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Rafe.Furst — Tue, 25 Nov 2008 00:05:04 CST

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Rafe.Furst — Tue, 25 Nov 2008 00:02:51 CST

This community is about exploring the complex adaptive nature of cancer, including the notion that cancer involves evolution by natural selection of cell populations within the body. more...

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Background

Rafe.Furst — Mon, 28 Jul 2008 12:35:40 CDT

Cancer as somatic evolution: wikipedia entry

Cancer is a hugely diverse, complex, unpredictable, non-linear, stochastic evolutionary process

The discovery of oncogenes and tumor suppressor genes firmly established the view that "cancer is fundamentally a disease of genomic alteration" and that the rational approach and is to identify and target critical genetic alterations or particular pathways of tumor cell evolution. The success of Gleevec in the treatment of chronic myelogenous leukemia (CML) provided "proof of principle" and was used to justify the overarching strategy of the National Cancer Institute: identify and target the genetic alterations of cancer. However, there is overwhelming evidence that cancer is actually a hugely diverse, complex, unpredictable, non-linear, stochastic evolutionary process. This conclusion, if true, falsifies much of what is believed to be true of cancer and invalidates most approaches being pursued to develop treatments for cancer patients. However, it also opens up new vistas and therapeutic approaches.[ for more detail read the draft attached below ]

Comments, criticisms, attempted refutations, discussion, debate, and posting of evidence and arguments related to the this topic would be greatly appreciated. Thanks. -- Arny Glazier

Additional Information

Cell Differentiation Patterns Suppress Somatic Evo lution. J. W. Pepper, K. Sprouffske, and C. C. Maley. 2007.PloS Computational Biology 3(12):e250.
Cancer as an evolutionary and ecological process, Lauren M.F. Merlo, John W. Pepper, Brian J. Reid and Carlo C. Maley, Nature Reviews (Dec 2006)
Cancer genome sequencing: the challenges ahead, Henry Heng, BioEssays, Vol 29, Issue 8, Pages 783-794
“Human Cancer Cells Express a Mutator Phenotype” by Bielas JH, Loeb KR, Rubin BP, True LD, Loeb LA. In Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18238-42
Editorial on cancer and tumor cell evolution, A.Glazier with E. Frei III, A.C. Upton, L.A. Loeb, C. Webb, H. Pass, B. Crespi, M. Liebman, R. Somiari, H. Heng
Cure Cancer Project website (beta)
The aneuploidy theory of cancer and the barriers to its acceptance (David Rasnick, 2002)
Why We're Losing the War on Cancer (Clifton Leaf, 2004, Fortune)
Untangling the roots of cancer (Wayt Gibbs, Scientific American, Oct 2004)
Also see Prior Discussions.

Robustness of Complex Systems

Simply connected complex systems can be inherently robust. Some references attached below.

Some Motivating Questions [click here]

Some Motivating Questions

Rafe.Furst — Fri, 25 Jul 2008 13:20:16 CDT

The following are intended to be answered or at least commented on. Please use the Thread feature at the bottom of the page for this.

If you have questions that you'd like to add, please do so on this page directly using the Easy Edit button at top.

Big Picture

To what extent is genetic mutation a "normal" part of multicellular life? If it were possible to eliminate or eradicate mutation completely, could the human organism continue to function, or is mutation somehow necessary for an individual organism?

On a macro level, is cancer an adaptive trait of multicellular organisms? For instance, after the age of reproduction isn't there selective pressure to die so as not to compete with offspring?

If we were somehow able to inhibit motility in cells that are shown to be both prolific and invasive, does this then by definition stop metastasis? Are there normal/essential processes that would be halted too?

How do the various levels of organization in biology play into cancer formation?

Is the micro-evolutionary process the entire story or do we need to study other complex systems models? What models are deserving of more attention than they are getting (even amongst complexity thinkers)?

Treatment, Prevention & Cure

Counter to the standard medical model, toxicity effects appear to be non-linear (c.f. Counterintuitive Toxicity article attached). Relatedly, in Henry Heng's work and others (c.f. Unintended Consequences article attached) there is mounting evidence that the use of chemo and other standard therapies may actually promote metastasis. What does all this mean for cancer treatment?

Given the role of micro-evolution in cancer, and given that this seems to be at the root of the seemingly limitless complexity of the problem, are there ways we can use the power of evolution to advantage? Can we evolve cures specific to each individual?

