Genetic Resistance to Leukemia

Unlike genetic mutations that are inherited directly from parents, somatic mutations are changes in the DNA that occur over a singular lifetime and accumulate. All the tissues in body are created and maintained by particular stem cells or progenitor cells. When mutations occur in stem cells or progenitor cells that give a survival advantage over the unmutated variety, they can grow via clonal expansion. The mechanism(s) of such expansion (clonal hematopoiesis) have been identified; however, the factors that may contribute to delaying this cell growth is poorly understood. Uncontrolled clonal expansion in hematopoietic stem cells or progenitors may lead to leukemia.

Human Leukemic White Blood Cells

In a recent article in the journal, Science, Agarwal et al. have studied and reported on an inheritable genetic variant that seems to protect against clonal hematopoiesis and its possible progression to leukemia.

According to the investigators in this study, “The focus of clonal expansion studies, which have led to the identification of aging-associated clonal hematopoiesis of indeterminate potential (CHIP). CHIP is defined by the presence of somatic mutations in at least one gene associated with cancer in white blood cells (the most frequently mutated genes being DNA methyltransferase 3 a, or DNMT3A; tet methylcytosine dioxygenase 2, or TED; and ASXL transcriptional regulator 1, or ASXLI), with a proportion of cancer-associated variant copies of a gene (variant allele frequency) of at least 2% in blood and bone marrow cells, and in the absence of another blood disorder. Most CHIP mutations give a competitive advantage to hematopoietic stem cells (HSCs) over normal HSCs, particularly in eroded and aged hematopoietic systems exposed to inflammation (2). The size of the mutant clone population is a major predictor of poor outcomes in CHIP carriers (3). In particular, CHIP is associated with a 10- to 12-fold increased risk of developing myeloid malignancy (4), a group of blood cancers. Notably, mutant HSC populations can stagnate and even shrink in an individual over a long period of time (5). Environmentally inherited factors that prevent or slow mutant clonal expansion may explain these variations.”

The researchers involved in this study went on to further elucidate the mechanism as described above. These data are exceedingly valuable in that they may ultimately lead to an effective diagnostic tool to more accurately identify the risk factors for age-associated clonal hematopoiesis.

Alcohol, Acetaldehyde and Cancer

It has long been understood that excessive drinking of alcohol can lead to serious impairments in various organs including the liver and brain.   However, it is now become clear that there is a real risk associated with chronic consumption of alcohol(ethanol) with increased risk of getting certain kinds of cancers including upper aerodigestive tract, the liver, the large intestine and the female breast.

In a recent paper that appeared in the journal Science, the etiology of this relationship has been demonstrated.  Multiple mechanisms have been elaborated to explain this relationship.  According to the authors, “Among those the action of acetaldehyde (AA), the first metabolite of ethanol oxidation is of particular interest.

Structure of Acetaldehyde – Black – Carbon; White – Hydrogen; Red - Oxygen

“AA is toxic, mutagenic and carcinogenic in animal experiments.  AA binds to DNA and forms carcinogenic adducts.  Direct evidence of the role of AA in alcohol-associated carcinogenesis derived from genetic linkage studies in alcoholics.  Polymorphisms or mutations of genes coding for AA generation or detoxifying enzymes resulting in elevated AA concentrations are associated with increased cancer risk.  Approximately 40% of Japanese, Koreans or Chinese carry the AA dehydrogenase 2*2 (ALDH2*2) allele in its heterozygous form.  This allele codes for an ALDH2 enzyme with little activity leading to high AA concentrations after the consumption of even small amounts of alcohol.  When individuals with this allele consume ethanol chronically, a significant increased risk for upper alimentary tract and colorectal cancer is noted.  In Caucasians, alcohol dehydrogenase 1C*1 (ADH1C*1) allele encodes for an ADH isoenzyme which produces 2.5 times more AA than the corresponding allele ADH1C*2.  In studies with moderate to high alcohol intake, ADH1C*1 allele frequency and rate of homozygosity was found to be significantly associated with an increased risk for cancer of the upper aerodigestive tract, the liver, the colon and the female breast.  These studies underline the important role of acetaldehyde in ethanol-mediated carcinogenesis.”

This article elaborated further,” Acetaldehyde is highly toxic, mutagenic and carcinogenic.  AA interferes at many sites with DNA synthesis and repair and can, consequently, result in tumor development [6, 7].  Numerous in vitro and in vivo experiments in prokaryotic and eukaryotic cell cultures as well as in animal models have shown that AA has direct mutagenic and carcinogenic effects.”

In conclusion, these data strongly reinforce the nature of the  relationship between the chronic drinking of ethanol and certain cancers.

 

 

Science - the Gateway to Reality

It has been through science and the application of the scientific method that significant progress has been made in the human understanding of how the universe works i.e. obtaining a clearer knowledge of the nature of reality.

