failed.
It is important to acknowledge that the war on cancer, announced by President Nixon in 1971 (https://www.youtube.com/watch?v=peb47Z-jPqc  at 15:03), has failed. Although cancer death rates have declined and survival is improving (https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf), cancer will soon be the leading cause of US death (https://www.cdc.gov/pcd/issues/2018/18_0151.htm). When a major problem persists despite the expenditure of substantial resources, it may be due to a fundamental misunderstanding of its nature.

2. Traditional biologic thinking is inadequate to understand cancer.Traditional biology relies on reductionism, namely that the behavior of the whole is equal to the sum of the behavior of the parts. According to this view, life is merely a collection of sophisticated machine-like systems with an aggregation of their individual properties (https://pubmed.ncbi.nlm.nih.gov/18174892/).  Reductionism is illustrated by my broken refrigerator. I neglected to vacuum the vents. This led to a buildup of heat in the refrigerator motor. It overheated and failed, causing the refrigerator to stop working. To solve this problem, the motor was replaced, the vent was cleaned, and to prevent a recurrence, I regularly vacuum the vents. The entire process is logical and predictable.

However, life functions as a complex system, not as a sophisticated machine. The properties of the entire system are greater than the sum of the properties of each part due to important interactions between the parts (http://natpernick.com/TheLawsJune2017.pdf). These interactions cause complex systems to exhibit many nontraditional properties.

(a) Complex systems have characteristics that often cannot be predicted, even with substantial knowledge. For example, protein function is based on three dimensional shape, but even if we know the amino acid sequence that determines the protein, we cannot predict how the protein will fold in three dimensions. We have to wait and see. In sickle cell disease, a single substitution of one nucleotide for another produces a marked change in the function of hemoglobin, which prevents red cells from bending when entering small blood vessels, causing severe pain and damaging organs. What will be the impact of a different mutation? It may be trivial or life threatening. We cannot predict because we don’t know how the resulting protein will fold and how it will interact with other proteins.

(b) This inability to predict may also be due to emergence, a bottom-up property due to agents that spontaneously self-organize. Larger entities arise through interactions among simpler entities and possess properties not found or even thought possible from the simpler entities. Water, for example, possesses properties completely different from hydrogen and oxygen. In biology, evolution uses existing structures, such as the jawbones, to build entirely different structures, such as the middle ear ossicles.

(c) Complex systems possess stability that makes them resistant to unwanted change under most circumstances. Our cells and organ systems can encounter a tremendous amount of biologic stress and still function well. This is due to “attractors”, a stable equilibrium state which develops even among networks that have components that are constantly in flux (https://pubmed.ncbi.nlm.nih.gov/19595782/). This explains why cancer arises only after decades of chronic biologic stress. But cancer cells themselves have attractors, which unfortunately makes them resistant to treatment.

(d) Finally, complex systems have adaptive properties that increase their survival in a changing environment. This explains why tumors may stop responding to treatment that initially is effective. Fortunately, my refrigerator does not evolve.

In summary, principles of complexity theory create a more robust framework for understanding the origins and dynamics of biologic systems, including cancer, and must be better understood if we are to significantly reduce the death and misery associated with this disease.

Future essays will provide more details on how life arises and how cancer disturbs the control mechanisms that typically maintain order.

17 May 2020: How cancer arises from chronic inflammation, based on complexity theory

I will present a paper entitled "How cancer arises from chronic inflammation, based on complexity theory", at the American Association for Cancer Research (AACR) Virtual Annual Meeting II, June 22-24, 2020. I am happy to answer questions about this paper or to hear your cancer stories. However, I cannot provide medical advice to you - instead, I suggest you contact your local medical center or medical school.

Abstract: https://www.abstractsonline.com/pp8/#!/9045/presentation/3692 and below

Abstract (PDF): http://www.natpernick.com/AACRAbstractChronicInflammationJune2020.pdf

Poster (PDF): http://www.natpernick.com/AACR2ChronicInflammation.pdf

Paper (PDF): http://www.natpernick.com/ChronicInflammationpaperMay2020.pdf

Abstract:

How cancer arises from chronic inflammation, based on complexity theory

Last revised 17 May 2020

Introduction: This paper discusses how cancer arises from chronic inflammation, based on complexity theory. We believe that this perspective may lead to new insights into cancer pathophysiology and treatment.

Methods: We reviewed the medical literature to identify cancer types strongly associated with chronic inflammation. We then classified the chronic inflammatory etiologies, determined general mechanisms through which they promote cancer and speculated on network changes involved in transforming cells from physiologic to cancer attractor states.