Are there any well-proscribed computational problems that could be attacked via a peer-to-peer effort like SETI@Home? Are there any problems that would lend themselves better to a "crowdsourcing" approach like Amazon's Mechanical Turk?

Scattered advances in detection (c.f. Visualizing Cancer article attached) and treatment (c.f. Express Delivery article attached) are being made which seem applicable to the pattern detection and targeting methodologies such as the one proposed by Arny Glazier. How far are we from being able to effectively and specifically detect and target cancerous patterns?

What do you think of the "apoptosis approach"? Scientific merits aside, what can we learn from their visual presentation of cancer biology to help explicate evolutionary/complexity concepts better?

What could existing databases tell us about cancer if analyzed with emerging technologies such as Google Maps and Yahoo! Pipes?

Societal Issues and Factors

As a society we spend billions each year on cancer research, yet the data shows no real progress since 1950(!), despite what the public is lead to believe. How come there isn't more public knowledge of the truth and more outrage? How can we get people to wake up to the reality?

What are the incentives to NOT cure cancer? E.g. do drug companies really want to cure cancer or are they better off promoting it and coming up with life-extending treatments that bring them a long-term recurring revenue stream?

Why do some demographic groups (e.g. Hispanics) do better in combating cancer than others?

How do the metaphors we use (such as "war on cancer") affect the approaches to the challenges of prevention, research and treatment?

Underserved communities are the hardest hit by cancer, yet addressing problems in the hardest hit communities will necessarily help all communities. Why then is funding and attention focused in just the opposite direction?

Scientific Methodology and Biases

The Placebo effect is well documented as accounting for 20 - 40% of the positive result of any therapeutic remedy for disease. The mind-body connection has also been positively correlated with curing cancer (c.f. Cancer Yoga article attached) as well as other diseases (c.f. Sniffle-Busting Personalities article attached). How come there hasn't been more research into the mechanisms of Placebo as well as the application of mind-body techniques to cure cancer in scientific settings?

Why are cases of spontaneous remission not researched more seriously? If we were to consider the notion that these people are not being cured by the chemo or other techniques that were being applied, what does this say about the nature of the disease? What about people who eschew traditional Western remedies and are able to achieve remission?

How do our various cognitive biases in reacting to disasters affect our view of the cancer problem? For instance, our reactions to natural disasters (like hurricanes) are very different than to chronic conditions, which is different than to infectious disease, etc.

Misc Attachments

Rafe.Furst — Fri, 30 May 2008 22:59:49 CDT

There is no abstract available for this page revision.

Research

cmaley — Fri, 30 May 2008 16:53:15 CDT

Please post brief summaries and links to any and all related research.

Why We're Losing the War on Cancer (and how to win it) by Clifton Leaf, Fortune Magazine (Mar 22, 2004)

Cancer as an evolutionary and ecological process, Lauren M.F. Merlo, John W. Pepper, Brian J. Reid and Carlo C. Maley, Nature Reviews (Dec 2006)

Broad and comprehensive review of work to date. A good lay summary can be found here on ScienceDaily.

Cancer genome sequencing: the challenges ahead, Henry Heng, BioEssays, Vol 29, Issue 8, Pages 783-794

Evolutionary and complex systems principles must be incorporated into cancer research. Genome level more important than gene level in cancer progression.

Elimination of altered karyotypes by sexual reproduction preserves species identity, Henry Heng, Genome 50: 517-524 (2007)a

A landmark paper that reverses the long and widely held misconception that sexual reproduction increases heterogeneity over asexual. Heng shows just the opposite.

Cure: Scientific, Social, and Organizational Requirements for the Specific Cure of Cancer by Arnold Glazier, MD

A comprehensive treatise on the logical implications of a complex evolutionary view of cancer which outlines both the technical and non-technical prerequisites for a cure to be found.

Women's reproductive cancers in an evolutionary context by Eaton, S. B., Pike, M. C., Short, R. V., Lee, N. C., Trussell, J., Hatcher, R. A., Wood, J. W., Worthman, C. M., Jones, N. G., Konner, M. J. & et al. Q Rev Biol 69, 353-67 (1994).

Malignant tumors in two ancient populations: An approach to historical tumor epidemiology. by Nerlich, A. G., Rohrbach, H., Bachmeier, B. & Zink, A. Oncol Rep 16, 197-202 (2006).