It has been through the discipline precision and thoroughness of scientific investigation that the once “mysterious” processes of life, the evolution of stars, formation of planets, the beginnings of and development of life on planet earth, the nature of inheritance, an understanding of how the human body functions, the etiology of disease in body and mind, the elucidation of the laws of physics and chemistry etc. have been thoroughly studied. Furthermore, the progress made in all these areas continues to grow.

These breakthroughs are the direct result of the collaborative efforts by many scientists throughout the world over many years of exhaustive study.  The resulting cumulative body of knowledge has helped elaborate and define the principles that underlie the many aspects of what we perceive as reality.

It is this understanding, that has led to the many benefits that are taken for granted in modern life including extraordinary discoveries in the treatment of illness, space travel and the advances in communication and information retrieval and transfer.

It is through the scientific process that the complex interrelationships between all of life on earth i.e. ecology has and continues to be elucidated.  In a similar fashion scientific study and analysis has shown the nature and sources of human-caused degradation of the natural environment. As a result of a growing understanding of the fundamental drivers of climate and weather, climatologists have defined the underlying danger of the accumulation of greenhouse gases in the atmosphere.

Accepting, supporting and encouraging science and the scientists that apply its principles is an essential ingredient for the continued viability of the human species on planet earth, for without the unabated acceptance and support of science in its quest to uncover the nature of the universe around us human progress would ultimately come to a halt leaving humanity without the necessary tools for continued survival.

 

Al Gore has an important message to convey regarding the state of this nation and humanity's future.

Over the past 2 years, Earth got hotter faster than ever before

The following article was taken from the Journal Science - November 28, 2024

Recent temperature records raise fears that global warming is accelerating.

It’s a record foretold: 2024 was the hottest year in human history, even hotter than the record-breaking year before it. Global surface temperatures were somewhere between 1.45°C and 1.6°C higher than the average from 1850 to 1900, multiple climate monitoring groups reported today. “We are now living in a very different climate from that which our parents and our grandparents experienced,” said Samantha Burgess, deputy director of Europe’s Copernicus Climate Change Service (C3S).

Another 1.5°C of warming would take the world back to the climate of the Pliocene, a time 3 million years ago when sea levels were many meters higher, said Gavin Schmidt, director of NASA’s Goddard Institute for Space Studies, in the agency’s announcement. “We are halfway to Pliocene-level warmth in just 150 years.”

What’s more, the spike over the past 2 years was the sharpest in modern history, Burgess said. It caught many climate scientists by surprise, surpassing what would be expected just from increasing greenhouse gases. A host of explanations has emerged, some familiar—an El Niño in the Pacific Ocean—and some worrying and enigmatic, including what appears to be a decadeslong decline in cloud cover. The fear is warming could be accelerating faster than expected, owing to a poorly understood feedback in the climate system.

Taking the temperature of the previous year has become an increasingly grim January tradition. In recent years, NASA and the National Oceanic and Atmospheric Administration in the United States and the United Kingdom’s Met Office have been joined by C3S, Berkeley Earth, and an international group of ocean scientists, with each group emphasizing different methods of stitching together the data from thousands of land-based thermometers, ocean buoys, and satellites. In the deep ocean, which is destined to absorb most of the energy from global warming, nearly every year is a new record. At the surface, not every year is—but each of the past 10 years has been among the hottest 10 years in history.

At first blush, the planet might seem to have passed the ambitious target of limiting warming to 1.5°C set by the Paris agreement in 2015. But because temperatures fluctuate naturally from year to year, climate scientists say, what counts is the long-term average, which currently sits between 1.2°C and 1.4°C. It may take 5 or 10 years for the Paris target to be clearly breached.

In some ways, 2024 was less exceptional than 2023, even if it was warmer, Schmidt said. In 2023, surface temperatures jumped by nearly 0.3°C in a year; this past year, they finished some 0.1°C higher than 2023. The 2023 jump coincided with a strong El Niño that set in during the second half of the year. With El Niño now having given way again to La Niña, its cooling counterpart, “the spike has ended,” says Shiv Priyam Raghuraman, a climate scientist at the University of Illinois Urbana-Champaign.

The pressing question for climate science is to understand what happened in 2023 and whether El Niño is the full explanation . Recent work by Raghuraman has shown that the arrival of El Niño after a prolonged La Niña from 2020 to 2022 could theoretically explain all of the temperature surge. But the surge began earlier than El Niño in 2023, especially in the North Atlantic Ocean, and lasted longer in 2024, which suggests other factors are at play. In fact, NASA estimated that El Niño only added 0.01°C of warming in 2023.

