By Vince Giuliano with major contributions from Jim Watson
This blog entry argues that the time has come to create a Grand Unified Theory of Aging. Such a theory will necessarily be a major part of a Grand Unfied Theory for Health and a GUT for Biology itself. Jim and I are not yet quite ready to lay out a complete GUT theory, However, we wish to telegraph that we are working on one and herein identify what we believe will be some of its central tenants. Here, I examine certain similarities and differences between physics and biology, physics being the area of science where GUTs have long existed. The entry looks at the question of “What is a theory, anyway?” I characterize some of the benefits a GUT for biology (GUTb) could provide. And, I convey some of my and Jim’s thoughts about properties and elements likely to be important in a GUTb.
The concept of a GUTb was introduced in my PowerPoint presentation Multifactorial Hormesis which examines the roles of stresses and stress responses in biology. This blog entry looks deeper at the issues concerned.
Here is the outline of thoughts that is pursued here:
- Theories of aging and biology
- What is a theory, anyway?
- What is a GUT?
- Similarities and differences between physics and biology
- Depth vs. Complexity
- Description vs theoretical framework
i. Physics in 1890 and biology today
ii. Benefits of unified theories in physics
- Neither the universe nor biology nor aging have a center
- Existence of fundamental entities – forces - relationships
- General properties that a GUT for biology must satisfy
- GUTb should offer the advantages of a GUT
- GUTb and evolution
- GUTb and information
- GUTb and emergening phenomena
- The four reversible modifications of proteins in GUTb
- Role of the Great God Gasses in GUTb
- A GUTb is unlikely to remain stable as science advances
1. THEORIES OF AGING AND BIOLOGY
There are no true GUTs in biology and the same is true for aging. There are, however, a large number of theories relating to aging. I laid out what I then viewed to be14 main ones and six auxiliary ones in my treatise over five years ago. They are:
- Oxidative Damage
- Cell DNA Damage
- Mitochondrial Damage
- Tissue Glycation
- Lipofuscin Accumulation
- Chronic Inflammation
- Immune System Compromise
- Neurological Degeneration
- Declines in Hormone Levels
- Susceptibility to Cancers
- Susceptibility to Cardiovascular Disease
- Telomere Shortening and Damage
- Programmed Epigenomic Changes
- Stem Cell Supply Chain Breakdown
- Incorrect protein folding
- Accumulation of Progerin
- Gene mutations leading to hellicase abnormalities
- Increasing mTOR signaling
- Declining hypoxic response
- Micronutrient triage with aging
Since drafting the treatise, I have come across at least another dozen such theories. I stopped trying to keep track of them. These theories are, in fact, still valid in that each explains and accounts for some phenomena of aging. They relate to different levels of biology or cross different levels. Many cross over from the whole-body level to the cell level and also have sub-cellular explanations – like items 1, 4, 5, 6,10,15 and 20. Some refer to particular organs or subsystems and also have cell-level and sub-cellular explanations like items 7, 8, and 11 . Some appear to go on in specific cell compartments such as the nucleus or mitochondria or endoplasmic reticulum – like items 2, 3, 12 and 13. . But on closer look, these theories discuss dynamics affected also by what goes on in other parts of the cell – and actually are affected by and affect whole organs and major body systems,
As to shift over time of my overall perspective, a central observation is that I no longer view the theories of aging described here as independent or even necessarily fundamental. They are all parts of an emerging new grand unified theory (GUT) of biology. For example, REDOX processes, central to the first theory of aging, actually play significant roles in each of the other theories(ref). Some of the theories are more basic and “upstream” of the others. Some like lipofuscin accumulation, telomere shortening and tissue glycation, and even cancers and heart diseases are definitely downstream in the causal chain.
Based on materials covered in past entries in this blog, it is possible to add a number of additional more-sophisticated theories of what-causes aging including aneuploidy, age-related DNA methylation of DNA promoter regions, global DNA demethylation, proliferation of DNA repeats and insertions, centriole pathologies, chromosomal translocations, global diminishing of REDOX potential, stem cell senescence, proliferation of circular RNAs, loss of autophagy, loss of mitophagy, decline of sirtuin expression, leakage of mitochondrial ROS, problems in the endosomal compartment, super-hormetic stresses of multiple kinds, communications with certain microbial species, dysregulation of important physiological coordinating centers such as the super charismatic nucleus, decline in production and communication of key signaling gasses including HO, H2S and NO2, loss of coordination between neurons and microglia, presence of a number of unwanted proteins and/or absence of certain wanted proteins. The list goes on and on. These topics have been discussed in multiple blog entries and hundreds of thousands of publications, but none set forth a final word. Again, roles and relationships among all these must be comprised in any comprehensive GUTb.
These theories and those in first list are of course not independent. Each offers only a partial perspective on aging and health. Some are subsumed in others, and they all seem to be tightly woven together. There are hundreds or thousands of complex published molecular diagrams showing how pathways crisscross. Everything important seems to be both upstream and downstream of nearly everything else that is important.,
While I appear to be focusing on human aging here, it is important to mention that every area of human biology is ultimately involved in aging – as well as many areas of bacterial and plant biology. Aging is intrinsically tied up with issues of health. The multiplicity of theories for aging simply mirrors the multiplicity of theories existing for biology itself. Everything seems to be connected to everything else in some kind of overall systems context. It will be impossible to create a GUT for aging without creating essential parts of a GUT for biology itself.
2. WHAT IS A THEORY, ANYWAY?
All scientific theories, regardless of area of science involved, are partial models of an underlying territory which may harbor additional unknown complexity. The central measure of a theory is how useful it is in describing phenomena and making predictions. In physics as well as in biology there may be no ultimate truths or final theories. All we have is partial models of what is going on related to an underlying reality that may or may not be completely knowable. Throughout history and probably going back early into our prehistory, we have created models to explain things. Such models have included ones like: “The earthquake occurred because the Gods were angry,” “Matter consists of tiny particles with little hooks that hold them together,“ “The plague happened because of the prevalence of sin,” “Aging is primarily a result of progressive telomere shortening associated with cell division,“ and “Aging is primarily attributable to loss of global REDOX potential in cells.” Some models explain things well, and some are poor at doing this. Some models address only special aspects of an underlying reality and predict certain things, and other models address other aspects of the same fundamental reality and explain and predict other things. These models are intellectual structures put together mainly using natural language and the language of mathematics. There is also ample use of specialized languages like Feynman Diagrams in physics. In biology, our models may depend heavily on the use of natural language and the language of chemistry. There are countless pathway diagrams encountered in biology research publications, likd this one for HCV-infected liver tissue. In general, biological organisms comprise vast networks of interacting loops (pathways) with positive and negative feedback characteristics. Important process loops are highly interconnected.
