Monday, August 14, 2006

Environment and the Laws of Genetics - The Rh Blood Protein and Respiration - A New Discovery Worthy of the Nobel Prize

We are subject to all kinds of laws and chief among these are the laws of genetics, which are definitely supreme over the laws made by men. Religious zealots of all persuasions should consider the fact that what some might view to be "God in action" is found in all of us in the unique genetic blueprint of each of our organisms, regardless of our religious affiliation.

A special category in genetics is comprised by our blood types, especially the ABO and Rh blood groups. In our modern age, many citizens of civilized nations know their own ABO blood group (A, B, O, or AB) and most also know whether they are Rh-positive or Rh-negative, since this knowledge can be essential for healthy childbearing.

A recent question from a reader of LexiLine about the origin and mutation of the Rh protein led the Law Pundit to do a bit of research, which is our specialty, leading to a remarkable potential discovery about the cause for the Rh-negative mutation.

For a bit of background information, we refer to a mathematically produced dendrite of the world distribution of blood groups, adapted from A. Kelus and J. Lukaszewicz (authors of Taksonomia wroclawska w zastosowaniu do zagadnien seroantropologii Archiwum Immunol. terap. Doswiadizalnej 1 245-254 , 1953), as presented in Ludwig Hirszfeld (also Hirschfeld or Hirsfeld), Probleme der Blutgruppenforschung (book review here, or see Footnote 1 below).

Also for background, we refer to a very short discussion of the prevalence of Rh-negative in certain ethnic groups by Steve Mack, Post-doc/Fellow, Molecular and Cell Biology, Children's Hospital Oakland Research Institute.

A chart of the ethnic distribution of Rh+ (Rh-positive) and Rh- (Rh-negative) blood alleles (based on data from the American Association of Blood Banks, AABS) is found at the bottom of the article at http://www.pjms.com.pk/issues/aprjun05/article/article14.html.
The distribution table is located just before the conclusion section of the article at the end.

All modern genetic DNA evidence points to an "out-of-Africa" origin for humanity. Hence, it is our view that Rh+ (Rh-positive) is the original Rh blood allele in humans, since black Africans in Africa who have not mixed either with white populations or with mixed-race persons have ONLY this Rh allele and no evidence of Rh- (Rh-negative).

Since Rh- (Rh-negative) is an allele which is found predominantly among white populations (ca. 40-45% in Europe), it must clearly be a mutation which followed after man's migrations from Africa to Europe.

Moreover, Rh-negative is found much more frequently among A and O blood groups, which are the major blood types in Western Europe, whereas Rh-negative is much rarer among persons with B and AB blood types. See http://en.wikipedia.org/wiki/Blood_type

New research has been published about the Rh protein by Sydney G. Kustu and William Inwood, and we think that it is so important that it will ultimately be awarded the Nobel Prize in Medicine because of its fundamental potential impact on biological and genetic research.

See http://www.berkeley.edu/news/media/releases/2005/05/25_rhesus.shtml and
S. Kustu and W. Inwood, Biological gas channels for NH3 and CO2: evidence that Rh (Rhesus) proteins are CO2 channels, Transfus. Clin. Biol. (Transfusion Clinique et Biologique (Paris), 13:103-10, 2006. [TCB (abstract)] and
Kwang-Seo Kim, Eithne Feild, Natalie King, Takuro Yaoi, Sydney Kustu, and William Inwood, Spontaneous Mutations in the Ammonium Transport Gene AMT4 of Chlamydomonas reinhardtii, Genetics, Vol. 170, 631-644, June 2005, [Abstract] [Full Text] [Supplemental Data] )

As noted in the Berkeley article (under the graphic caption) the Rh protein plays a significant role as a channel for CO2 gas (carbon dioxide) across cell membranes in the body:

"Rh proteins act as gas channels that help speed the transfer of carbon dioxide (CO2) in and out of red blood cells. CO2 can also pass through the cell membrane unaided (above right), but not quickly enough."