Early on, some researchers thought cleaner, clearer air due to falling pollution from China and a switch to cleaner ship fuels could explain a significant chunk of the rise. But 2023 might fit into a more alarming trend. For 2 decades, NASA instruments in space have tracked a growing imbalance in Earth’s solar energy budget, with more energy entering than leaving the planet. Although greenhouse gases explain most of the imbalance, the data have also shown the planet is growing less reflective, beyond even what is expected from a decrease in light-reflecting air pollution.

A recent study has suggested a decrease in reflective clouds played a role in the 2023 warming, though what drove those changes is unclear. But more concerning is work presented last month at the annual meeting of the American Geophysical Union and reported by Science, showing that reflective cloud cover has dropped for 2 decades. If this decline holds up, and is found to be caused by global warming—which it then amplifies—then the 2023 spike in temperature may not be an anomaly. It may be a harbinger.

Author

Paul Voosen is a staff writer who covers Earth and planetary science.

A Model for the organization of DNA in living organisms

 

This model was proposed in the 1970s

I must first remind the reader that the model I intend to postulate is purely speculative and is open to whatever criticisms and modifications that time and hard scientific evidence might demand. It seems to me that the basic strength of the scientific perspective is the use of the paradigm and the willing openness to allow empirical data to decide the ultimate usefulness of any conceptual model.

However, science like any other modern human institution has the tendency to become rigid in its outlook. I believe that at the present time there is a strong tendency to take a narrow and unbending stand concerning the evolution of life on the planet earth. No one who accepts the basic premise of scientific investigation is about to deny the existence of DNA, its inherent structure, and the role it plays in heredity. Also it is quite apparent that we as human beings coexist on the planet with a vast variety of living things each with its unique structures and adaptations. Various theories of evolution have attempted to explain the mechanism by which these forms have come into existence. Darwin, Mendel, and the brilliant work of modern molecular geneticists have elucidated the molecular structure and function of the actual genetic material. It has been clearly demonstrated how DNA by the very nature of its structure is capable of holding the biochemical information necessary for life; how it conserves this information, and how living things are able to call upon this information to organize the functions that are the definitive prerequisites for life. These mechanisms are not open to dispute since they represent hard data demonstrated over and over again.

However, it is my intention to show that there are certain explanations of phenomena that are strongly held but in fact rely on tenuous proofs. It is currently held that evolution has proceeded on planet earth through a process of spontaneous mutation of genetic material in which the resulting changes in characteristics of living forms are either rejected or reinforced by natural selection pressures. Allow me to give some examples. There exists now a variety of bacteria, Neisseria gonorrhoeae, that is the causative agent for the disease referred to as gonorrhea in humans that has become immune to penicillin. The argument to explain this event would be the following: a fortuitous mutation of the genetic material in this organism produced the ability to negate the effect of the antibiotic. This event was independent of the presence of penicillin in the environment of the organism. With this new characteristic the particular strain of bacteria that held the immunity of course would survive where its cohorts would perish. Hence the new natural condition selected for the organism with the immunity. This same rationale has been extended to encompass the entire evolution of living organisms on planet earth.

The contemporary view is that the information contained in the DNA is carefully conserved and fixed and is not generally subject to alteration by its environment except in the limited area of fortuitous mutational events. In my estimation A rigid model forbidding any sort of adaptive mechanism in the genetic material itself and if living structures actually adhered to such a model the planet earth would be probably be devoid of the richness and variety of the life that it in fact supports.

This perspective is not an original view of mine.  It is conceivable that within the organization of DNA there exists an inherent mechanism to allow for a non-random interaction between the environment and the structure of the information store.  It is with this thought in mind that I propose the following model:

1 -that there is a portion of the DNA that is rigidly fixed in information content in what is now referred to as genes in general and in the so-called introns in particular. Billions of years in the biosphere have established this information as being essential for life and substantial changes in this structure can prove deleterious.

2-there is a large portion of the DNA in organisms that has no apparent information content by nature of its seeming random and repetitive sequences. This DNA is far from trivial and some of this structure represents the basic language store from which the genetic material responds to environmental signals; allow me to elaborate.

Proteins, especially enzymes, are the intermediaries between the information stored in the DNA and the expression of this information into discrete characteristics. In point of fact discrete genes hold the information for the structure of discrete proteins. The genetic code has of course been definitely worked out. It is these proteins that act on the cellular environment of living things. Enzymes are specialized proteins and are responsible for the catalysis of all the diverse chemical reactions taking place within each and every living cell. Enzymes mediate cellular activity.

3 -The model I am proposing predicts the existence of quite another mechanism operating within the genetic material. The specificity of enzymes for their substrates has been well established. This specificity cannot be accidental but must rely on discrete and well-established chemical laws. In other words, there exists a particular relationship between amino acid sequences of enzymes and the exact structure of a particular enzyme allowing it to act upon a particular substrate, and also establishes the nature of that reactivity i.e. whether oxidative cleavage, reduction, synthesis etc.