Popular Writing

Rafe.Furst — Sun, 06 Apr 2008 12:51:54 CDT

Contagious Cancer (David Quammen), Harper's Magazine, April 2008.

Prior Discussions

Rafe.Furst — Mon, 03 Dec 2007 12:30:31 CST

This section is for informal correspondence that predates this community. Going forward, please use the Discussion Forum.

Pepper & Maley Prior Discussions

Rafe.Furst — Mon, 03 Dec 2007 12:29:10 CST

Rafe: I read your working paper on animal cell differentiation patterns and the Nature Review of cancer as an evolutionary and ecological process, both with great interest. I have some questions from these:

Is there a hard and fast definition of stem cell be it somatic, cancer or otherwise? Or is "stemness" a property on a continuum?

Pepper: If there is any hard and fast definition of a stem cell, it would be something like "A cell (of an animal) with unlimited replicative potential." But of course, some cells are more limited than others, so there's really a continuum. In my paper with Carlo on differentiation patterns, we reference a paper by Kirkland (2004) that explicitly represents 'stemness' as a continuum.

Maley: This is a subject of debate, so it is probably safe to say there isn't a hard a fast definition, particularly of a cancer stem cell. It is important to distinguish between normal stem cells and cancer stem cells (which may have no relation to a normal stem cell). It also depends on context. If you are a developmental biologist, a stem cell is a totipotent cell (can become any type of cell). John and I usually think about somatic stem cells (sometimes called "progenitor cells") which are already committed to a tissue but continually renew that tissue. Most stem cell definitions require that they be self-renewing and at least multipotent. In the cancer literature, a cancer stem cells is one that is capable of self-renewal and regeneration of the entire neoplasm (including both cancer stem and non-stem cells). On top of this is usually an operational definition that it must be capable of serial transplantation (so it must engraft in a mouse and then re-engraft in other mice). There is debate if stemness is an intrinsic property of a cell or a matter of the cell being in a physical niche that makes it act like a stem cell. In the later case, given some kind of gradient, stemness would probably exist on a continuum. On top of this, Potten et al. think that the early stage transient amplifying cells are capable of dedifferentiating to replenish the stem cell compartment if all the stem cells die (e.g., when exposed to low dose radiation).

Rafe: Similarly, is there a standard accepted definition of (epi)genetic stability? It seems to me that it's much like complexity in that there are some different approaches to defining it. It also seems as though complexity and stability are related in an intrinsic way.

Pepper: Again, there's probably a continuum there.

Maley: No. People usually define stability in an ad hoc manner depending on their assay. We don't have a good grip on what the normal rate of (epi)genetic lesions is, which makes it hard to define an abnormal rate. Most people focus on "instability" and identifying that, which usually comes down to "lots of things wrong" with the genome.

Rafe: You mention that there are several possible evolutionary approaches to cancer therapy and prevention. I am wondering what your thoughts are on Arny Glazier's PRTT approach? I realize the review paper was written before Carlo and I attended that conference.

Pepper: I'm not really familiar with Glazier's PRTT approach. Can you send a reference, or even a paper?

Maley: I'm not yet convinced that his approach is possible, but it may be. I think it would be a great advance if we found a way to design drugs in a modular way such that they could select for cells described by a logic statement (e.g. kill all cells that have phenotypes A and B but not C). That is a precondition of his approach, so I say, go for it.

Rafe: There are various therapeutic approaches that target one hallmark of cancer at a time. Is there anyone (besides Arny) making the case for the logical necessity of targeting all (or as many as possible)?

Pepper: Not that I know of. It makes perfect sense to me though. Combination therapies have been very successful at preventing the evolution of drug resistance in other diseases - most notably HIV.

Maley: Have you read Leaf's article from Fortune? The problems with combining drugs are currently on the legal side because the companies that own the different drugs have a hard time playing nice with each other. I think our current successful drug options are limited enough that we don't have a lot of liberty to pick and choose drugs by any strategy, such as targeting different hallmarks. But I could be wrong about that. It is certainly a reasonable approach. I would worry most about choosing drugs that require different mutations for resistance (are not vulnerable to multi-drug resistance).

Rafe: Regarding cooperative relationships within neoplasms, couldn't the existence/emergence of the neoplasm itself be considered the ultimate form of cooperation?