The PubMed Abstract writes:

"Department of Plant and Microbial Biology, 111 Koshland Hall, University of California, Berkeley, Berkeley, CA 94720-3102, USA. kustu@nature.berkeley.edu

Physiological evidence from our laboratory indicates that Amt/Mep proteins are gas channels for NH3, the first biological gas channels to be described. This view has now been confirmed by structural evidence and is displacing the previous belief that Amt/Mep proteins were active transporters for the NH4+ ion. Still disputed is the physiological substrate for Rh proteins, the only known homologues of Amt/Mep proteins. Many think they are mammalian ammonium (NH4+ or NH3) transporters. Following Monod's famous dictum, "Anything found to be true of E. coli must also be true of elephants" [Perspect. Biol. Med. 47(1) (2004) 47], we explored the substrate for Rh proteins in the unicellular green alga Chlamydomonas reinhardtii. C. reinhardtii is one of the simplest organisms to have Rh proteins and it also has Amt proteins. Physiological studies in this microbe indicate that the substrate for Rh proteins is CO2 and confirm that the substrate for Amt proteins is NH3. Both are readily hydrated gases. Knowing that transport of CO2 is the ancestral function of Rh proteins supports the inference from hematological research that a newly evolving role of the human Rh30 proteins, RhCcEe and RhD, is to help maintain the flexible, flattened shape of the red cell.
PMID: 16563833 [PubMed - in process]
"

Hence, it would seem to be a likely hypothesis to this observer, presented here for the first time, that Rh- (Rh-negative) developed due to a (presumably beneficial) change mandated in our human breathing of the Earth's air in the more northerly European latitudes.

This would make sense since there is in fact a global air-sea flux of CO2 (carbon dioxide) which could correspond to the mutation we see in Rh from Africa (Rh+) to Western Europe (Rh-). As noted in a Colloquium of the US National Academy of Sciences:

"Temperate and polar oceans of the both hemispheres are the major sinks for atmospheric CO2, whereas the equatorial oceans are the major sources for CO2. The Atlantic Ocean is the most important CO2 sink, providing about 60% of the global ocean uptake, while the Pacific Ocean is neutral because of its equatorial source flux being balanced by the sink flux of the temperate oceans. The Indian and Southern Oceans take up about 20% each."

(The above is quoted from the Abstract of Taro Takahashi, Richard A. Feely, Ray F. Weiss, Rik H. Wanninkhof, David W. Chipman, Stewart C. Sutherland, and Timothy T. Takahashi, Global air-sea flux of CO2: An estimate based on measurements of sea–air pCO2 difference, Proc. Natl. Acad. Sci. USA, Vol. 94, pp. 8292–8299, August 1997, colloquium paper presented at a colloquium entitled "Carbon Dioxide and Climate Change," organized by Charles D. Keeling, held November 13–15, 1995, at the National Academy of Sciences, Irvine, CA.)

In other words, the Rh mutation from Rh-positive to Rh-negative is arguably environmental in cause, with the human body adjusting to different CO2 and oxygen conditions as present in Western Europe and as opposed to those prevalent in the original homeland of Africa, as evidenced by the differing atmospheric CO2 sinks prevailing in oceans bordering on the two different geographic locations. Presumably, the reason for the mutation was in part "the air" (and climate) and the human body's changed oxygen (O2)/carbon dioxide (CO2) balance.

We presume that the reason for the mutation can also be analogized to the body's reaction to decreased levels of oxygen at higher altitudes, which leads to substantial biological reactions:

"Adaptation to a lower oxygen environment causes the body to produce a chain of biological reactions. The heart and lungs are stimulated to increase their functions and even over the long term, to increase in size. Blood vessels dilate and new capillaries are formed in the heart, brain and skeletal muscles. In the blood, levels of erythropoietin (EPO), haemoglobin, myoglobin and 2,3 diglycerophosphate increase. All these factors make the blood capable of carrying more oxygen and on a cellular level there is a growth of the cellular structures needed for the metabolism of oxygen. After IHT (Intermittent Hypoxic Treatment) the lactate threshold increases indicating that the body is utilising available oxygen more efficiently."

The same holds true for thermoregulation, i.e. the body's response to temperature. The Medical Department of the U.S. Army has published a book titled Medical Aspects of Harsh Environments (Volume I), which contains a great amount of relevant information about human adaptation and human physiological responses to heat and cold. A map of the average wet bulb globe temperature (WBGT) index in the northern hemisphere during July is shown at page 103 of that volume and a similar map at page 105 of that volume shows the relationship between selected regional skin temperatures and core body temperature at rest over a range of temperate and hot climatic conditions.

It is clear from the discussion in subsequent pages of that volume that thermoregulation is related to oxygen uptake and thus of course, conversely, to carbon dioxide expulsion. Moreover, not only does the respiratory system react significantly to heat and cold (see page 366 of that volume), but this is accompanied by changes in the solubility of oxygen and carbon dioxide in the blood (p. 368): "as the temperature decreases, the solubility of carbon dioxide in blood increases."

Since the Rh protein affects the rate at which carbon dioxide "channels through" cell membranes, its role may well be comparable in respiration to that found for ion pathways in the plasma membrane. As noted at page 179 of that volume:

"Ions do not readily cross lipid bilayers despite their large concentration gradients across plasma membranes. In general, they require specialized channels or carriers to do so..... Membrane channels are proteins that contain hydrophilic pores that penetrate the lipid bilayer, permitting the diffusion of specific ions down their electrochemical gradients to enter or leave cells."

