Mendelian Inheritance: Basic Genetics or Basic Mistake? Part IV

So, if we are right that 'Mendelian' inheritance is fundamentally mistaken--or, at best, generally inaccurate and misleading--then what kinds of conclusions can we draw and how can some of the basic attributes of life be accounted for?  We have to assume that life evolved and that to a great extent means genes, broadly defined.  Indeed, we may be worse off than we think if, as we tried to show in an earlier post, even what a gene is, is elusive with current knowledge.

Waterhouse, A Mermaid

In our book after which this blog is eponymously named, we argued that there has been too much attention placed on evolution (and a competition-centered view of life at that), relative to the more ubiquitous properties found at life's other time scales--of development and maintenance of an organism, and of the interaction of factors on the ecological scale.

The idea of Mendelian inheritance, which is widely extended to the vast majority of gene-trait relationships that clearly are not following the monk's principles, is of discrete states one of which dominates in their various combinations.  This was (and is) extended to evolution, with our grossly inadequate 'winner take all', 'survival of the fittest' notion of one best -- fitness-wise dominant -- variant that natural selection favored into success just as surely as a dominant allele was favored ineluctably into manifestation in the organism.

But if you think of the other properties of life, which we center our book around and will briefly name here, you might ask how Mendelian thinking, which only by deep contortions can be related to those principles, could ever have taken hold, unless it's by what amounts to an ideology, a takeover of a certain highly deterministic, simplistic view of the living world--a view that simply, for decades, wrote off into alleged irrelevance the actual way in which organisms work.

Sequestration and modularity
From DNA on up, life is organized as hierarchically nested partially sequestered units.  DNA has functional sequence elements arranged  together along chromosomes, but partially isolated in that they can serve their individual functions.  The units (such as amino acid codons) are repeated many times.  Proteins have partly separated functional units, too.  Cells are packaged units that have many different partially isolated subunits within them, such as organelles like mitochodria, isolated areas like the nucleus, and local differences in what is present in the cell membrane (e.g., a cell may have a front and back end, so to speak).

An organism (or even collections of organisms as in bacterial biofilms) is made of large numbers of cells.  These are repeated units that communicate with each other via combinations of signaling and other molecules, and this is what leads them to express particular, context-dependent sets of genes.  So that they are repeated, but different.  This process occurs hierarchically during development, and in response to environmental changes during life.  An organism is divided into organs and organ systems, like brain, heart and vessels, digestive organs, and so on.

Organs are made of nested, repeated units.  Intestines are segmented along their length, and their surface is littered with repeated structures called 'villi'.  Skeletons are made of repeated, partially different but interaction bones.  Trees are made of leaves and so on.  Plants and animals alike are constructed by repetition and branching.

Yet, importantly, each organism has only the one genome that it inherited from its parents!  So the same genome makes brains and braincases, that are as different from each other as any two things in all of life.

These processes are both qualitative: each leaf or bone is a separate structure; and quantitative: each such structure is somewhat different.  This is the natural variation that is the material on which evolution can work.

If you just think about this, you would have to wonder how it could be brought about by Mendelian inheritance.  How could just two states at a single gene be responsible for such complexity and quantitative internal organization?

It is perhaps easier to see how breaking a gene could cause a major state change, and thus a normal and dead alternative at a gene could be manifest in Mendelian inheritance terms.  Or if the trait is very close to a protein coded by a single gene, two major alleles (variants) at that gene could have big differences (yellow vs green peas, for example).  But as a rule, Mendelian inheritance makes little sense.  Partly that's because, as mentioned in earlier parts of this series, we confuse inheritance of traits with inheritance of genes.  Genes--specific stretches of DNA--are clearly inherited in a Mendelian way (with some exceptions that don't matter in this context here).  But traits generally are not.

The reason for all of this is that the basic principles of life, that include the above descriptions (see our book for detailed discussion in this context), involve cooperation--that is, co-operation or contemporary interaction--among many different elements, each of them variable in a population.  What an individual inherits are sets of genomic variants from its parents.  The traits an individual manifests are the net results of these variants acting in the particular environments in which they find themselves.

Every organism is unique, but we all become unique in the same way

We've just run across a 2004 Nature paper by André Pires-daSilva and Ralf Sommer about the evolution of signaling in animal development. This paper, of which we were not aware but should have been, is highly related to some main themes of our book The Mermaid's Tale, which deals with fundamental aspects of how life works including, but not focused on, how it evolved.

The authors write that only seven signaling pathways are responsible for most of the cell-cell interactions that control the development of a single cell into the organism it becomes. They are used repeatedly at every stage of development, and have been co-opted through evolutionary time in the development of new morphological traits and systems.

After millions of years of evolution, signalling pathways have evolved into complex networks of interactions. Surprisingly, genetic and biochemical studies revealed that only a few classes of signalling pathways are sufficient to pattern a wide variety of cells, tissues and morphologies. The specificity of these pathways is based on the history of the cell (referred to as the 'cell's competence'), the intensity of the signal and the cross-regulatory interactions with other signalling cascades.