Thousands of such diagrams have been published. Following is another randomly-selected example, in this case illustrating metabolic pathways. These diagrams do start to illustrate the point that everything is related to everything else on biology and affects it indirectly. The diagrams are fairly useless for predicting impacts of one thing on another, however, because the strengths of the links are not quantified and directionality of a link is not always clear. Diagrams like this one are so complicated that it takes a lot of focus even to start to comprehend the implied systems behavior. A lot of credit goes to the scientists who create them. However, a vast amount of relevant detail is necessarily left out of any of them.
It is important not to sweep away all old models because newer more-sophisticated models show they are wrong. In both physics and biology, for any phenomena there are multiple levels of explanation which can all be valid and useful on their own terms. Some very simple explanation can be very useful despite the fact that from a more sophisticated viewpoint an explanation is crude or incorrect. Newtonian physics is all you need to design the mechanical components of a well functioning BMW. Eating a lot of fresh fruits and vegetables and getting plenty of exercise is still excellent general health advice. Eleven-dimensional String Theory may bring the two GUTs of Particle Physics and Relativity closer together but is quite useless for a pool or tennis player. A detailed treatise on making and breaking disulfide bonds in cysteine thiols may help us understand REDOX states, but most people just want to know what to eat and what to do to stay healthy. Diagrams such as the one just illustrated may be interesting to researchers, but can’t be understood by most old people with advancing diabetes, or even understood by the doctor who treats him.
Systems biology offers an approach to dealing with the complexity, but is not likely to get far until we discover ways of quantifying inter and intra-cellular signal strengths and creating equations that reflect how signaling works in real organisms.
In any event, to quote a wise old statement it is important not to confuse the map with the actual territory. No how effective we become in creating a sophisticated map, the result will still be only a map and will miss some of the features of the real territory. We are descendents of beasts that grunted and howled and waved our arms to signal to each other. This gave us an important evolutionary advantage. We eventually learned how to communicate some of the essential features of our territory to other beasts in our species. This was also advantageous to our mutual survival. That is still the situation and is what we are trying to do here. Our cherished theories are sophisticated descendents of our grunts and howls. Even our GUTs are no more than that. Let’s not get so far carried away by our complicated ideas that we forget that.
3. WHAT IS A GUT?
|A Grand Unified Theory is a meta-theory that lends sense, organization, structure and unity to a number of specialized theories that purportedly relate to the same underlying reality. A GUT explains a large variety of observable phenomena in terms of a simple universal set of entities, forces and principles, (My definition).So far, we have GUTs only in the domain of physics. Definitions of GUTs in physics include “A theory of elementary forces that unites the weak, strong, electromagnetic, and gravitational interactions into one field theory and views the known interactions as low-energy manifestations of a single unified interaction(ref),” and “Any of a number of theories of elementary particles and fundamental interactions designed to explain the gravitational, electromagnetic, strong, and weak interactions in terms of a single mathematical formalism.” See Grand Unified Theory.GUTs in physics embrace and subsume the so-called Standard Model of particle physics, a model that has been around for over 40 years now. Because of important similarities between physics and biology, I digress a bit to examine this Standard Model. From a CERN document The Standard Medel: “The theories and discoveries of thousands of physicists since the 1930s have resulted in a remarkable insight into the fundamental structure of matter: everything in the universe is found to be made from a few basic building blocks called fundamental particles, governed by four fundamental forces. Our best understanding of how these particles and three of the forces are related to each other is encapsulated in the Standard Model of particle physics. Developed in the early 1970s, it has successfully explained almost all experimental results and precisely predicted a wide variety of phenomena. Over time and through many experiments, the Standard Model has become established as a well-tested physics theory. — Matter particles All matter around us is made of elementary particles, the building blocks of matter. These particles occur in two basic types called quarks and leptons. Each group consists of six particles, which are related in pairs, or “generations”. The lightest and most stable particles make up the first generation, whereas the heavier and less stable particles belong to the second and third generations. All stable matter in the universe is made from particles that belong to the first generation; any heavier particles quickly decay to the next most stable level. The six quarks are paired in the three generations – the “up quark” and the “down quark” form the first generation, followed by the “charm quark” and “strange quark”, then the “top quark” and “bottom (or beauty) quark”. Quarks also come in three different “colours” and only mix in such ways as to form colourless objects. The six leptons are similarly arranged in three generations – the “electron” and the “electron neutrino”, the “muon” and the “muon neutrino”, and the “tau” and the “tau neutrino”. The electron, the muon and the tau all have an electric charge and a sizeable mass, whereas the neutrinos are electrically neutral and have very little mass. — Forces and carrier particles There are four fundamental forces at work in the universe: the strong force, the weak force, the electromagnetic force, and the gravitational force. They work over different ranges and have different strengths. Gravity is the weakest but it has an infinite range. The electromagnetic force also has infinite range but it is many times stronger than gravity. The weak and strong forces are effective only over a very short range and dominate only at the level of subatomic particles. Despite its name, the weak force is much stronger than gravity but it is indeed the weakest of the other three. The strong force, as the name suggests, is the strongest of all four fundamental interactions. — Three of the fundamental forces result from the exchange of force-carrier particles, which belong to a broader group called “bosons”. Particles of matter transfer discrete amounts of energy by exchanging bosons with each other. Each fundamental force has its own corresponding boson – the strong force is carried by the “gluon”, the electromagnetic force is carried by the “photon”, and the “W and Z bosons” are responsible for the weak force. Although not yet found, the “graviton” should be the corresponding force-carrying particle of gravity. The Standard Model includes the electromagnetic, strong and weak forces and all their carrier particles, and explains well how these forces act on all of the matter particles. However, the most familiar force in our everyday lives, gravity, is not part of the Standard Model, as fitting gravity comfortably into this framework has proved to be a difficult challenge. The quantum theory used to describe the micro world, and the general theory of relativity used to describe the macro world, are difficult to fit into a single framework. No one has managed to make the two mathematically compatible in the context of the Standard Model. But luckily for particle physics, when it comes to the minuscule scale of particles, the effect of gravity is so weak as to be negligible. Only when matter is in bulk, at the scale of the human body or of the planets for example, does the effect of gravity dominate. So the Standard Model still works well despite its reluctant exclusion of one of the fundamental forces.”I will return below to how the “fudge factors” of dark matter and dark energy had to be adopted to keep the Standard Model and Relativity Theory workable in the presence of unexpected but definitive astronomical observations.