Given the fact that "the Rh polypeptide is a major fatty acid-acylated erythrocyte membrane protein", i.e. an element of our red blood cells - which transport oxygen to the blood, the discovery that Rh proteins act as gas channels for carbon dioxide in living organisms is one of the most important discoveries made in medicine (and genetics) - ever.

__________
Footnote 1

The book review in German at SpringerLink.com by L. Ballowitz of Hirszfeld, L, Probleme der Blugruppenforschung, is reproduced here:

"BUCHBESPRECHUNGEN

Hirszfeld L.: Probleme der Blutgruppenforschung. Mit einem Geleitwort von Prof. Dr. O. Prokop, Berlin. 160 Seiten, 29 Abbildungen, 64 Tabellen. VEB Gustav Fischer Verlag, Jena 1960. Preis: Gln. DM 22,-

Für jeden, der an blutgruppenserologischen Fragen interessiert ist, wird diese ausgezeichnete Zusammenschau über die Entwicklung der Lehre von den Blutgruppen äußerst anregend sein. Hirszfeld ist seit etwa 40 Jahren durch zahlreiche, zum Teil bahnbrechende Arbeiten mit an dem raschen Anwachsen der Kenntnisse auf diesem Gebiet beteiligt. Auch in dem vorliegenden Buch ist vor allem die äußerst vielseitige, weitschauende und doch kritische Interpretation der erhobenen Befunde bemerkenswert. Besonders ausführlich sind Fragen der Vererbung von Blutgruppen, solche der Anthropologie, ferner Möglichkeiten der Vaterschafts- und Mutterschaftsausschließung sowie die Immunpathologie der Schwangerschaft abgehandelt. Eine gute Orientierung ist über die von dem Verf. entwickelte Pleiaden- und Abortus-Theorie möglich. Durch das Einfügen persönlicher Erfahrungen wird die Darstellung angenehm aufgelockert. Prokop gebührt Dank, daß er die Veröffentlichung dieses 1953 abgeschlossenen und vom Verf. hinterlassenen Buches möglich machte.

L. Ballowitz, Berlin
"

Environment and the Laws of Genetics - The Rh Blood Protein and Respiration - A New Discovery Worthy of the Nobel Prize

We are subject to all kinds of laws and chief among these are the laws of genetics, which are definitely supreme over the laws made by men. Religious zealots of all persuasions should consider the fact that what some might view to be "God in action" is found in all of us in the unique genetic blueprint of each of our organisms, regardless of our religious affiliation.

A special category in genetics is comprised by our blood types, especially the ABO and Rh blood groups. In our modern age, many citizens of civilized nations know their own ABO blood group (A, B, O, or AB) and most also know whether they are Rh-positive or Rh-negative, since this knowledge can be essential for healthy childbearing.

A recent question from a reader of LexiLine about the origin and mutation of the Rh protein led the Law Pundit to do a bit of research, which is our specialty, leading to a remarkable potential discovery about the cause for the Rh-negative mutation.

For a bit of background information, we refer to a mathematically produced dendrite of the world distribution of blood groups, adapted from A. Kelus and J. Lukaszewicz (authors of Taksonomia wroclawska w zastosowaniu do zagadnien seroantropologii Archiwum Immunol. terap. Doswiadizalnej 1 245-254 , 1953), as presented in Ludwig Hirszfeld (also Hirschfeld or Hirsfeld), Probleme der Blutgruppenforschung (book review here, or see Footnote 1 below).

Also for background, we refer to a very short discussion of the prevalence of Rh-negative in certain ethnic groups by Steve Mack, Post-doc/Fellow, Molecular and Cell Biology, Children's Hospital Oakland Research Institute.

A chart of the ethnic distribution of Rh+ (Rh-positive) and Rh- (Rh-negative) blood alleles (based on data from the American Association of Blood Banks, AABS) is found at the bottom of the article at http://www.pjms.com.pk/issues/aprjun05/article/article14.html.
The distribution table is located just before the conclusion section of the article at the end.

All modern genetic DNA evidence points to an "out-of-Africa" origin for humanity. Hence, it is our view that Rh+ (Rh-positive) is the original Rh blood allele in humans, since black Africans in Africa who have not mixed either with white populations or with mixed-race persons have ONLY this Rh allele and no evidence of Rh- (Rh-negative).