This relationship will be found to be quite simple - computer analysis of amino acid sequences of different categories of enzymes i.e. proteases and oxidases as an example will reveal certain relationships. It is my prediction that it will eventually be shown that there exists particular patterns, arrangement and spacings of amino acids that give rise to certain classes of enzymes and that these patterns since they occur in proteins will be represented in the DNA of the gene having the information for the synthesis of that enzyme as is already understand.

It is my contention that the exact structure of a particular substrate contains enough information for the synthesis of a protein that can interact with it - there are only a limited number of ways cellular enzymatic systems can chemically modify substrates in its environment.  Examples of these are pathways for synthesis, degradation, oxidation or reduction, cleavage, methylation etc.  It is my contention that DNA sequences that correspond to the relationships between amino acid sequence and enzymatic activity are pre-existing within the seemingly random array of sequences within the genome that have no known purpose.   

Such arrays can be mobilized and activated by the appearance of new substrates in the cellular environment. Such a mechanism proposes the de-novo synthesis of a novel gene that has the information to create a novel enzyme to interact with the new substrate presented to the cellular environment.  This particular aspect of the model as of yet cannot fully explain the relationship between environmental change, the appearance of new substrates and enzymatic populations as related to gross characteristics. In multicellular organisms the degree of complexity is exceedingly high.

The above model describes a transient mechanism for adaptive change in genetic material .  In addition, I propose that there exists a mechanism for transferring these de-novo genes to the conserved population of DNA in other words into inheritable genes. If the environmental change persists then the new messenger RNA containing the information for the protein designed to interact with the novel substrate will exist over a prolonged time frame and therefore allowing reverse transcriptases the opportunity to integrate this new sequence within the genome.  It is at this stage that selection pressures play a significant role.

• The following is a modification in part three of my proposition - dated July 19, 1982

Within the intervening sequences, the exons are composed of sequences of DNA that code for pieces of the primary sequence of proteins that are essential for determining the overall three-dimensional configuration of the resulting protein which in the case of an enzyme such as cytochrome P-450 or an antibody will also determine its specificity. Although these essential pieces can be fit together in innumerable ways there are only a finite number of mini sequences of amino acids probably containing highly conserved hydrophobic residues that produce configurational patterns resulting in active proteins.

The most essential feature of this model as I see it is that the capacity to respond to any new environmentally introduced signal i.e. to produce a novel protein with the required specificity that relies upon the existence of preformed genetic units, exons, that with the appropriate environmental signal can be recombined to allow for the synthesis of a de-novo protein. The advantage of this model is that it allows for more than merely a random selection process for the evolution of new biological activity.

The weakness of this model however lies with the fact that it rests upon the assumption that there exists a pre-existing mechanism that can be activated upon the appearance of a novel substrate and that can ultimately lead to the production of a particular sequence of amino acids and therefore into reproducible 3 dimensional configurations with discrete specificities that can bind to the new substrate.

However the existence or non-existence of such a mechanism is experimentally accessible either by direct synthesis of model sequences or sophisticated computer analysis of the many, many proteins in which both the three-dimensional configurations and primary sequences are already known. If such a language were indeed uncovered the possibilities would be endless for it would then be plausible to synthesize a protein de-novo with novel and predictable activity which in collaboration with genetic engineering could lead to the production of novel synthetic genes.

Exciting New Results in the Development of an Anti-Malaria Vaccine

 

An exciting recent development has been reported in the prestigious journal Science regarding the development of a anti-malaria vaccine that has been shown to substantially reduce childhood victims of this disease. This vaccine is referred to as RTS, S. or Mosquirix and made by GSK.

Analysis of the efficacy of this vaccine approved to combat the death of the young children demonstrated a 13% drop in mortality during a nearly 4 year duration. This result was reported by the World Health Organization (WHO). In addition it was also found that there was a 22% reduction in the incidence of severe malaria in children young enough to receive a three-shot series.

According to John Tanko Bawa, director of the malaria vaccine implementation at the Program for Appropriate Technology in Health (PATH) stated, “The RTS,S malaria vaccine is already saving lives.” Furthermore he noted that, “What we have seen is a considerable impact of a vaccine described as having modest efficacy.”

The results of this analysis is so impressive that it has been estimated that the mortality decline could ultimately save tens of thousands of lives if RTS,S, is more broadly utilized.

In regard to the actual mode of action of RTS,S vaccine, it binds to the circumsporozoite protein on the surface of P. falciparum parasite before it infects liver cells disrupting its life cycle so that it is unable to infect circulating red bloods where it exerts its deadly effect – a pre-erythrocytic vaccine.

This is a profoundly important development in regard to the control of the spread of malaria among susceptible human populations.