Maley: Are you saying the cells in a neoplasm are cooperating with each other to grow the neoplasm? That isn't clear to me. That would mean that the cells gain a benefit from the presence of the other cells. I think it is mostly a competitive relationship but I'm interested in looking at/for cooperation.

Rafe: There is a sense in which neoplastic cells cooperate in a sort of figure-ground relationship with normal cells (which are ultra-cooperative). If individual cellular fitness is increased through cooperation of the standard kind in a normal body, then cancerous cells will gain relative fitness by breaking up that cooperation and reducing the fitness of normal cells.

Maley: Hmm, good thought. We would have to characterize the cooperative interaction between normal cells, but then it should be pretty easy to look for disruptions of that cooperation due to neighboring neoplasms.

Rafe: Very little seems to be done to study the role of the neoplastic microenvironment, despite the fact as you point out that it has a huge impact on progression. Prevention practices are aimed at buttressing the microenvironment against progression, albeit in a very indirect way. Do you know of anyone trying actively to close the loop, working directly at (or near) the cellular tissue level on the microenvironment itself?

Pepper: The only person who comes to mind on that is Robert Gatenby

Maley: There is a lot of interest/funding on tumor microenvironment these days, though not from an evolutionary point of view. People tend to focus on extracellular matrix and interactions with stroma. As far as I know, most of this is still in discovery science and not near to translation to the clinical trials.

Rafe: You say that neoplasms (with a few exceptions) "do not contain many species". What does this mean? What is a "species" in a population of asexually reproducing organisms?

Pepper: That statement doesn't mean much, except as a contrast to classical ecology, which is about the interaction of multiple species.

Maley: In microbial biology, a "species" of asexually reproducing single cellular organisms is basically the set of cells that have a similar niche and phenotype. If a subclone grew out to start metabolizing a different substrate and evolved a different way to live, we would probably call it a new species. In a neoplasm, the clones are probably behaving (and making a living) in similar ways, so there are probably few dramatic distinctions between clones, though there may be a few (e.g., angiogenic clones and their free-rider competitors).

Rafe: Actually, I just learned about Henry Heng’s argument for cellular species differentiation based on chromosomal isomorphism.

Maley: I know Henry has been doing some yeoman work generating SKY data to measure different chromosomal patterns within neoplasms. There certainly is a lot of chromosomal level instability in neoplasms. I just don't know if it leads to specialization into different "species." That would also be very interesting.

Rafe: I don't want to mis-characterize Henry's findings or argument, but I think he's claiming that by looking at patterns at the chromosomal level (which look like noise at the gene level) and correlating them with phenotypic changes at the cellular level, there is a striking correspondence. Enough so that it makes sense to look at this level as species definitional, at least for single cells. The patterns are only really clear once you see the sort of heterogeneity exhibited in cancerous cell populations.

Rafe: You say that in "normal tissue" we "have access to the ancestral genotype". My understanding (which is probably flawed) is that there is no such thing as a "normal" cell and that on average each cell in the human body has 1 point mutation. If we do have access to an ancestral genotype, couldn't we somehow replace cells (all of them) prophylactically?

Pepper: I guess in this context 'normal' means 'non-neoplastic' Replacing neoplastic cells with those having the original (ancestral) genotype is what happens in a successful surgical treatment. To do it on a finer scale, we don't have the technology yet.

Maley: That's a good point. We assume that the mutation rate in the normal cells should be low enough that with a few samples of different tissues, you could infer the zygote's genotype. In practice, we probably can get away with just sampling one normal tissue and accepting that there may be a few somatic mutations in it.

Rafe: The Nature piece says "this new picture implies that the problem would lie with TAC mutations that interfere with differentiation". This implies that there is a single "key" to "the" problem. But if the problem is one of evolution of cell populations, then TAC mutations interfering with differentiation is just one of potentially intractably many pathways to carcinogenesis. I've heard the argument (and I think I remember reading you suggested this in one of your articles), that given the number of cells in the body, number of generations in a normal lifespan, etc, the landscape is sparse with higher fitness peaks for natural selection (NS) to achieve with cancer, and the pathways to get there would almost assuredly co-opt normal cellular machinery. But it's not clear that the number of potential pathways is small (and empirical evidence is to the contrary). So if you solve the TAC mutation issue, NS is "smart" enough to just route around and find another way generally not taken. Remove one bottleneck, and the next one appears.