4. SIMILARITIES AND DIFFERENCES BETWEEN PHYSICS AND BIOLOGYA.
DEPTH VS. COMPLEXITY
Along with others I have observed that “While physics is infinitely deep, biology is infinitely complex(ref).”
A physics lecture
This distinction may, however, mainly reflect the fact that in physics we have GUTs and in biology we do not have any. As we move towards a GUT in biology, the field will become greatly deeper. At the same time, disturbing new observations in physics that require extensions of the Standard Model are making that field more complex.
B. DESCRIPTIVE CHARACTERIZATION VS THEORETICAL FRAMEWORK
As has been the case for almost all sciences, in the early stages the work of a science is almost all descriptive, involving characterizations and classifications of observations describing what seems to exist. In the later stages of development of a science, theoretical frameworks are created to bring together these descriptions. In physics, the theoretical work has already culminated in the creation of GUTs. Biology got off to a later start than physics as a science, and the sheer number and complexity of biological entities is staggering. The job of classification and description really did not get seriously underway until the seminal work of Charles Darwin. So it is not surprising that the development of theoretical frameworks in biology have come later than the development of such frameworks in physics. There are a great many such theoretical frameworks in areas such as genetics, proteomics, epigenetics, transcriptomics, post-translational protein modifications, cell senescence and other areas of molecular biology, But they have not yet been brought together in a GUT for biology. The state of theoretical integration in biology today is probably comparable to the state of theoretical integration in physics in 1895. Of course, the observed complexity in biology is vastly greater, so biologists are not to be blamed for this lag.
PHYSICS IN 1890 AND BIOLOGY TODAY
Back in the late 1800s and early 1900s, a number of new exciting discoveries over the previous century had thrown the field of physics into relative chaos: cathode rays, black body radiation, electricity and electromagnetic effects, geometrical optics, chemical discoveries like the periodic table, physics discoveries related to atoms and molecules, thermodynamics, behavior of gases, radioactivity, the photoelectric effect, new astral bodies and celestial phenomena beyond those previously known. The scene was characterized by many exciting developments, but nobody knew quite how all these phenomena fit together. Different people studied different segments of the puzzle often ignoring the works of others studying other segments. Specialized theories abounded. By the 1920s, two major Grand Unifying Theories of physics were emerging: Quantum Mechanics and Relativity. These theories were highly predictive as well as explanatory and formed the basis for modern electronics, atomic energy, lasers and masers and many other practical developments we take advantage of today. And, most remarkably, these theories have mostly survived test after test, and have been extended. Both stand fairly solid still today, a century later.
Biology today i a bit like physics was 120 years ago. It is extremely complex with tens of thousands of key genes, proteins and countless biological pathways interacting in complex ways. Pick any biological phenomenon, like microtubule networks or protein acetylation, and there is layer after layer after layer of increasingly complex phenomena underneath it or related to it. Researchers studying some biological systems know little of the work of other researchers studying other systems. And discoveries of drugs and disease treatments is mostly hit-or-miss, based on narrow slices of knowledge.
Consider what is said here about the state of physics over 100 years ago, before the development of quantum theory and the state of biology today. The Standard Model of course powerfully subsumes quantum theory as must any GUT for physics. From One hundred years of Quantum physics: “To understand the revolutionary impact of quantum physics one need only look at pre-quantum physics. From 1890 to 1900 physics journals were filled with papers on atomic spectra and essentially every other measurable property of matter, such as viscosity, elasticity, electrical and thermal conductivity, coefficients of expansion, indices of refraction, and thermo-elastic coefficients. Spurred by the energy of the Victorian work ethic and the development of ever more ingenious experimental methods, knowledge accumulated at a prodigious rate. — What is most striking to the contemporary eye, however, is that the compendious descriptions of the properties of matter were essentially empirical. Thousands of pages of spectral data listed precise values for the wavelengths of the elements, but nobody knew why spectral lines occurred, much less what information they conveyed. Thermal and electrical conductivities were interpreted by suggestive models that fitted roughly half the facts. There were numerous empirical laws but they were not satisfying. For instance, the Dulong-Petit law established a simple relation between specific heat and the atomic weight of a material. Much of the time it worked; sometimes it didn’t. The masses of equal volumes of gas were, for the most part, in the ratios of integers. The Periodic Table, which provided a key organizing principle for the flourishing science of chemistry, had absolutely no theoretical basis.” You may notice the resemblance to the state of biology today.
Development of the essentials of quantum particle theory took only three years, once a critical tipping point in physics research was reached. And that was long before the telephone, airplanes, Internet, e-mail, PubMed, bio databases, sequencing and blogs. So today, three years is a very long time for things in science to happen. I think we have reached the tipping point in biology.
C. BENEFITS OF UNIFIED THEORIES IN PHYSICS
Now, what were the benefits of quantum theory? Going on(ref): “Among the greatest achievements of the revolution is this: Quantum mechanics has provided a quantitative theory of matter. We now understand essentially every detail of atomic structure—the Periodic Table has a simple and natural explanation, and the vast arrays of spectral data fit into an elegant theoretical framework. Quantum theory permits the quantitative understanding of molecules, of solids and liquids, and of conductors and semiconductors. It explains bizarre phenomena such as superconductivity and superfluidity, and exotic forms of matter such as the stuff of neutron stars and Bose-Einstein condensates, in which all the atoms in a gas behave like a single superatom. Quantum mechanics provides essential tools for all the sciences and for every advanced technology.”
It took a radical steps over 100 years ago to start down the road to a GUT for physics by creating quantum physics. Some first-rate physicists like Albert Einstein died never fully accepting it. And it contradicts our experience and knowledge about how normal reality works. However, quantum physics turns out to be “the most precisely tested and most successful theory in the history of science(ref).” After more than 100 years, quantum physics still stands tall and valid, and quantum phenomena underlies modern electronics and communications and many other aspects of current science and engineering. And more-recently, it is being increasingly recognized that quantum effects play important roles in biology. See the blog entry Quantum Biology.
