Can thermodynamics help us better understand human cancers?

The thermodynamic lung cancer-specific gene (mRNA and miRNA) signature. This figure illustrates that genes that up-regulated in the lung cancer state are down regulated in normal controls, and genes that are highly up-regulated in the normal controls are down-regulated in the lung cancer state. There is a clear, correlated gene-expression behavior present that not only characterizes the lung cancer state but can also be used to distinguish cancer patients from non-cancer patients. Credit: PNAS/Sohila Zadran, Raphael Levine, Francoise Remacle

(Medical Xpress)—When the "war on cancer" was declared with the signing of the National Cancer Act in 1971, identifying potential physical traits, or biomarkers, that would allow doctors to detect the disease early on was a significant goal. To this day, progress in the battle against cancer depends on understanding the underlying causes and molecular mechanisms of the disease.

In a new study, UCLA researchers analyzed the gene-expression profiles of more than 2,000 patients and were able to identify cancer-specific gene signatures for breast, lung, prostate and ovarian cancers. The study applied an innovative approach to gene-array analysis known as "surprisal analysis," which uses the principles of thermodynamics—the study of the relationship between different forms of energy—to understand cellular processes in cancer.

The research appears in the early online edition of Proceedings of the National Academy of Sciences and will be published in an upcoming print edition.

Surprisal analysis allows researchers to observe how cellular energy is expended in cancer cells and how this process affects the way in which these cells choose to express certain genes. In particular, scientists can look at how cancer cells decide to use energy when expressing critical genes that allow them to persist and grow.

By identifying such cancer-specific gene signatures, scientists are able to distinguish, with high fidelity, the biopsy samples of cancer patients from control samples and potentially to identify novel cancer for early detection of the disease and the development of new therapies.

Research co-author Raphael Levine, a UCLA distinguished professor of chemistry and biochemistry and of medical and molecular pharmacology, and his fellow researchers hope the cancer-specific signatures they identify using surprisal analysis will provide "thermodynamic targets" against cancer.

"We believe that this paper introduces a new hallmark of cancer—a thermodynamic signature—where the free energy redistributions among cellular biomolecules in the cancer state, not seen in the non-cancer state, sustain the disease," said Levine, a faculty member in the UCLA College of Letters and Science. "A further, future power of surprisal analysis is in its ability to detect 'patient potentials,' meaning patient-specific differences can be detected in the analysis, reintroducing the possibility of personalized medicine to the cancer arena."

The same year the war on cancer was declared, Levine first formulated surprisal analysis with his colleagues, the late Richard Bernstein of UCLA and Avinoam Ben-Shaul, recognizing a need to better understand and characterize how systems utilize energy. Since then, surprisal analysis has become a critical tool for the analysis of chemical, nuclear and physical dynamics. For this research, Levine was awarded the prestigious Wolf Prize in chemistry in 1988.

In the last few years, Levine and his colleges have attempted to extend surprisal analysis to biological systems. Because the theoretical approach enables the monitoring of small systems that are not in thermodynamic equilibrium, living provide a very suitable opportunity for study.

Progress toward personalized medicine is expected to transform the cancer therapeutics field. But identifying an approach that can give researchers a feasible, quantitative method to identify cancer-specific gene signatures and characterize individual patient cancers has remained "an ultimate challenge," said Levine, a member of the U.S. National Academy of Sciences.

The new research suggests there may be an effective approach to identify cancer-specific signatures. While encouraging, Levine and his co-authors emphasize that the results are preliminary and that any practical diagnostics resulting from this research would require considerable additional and extensive scientific validation.

Cancer deaths have declined only slightly in the past decade, mostly due to preventive health efforts such as smoking cessation and routine examinations. Identifying cancer-specific markers remains a challenge. However, modern genetic sequencing technology can measure the expression levels of many genes. The recent development of large-scale genomic approaches and sequencing initiatives have produced several candidate biomarkers for detection, but very few have been robust enough to work well in practice. The inability to extend these biomarkers from the bench to the clinic arises from a limited ability to separate the wheat from the chaff while sifting through the often-insurmountable data retrieved from genomic technologies, Levine said.