Do you agree with this reasoning? I suspect the Nature piece was just a little imprecise in implying something that perhaps you didn't intend.

Pepper: The real situation is complex, and shouldn't be over-simplified. But I think the approach I outline does allow some legitimate simplifying, or at least categorizing. There are innumerable relevant biochemical pathways, and even more potential mutations. But the legitimate simplifications I would argue for are these:

Cancer is a likely outcome IFF there is strong somatic cell-level selection.
The above requires that two conditions both are met in the same cell population:
substantial cell proliferation and turnover
self-renewal of the cell population.

In normal tissue, condition 1) is met only by TACs, while condition 2) is met only by somatic stem cells. Neither meets both conditions, thus neither generates strong cell-level selection. Thus all routes to oncogenesis can be grouped into two major categories:

TACs acquire self-renewal (by a breakdown of normal differentiation) or,
stem cells acquire substantial cell proliferation and turnover (either by genetic lesion, or by environmental conditions such as chronic wounding and healing)

In trying to prevent or treat any specific type of cancer, the first question I would ask is, "which of the above two routes does it arise through". The answer would illuminate the whole research program.

The key is that, as you put it, "NS is 'smart' enough to just route around" any specific obstacle. So what we must do is to “route around" somatic NS itself.

Rafe: I'm also interested in knowing if there are any standardly-used agent simulation systems that I can check out.

Pepper: Yes, there are several. There are some closed systems that are a very quick start for people without much software experience. My current favorite in that category is is NetLogo: http://ccl.northwestern.edu/netlogo/ (free download).

But for somebody like yourself with degrees in CS, I would recommend any of several good libraries for agent-based simulation. The one I have used the most and like is Swarm: http://www.swarm.org/wiki/Swarm_main_page

Another toolkit that I hear good reports on is called Repast: http://repast.sourceforge.net/index.html.

Henry Heng Prior Discussions

Rafe.Furst — Wed, 28 Nov 2007 12:40:46 CST

From: Rafe Furst
To: Henry Heng
Subject: David Freedman article

Henry, I just was able to read the article and am wondering if you can comment on the "promising" approaches discussed in the article. Do they take the logic of complex evolutionary systems far enough, or are they likely doomed to the same outcome? This quote in particular made me skeptical:

"There may be a hundred genes involved in instabilities," he says. "That would be disappointing."

Do you think the number is closer to "all" than hundreds? If so, would that mean that we need to look at levels closer to cellular tissue?

From: Henry Heng
To: Rafe Furst
Subject: Re: David Freedman article

I agree with you that we need to look at level above the gene. For example, the genome, the cellular tissues and more importantly the individual level (from a multiple levels system perspective). It is most likely that more than hundreds of genes are involved in the instability of cancer, and in a way, cancer is a disease of system instability. The key to preventing cancer progression is to maintain system or genomic stability. I have submitted a review on this topic, and I will send you a copy as soon as it is accepted by the journal.

From: Henry Heng
To: Rafe Furst
Subject: Genome-centric viewpoint

Using the "genome centric" viewpoint of thinking, I just published a small but possibly significant piece that rethinks the function of sexual reproduction, an example of the re-examination of a "well known concept".

[upload article via "Add an Attachment" feature on RHS]

From: Rafe Furst
To: Henry Heng
Subject: Re: Genome-centric viewpoint

Very interesting article. I don't have enough of a biology background to understand the details, but I think I understand it at a high level.

I'm not sure how familiar you are with John Holland's work on genetic algorithms, but it might be an interesting corroborating piece of evidence. One of the things that he notes in computer models of evolution is that sexual crossover preserves what he calls schemas. These are patterns of genetic code (meta level) that I think are analogous to the genome. Point mutation erodes schemas.

The focus of genetic algorithms is slightly different than real genetics. In GAs typically you are not trying to model actual evolution but rather use evolutionary models to solve optimization problems. Sexual crossover is superior to strict (asexual) mutation in GAs because of two factors: (1) adaptive schemas are preserved and built upon, and (2) crossover can create quantum leaps in fitness space that can get the system off of a local maximum onto a higher peak, whereas cloning with point mutations tend to get stuck in local maxima. If you increase the mutation rate in order to reach more global fitness, you end up destroying good schemas that would eventually lead to better solutions even if they are not immediately presenting. If I remember correctly, the best GAs involved both crossover and low-level point mutation.