D. IN OUR MODELS, NEITHER PHYSICS NOR BIOLOGY OR AGING HAVE A CENTER
Consider the following dialog from a recent e-mail exchange, starting with a question from out in the audience: “So, Dr. Giuliano, where exactly do you stand on aging?”
My reply was: “First of all I am not standing. I could hardly afford to do that. I appear to be running, attempting to pace myself to keep my breath going regularly. Second, I seem to be everywhere and nowhere, moving upwards and sideways in a directionless space of research, one everywhere spawning new dimensions. Perhaps it is an infinite-dimensional Hilbert Space. The good news is that I am slowly getting familiar with central parts of that space, criss-crossing them over and over, each time seeing old theories from a slightly different perspective. I like being there with my colleagues. It is all starting to make more and more sense.”
This was a subjective and metaphorical response, but is one that curiously makes sense. Jim Watson posed the question “Where are the central drivers of aging?” And his answer was “In the same place where the center of the universe is. Everywhere; there is no center.” Biological research offers a vast network of theories of aging, and this network has no center.
Here is what Jim has had to say about this issue of centrality:
“Why there is no Center to the Universe — Ancient astrologers claimed that the sun, planets, and stars revolved around the earth (Ptolemey). Mathematicians tried to explain the periodic, retrograde motion of planets as they passed through the twelve Zodiac constellations by constructing complex “circles within circles”. Unfortunately, this “crazy math” did not fit the data. Copernicus, Galileo, and Kepler could explain things much better with their heliocentric view of the universe, Galileo’s challenge to orthodoxy brought on the wrath of the Catholic Church. To avoid Galileo’s fate, Kepler delayed publicizing his mathematical derivations of the laws of orbital motion, allowing their publication to only occur after he died. With time, however, the heliocentric theory became the “new orthodoxy”. The sun was at the center of the universe. Still, little was known about the universe beyond our galaxy until William Hubble identified Cepheid variables in the Andromeda “nebula”, allowing him to determine that this “nebula” was actually a galaxy that was at least 2 million light years away. This was an astonishing discovery. Hubble and Sharply then found hundreds of other galaxies and noted that the light was red shifted most of these galaxies. The led him to the concept of an expanding universe. Almost exactly 70 years later, two independent astronomy groups discovered that the universe is expanding faster and faster (i.e. accelerating expansion rate). In the modern view of the universe, THERE IS NO CENTER TO THE UNIVERSE! Even though the universe began with a very hot, bright event called the “Big Bang”, it is the “space of the universe” that is expanding, not the objects within the space. Much like a loaf of raisin bread that is rising in the bread pan, the loaf gets bigger but the raisins stay the same size. From any point inside the loaf of raisin bread, the raisins would appear to be receding from each other.”
Continuing, Jim points out: “Metaphorically speaking, Aging” may be analogous to the Universe – There is no center — The universe is a physical structure with visible objects inside the space, yet the space itself has no center. Using this analogy, aging is a physical structure made up of visible molecules that make up pathways, but the pathways of aging may have no center, much like the space of the universe. Such a metaphor for aging allows all current aging theories to explain part of the phenomena, but none of these theories may occupy a central point in a Grand Unified Theory (GUT) of aging. To properly explain this metaphor, I will below describe each of the major molecular pathways of aging much like the four forces of physics (weak force, strong force, electromagnetic force, and gravitational force). I will then propose that all of them are components of a GUT of aging, but that none of them alone are the “center of aging”. If this concept is hard to grasp, go back to astronomy textbooks and review the explanation of why the universe has no center. Then go back to physics textbooks and review the four forces of nature. As an analogy, I have described the four forces of aging through the molecular mechanisms of post translational modifications of proteins – ROS signaling, the redox status of the cell, the acetylome, and the The Four Forces of Aging – The Redox proteome, Acetylome, Phosphoproteome, and Methylome.” (More from Jim on these four forces below,)
E. EXISTENCE OF FUNDAMENTAL ENTITIES/FORCES/PROCESSES
As mentioned above, fundamental to the GUT of physics is the unification in one theory of four fundamental forces of nature that explain everything: Weak Force, Strong Force, Electromagnetic Force, and Gravitational Force.
Right after the Big Bang and at high enough temperature, these four forces are unified. Further, each exercises its influence via associated fundamental particles: gravitons for Gravity, W and Z bosons for the Weak Force, photons for the Electromagnetic Force, quarks, gluons and gauge bosons for the Strong Nuclear Force.
As Jim mentions above, there may be comparable universal entities that can explain multiple phenomena in biology and aging. In particular, he has suggested that there are four most-common reversible modifications of proteins that are involved with aging and longevity – 1. redox modifications of cysteine thiols, 2. acetylation of lysine, 3. phosphorylation of serine, threonine, and tyrosine, and 4. methylation of lysine and arginine. These processes are described further below. Each of these processes is associated with specific molecules. Further, early enough in the process of biological evolution, these reversible modifications did not exist.
Biology probably did not start with a Big Bang, but instead started with a number of Little Bangs, chemical reactions probably happening near geothermal vents deep in absolutely dark and largely oxygen-free primordial oceans. These reactions created the first living biological organisms. And the gasses and elements responsible for these first life-creations still play important biological signaling functions today. In fact, they are responsible for key aspects of our mammalian physiology and have a lot to do with how we feel, act and behave, and how healthy we are. But I am starting to get ahead of the basic story. I can only telegraph a small part of that GUTb story here.
Other–phenomena we see as extremely fundamental in biology and that must be included in GUTb, observable in virtually all biological entities, include, in a short starter list:
5. GENERAL PROPERTIES THAT A GUT FOR BIOLOGY MUST SATISFY
A. GUTb should offer the advantages of a GUT
Creating a GUTb sounds like a pretty tall order, and it probably is. On the other hand, personally I hold that if I am going to play a professional game in life, I would like it to be a big and important game like this one. As T.S. Eliot once pointed out “Only those who will risk going too far can possibly find out how far one can go.” Also, I will be satisfied if I am only a player in creating GUTb, even a minor one. Quantum theory was formulated through cooperative interaction and communications among a number of scientists. That is also likely to be the case for GUTb.
There are most-likely a number of other properties a GUTb must satisfy. I comment here only on properties related to evolution and information communication.
