Coming Full Circle

"Coming Full Circle—From Endless Complexity to Simplicity and Back Again.", discusses how cancer research is once again back in the "incredibly complex" stage of its evolution:

"In the mid-1970s, ...the mechanisms by which cancer started and spread were a total mystery. Half a century of cancer research had generated an enormous body of observations about the behavior of the disease, but there were essentially no insights into how the disease begins and progresses to its life-threatening conclusions. As a result, the field of cancer research was held in ill-disguised contempt by the growing crowd of molecular biologists, geneticists, and biochemists. Even the cancer researchers had become rather disillusioned with the vast body of essentially incoherent phenomena that constituted ‘‘cancer research’’: as one particularly jaundiced cancer researcher told me at the time ‘‘one should never, ever confuse cancer research with science!’’

Then, everything got "simple". Cancer was seen as a tissue disorder in which cells just 'went crazy.' 

"From the point of view of the reductionist hoping that a small number of molecular events might explain cancer, things went downhill from there for the next 30 years."

Later, after decades of massive spending on a cure for cancer with very little to show for the efforts, cancer is once again seen as much more complex that before imagined.

"Beyond these complex, currently intractable large data sets, there are problems that cancer researchers haven’t even begun to confront. How do the transcriptomes of cancer cells interact with their mutant genomes to orchestrate cancer cell behavior? How do the differentiation programs of the normal cells-of-origin influence the behavior of their neoplastic descendants that have sustained large numbers of genetic and epigenetic changes? How do the multiple distinct cell types that form the tumor microenvironment (composed of inflammatory and immune cells and cells forming the microvessels) intercommunicate with one another and influence the behavior of nearby neoplastic cells? Physicists have wrestled unsuccessfully with the threebody problem. What will become of us who try to deal with eight or ten distinct independent agents, each a distinct stromal cell type that is recruited into a tumor and interacts bidirectionally with the other recent recruits?"

But, I think in all this complexity, simplicity is emerging for those of us who simply want to avoid ending up in the cancer ward: The immune system. While none of us living today may ever fully understand our immune system (and if anyone says they do, they are lying!), we can learn what keeps our immune system healthy.

Maybe even more "full circle" is the surprising new research that looks eerily like descriptions of cancer from the 1800's and before when cancer was seen as a living creature, living and traveling throughout its host at will. The 2014 research paper, "Tumor and the Microenvironment: A Chance to Reframe the Paradigm of Carcinogenesis?" looks closely at cancer as more than the random mutations we've been chasing for decades:

"Within that perspective, the tumor microenvironment cannot be merely considered akin to new “factor” to be added to an already long list of “signaling factors”; microenvironment represents the physical-biochemical support of the morphogenetic field which drives epithelial cells towards differentiation and phenotype transformation, according to rules understandable only by means of a systems biology approach."

In other words, they are once again seeing cancer as "alive" and not just "cells gone crazy." But what could be driving this cancerous life?

Horizontal Gene Transfer...also Full Circle

This talk of "Horizontal Gene transfer" we've been doing in the last several posts is maybe a clue. Cancer tumors are often found to contain genes that shouldn't be there. This paper describes bacterial genes found in cancer cells:  "Bacteria-Human Somatic Cell Lateral Gene Transfer Is Enriched in Cancer Samples"

"There are 10× more bacterial cells in our bodies from the microbiome than human cells. Viral DNA is known to integrate in the human genome, but the integration of bacterial DNA has not been described. Using publicly available sequence data from the human genome project, the 1000 Genomes Project, and The Cancer Genome Atlas (TCGA), we examined bacterial DNA integration into the human somatic genome."