As an aside, in college I did an experiment that compared the standard crossover mechanism with one that used two crossover points instead of one. It turned out that the two point crossover was superior, but not by a lot.

Biological systems are much more complex than GAs, so I take the analogies with a grain of salt, but to the extent that all evolutionary systems share a "fitness optimization" force, it's probably worth looking at GAs as "pure" models in this regard. I have been meaning to re-read Holland's seminal work, Adaptation in Natural and Artificial Systems, now that I understand a bit more about evolutionary systems.

From: Henry Heng
To: Rafe Furst
Subject: Re: Genome-centric viewpoint

I am very interested in your comments regarding the similarity between the genome and Holland’s concept. I am not familiar with his work of using GAs to study the sexual reproduction but I am interested in reading more about it later.

Relative to our discussion, I am now working on a piece that will study the relationship between the gene and the genome. I have a feeling that moving away from the gene centric viewpoint would move cancer research and biological research forward by accepting a new way of thinking.

From: Rafe Furst
To: Henry Heng
Subject: Re: Genome-centric viewpoint

Are you using genome and chromosome interchangeably? If not, what is the important nuance?

What is meant by stability/instability at the genome level and at the gene level? How do these types of stability differ?

From: Henry Heng
To: Rafe Furst
Subject: Re: genome-centric viewpoint

The genome is equal to all the sets of chromosomes of a given species. There is no paper discussing the relationship between the gene and genome. I am currently writing one. Traditionally, people have ignored the function of the genome as almost all efforts have been focused on the gene.

Instability of genes might refer to the mutation rate or status. Instability of the genome simply refers to the degree of stochastic chromosome aberrations which leads to genome diversity. We have established that stochastic genome variations, such as the frequency of NCCAs (non clonal chromosome aberrations) can be used to monitor genome instability. Genome level changes are more significant than gene level changes.

From: Rafe Furst
To: Henry Heng
Subject: Evolutionary theory

Generally speaking, my current understanding of evolutionary processes has evolved (pardon the pun) to the point where I get nervous that, even amongst knowledgeable evolutionary theorists, models are too narrow; while an evolutionary view is critical to understanding what is going on, a narrow view (or gene-centric view, ala Dawkins) could obfuscate deeper understanding...

From: Henry Heng
To: Rafe Furst
Subject: Re: Evolutionary theory

I am in fact writing a piece calling for a new evolutionary theory that departs from the gene-centric view. The selfish gene is just one side of the story. Now realizing the conflict that exists between the gene and the genome, I have finally developed a plan to establish a new way of thinking. I will keep you posted.

Another thought, has anyone discussed this concept? For a given complex system, when there are so many elements involved, any one of the causative relationships between two elements become insignificant. Is there any theory you know behind this thinking?

From: Rafe Furst
To: Henry Heng
Subject: Re: Evolutionary theory

Yes, there has been a lot of work recently in network theory to describe complex systems. Simulations and networks found "in the wild" such as the internet, biological pathways, natural ecologies and food chains, etc. exhibit some very similar dynamics if they are of similar network "types". One type of network that is prevalent in nature is the "small world" network, where they are formed by "preferential attachment". Meaning that not all nodes receive the same number of links, rather you see a power law distribution, aka the 80/20 rule, where 80% of the links are conferred to 20% of the nodes (and often it's more like 95/5 or steeper). Another common feature of these networks is that there are many local subnetworks that are connected non-locally by a few long-haul links, such as is found with the internet. In such systems, it turns out that the systems are normally very robust and you can knock out a huge portion of the nodes and links and the system remains very stable. But their achilles heels are the few nodes which have the largest numbers of links and the few long-haul links; if just a few of these are knocked out, the entire system collapses pretty quickly.

My personal opinion is that the focus in network theory research has been very superficial thus far and really only targets statistical measures. I liken it to MRI and other gross tools that study brain activity. I believe that some breakthroughs will occur once network theory is advanced with much more simulation and when it is applied to many different systems in nature. The simplest simulations involving networks already exhibit striking similarities to complex systems found in nature, including "punctuated equilibrium", population dynamics, infectious disease dynamics, far-from-equilibrium economics, etc.