B. GUTb AND EVOLUTION
An effective GUTb must encompass a greatly expanded theory of evolution. That is, the GUTb must not only explain phenomena but also explain why and how evolution led to those phenomena – hopefully starting with properties of the physical universe manifest on earth prior to biological life. Some important expansions on conventional evolutionary theory include:
On the smallest level we have atoms and some molecular structures much affected by quantum effects. Next up we have molecules and molecular assemblages – entities of chemistry. Further up there are the cellular sub-structures and organelles, then cells themselves. Then there are cell complexes and organs, body systems, whole plants or animals, then the society the plants or animals live in, then their habitat. How evolution or biological processes happen is a result of interactions both within and across levels. An organ transplant can succeed or fail based on the presence or absence of a key protein. Epigenetic evolution in the muscles of an exotic snake in a rainforest can be cut short by predators eating the snakes or society deciding to cut down the rainforest. A newly-evolved virus can jump from animals to humans and create a major pestilence. Quantum resonance effects make certain molecular structures possible which may drive such phenomena as protein folding which in turn is vital for life as we know it.
Evolution of an organism is therefore inevitably multilayered. It can happen in a component in cells such as mitochondria in muscle cells, it can happen in cells themselves, it can happen in organs such as muscles, it can happen in organ systems and in whole organisms, whether they be fruit flies or humans.
Biological evolution can frequently happen as a result of evolution of social systems, whether this evolution is within a colony of bees or in a community of humans or crossing over different species. Global climate change today is largely a consequence of human evolution leading to massive consumption of carbon fossil fuels resulting in high levels of atmospheric CO2. Learning to power our societies with fossil fuels was a social evolutionary process. Countless other species are being affected by this climate change. Some species are dying out. Others are undergoing evolutionary change. Humans cut down rain forests, create genetically modified foods, change the nature of oceans - so the evolutionary consequences of human development are profound. This has been going on a long time. Between 1.5 and 2.5 million years ago, early humans learned cooperative hunting habits and drove many species of carnivores in Africa into extinction. Later here, I discuss how the social adoption of antibiotics has driven evolution of bacterial species. The idea of social evolution driving biological evolution is an important expansion of the traditional concept of evolution – the one I learned as a child that says evolution is about random variation and natural selection. And it is a vast expansion of the view that biological evolution mainly that takes place through random mutations in genes.
Evolution usually involves interactions with competing and mostly synergistic species. We humans got here via multi-species interactions, and such interactions keep going on. In the classical view of evolution, the role of collaboration among species has probably been greatly under-played. And the role of competition among species has probably been overplayed. Even “enemy” species sometimes collaborate with each other in surprising ways. They can make treaties and live in peace together. And sometimes, normally symbiotic commensal species can form alliances and go to war with each other. From the viewpoint of evolution, not all such wars are bad. Some can produce stresses resulting in evolutionary advances. We have about 23,000 human genes. But, if we take our gut and other bacterial biomes into account, there are perhaps 8 million genes out there affecting our health and wellbeing.
An important corollary is evolution is never in isolation. Co-evolution is the rule, not the exception. Bees and the plants they feed on co-evolve. So do mitochondria and all the key systems they relate to. Systems on every layer co-evolve to the extent that they are dependent on systems on other layers or other systems with which they interact.
It is not just through slow-moving gene mutations and a prolonged period of natural selection based on survival. Epigenetic changes account for much more rapid biological changes than mutational changes in the gene stock. Epigenetic changes can rapidly happen as a result of physical environmental changes or social environment shifts. A shift in diet or changing an important lifestyle pattern can trigger such epigenetic changes – and then some of those epigenetic changes can drive can be inherited. Epigenetics shifts can in turn drive mutations in DNA. And social evolution can drive epigenetic changes. Epigenetics shifts, such as might produce an increase propensity to obesity, can lead to social initiatives such as research on how to combat obesity. The multi channel nature of the feedback leading to evolution is ubiquitous. How else could Americans grow significantly taller and live much longer in the course of just three generations?
A few examples:
Consider that an animal species confronts a change in food supply due to a climate change, say a shift from more of a vegetarian diet to more a meat-based one.
The point is that these systems co-evolve, each one affecting the other to a greater or lesser effect.
All biological organisms on each level contain feedback systems that determine their responses to stresses. These feedback systems are designed to neutralize any negative effects of normally encountered stresses if the stresses are within ranges ordinarily consistent with the evolutionary history of that organism. Stresses encountered within a normal operating range of strength tend to strengthen and enhance the health of the organism. If a stress is too great or too sustained for the normal survival of an organism, mechanisms of increased evolutionary susceptibility kick in that lead to the evolution of that organism. That is, unless the stress is so overwhelming that it kills all the members of a species. See the PowerPoint presentation on Multifactorial Hormesis.
Bacterial resistance to antibiotics provides an additional example beyond those mentioned previously. As social scientific initiatives, humans adopted or developed antibiotics to combat infectious diseases. Many of these antibiotics, like penicillin, were molecules that play antibiotic roles in nature. As social initiatives, we begin to use these antibiotics widely to combat infectious diseases. Abuses developed as doctors started to give antibiotics to people with virus infections or just to make them happy, or to protect against lawsuits. And big livestock feedlots started including our favorite antibiotics on a massive scale in animal feeds. This served to improve the economics of meat production – in part because It became possible to crowd animals together under unsanitary conditions. Pathogenic bacteria in turn, facing antibiotics everywhere started to evolve to develop resistances. Increasingly we see strains of common bacteria that do not respond to any antibiotics at all, and they are increasingly killing people. There is concern that we will soon see the end of the era of antibiotics. This is an example of biological evolution. At the same time, big pharma companies prefer making and selling other medicines besides antibiotics for business reasons. (Antibiotics are not big money-makers because they are only used until the disease goes away, unlike the drugs for diabetes, heart conditions, HIV, etc. that people have to take for the rest of their lives. Further, antibiotics are expensive to develop since the conventional approaches to discovering new antibiotics have become less productive.) So, most pharmaceutical companies have stopped any development of new antibiotics. This has been a social interaction among humans, one having to do with economics of private industry, not with biology. As a consequence, there are more and more disease strains that are untreatable, and infectious disease doctors are extremely concerned. Much simpler examples of social-biological interactions in evolution can be seen, such as among single-cell bacteria. Signaling among bacteria can cause them to form colonies, form biofilms, and turn virulent. See the blog entries Quorum sensing part 1 and Quorum Sensing Part 2. Further, such social interactions may also be multispecies and stress-related. Wound healing may involve complex interactions among multiple bacterial species and host cells(ref). There is increasing recognition that cells in bacterial biome species present in a human body outnumber our human cells by a factor of at least 10, that there is an incredible amount of signaling between these bacterial cells and our own cells, and that the not-us species play a very important role in our health and longevity.
