Cancer: Selected Somatic Mutant Clones? Warped Epigenetic Landscape? Both?

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The Epigenetic landscape model compares cells to marbles rolling down rivulets of a valley. Jesse Dill/via Flickr hide caption

itoggle caption Jesse Dill/via Flickr

There is an overwhelmingly prevailing view of cancer: some cells of your body, somatic cells, accumulate mutations, called "somatic mutations." Those that grow uncontrollably as single cells or by forming a cancer tissue, are selected by natural selection in your body and yield cancer, eventually metastasis, and are now treated with chemotherapy, radiation, surgery, and increasingly, monoclonal antibodies — single types of antibodies directed at the cancer cells specifically and killing them.

In the wings there is an emerging alternative view: Your body developed from the single fertilized egg, which grew and divided some 15 times to create different sorts of normal cells, liver, kidney tubule, nerve, skin, teeth, in a miracle of "ontogeny". An early image of this is that of famous evolutionary biologist, C. H. Waddington, "The Epigenetic Landscape." Here one pictures a gentle landscape of hillsides and valleys which funnel downhill and divide into subvalleys, which subdivide further. The fertilized egg, the zygote, sits at the top of the hill and its progeny cells roll down this landscape, dividing into branching pathways to yield the cell types of the normal adult organism.

Both views of cancer may well be correct. But only the former commands the attention of doctors and biologists. It is time to bring the two views together.

Happily that time is arriving.

Happily, my colleague, Dr. Sui Huang at the University of Calgary, and I, are trying to play the role of marrying the two views. I have left the University of Calgary, done with my role as Director of its Institute for Biocomplexity and Informatics, and am now part-time at the University of Vermont, where I write this blog on our third day in beautiful Burlington, a short walk from lovely Church street, no cars, abundant restaurants and the charm of just arrived undergraduates bubbling.

Less happily, I have in the past three weeks, been diagnosed with chronic lymphocytic leukemia, CLL, often an indolent mild leukemia with a long, slow progressive course. My own case may as well serve as a fulcrum around which to construct this blog.

First note: Ursula has written wisely that she finds solace in the fact that all sexual multicelled organisms die. So do we and it would be stupid for me not to make the most of the, hopefully, many years of good health I have left.

Second note: This is my own field of research for more than 40 years and it would be stupid of me not to bring to bear what Sui and I and friends have learned in support of Waddington's epigenetic landscape view of normal development, known developmental genetics and our own research on inducing cancer cells to differentiate, or change cell types, to become non-proliferating adult terminal cells. Sui and I have early positive results with a long way to go scientifically and clinically.

Here is a brief summary of my case: My and your blood cells derive from adult hematopoetic STEM cells. These cells make a series of binary decisions: 1) between forming red blood cells and related cells versus white blood cells. This decision is underlain by two genes, we think, PU1 and GATA1, each of which inhibits the other, so it is a bistable circuit: PU1 "on", GATA1 "off" is one branch of this lineage choice. PU1 "off', GATA 1 "on" is the other branch of this lineage choice. Red cell versus white cell.

Sui has used the added data showing that GATA1 activated itself, and PU1 activates itself, to show that this little hematopoetic stem cell is actually tristable, with the chosen steady state red cell vs white cell choices made, and a "metastable state" with GATA1 and PU1 both partially active: We think this metastable state is the stem cell states.

One step down further in the white cell lineage is another unknown circuit that makes the decision between lymphocytes and granulocytes, the two major branches of the white cell lineage in your and my blood formed in the marrow. Unfortunately that circuit is as yet unknown.

The above little GATA1 PU1 tristable circuit is an introduction to a broader view supporting Waddington's epigenetic landscape view put forth about 55 years ago and ignored in the rush of molecular biology for all this time.

Your genome has about 23,000 genes that encode proteins. Of these about 2,000 genes encode "transcription factor" genes whose proteins bind to "cis" sites, controlling DNA sequences near your 23,000 genes, tending to turn those genes ON or OFF, often in combinatorial logic with two or more transcription factors regulating any one gene. Thus a given gene might be activated to make its messenger RNA and hence protein, if both its two transcription factors are simultaneously present, the logical AND function, or if either one, the other, or both were present, the logical OR function.

So your genetic regulatory network really is a vast nonlinear control network.

It is this network that is the fleshing out of Waddington's intuitive insight.

Why?

