Al Gore has an important message to convey regarding the state of this nation and humanity's future.
An understanding of science in this the 21st century is an essential ingredient for leading a productive and rewarding life.
The following article was taken from the Journal Science - November 28, 2024
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.
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.
Introduction
It is currently estimated that one in eight women (12.5%) in the United States will be diagnosed with breast cancer. For example, In the year 2014 232,670 new breast cancer cases and 40,000 deaths were reported for women living in the United Sates. Age is the strongest risk factor for breast cancer. Surprisingly, breast cancer begins to rise in the third decade of life. This unusual aspect of breast cancer, is postulated to be related to the effects of ovarian hormones – especially estrogen and progesterone - on breast tissue. More than 2/3 of all new cases occur after the age of 55 and women older than 65 have a relative risk greater than 4.0 when compared with those younger than 65.
For this reason, it is imperative that causative agents responsible for the transformation of normal breast tissue cells to a cancerous state be more fully understood; that women be encouraged to undergo the appropriate screening and health checkups; and that more anti-breast cancer therapies be developed to combat this disease.
Additional Risk Factors
In addition to the endogenous ovarian hormones as cited earlier, there are the following factors that may play a significant role in the etiology of breast cancer –
Endogenous Estrogen Levels and the Etiology of Breast Cancer
The Data accumulated in the past few decades indicate that endogenous estrogens play a very important role in regard to the etiology of breast cancer. For this reason it is important to understand how estrogens are produced and metabolized in the body. Estrogen and Progesterone are steroid hormones, and the first step involving steroidogenesis in the human ovary is the transport of their precursor, cholesterol into the mitochondria. This is followed by a number of enzyme-mediated steps that lead to the formation of Pregnenolone that is the precursor for all steroid hormones, and eventually to estrogen.
In premenopausal women, estradiol synthesized in the ovaries is the most predominant form; whereas in postmenopausal women, estrone is the most prevalent and is synthesized in the peripheral tissue. Estrone is reversibly converted to estradiol through an enzyme-mediated reaction. Testosterone, in turn, is converted to estradiol by the action of aromatase enzyme in the peripheral tissues. Aromatase is the enzyme that mediates the rate-limiting step in the conversion of androgens like testosterone into estrogens. On account of the paramount importance of this metabolic step, pharmaceuticals that can effectively block aromatase activity have proven to be important aspect of the treatment of estrogen-dependent diseases such as breast cancer, endometriosis, and endometrial cancer.
It has been well established that active genes within the DNA serve as molecular blueprints for the production of unique proteins. The steps in chemical metabolism within all the cells in the human body are mediated by specific enzymes that act as highly specialized chemical catalysts. Enzymes are proteins. Without enzymes life on earth would not be possible. The dictum, “one gene one enzyme” can be applied universally throughout life.
It is important to keep in mind that by the very nature of their integration into DNA, genes are inheritable. It is not uncommon to find polymorphisms within genes that are slight variations in the structure of those genes and what is referred to as single nucleotide polymorphisms (SNPs) that represent a singular change in the gene. These variations in genetic structure produce corresponding variations in the proteins that are encoded in the genes that are the blueprints for these proteins.
Given this overall view, genetic research in regards to breast cancer is guided by an investigation of the genes that encode the structure of the enzymes involved in estrogen production. The driving motivation of some of this work is to find the answer to the following question – Could the polymorphisms and SNPs in the genes responsible for the production of estrogens that are found in breast cancer patients result in an over-production of estrogens? Secondly, could this over-production trigger the onset of breast cancer?
Clinical data that reinforces the primacy of estrogens in the onset of breast cancer are the following:
In fact, circulating primary hormones in postmenopausal women, increased circulating concentrations of estradiol, estrone, estrone-sulfate, and androstendione have been shown to correlate with higher breast cancer risk. A thorough analysis of 663 women who developed breast cancer and had not received any hormonal-based therapy, demonstrated that the risk of breast cancer significantly increased with higher endogenous levels of total estradiol, free estradiol, estrone, estrone-sulfate, androstenedione, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and testosterone. Since this analysis was published, a few more prospective and case-control studies have been reported that have found similar results. It should be noted that the majority of populations studied were general populations with average breast cancer risk who were not taking any exogenous sex hormones.
In addition the levels of endogenous estrogens were studied in those patients that had a number of breast cancer risk factors including obesity, reproductive, demographic, and life style factors has been investigated by the Endogenous Hormones and Breast Cancer Collaborative Group in several studies. The results of these studies did not a show a statistical significance for the association between BMI (a metric whose value can be indicative of obesity) and breast cancer risk. However, in another cross-sectional analysis of 13 prospective studies by the same group, “estrogen and androgen levels were positively associated with obesity, smoking (15+ cigarettes daily) and alcohol consumption (20+g alcohol daily), and inversely linked with age.”
Although this summary does not include any data regarding the role of the level of endogenous androgens or progesterone in regard to the onset of breast cancer, the role of estrogens in the biology of breast cancer is very significant, and has led to the development of hormonal therapy medications as a way to limit the exposure of breast tissue to circulating estrogens. What follows is a more detailed look at these therapeutic approaches.
“Hormonal therapy medicines are used in four ways: (Jenni Sheng, MDJohns Hopkins University School of Medicine, Baltimore, MD)
“If the breast cancer is large and hormone receptor-positive, your doctor may recommend hormonal therapy before surgery to shrink the cancer. Treatments given before surgery are called neoadjuvant treatments, so hormonal therapy given this way is called neoadjuvant hormonal therapy.