For most people, evolution happened millions of years ago and you can learn about it in a museum of natural history. It is about monkeys turning into people In the expanded view of evolution I have outlined it is happening right now, it is happening here in and around us, and it is affecting us profoundly. I can change its course by many simple actions, such as by taking an antibiotic.
C. GUTb AND INFORMATION
BIOLOGICAL PROCESSES ARE ALL ABOUT COMMUNICATIONS, SENSING AND STORAGE
At every level of biology we find information sensing, information storage, information communication, information processing and creating physical changes based on information.
Information sensing: Molecules sense what is going on in neighboring molecules according to the laws of chemistry. Within cells, all key structures sense what is going on with in others, as based on molecular information messengers. Mitochondria sense messages from the nucleus and the other way around. Microtubules sense the development stage of a cell. The cell’s nucleus senses the status of metabolic processes in mitochondria. Cells sense messages from other cells and status of larger systems via surface antigens, neurons sense information from other neurons via electrical signals at synapses. We humans sense the status of some biological systems via diagnostic tests and biomarkers, microscopes, MRIs and x-ray machines of all kinds. We sense the status of biological science via reading the research literature. We use our eyes and ears to sense dangerous situations for our bodies, etc. Cell-to-cell communications can be via multiple means. It can be as simple as the release of a signaling gas into the environment. It can take place by chemical messengers such as hormones, it can involve membrane bridging among cells, it can involve packaging of sophisticated messaging components into exosomes which are targeted to other specific cells, Communications are inter-species as well as intra-species. Within a cell there are multiple forms of important signaling and molecular communications. Most mitochondrial proteins are manufactured in response to signals sent from the mitochondria to the cell nucleus Needed proteins are shipped to the mitochondria, they are unfolded so that they can cross the mitochondrial membrane, and once inside are folded again. Proteins and whole organnels are shipped from one part of a cell to another, propelled by motor proteins that run on microtubules which function like rail lines within cells. The articulation of all these processes is extremely complex and fine tuned, requiring well-functioning informational control circuits.
Information storage: Information is clearly stored in genes and in epigenetic markers in cells. It is stored in non-coding RNAs. It is stored in our conscious memories and in our subconscious minds. It is stored by biochemical processes in brain and nervous systems. On the societal level information is stored in publications, books and other media. And today it is stored in massive electronic data archives. And on every level information is stored in the very structures of biological and physical elements. The very structure of the hippocampus or a liver or a heart reflects stored information, as does the structure of a building or city.
We learned a lot about information and information theory in the course of the 20th century. We will need to use some of that knowledge to build an effective GUTb.
D. GUTb AND EMERGING PHENOMENA
The history of the universe as well as that of all areas of science are characterized by emerging phenomena. Within physics, looking back to when the universe was an extremely hot spot, there would be no way to predict the differentiation of a unified force into four fundamental forces. What we now call the four fundamental forces were emergent phenomena. These forces and some of the laws of physics existed in the early universe before there were atoms and molecules and therefore before chemistry existed. There is no way to derive the laws of chemistry from the laws of physics starting with quarks. These laws of chemistry were emergent phenomena. The laws of chemistry had to be consistent with those of physics but emerged only as the universe cooled. Similarly, the phenomena and laws of biology cannot be predicted from knowledge of chemistry. The laws and structures of biology had to be consistent with those of chemistry but in no way could be derived from them. The forms of life we know were shaped not only by laws of chemistry but also by geological and other physical conditions in the early earth. They too were emergent phenomena. Within biology itself there have been a succession of emergent theories such as understanding of Microbes and Their Roles, Cell Biology, the Nature and Roles of DNA, Genetics and then Epigenetics. It is a bit presumptuous to assume that there won’t be more important emergent theories as time progresses.
Going on, what is known about human biology is insufficient to predict social behavior of human beings, and the same is true for social behavior of other species. Social behaviors are also emergent phenomena.
Looking forward, given that evolution is multi-layered, multi-species, ongoing, and driven by social as well as biological developments, I believe new phenomena may emerge that we are now incapable of predicting, phenomena that are not envisaged in our current thinking. We do not know where the game of evolution will ultimately carry us and our companion life forms. A GUTb should respect the existence of emergent phenomena.
6. THE FOUR REVERSIBLE MODIFICATIONS OF PROTEINS IN THE GUTb
As mentioned above, Jim suggests that we consider the post-translational processes of the four most common reversible modifications of proteins that are involved with aging and longevity – 1. Redox modifications of cysteine thiols, 2. Acetylation of lysine, 3. Phosphorylation of serine, threonine, and tyrosine, and 4. Methylation of lysine and arginine. Jim has written:
“1. Reversible modifications of cysteine thiol groups – this includes the subject of the interactions of H2O2, NO, H2S, GSSG, with the “redox proteome”. This will cover both the concept of ROS signaling, RNS signaling, the redox status of the cell [NAD(P)/NAD(P)H, GSSG/GSH], cysteine S-nitrosylation, S-sulfhydration, and the covalent bonding of glutathione with cysteine thiols. Consideration must be accorded to the roles of the “redox gases” with these cysteine thiols and what these modifications mean in the activation or inhibition of proteins. Also, consideration must be given to cytoplasmic, mitochondrial, and nuclear redox events in gene expression. See Dan Campagnoli’s essay, The Master Regulator of Aging? – Redox, Glutatione and Cysteine, Part 1
2. Reversible acetylation of lysine ω-amino groups – this has been described as the “mammalian acetylome” and includes the subject of the acetylation/deacetylation events in the cytoplasm, the mitochondria, and the nucleus. According to recent estimates, approximately 20% of mitochondrial proteins (~300) are acetylated and three NAD+ deacetylases (SIRT3, 4, and 5) are present in the mitochondria. Most of these are still poorly understood and many are involved with longevity. In the cytoplasm, a lower percentage of proteins form acetylysine, but their role in aging is also critical. In the nucleus, acetylation is the most common histone modification associated consistently with euchromatin. Several earlier blog entries have discussed histone acetylation and deacetylation as related to both health and aging, including the Three Dragon series, Part 1, Part 2 and Part 3.