Co-authors of the study are Francoise Remacle, a professor of chemistry at the University of Liege in Belgium and director of research at the Belgian National Scientific Research Foundation (FNRS), and lead author Sohila Zadran, a junior faculty fellow at the David Geffen School of Medicine at UCLA.

More information: www.pnas.org/content/early/201… 991110.full.pdf+html

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Benni
1 / 5 (3) Oct 12, 2013
When energy is applied to an enclosed system, all BTU (or Caloric) intake must be accounted for. If more energy is injected into a closed system than the system was designed to consume, the system overheats, if overheating becomes extreme in a closed system an explosion can result, this is what we're dealing with here in the human body. The human body is an energy consuming mechanism, and if it is "over energized" the excess energy will be accounted for in a manner that will be detrimental to the system. Over energize an internal combustion engine, it can blow up & or at the very least will begin operating very inefficiently as it tries to absorb the excess energy created by a more dense entropic environment.
JVK
1 / 5 (5) Oct 12, 2013
Let's thermodynamically differentiate maladaptive mutation-initiated "natural" selection from accurate representations of nutrient-dependent pheromone-controlled adaptive evolution via the requirement for organism-level thermoregulation.

I'll start: Thermodynamically "futile" cycles of RNA transcription and degradation cause changes in pheromone production that enable accelerated changes in nutrient-dependent adaptive evolution controlled by the microRNA/messenger RNA (miRNA/mRNA) balance. Environmental cues, like those that signal the availability of glucose, cause changes in the miRNA/mRNA balance that enable gene expression during developmental transitions required for successful nutrient-dependent reproduction in species from microbes to man.

Cancer doesn't fit into the constraints of adaptive evolution via the physiology in my model that links physics and biology. http://figshare.c..._/643393
Torbjorn_Larsson_OM
5 / 5 (2) Oct 12, 2013
To respond to the article and previous comments (unfortunately including what we now know as insane "pheromone" trolling/marketing), this work has nothing to do with thermodynamics as such. Surprisal analysis is information theory mimicking thermodynamic principles. [ http://en.wikiped...Analysis ]
Torbjorn_Larsson_OM
5 / 5 (1) Oct 12, 2013
@Benni: Organisms doesn't "explode".

There are variants of thermodynamic regulation that may or may not fail, some of which are deemed symptomatic. I.e. if people can't sweat (which cause can be genetic) and/or can't access water they will more easily overheat. And there are early ideas of mitochondrial functions and/or diseases, where ATP regulation can be problematic.

None of which have been correlated with cancer.

Also, there are no "more dense entropic environments" on Earth. It radiates to space, so average entropy is low.* The problem with closed environments are overheating (no heat sink) not overentropy (increased internal entropy). A cell doesn't change entropy much.

* Keep in mind that "entropy flow" is a toy model that don't mirror the actual physics and so easily breaks down. In statistical physics entropy is an internal measure of amount of available microstates at given energies.
Benni
1 / 5 (3) Oct 12, 2013
@Tor Lar:

If what you've just posted about Thermodynamics & Entropy is all you know about the subject, then you sure sure don't know very much. Like "entropy flow is a toy model"? So are asymptotic pseudo-tensors, but I'm sure you believe in those.

JVK
1 / 5 (5) Oct 12, 2013
Torbjorn wrote:
this work has nothing to do with thermodynamics as such....


This article exemplifies nutrient-dependent pheromone-controlled adaptive evolution as it was presented in August at the ISHE Summer Insititute -- for comparison to theories incorporating mutation-initiated natural selection. I've been detailing the likely involvement of sensory input that links the epigenetic landscape to the physical landscape of DNA via changes in the microRNA / messenger RNA balance for more than 6 months.

The changes link the thermodynamics of intercellular signaling to organism-level thermoregulation -- precisely what this article shows is required. Clearly, either Torbjorn has not read this article or knows nothing about biophysics.

Yet, he insists on calling me a troll. A link to his latest publication or presentation would reveal that he is the troll. That's why I linked to my poster, and why he links to wikipedia.