“To reduce recurrence risk: If you’ve been diagnosed with early-stage hormone receptor-positive breast cancer, your treatment plan will include hormonal therapy after surgery and possibly other treatments to reduce the risk of the cancer coming back (recurrence). Treatments given after surgery are called adjuvant treatments, so hormonal therapy given this way is called adjuvant hormonal therapy.
“To stop advanced-stage cancer from growing: If you’ve been diagnosed with advanced-stage, hormone receptor-positive breast cancer, hormonal therapy can be used to help stop the cancer from growing.
“To reduce the risk of a first diagnosis: Hormonal therapy also can be used to reduce breast cancer risk in certain women who haven’t been diagnosed. Women with a much higher than average risk of breast cancer may take a hormonal therapy medicine preventively to reduce the risk of hormone receptor-positive breast cancer developing.
“How does hormonal therapy treat breast cancer?
Hormonal therapy medicines work in two ways:
“Hormonal therapy is not a treatment option for hormone receptor-negative breast cancer.
“It's important to know that hormonal therapy for breast cancer is different than hormone replacement therapy (HRT) for treating symptoms of menopause. HRT isn't used to treat breast cancer. HRT is taken by some women to treat troublesome menopausal side effects such as hot flashes and mood swings. HRT is used to raise estrogen levels that drop after menopause. HRT contains estrogen and can contain progesterone and other hormones. Hormonal therapy for breast cancer is exactly the opposite — it blocks or lowers estrogen levels in the body.
“Types of hormonal therapy to treat breast cancer
“There are three main types of hormonal therapy medicines used to treat breast cancer:
• Aromatase inhibitors stop the body from making estrogen.
• Selective estrogen receptor modulators (SERMs) block the action of estrogen on certain cells.
• Selective estrogen receptor downregulators (ERDs) block the action of estrogen on certain cells.
• Aromatase inhibitors
“Aromatase inhibitors lower estrogen levels by stopping the enzyme aromatase from changing other hormones into estrogen. In estrogen receptor-positive breast cancer, the hormone estrogen can stimulate the growth of breast cancer cells.
“There are three aromatase inhibitors used to treat breast cancer:
• Arimidex (chemical name: anastrozole)
• Aromasin (chemical name: exemestane)
• Femara (chemical name: letrozole)
“Selective estrogen receptor modulators (SERMs)
“Selective estrogen receptor modulators (SERMs) block the effects of estrogen on breast cancer cells by sitting in the estrogen receptors. If a SERM is in the estrogen receptor, estrogen can’t attach to the cancer cell and the cell doesn’t receive estrogen’s signals to grow and multiply.
“There are three SERMs used to treat breast cancer:
• Tamoxifen in pill form, also called tamoxifen citrate (brand name Nolvadex), and in liquid form (brand name: Soltamox)
• Evista (chemical name: raloxifene)
• Fareston (chemical name: toremifene)
“Selective estrogen receptor downregulators (SERDs)
“Selective estrogen receptor downregulators (SERDs), much like SERMs, block the effects of estrogen on breast cancer cells by sitting in the estrogen receptors. SERDs also lower the number of estrogen receptors and change the shape of breast cell estrogen receptors so they don’t work as well. There are two SERDs used to treat breast cancer:
• Faslodex (chemical name: fulvestrant)
• Orserdu (chemical name: elacestrant)
“Hormonal therapy side effects
Each hormonal therapy medicine may cause different side effects.
The most common side effects of the aromatase inhibitors are:
• joint and bone pain
• hot flashes
• fatigue
• weakness
“The most common side effects of the SERMs are:
• hot flashes
• vaginal discharge
• mood swings
• fatigue
“The most common side effects of the SERDs are:
• nausea
• bone pain
• fatigue
• hot flashes
• injection site pain (for Faslodex only)
“For many years, women took hormonal therapy for five years after surgery for early-stage, hormone receptor-positive breast cancer. In most cases, the standard of care is five years of tamoxifen, or two to three years of tamoxifen followed by two to three years of an aromatase inhibitor, depending on menopausal status.
“Recent research has found that in certain cases, taking tamoxifen for 10 years instead of five years after surgery lowered a woman’s risk of recurrence and improved survival.
“In most cases, a post-menopausal woman diagnosed with early-stage, hormone receptor-positive breast cancer would take an aromatase inhibitor for five years after surgery to reduce the risk of recurrence. After that, if breast cancer had been found in the lymph nodes, called node-positive disease, a woman would take an aromatase inhibitor for an additional five years, for a total of 10 years of hormonal therapy treatment.
“Doctors call taking hormonal therapy for 10 years after surgery extended adjuvant hormonal therapy.
“Ovarian suppression or removal
“In pre-menopausal women, most of the estrogen in the body is made by the ovaries. In some cases, medicine may be used to stop the ovaries from functioning temporarily, called ovarian suppression or ovarian shutdown. Two medicines commonly used are:
• Zoladex (chemical name: goserelin)
• Lupron (chemical name: leuprolide)
“These medicines are given as injections once a month for several months or every few months. They can be used alone or in combination with other hormonal therapy medicines to treat pre-menopausal women.
“Once you stop receiving the medicine, your ovaries usually begin functioning again. The time it takes for the ovaries to recover varies from woman to woman.
“Some women with a much higher than average risk of breast cancer may choose to have their ovaries removed, called prophylactic or preventive ovary removal, either before or after being diagnosed with breast cancer.”
This article is designed to summarize the known relationship between estrogen levels and the majority of breast cancers (ER+). It is important to keep in mind that this area of scientific, medical and clinically-based research is constantly generating new data, and the findings presented above do not represent the last word on the understanding of this devastating illness.