3. Reversible phosphorylation of serine, tyrosine, and threonine – this is the most common and most well understood post-translational modification of proteins in all compartments of the cell. In fact, 1.7% of the entire human genome codes for protein kinases. The scope of signal transduction covered by the “phosphoproteome” is so large that we cannot start to cover it here. However, the kinase cascades involved with longevity must be well-subsumed and considered in detail in the GUTb. The GUTb must include the dynamics of the Insulin/IGF pathway, the mTOR pathway, the AMPK pathway, as well as the role of phosphorylation in the MAPK family of kinases, including ERK1/2, p38/MAPK, etc.
4. Reversible methylation of lysine and arginine groups, as well as DNA cytosines – These methylation events are most-closely associated with the cell nucleus and rarely occur outside of the nuclear membrane. These post translational modifications are mostly made on histone proteins – the basic, positively charged proteins that neutralize the acidic, negatively charged DNA – which allows the DNA to be compacted into the tight “suitcases” called nucleosomes. The nucleosomes can then be condensed into chromatin, allowing over 1 meter of DNA to be compacted into a very small space. In addition to the compacting function of histones, the “tails” of the histone proteins are acetylated or methylated at “site-specific” locations which allow for different “Histone reader proteins” to recognize the binding sites. Thus, these methylations of lysine and arginine on the histone tails, in addition to the acetylation of lysines results in a “histone code” that can be written, read, and erased by a large family of epigenetic proteins. “
GUTb must subsume these four reversible protein modifications not only individually but also in their interactions.
7. ROLE OF THE GREAT GOD GASSES IN GUTb
Four compounds can be singled out because they played key roles in early evolution and because the perform key signaling functions today and are vital to health and longevity: H2O2, NO, CO, and H2S (hydrogen peroxide, nitric oxide, carbon monoxide. hydrogen sulfide). Three of these are gasses and all perform key functions in REDOX interactions. Here is an excerpt from an introduction to these gasses written by Jim: “The story is about four of the simplest molecules found on earth – molecules that were present at the dawn of creation and are still present in every cell in your body. Long ago, they occurred de novo (existed when the earth was formed), but today they are actively synthesized by enzymes within the cell. These simple molecules are found in virtually every life form that exists today – bacteria, yeast, protozoa, plants, and animals. In simple terms, they serve as “molecular language” that allow larger molecules to “talk to each other”. These molecules can be easily synthesized without enzymes at the high pressures and temperatures found on the sea floor hydrothermal vents, in the presence of iron, copper, and other ions called “transition metals”. Today, cells have enzymes to both both synthesize and degrade these “molecular words” and control their levels with extreme precision. Low levels of these molecules all are needed for normal cellular function. Higher levels are induced with cellular stress, or for thinking, walking, talking, sex, or to fight off invaders such as bacteria. At levels of 800 parts per million (ppm), each one of these molecules will kill the cell, thereby functioning as a “cellular Grim Reaper”. What is unique about the “death function” of these molecules is that no “death program” is needed, such as the complex programmed cell death called apoptosis. When the level of any one of these molecules reaches 800 ppm, the cell just dies – no program needed! Therefore control the level of these molecules is critical to life and death. The primary molecular “talkers” in this story are hydrogen peroxide, nitric oxide, hydrogen sulfide, and carbon monoxide. All of these “molecular talkers” are considered poisons by the US government and by toxicologists, yet they are all actively synthesized in your body. Without these molecules being present at healthy, normal levels, you would be dead. (It is time for the government to go to school and learn some molecular biology!) These molecular “talkers” are so simple can be easily derived from water, ammonia, sulfur, and smoke. Today they are actively synthesized from oxygen, amino acids, and heme. They play a central role in practically every intracellular “talking” pathway, many cell-to-cell “talking pathways”, and even many organ-to-organ “talking” pathways. The strongest proof of their significance is that the enzymes that synthesize and degrade these “talking molecules” are evolutionarily conserved. This means that they are present in all life forms, even those that are billions of years old. Inside the cell, the “talking function” of these molecules is called a “signal transduction network”. Outside the cell, these molecules are called “gasotransmitters” and are an essential part of normal “cell talk” inside the brain, the gut, the vascular system, and the sex organ system. We believe they can even serve as organ-to-organ signalers between the brain and various peripheral organs, thereby explaining many unexplainable phenomena such as the placebo effect, psychosomatic illness, the health benefits of laughter and the spiritual effects of prayer. These signaling molecules often appear to be hidden in the “big picture”, like the hidden child Waldo in the children’s book “Where’s Waldo” (Waldo is hidden in many locations in a large picture full of hundreds of people and it takes some time to find him in the big picture). What triggered this molecular signaling system to evolve? The explanation in this story will literally “shock” you. The “shock” was an Act of God.”
This is just a teaser introduction to a long and fascinating story about these four “God” substances that will eventually be published. The key point is that these substances are ubiquitous, have played key biological roles since the beginning of biology, probably played a role in the creation of the first biological entities, and are extremely important for many aspects of health and aging today. So, we expect that these substances will play a central roles in GUTb
8. NO GUT IS LIKELY TO REMAIN STABLE AS SCIENCE ADVANCES
It would be a mistake to think that it is possible to create a GUTb that is the final word. Going back to physics where GUTs exist, the basic Standard Model component of the GUTs seems to be in trouble, possibly deep trouble. It is a matter of physics and fudge factors, namely dark matter and dark energy.
To make observations conform with the Standard Model and our other established theories of physics, astrophysicists have postulated the existence first of dark matter and second of dark energy. These entities represent the majority of what is presumed to exist in the universe. However, they have never been directly observed despite gargantuan efforts to do so. This seems to be fine with the astrophysicists. Dark matter and dark energy are in essence gigantic fudge factors, playing roles comparable to the roles of ether and phlogiston in earlier models of physics. They keep the Standard Model and the GUTs of physics relatively whole. But at a price, which is complete absence of direct experimental evidence.