Since Rh- (Rh-negative) is an allele which is found predominantly among white populations (ca. 40-45% in Europe), it must clearly be a mutation which followed after man's migrations from Africa to Europe.

Moreover, Rh-negative is found much more frequently among A and O blood groups, which are the major blood types in Western Europe, whereas Rh-negative is much rarer among persons with B and AB blood types. See http://en.wikipedia.org/wiki/Blood_type

New research has been published about the Rh protein by Sydney G. Kustu and William Inwood, and we think that it is so important that it will ultimately be awarded the Nobel Prize in Medicine because of its fundamental potential impact on biological and genetic research.

See http://www.berkeley.edu/news/media/releases/2005/05/25_rhesus.shtml and
S. Kustu and W. Inwood, Biological gas channels for NH3 and CO2: evidence that Rh (Rhesus) proteins are CO2 channels, Transfus. Clin. Biol. (Transfusion Clinique et Biologique (Paris), 13:103-10, 2006. [TCB (abstract)] and
Kwang-Seo Kim, Eithne Feild, Natalie King, Takuro Yaoi, Sydney Kustu, and William Inwood, Spontaneous Mutations in the Ammonium Transport Gene AMT4 of Chlamydomonas reinhardtii, Genetics, Vol. 170, 631-644, June 2005, [Abstract] [Full Text] [Supplemental Data] )

As noted in the Berkeley article (under the graphic caption) the Rh protein plays a significant role as a channel for CO2 gas (carbon dioxide) across cell membranes in the body:

"Rh proteins act as gas channels that help speed the transfer of carbon dioxide (CO2) in and out of red blood cells. CO2 can also pass through the cell membrane unaided (above right), but not quickly enough."

The PubMed Abstract writes:

"Department of Plant and Microbial Biology, 111 Koshland Hall, University of California, Berkeley, Berkeley, CA 94720-3102, USA. kustu@nature.berkeley.edu

Physiological evidence from our laboratory indicates that Amt/Mep proteins are gas channels for NH3, the first biological gas channels to be described. This view has now been confirmed by structural evidence and is displacing the previous belief that Amt/Mep proteins were active transporters for the NH4+ ion. Still disputed is the physiological substrate for Rh proteins, the only known homologues of Amt/Mep proteins. Many think they are mammalian ammonium (NH4+ or NH3) transporters. Following Monod's famous dictum, "Anything found to be true of E. coli must also be true of elephants" [Perspect. Biol. Med. 47(1) (2004) 47], we explored the substrate for Rh proteins in the unicellular green alga Chlamydomonas reinhardtii. C. reinhardtii is one of the simplest organisms to have Rh proteins and it also has Amt proteins. Physiological studies in this microbe indicate that the substrate for Rh proteins is CO2 and confirm that the substrate for Amt proteins is NH3. Both are readily hydrated gases. Knowing that transport of CO2 is the ancestral function of Rh proteins supports the inference from hematological research that a newly evolving role of the human Rh30 proteins, RhCcEe and RhD, is to help maintain the flexible, flattened shape of the red cell.
PMID: 16563833 [PubMed - in process]
"

Hence, it would seem to be a likely hypothesis to this observer, presented here for the first time, that Rh- (Rh-negative) developed due to a (presumably beneficial) change mandated in our human breathing of the Earth's air in the more northerly European latitudes.

This would make sense since there is in fact a global air-sea flux of CO2 (carbon dioxide) which could correspond to the mutation we see in Rh from Africa (Rh+) to Western Europe (Rh-). As noted in a Colloquium of the US National Academy of Sciences:

"Temperate and polar oceans of the both hemispheres are the major sinks for atmospheric CO2, whereas the equatorial oceans are the major sources for CO2. The Atlantic Ocean is the most important CO2 sink, providing about 60% of the global ocean uptake, while the Pacific Ocean is neutral because of its equatorial source flux being balanced by the sink flux of the temperate oceans. The Indian and Southern Oceans take up about 20% each."

(The above is quoted from the Abstract of Taro Takahashi, Richard A. Feely, Ray F. Weiss, Rik H. Wanninkhof, David W. Chipman, Stewart C. Sutherland, and Timothy T. Takahashi, Global air-sea flux of CO2: An estimate based on measurements of sea–air pCO2 difference, Proc. Natl. Acad. Sci. USA, Vol. 94, pp. 8292–8299, August 1997, colloquium paper presented at a colloquium entitled "Carbon Dioxide and Climate Change," organized by Charles D. Keeling, held November 13–15, 1995, at the National Academy of Sciences, Irvine, CA.)