Results: Bacterial and viral infection, predominantly Helicobacter pylori, human papillomavirus and hepatitis B and C virus, are a common etiology of chronic inflammation associated cancer and cause 15% of cancer cases worldwide. Other etiologies are parasitic infestations by Opisthorchis viverrini, Clonorchis sinensis and Schistosoma haematobium; autoimmunity in Hashimoto thyroiditis, Sjögren syndrome and celiac disease; local trauma due to gastroesophageal reflux and hot beverages; excess weight; diabetes; Western diet (high fat, low fiber, low consumption of fruit and vegetables); aging and immune system dysfunction. General mechanisms through which these etiologies cause cancer are immune system activation that damages DNA by producing reactive oxygen and nitrogen species and nitrosamines; tumor immune evasion via immune suppression and immune senescence; antigen driven lymphoproliferation; continuous mitotic activity due to repair; synergy with other chronic stressors; creation of a tumor nurturing microenvironment; development of a “runaway” immune system; and microbiome changes that produce carcinogens or activate inflammation. Immune system dysfunction and germ line variations of inflammatory mediators can promote each step. From a network perspective, the usual physiologic state for many cellular processes consists of a delicate balance between stimulating and dampening forces, maintained by inherent network features and evolved control systems. Chronic inflammation may disturb this balance, leading to propagation of network instability throughout the cell, across adjacent tissues and ultimately systemically. This may create identifiable network hierarchies and intermediate states (hyperplasia, metaplasia or dysplasia), but some changes in network and molecular patterns may not alter histology. Ultimately, cells may move to a cancer attractor state.

Summary: Chronic inflammation causes cancer by initiating local changes to cellular networks and their microenvironment which facilitate their escape from physiologic states towards intermediate and cancer attractor states. This suggests that early detection and reduction of these inflammatory changes may reduce cancer mortality. Novel treatment options include more diverse treatment combinations, destabilizing existing cancer attractors and their microenvironment, stimulating physiologic pathways that steady networks, reducing other chronic stressors and optimizing rational medical care.

This manuscript has not received any outside funding. There are no known conflicts of interest.

Please visit NatPernick.com for related articles. Email NatPernick@gmail.com with comments or questions.

12 April 2020: We should also practice "evil distancing"

In response to the COVID-19 pandemic, I suggest we not only practice physical distancing (this term is preferable to social distancing, see https://www.washingtonpost.com/lifestyle/wellness/social-distancing-coronavirus-physical-distancing/2020/03/25/a4d4b8bc-6ecf-11ea-aa80-c2470c6b2034_story.html), but also “evil distancing.”

What is evil distancing? Any prominent person, institution or media outlet that called the pandemic a hoax or downplayed its significance helped kill thousands of Americans who listened to them. There never was any actual medical controversy - they perverted the truth for unjustified reasons. As we think about rebuilding a post-pandemic society, I suggest we distance ourselves, to the extent possible, from those who did this evil.

23 March 2020: Ask Donald Trump to resign

This was my comment to the New York Times opinion piece by David Leonhardt:
https://www.nytimes.com/…/03/22/opin…/trump-coronavirus.html

There is an answer. Start a campaign pushing Trump to resign. He is not capable of leading at this time. I have no doubt Vice President Pence could do a better job if he did not have to worry about crossing Trump. I have written Trump to ask him to resign, but I am an "ordinary" citizen. Why not start a campaign, Mr. Leonhardt? It might work, or it might spur him to act.

So, Facebook visitor, please do what you can to advance this campaign. Perhaps your efforts won't amount to anything, but if enough grains of sand are dropped on a sand pile, it will start to move. So I suggest doing something!

9 September 2019: News about vaccines

Here are updates on the HPV and Measles vaccines:

HPV:

"While common and generally not life-threatening, HPV also can trigger a host of cancers, and rates are rising: 43,371 cancers were associated with the virus in the United States in 2015, up from 30,115 in 1999, according to a report in August by the U.S. Centers for Disease Control and Prevention." See https://www.bridgemi.com/michigan-health-watch/hpv-cancer-rates-are-yet-many-michigan-doctors-wont-talk-about-it

Most of the US population of reproductive age is infected with HPV, which means that all in this age range are likely to get exposed unless vaccine use increases dramatically. Don't pretend you can avoid it by being "careful." That assumes that everyone communicates honesty and accurately about their histories, and that you are only exposed to people who themselves were never exposed or were vaccinated and developed antibodies.

For more information on how HPV causes cervical, head & neck and skin cancer, see page 20 of my December 2017 paper at http://www.natpernick.com/HowCancerArises.pdf.

Measles:

Yes, measles kills healthy people. See https://www.cnn.com/2019/08/13/health/israeli-flight-attendant-measles-death. When physicians give our opinions on medical matters, we put our reputation and license on the line. We cannot easily just state our opinion because we feel like it. We also have extensive training and experience. Of course, we could be wrong, and there are "bad apples" in the medical profession, but it is usually obvious that they are "outliers." This is not the case with those who write anonymous flyers.

3 September 2019: Be Optimistic to Live Longer (or does it only seem longer?)

Good news for the cheery: A Boston study published this month suggests people who tend to be optimistic are likelier than others to live to be 85 years old or more.

Click here.

26 July 2019: How Cancer Arises based on Complexity Theory, 2019 update

I have updated this paper, originally published in December 2017, see http://www.natpernick.com/HowCancerArises.pdf. I plan to present it at a cancer research conference in Spring 2020. The Abstract and Executive Summary are below. I am happy to answer questions about this paper or cancer in general, but cannot answer patient specific questions.