No matter how hard they have looked, astronomers have been unable to find enough observable matter in the universe to account for the gravitational and inertial behavior of galaxies and large scale structures in the universe. The numbers just did not work out if the Standard Model and most of the rest of what we understand about physics is in fact correct, Based on observable matter, there was not enough of it around to hold things together and explain the motion of celestial bodies. So, the astrophysicists postulated the existence of more matter, just enough so the cherished equations of the Standard Mode and The Theory of Relativity should work.
“Astrophysicists hypothesized dark matter due to discrepancies between the mass of large astronomical objects determined from their gravitational effects and the mass calculated from the “luminous matter” they contain: stars, gas, and dust. It was first postulated by Jan Oort in 1932 to account for the orbital velocities of stars in the Milky Way and by Fritz Zwicky in 1933 to account for evidence of “missing mass” in the orbital velocities of galaxies in clusters. Subsequently, many other observations have indicated the presence of dark matter in the universe, including the rotational speeds of galaxies by Vera Rubin, in the 1960s–1970s, gravitational lensing of background objects by galaxy clusters such as the Bullet Cluster, the temperature distribution of hot gas in galaxies and clusters of galaxies, and more recently the pattern of anisotropies in the cosmic microwave background. According to consensus among cosmologists, dark matter is composed primarily of a not yet characterized type of subatomic particle. The search for this particle, by a variety of means, is one of the major efforts in particle physics today. (ref)”
But the dark matter, if it exists cannot be observed via any electromagnetic radiation nor isolated or shown to be associated with any observable particles. An incredible Snark Hunt has been going on for decades to identify the particle nature or otherwise confirm the existence of dark matter. They are thought to be Weakly Interacting Massive Particles (WIMPS) Dark matter was first postulated in 1932 and the unsuccessful Snark Hunt for WIMPS goes on today 81 years later. (The Snark is “a fictional animal species created by Lewis Carroll in his nonsense poem The Hunting of the Snark. His descriptions of the creature were, in his own words, unimaginable, and he wanted that to remain so (ref)” Because the Snark is fictional, hunt as you may, you won’t find him.)
In the news this week was continuing failure to find the elusive Snark –“Evidence has been building for decades that most of the matter in deep space is invisible. The gravitational pull of unseen dark matter bends light from distant regions of the cosmos. It keeps galaxies like our own Milky Way from flying apart, and clusters of galaxies from dispersing out into the void. Without dark matter, there would not have been enough gravity to form galaxies in the first place. Based on all those lines of evidence, the dark stuff must outweigh visible matter 6 to 1. But its true nature remains a mystery, because nobody has been able to detect it directly. — The new LUX detector, situated 4,850 down in an abandoned gold mine in South Dakota, is designed to bring dark matter into view. At a seminar today, physicists Rick Gaitskell of Brown University and Dan McKinsey presented results from the first full run of their experiment. They haven’t found dark matter yet–nobody dared to hope it would be so easy–but the results are a major advance all the same. After just three months of operation, the two-story-tall LUX detector has achieved 3 to 20 times the sensitivity of any other dark matter experiment. — Those LUX results cast serious doubts on other, controversial claims by competing teams who say they’ve seen evidence of dark matter particles crashing into ordinary atoms. If those results were correct, the more sensitive LUX would see a veritable barrage of dark collisions–but no go. A bummer, in some ways, but LUX is now sweeping away a decade of uncertainty and leading by far the best search ever for the dark universe. Over the next year LUX will continue to collect data, getting a better and better view of what is out there. — If LUX can’t do the job, Gaitskell and company are already thinking about the next step: An upsized version of LUX called, in rock and roll fashion, LUX-ZEPLIN. So when will the real dark matter discovery come? Gaitskell refuses to take the bait(ref).”
I am not quite sure how not finding something that may not exist is an advance.
The plunge into the hypothetical became even deeper when we invented dark energy. “In physical cosmology and astronomy, dark energy is a hypothetical form of energy that permeates all of space and tends to accelerate the expansion of the universe. Dark energy is the most accepted hypothesis to explain observations since the 1990s that indicate that the universe is expanding at an accelerating rate. According to the Planck mission team, and based on the standard model of cosmology, the total mass–energy of the universe contains 4.9% ordinary matter, 26.8% dark matter and 68.3% dark energy.Measuring the equation of state for dark energy is one of the biggest efforts in observational cosmology today(ref)”
But let’s state honestly what happened: 1. Our cherished Standard Model and our usual equations of physics produced predictions completely incompatible with observational results. The discrepancies were very large. 2. We had to change either our theoretical frameworks or cast in doubt the observational results. We chose to keep the theoretical framework and put our observational results in doubt – saying that there must be a lot more matter out there that can’t be observed. We invented dark matter. Then later, we could not explain accelerating expansion of the universe even taking dark matter into account, so we invented dark energy. Neither have ever been directly observed. Is this science? Most physicists think so. Since the concepts of dark matter and dark energy have been around so long, their fudge-factor nature seems to have been forgotten. So, the Snark Hunts for dark matter and dark energy go on and on. We don’t want to consider the idea that a completely new theoretical framework may be needed.
So, if our GUTs in physics are in trouble and need fudge factors to keep them alive, the same could also be true of a GUTb. Again, we may just keep discovering more and more and developing more and more sophisticated models, and never get to the point where we have completely characterized the underlying reality.
Most of human DNA still has unknown or poorly understood functionality. Only about 3% of our genome encodes information for making proteins. Other parts, non-coding RNAs including pseudogenes, are known to serve a number of developmental and other important functions such as transcriptional and translational regulation. As to the rest – still a very considerable part – its functions remains still largely unknown. Is that biology’s counterpart to dark matter?
FINAL OUTSIDE THOUGHTS
What if biology is in fact so complicated that nobody can get their minds around it, but that it still has a definable structure? Could a GUTb consist of a systems dynamics model with thousands of variables created entirely by a computer and laid out in a complicated set of computer programs and databases – but not be very explainable to even well-educated people? The GUTs in physics are not at all easily explainable. For a GUTb to exist, does somebody have to understand it?
Is the GUTb concept appropriate for biology? It is an established way of thinking drawn from Physics, a much simpler area of science. My colleague Melody Winnig has pointed out “The solution doesn’t necessarily arise from the same way of thinking that created the problem.” The GUTs in physics were based on quantum mechanics and relativity theory, radically different new ways of thinking. Perhaps a new and radically different way of thinking about biology is needed and will emerge.