In other words, the Rh mutation from Rh-positive to Rh-negative is arguably environmental in cause, with the human body adjusting to different CO2 and oxygen conditions as present in Western Europe and as opposed to those prevalent in the original homeland of Africa, as evidenced by the differing atmospheric CO2 sinks prevailing in oceans bordering on the two different geographic locations. Presumably, the reason for the mutation was in part "the air" (and climate) and the human body's changed oxygen (O2)/carbon dioxide (CO2) balance.

We presume that the reason for the mutation can also be analogized to the body's reaction to decreased levels of oxygen at higher altitudes, which leads to substantial biological reactions:

"Adaptation to a lower oxygen environment causes the body to produce a chain of biological reactions. The heart and lungs are stimulated to increase their functions and even over the long term, to increase in size. Blood vessels dilate and new capillaries are formed in the heart, brain and skeletal muscles. In the blood, levels of erythropoietin (EPO), haemoglobin, myoglobin and 2,3 diglycerophosphate increase. All these factors make the blood capable of carrying more oxygen and on a cellular level there is a growth of the cellular structures needed for the metabolism of oxygen. After IHT (Intermittent Hypoxic Treatment) the lactate threshold increases indicating that the body is utilising available oxygen more efficiently."

The same holds true for thermoregulation, i.e. the body's response to temperature. The Medical Department of the U.S. Army has published a book titled Medical Aspects of Harsh Environments (Volume I), which contains a great amount of relevant information about human adaptation and human physiological responses to heat and cold. A map of the average wet bulb globe temperature (WBGT) index in the northern hemisphere during July is shown at page 103 of that volume and a similar map at page 105 of that volume shows the relationship between selected regional skin temperatures and core body temperature at rest over a range of temperate and hot climatic conditions.

It is clear from the discussion in subsequent pages of that volume that thermoregulation is related to oxygen uptake and thus of course, conversely, to carbon dioxide expulsion. Moreover, not only does the respiratory system react significantly to heat and cold (see page 366 of that volume), but this is accompanied by changes in the solubility of oxygen and carbon dioxide in the blood (p. 368): "as the temperature decreases, the solubility of carbon dioxide in blood increases."

Since the Rh protein affects the rate at which carbon dioxide "channels through" cell membranes, its role may well be comparable in respiration to that found for ion pathways in the plasma membrane. As noted at page 179 of that volume:

"Ions do not readily cross lipid bilayers despite their large concentration gradients across plasma membranes. In general, they require specialized channels or carriers to do so..... Membrane channels are proteins that contain hydrophilic pores that penetrate the lipid bilayer, permitting the diffusion of specific ions down their electrochemical gradients to enter or leave cells."

Given the fact that "the Rh polypeptide is a major fatty acid-acylated erythrocyte membrane protein", i.e. an element of our red blood cells - which transport oxygen to the blood, the discovery that Rh proteins act as gas channels for carbon dioxide in living organisms is one of the most important discoveries made in medicine (and genetics) - ever.

__________
Footnote 1

The book review in German at SpringerLink.com by L. Ballowitz of Hirszfeld, L, Probleme der Blugruppenforschung, is reproduced here:

"BUCHBESPRECHUNGEN

Hirszfeld L.: Probleme der Blutgruppenforschung. Mit einem Geleitwort von Prof. Dr. O. Prokop, Berlin. 160 Seiten, 29 Abbildungen, 64 Tabellen. VEB Gustav Fischer Verlag, Jena 1960. Preis: Gln. DM 22,-

Für jeden, der an blutgruppenserologischen Fragen interessiert ist, wird diese ausgezeichnete Zusammenschau über die Entwicklung der Lehre von den Blutgruppen äußerst anregend sein. Hirszfeld ist seit etwa 40 Jahren durch zahlreiche, zum Teil bahnbrechende Arbeiten mit an dem raschen Anwachsen der Kenntnisse auf diesem Gebiet beteiligt. Auch in dem vorliegenden Buch ist vor allem die äußerst vielseitige, weitschauende und doch kritische Interpretation der erhobenen Befunde bemerkenswert. Besonders ausführlich sind Fragen der Vererbung von Blutgruppen, solche der Anthropologie, ferner Möglichkeiten der Vaterschafts- und Mutterschaftsausschließung sowie die Immunpathologie der Schwangerschaft abgehandelt. Eine gute Orientierung ist über die von dem Verf. entwickelte Pleiaden- und Abortus-Theorie möglich. Durch das Einfügen persönlicher Erfahrungen wird die Darstellung angenehm aufgelockert. Prokop gebührt Dank, daß er die Veröffentlichung dieses 1953 abgeschlossenen und vom Verf. hinterlassenen Buches möglich machte.

L. Ballowitz, Berlin
"

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