Abstract

Background: The War on Cancer has failed, due in part to its reliance on reductionist thinking to understand how cancer arises.

Methods: We reviewed prominent cancer risk factors at major sites and categorized them based on a complexity theory approach that focuses on early changes to network behavior instead of later changes to oncogenes.

Results: Cancer is caused by nine sources of chronic cellular stress that often interact to provide the multiple “hits” that produce malignancy. They are: chronic inflammation (due to infection, infestation, autoimmune disorders, trauma, overweight, diabetes and other causes); exposure to carcinogens; reproductive hormones; Western diet (high fat, low fiber, vegetable and fruit consumption); aging; radiation; immune system dysfunction; germ line changes and random chronic stress or bad luck.

Conclusions: Cancer is an inevitable tradeoff of human biologic design that will always be with us, particularly as life expectancy increases. However, we can often prevent it, we can detect it earlier and we can treat it more effectively. Most cancer is caused by chronic cellular stress that disturbs the delicate balance of our interconnected biologic networks. Malignancy arises due to a buildup of dysfunctional hierarchical structures, in which combination of agents (biomarkers and networks) at one level become agents at the next level. These dysfunctional structures are identifiable by patterns of network changes, molecular changes or possibly histologic changes. New treatment approaches include targeting multiple tumor features to overcome tumor heterogeneity, targeting the chaotic nature of some tumors, moving tumor cells into less lethal network states by emulating physiologic mechanisms and reducing chronic stressors.





Executive summary

1. Cancer is an inevitable tradeoff of human biologic design. It will always be with us, particularly as life expectancy increases. However, we can often prevent it, we can detect it earlier and we can treat it more effectively.

2. Most cancer is caused by chronic cellular stress, which disturbs the delicate balance that exists in our interconnected biologic networks. In the correct microenvironment, it pushes susceptible stem or progenitor cells into increasingly dysregulated and unstable network trajectories that are ultimately associated with uncontrolled cell growth. It is foreseeable that some chronic cellular stressors will cause cancer but which stressors will be important, where the cancers will arise and what their molecular and histologic features will be is not predictable due to the nonlinear nature of complex systems.

3. There are nine important sources of chronic cellular stress that cause cancer and often interact to provide the multiple “hits” (genetic or network aberrations) that produce malignancy:

* Chronic inflammation (due to infection, infestation, autoimmune disorders, trauma, overweight, diabetes and other causes)
* Exposure to carcinogens
* Reproductive hormones
* Western diet (high fat, low fiber, vegetable and fruit consumption)
* Aging
* Radiation
* Immune system dysfunction
* Germ line changes
* Random chronic stress or bad luck

These chronic stressors typically create a field effect; i.e., large areas are affected by a single aberration.

4. Complexity theory helps us better understand how cancer arises:

A. To understand cancer, it is important to think about how life arose from cellular networks because the same principles guide the pathophysiology of cancer. Focusing too much on specific details of the networks, such as characteristics of individual molecules in the network, ignores the overriding theme that the emergence and disturbance of generic network features is independent of these details.

B. Living systems require fine tuning of cellular networks to enable rapid transitions during fertilization, embryogenesis and repair of external or internal damage via inflammation, as well as slower transitions during fetal growth, childhood growth, puberty and response to environmental changes. Living systems must also have enough flexibility to promote and tolerate evolutionary change. Robust control mechanisms prevent these transitions from being activated inappropriately, but the chronic stressors may disrupt these control mechanisms.

C. Malignancy arises due to a build up of hierarchical structures, in which combination of agents (biomarkers and networks) at one level become agents at the next level. Hierarchical structures may be identifiable by patterns of network changes, molecular changes or histologic changes.

D. We can acquire new insights about malignancy by analyzing patterns of network behavior (such as the creation of new hierarchical structures or increasing instability) that are more uniform than changes to downstream oncogenes.

E. Self-organized criticality describes how enormous transformations (“catastrophes”) occur in living and nonliving systems. Similarly, malignant change does not occur through gradualism but by bursts of activity.

5. Treatment approaches based on complexity theory focus on interacting cellular networks, not just killing tumor cells where they exist. Curative treatment must combine multiple strategies that target existing tumors, prevent future tumors from arising and optimize the overall health of the patient:

* Cytotoxic cancer therapy should kill as many tumor cells as possible.
* Curative treatment for adult tumors must address tumor heterogeneity to a greater extent than curable childhood tumors.
* It may be useful to move cancer networks into less lethal states using biomolecules that influence malignant-type behavior or that alter pathways that promote malignant-type behavior.
* Reducing the chronic stressors is important because current knowledge is often inadequate to reverse network changes caused by even the simplest carcinogens.
* Novel treatments may take advantage of the sophistication present in physiologic cells but lost in the somewhat chaotic cells of advanced and aggressive cancers.
* Targeting the microenvironment that nurtures the tumor cells may have therapeutic value.
* More effective screening is important, both for premalignant and malignant lesions.
* Promoting rational medical care is important at the individual and societal level to more easily detect signs and symptoms associated with malignancy and to increase the range of possible treatments.

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