Well, the whole network tends to have Waddington's epigenetic landscape, with hills and valleys. The bottom of the valleys are called, mathematically, "attractors," because they "attract" the coordinated activities of the genes to flow to distinct patterns of gene activities, which we think are the distinct cell types of your body. The valleys represent distinct cell types of your body, each with a different pattern of activities among the 23,000 genes.

This mathematics, now called Systems Biology, an emerging field, is the first major step forward since Waddington's image, toward understanding the integrated behavior of your genetic regulatory system.

What do mutants do? Well, most of the 23,000 genes do not regulate on another's activities. Hemoglobin is an example, it absorbs oxygen for transport in your lungs for delivery to your cells. Mutants of such genes alter different molecular functions in the body. But mutants in transcription factor genes warp the epigenetic landcape, typically, in mathematical models of the still unkown genetic network, creating a few new valley cell types, perhaps all my CLL cell type, and making a few old valleys become hill tops, so those valley cell types disappear.

In addition, chemical conditions and physical conditions, perhaps the concentration of protons per cell, your pH, normally at 7.35 in most cells of your body, are "bifurcation parameters. Changing parameter values can warp the landscape, like mutations, making new valleys, perhaps my CLL valley, and making hill tops out of old valleys, eliminating those cell type valleys.

Almost certainly Waddington's epigenetic landscape view is the integrated, holistic view of the behavior of the genetic regulatory system, and the framework into which to put the effect of somatic mutations on cells and the tissues they create.

In short, Waddington's intuited epigenetic landscape is almost certainly the right way to think about, research, and fund, much of cancer research.

Then the mutant clonal selection view of cancer can be placed in a broader context. If and when cancer is due to a somatic mutation, it is still a "cell type,"and a hoard of normal cell types still abound.

Based on this Sui Huang and I are trying to induce a mild breast cancer cell type to differentiate into normal adult breast cell types. We have screened 1,500 FDA approved drugs and found 16 that cause the cancer cells to differentiate into normal adult breast cells. That is the happy news. However, only 80 percent of the cells differentiate. We have to trick the remaining 20 percent to differentiate.

What does chemotherapy do? It kills rapidly dividing cells. But Sui and his post doc, Amy Brock, have just shown that treating a mild cancer cell with a chemotherapeutic agent also causes that cell to jump to to another valley cell type attractor, they think. So chemotherapy kills cells, but also scatters them in still unknown ways across the epigenetic landscape, perhaps creating NON mutant abnormal cell type valleys that may outcompete normal cells.

We just don't know, and in general, there is the standard view that chemotherapy is selecting out further somatic mutations that afford the further mutated cell further selected advantages, hence resistance to a succession of chemotherapeutic agents.

Sui and I now offer an alternative and complementary view: even without any or the same somatic mutations, cancer may often be a disease of differentiation, with cells hopping across the epigenetic landscape to new, unused, cell type valleys that have selective advantages in your body, so the cancer cells "win." Hence our hope for "differentiation therapy".

But differentiation therapy lives in the broader context of Waddington's Epigenetic Landscape view. Here paramter changes may warp the landscape and make new valleys or cells in old valleys may be bumped into new valleys.

Evidence: A third instar fruit fly, Drosophila larvae, exposed to borate saltsconverts its antenna to a leg, mimicking a mutation called Nasobemia, although the fly is genetically normal. Many such examples exist. Ether in the earliest stages of development cause the fruit fly to develop a second pair of wings, mimicking the bithorax mutant.

Now to my case as a specific example, I am fine, but 31 percent of my lyphocytes share the same cell surface proteins. This is taken by oncologists as the mutant clone that switched on these four surface antigens via the genetic network as the downstream controlled genes of the unknown hypothesized upstream mutant gene.

Alternatively, we do not use all the cell type valleys of our epigenetic landscape in our normal development, and some bumped some of my cells into this CLL attractor valley.

And again alternatively, I may be a bit on the acid side of pH 7.35, with too many protons running around in my cells, bifurcating a new CLL valley cell type.

No one, I emphasize, no one, knows.

So I have a harmless and maybe helpful course of action: trying to assure my cells are at pH 7.25, normal, by drinking vegetable juices, pH 9.4 water and avoiding acidotic foods.

Do I know this will help?

No, but there is no harm in trying.

If Waddington's view is right, I just might reduce the 31 percent "clone" to a lesser fraction of my lymphocytes over a year or so, rather than seeing the fraction double in about 2.5 years.

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