These researchers go on to make a fantastic claim, that bacteria can inject their "code" into animal cells, turning them cancerous, yet go unnoticed:

"We sought to establish if bacterial cells insert their own DNA into the human genome. Such random mutations could cause disease in the same manner that mutagens like UV rays from the sun or chemicals in cigarettes induce mutations. We detected the integration of bacterial DNA in the human genome more readily in tumors than normal samples. In particular, extensive amounts of DNA with similarity to Acinetobacter DNA were fused to human mitochondrial DNA in acute myeloid leukemia samples. We also identified specific integrations of DNA with similarity to Pseudomonas DNA near the untranslated regulatory regions of four proto-oncogenes. This supports our hypothesis that bacterial integrations occur in the human somatic genome that may potentially play a role in carcinogenesis. Further study in this area may provide new avenues for cancer prevention."

Sounds incredible, no?  And what if other microbes could do the same thing?  There is another likely denizen of the cancer underworld: Fungi.

Fungal Full Circle

While most people aren't familiar with the "Tree of Life", it's a well-known feature of biology and anyone who studies biology will know that on the Tree of Life, humans share some branches with a organisms known as "fungi."  Certain fungi have become reliant on humans to complete their lifecycles. The Candida family of yeasts, for instance, inhabit every human. When the human host has a robust immune system, Candida is our friend--keeping bacteria, viruses and other yeasts at bay. When the immune system falters, Candida can cause problems that are nearly impossible to clear up, especially with the modern arsenal of anti-fungal drugs commonly prescribed. 

Too Long/Didn't Read Summary:

Fungi and cancer share some amazing similarities, and I hope to get into this more in the future here on Vegetable Pharm. But just so you know, I'm not holding anything out on you! I don't have a secret potion I'm going to try to sell you once I have you hooked. The answer, in fact, may be very simple: your immune system.

But maybe the "take-away" of this post should be that no one, from the leading cancer researcher to the latest cancer guru, really understands what causes cancer and how to best treat it! sure, they can blast it with radiation, flood it with chemicals, or cut it out, but it's all guess-work. 

One of the most striking similarities between cancer and fungus is that neither can overpower a strong immune system. A well-working immune system should lead to a life free from fungal infections, and cancer. As a bonus, you'll also be not likely to have inflammation and auto-immune disorders. If it's all tied together, the immune system is the core.

More to come later, thanks "Gemma" for the push and papers.

Later,
Tim

Addendum by Gemma, March 11, 2015: 

The pure irony is that the "Coming Full circle" paper is authored by one of the most prominent cancer researcher of the last decades, Dr. Robert Weinberg, author of two seminal papers on cancer, among others:

The hallmarks of cancer. (2000), cited by some 3764 other papers

Hallmarks of cancer: the next generation. (2011), cited by 3106 papers

That means the cancer research has never really found out what cancer really is and why it behaves as it behaves, and Dr. Weinberg is forced to admit he doesn't know what to do with the vast amount of data the research generated, and says (emphasis mine):

"We lack the conceptual paradigms and computational strategies for dealing with this complexity. And equally painful, we don’t know how to integrate individual data sets, such as those deriving from cancer genome analyses, with other, equally important data sets, such as proteomics. This is most frustrating, since it is becoming increasingly apparent that a precise and truly useful understanding of the behavior of individual cancer cells and the tumors that they form will only come once we are able to integrate and then distill these data.
So, perhaps ironically, we have come full circle, beginning in a period when vast amounts of cancer research data yielded little insight into underlying mechanisms to a period (1980–2000) when a flurry of molecular and genetic research gave hope that cancer really could be understood through simple and logical reductionist thinking, and finally to our current dilemma. Once again, we can’t really assimilate and interpret most of the data that we accumulate. How will all this play out? I wouldn’t pretend to know. It’s a job, as one says on these occasions, for the next generation. Passing the buck like this is an enormously liberating experience, and so I’ll keep on doing it!

Or, as summarized in the above mentioned paper "Tumor and the Microenvironment: A Chance to Reframe the Paradigm of Carcinogenesis?":

"The core message of Weinberg's admissions is that current SMT-based cancer research provided no meaningful results to solve the cancer puzzle because it lacks a well-founded and robust theory of biological phenomena."  

(SMT = somatic mutation theory of carcinogenesis)