From: Rafe Furst
To: Henry Heng
Subject: Sexual vs Asexual Reproduction

Here's a passage from Complex Adaptive Systems which summarizes (what I believe to be Holland's discovery about) schemas:

"The benefits of crossover stem from the fact that good partial solutions, known as building blocks or schema, are present in the population. The current theory of genetic algorithms suggests that crossover effectively preserves and combines building blocks, allowing good solutions to be built from the bottom up."

This seems consistent with the your finding that sexual reproduction is more preservative and yields less genetic diversity than asexual which relies on random mutation.

From: Henry Heng
To: Rafe Furst
Subject: Re: Sexual vs Asexual Reproduction

I think that the idea of schema could be applied to the genome level more than gene level. From the description, it seems that the author made conclusions based on the idea of building blocks (that contain many genes). However, this idea is consistent with the current gene based genetic algorithms for crossover advantages to select “good" building blocks. I am interested in knowing whether their findings (from simulations) more closely fits our findings than combinations of some loci. We propose that the genome framework (that could represent a higher order than building blocks) is more preservative than a number of genes. Within the genome defined system, genes can change…increasing diversity, conserving good building blocks…but the boundary is defined by the sexual filter permitted by the genome. It seems that the fixed framework allows good solutions to be built and allow diversity within a system. In this sense, our recent work confirms it empirically.

From: Rafe Furst
To: Henry Heng
Subject: Re: Sexual vs Asexual Reproduction

I'm not sure I understand what you are saying so I will paraphrase it:

• A set of individual but co-varying genes is a schema (of genes), aka a building block
• A chromosome is a set of genes, and hence a schema
• But it also has additional structure beyond set structure, defined by the sexual filter which is to say crossover (is there more to it than this?)
• This additional structure leads to decreased diversity at the gene level
• This additional structure leads to (more? less?) stable building blocks of genes (including genome-level structures)
• If we pop up a level and look at the genome level, we can identify schema of chromosomes
• Chromosome-level schemas also exhibit properties of diversity and stability, but at the level above the genes
• There is a correlation between diversity (or stability) at the genome level and the gene level. What is that correlation?

From: Henry Heng
To: Rafe Furst
Subject: Re: Sexual vs Asexual Reproduction

I agree with most of your analyses including considering a chromosome as a schema. I only want to emphasize that the genome context (that is maintained by the sexual filter) is significantly more important than any gene or gene combination in terms of specie identity. Thus, it is beyond a simple combination of genes.

Maintaining the same genome context will reduce diversity at the genome level. At the same time, the mechanism for sexual reproduction does provide a means for genetic recombination at the gene level. My point is that genome level identity is the key to defining a given species, and gene level diversity does not define a species but will result in modification of an existing species.

A few months ago, you asked if there were any reviews discussing gene context. Please find one of my papers (that will come out in a few weeks) for your information.

[Attach paper here]

A few days ago, a UK group reported that they have illustrated genetic diversity in asexual reproduction. This report has generated some news for the general public. I have also provided my comments. Please find it at the following link.

I am also sending a link to you regarding the Discovery Channel show our lab participated in. There are five parts, one of them is as follows.

From: Rafe Furst
To: Henry Heng
Subject: Re: Sexual vs Asexual Reproduction

By sexual filter, do you mean crossover? What more is there to "genome context"?

More generally, what would you say are the distinct (and non-isomorphic) genetic levels and what characterized their distinctions? Here are some terms that I see you use that I think refer to the various genetic levels: gene, epi-genetic, gene network, genome, sub-chromosome, genome context, regulation elements, protein, protein sequence. I would love to see a diagram that visualizes these levels and their relevant features (from an information processing standpoint) and the organization of these levels between one another (are they strictly one on top of another, or is there some overlap and feedback?)

It seems to me that the understanding of this is a key to really understanding the nature of cellular evolution and other dynamics such as metabolism. As you mention, evolutionary processes are so poorly understood by most natural scientists, that there will need to be more than one shift in perspective for people to grasp cancer.

From: Henry Heng
To: Rafe Furst
Subject: Re: Sexual vs Asexual Reproduction

By sexual filter, do you mean crossover?

Sexual filter refers to multiple elimination steps to clear up abnormal karyotypes, and these steps include meiosis-see Genome paper, page 520-521.

I would love to see a diagram that visualizes these levels and their relevant features (from an information processing standpoint) and the organization of these levels between one another (are they strictly one on top of another, or is there some overlap and feedback?)?