These ubiquitous pathways are the Hedgehog, Wnt, transforming growth factor-, receptor tyrosine kinase, Notch, JAK/STAT and nuclear hormone pathways. How can the wide diversity of life around us be produced by so few ways for cells to communicate with each other?

Given the flexibility of signalling pathways, research in the past decade has concentrated on the question of how specificity is achieved in any signalling response. There is now clear evidence that the specificity of cellular responses can be achieved by at least five mechanisms, which in some cases act in combination, highlighting the network properties of signalling pathways in living cells.

First, the same receptor can activate different intracellular transducers in different tissues.

Second, differences in the kinetics of the ligand or receptor might generate distinct cellular outcomes.

Third, combinatorial activation by signalling pathways might result in the regulation of specific genes. Several signalling pathways can be integrated either at signalling proteins or at enhancers of target genes.

Fourth, cells that express distinct transcription factors might respond differently when exposed to the same signals.

Fifth, compartmentalization of the signal in the cell can contribute to specificity. The recruitment of components into protein complexes prevents cross signalling between unrelated signalling molecules or targets multifunctional molecules to specific functions.

The idea that a handful of networks can be responsible for most of the cellular 'decision-making' that is development is a beautiful example of core principles of life that we write about. The different ways that cells respond, the different developmental cascades that can be triggered by the same signaling networks, the interaction of different signaling pathways to trigger specific responses, and so forth all demonstrate the importance of modularity, signaling, contingency, sequestration and chance over and over again. How the components of these signaling pathways have evolved -- co-evolved -- is not yet well-understood, but it has to be that the interactions are tolerant of imprecision, and indeed, that tolerance (variation in the affinity of receptor/ligand binding) has been built into the system and leads to the evolutionary novelty.

The keys to this are partial sequestration of components of an organism so that local cells in different parts of the plant or animal can behave in different ways, so they can sense and respond to their environment (by signalling), and the arbitrary combinatorial codes by which signalling systems -- like the ones discussed in the 2004 paper -- work. That the same systems can produce diverse organisms reflects the logic of development, that is, the relational principles by which life is organized. Notch signaling is about the code specified by Notch, its receptor and related proteins, in combination with other such systems--and not by any particular property of the Notch proteins per se.

Every organism is unique, but we all become unique in the same way. It is basically the open-ended use of these very simple processes involving a limited number of components that enables this essentially unlimited diversity of living Nature.

Scat CAT! Get the picture?

A story on the Dec 15th NPR site (Radiation From CT Scans May Raise Cancer Risk) provides a discussion of the risks of cancer induced by the proliferating use of CT scans in medicine. The estimate is that as many as 29,000 future cancers may be caused by the 72 million CT scans done in 2007 alone, and as many new cases induced each coming year if practices don't change. The story also presents a graph of these possible cases (and about 15,000 of them estimated to be fatal).

It's sometimes said, reassuringly, that the amount of radiation a patient receives from one chest scan is equivalent to the natural radiation exposure from one transcontinental flight, but the amount of radiation can vary so much per scan that some are equivalent to 500 transcontinental flights. Or even the dose received by survivors of the atomic bombs dropped on Hiroshima or Nagasaki. And those caused, and are still causing, increases in cancer rates in those survivors (more or less so, depending on distance from the epicenter). This is no joke, if you get the picture.

We've said many things before about competing risks, and this is an excellent example. It is directly comparable to the recent controversies about mammography, though (as we've discussed in previous posts) the recent controversy has been about over-detection of tumors that would regress on their own, rather than about the risk of x-ray induced cancer, but that was a major reason why the recommendation has been not to start until menopausal or post-menopausal years.

A major part of our book is devoted to describing how life is characterized by partially sequestered environments -- in this case, cells -- that respond to each other and behave as a result of signaling and related processes. Radiation damages DNA and can cause a gene to be mutated and or misexpressed, altering the cell's function. Our cells have DNA-repair mechanisms that can detect changes under some conditions (e.g., when the two strands no longer match and fit closely together because one of the corresponding nucleotides has been altered).

But if the cell doesn't detect and repair the change, the cell permanently is on a misbehavior track. This can be especially dangerous when the mutation is in the genes responsible for DNA repair itself.

Since a tumor cell, unlike a bacterial cell, is part of you, your immune system may not be able to tell that it's not doing its proper job. It or other tissue-order-retaining mechanisms may thus fail to maintain the proper order. The tumor cell divides, and divides, and divides: it is an internal engine of life that is no longer receptive to external signals, and the external police can't detect it.

But the whole picture is more than a CT inset. If CT is useful, it's presumably because it detects serious disorders. We know now that a fraction of those would not actually need to be treated, as in the case of mammography and other diagnostic tests. That means needless cost and morbidity. On the other hand, if the CT scans do lead to effective treatment of serious disease, then people will live longer. This means that some of them will get cancer (unrelated to the CT radiation exposure) or other diseases of aging, as well as the iatrogenic (doctor-induced) cancers. So there's no simple winning or losing here.