A great idea. Even though there is feedback at various levels, the difference between higher and lower levels is strict and should not be confused.

It seems to me that the understanding of this is a key to really understanding the nature of cellular evolution and other dynamics such as metabolism.

I agree. That’s why we like your idea of organizing some meetings to promote the concept of complex systems and evolution.

From: Rafe Furst
To: Henry Heng
Subject: Re: Sexual vs Asexual Reproduction

So it's clear from your papers that prior to the crisis stage, the karyotype of each cancer cell is different from all others (i.e. different species from your definition). How does this compare to "normal" cells? Assuming a normal cell can be recognized at the chromosome level, could we simply target for destruction all cells which have non-normal karyotypes? Could this be done prophylactically and thereby forestall other diseases involving chromosomal aberrations accumulated after ontogenesis?

From: Henry Heng
To: Rafe Furst
Subject: Re: Sexual vs Asexual Reproduction

Normal cells should display far less dynamics at the genome level due to system stability. It would be a great challenge to target some systems but not others. It will be very interesting to see if the degree of dynamics can be used as a target, as we know that such information can be potentially used as a diagnostic tool.

From: Henry Heng
To: Rafe Furst
Subject: Re: dynamics of cancer chromosomes and genomes

I just read your paper:

Ye CJ, Liu G, Bremer SW, Heng HH. (2007). The dynamics of cancer chromosomes and genomes. Cytogenet Genome Res 118:237-246.

and have some questions.

"All evidence points in the direction that stochastic genome aberrations coupled with stochastic mutations (rather than mutations themselves) play a significant role in cancer formation and natural speciation."

I presume you are reserving the word "mutation" (or "stochastic mutation") to apply to gene level, and "aberration" for the genome level? And you are highlighting the coupling of changes at both levels as opposed to the (standardly focussed on) gene level, or even the (universally discounted) genome level alone? To what extent can we ignore the gene level altogether and just focus on genome?

My personal feeling is that the majority of focus should be on the genome.

Does "stochastic chromosomal changes" refer to NCCA? Does the "clonal" in CCA refer to the cloning (mitotic?) process itself yielding aberrations as opposed to stochastic aberrations which happen anywhere outside of the cloning process?

NCCAs and the unpredictable relationship with CCAs explains the mechanism of stochastic chromosome changes.

Are there any sexually reproducing organisms that either don't get cancer in the wild or which cannot be induced to get cancer? Can asexually reproducing multi-celled organisms get cancer? Has any work been done on cataloging species based on their susceptibility to cancer?

Interesting questions and I would like to get the answers as well.

You talk about the genome being the highest level of organization of genetic information. How important (relatively speaking) are the levels above genome in cancer evolution? For instance, cell metabolism, cellular matrix and microenvironment, immune system, etc.?

Cell metabolism clearly is determined by the genome. Cell interaction and cellular response to micro-environments is also determined by the genome. Examples can be illustrated by cancer genomes. The other levels of evolutionary selection are achieved through the genetic system. In addition, the degree of response is also defined by the genome system.

Regarding system dynamics you say "Such dynamics are necessary for a system to function by providing adaptability but also could cause damage to the system itself." This relates directly to Burton Voorhees' notion of virtual stability. Are you familiar with his work?

I have not read about virtual stability until now and I am still thinking about it.

You mention a feedback loop and resultant non-linearity that can occur in the damaged repair mechanisms. In general I find that scientists systematically ignore the potential for non-linearities. I think is a very basic problem in at least Western thought, and maybe it's a basic cognitive limitation. Much enlightenment can be gained by assuming non-linearity everywhere and giving up the notion of single cause explanations. I've been meaning to ask you whether you think your native language (is it Mandarin?) and growing up with non-Western thought systems has had a big impact on your ability to see these things more clearly than others?

My native language is Mandarin. Growing up within a non-Western thought system sometimes helps. I try to use my imagination when considering these ideas and I tend to read slower and my writing style may give me some advantage to digest some of these ideas more thoroughly. I try not to allow the dominant ideas to overly influence my thinking.

Events

Rafe.Furst — Wed, 14 Nov 2007 15:16:45 CST

If you are hosting, or know of any events related to cancer complexity, please update this page.

May 18 to May 23, 2008 • Working Group—"Integrating Evolutionary Theory into Cancer Biology," John Pepper (University of Arizona & SFI), Santa Fe Institute.