September 24, 2012
to be posted on

Nathaniel Comfort
Associate Professor
History of Medicine
Johns Hopkins University
1900 E. Monument St.
Baltimore, MD 21205
twitter: @nccomfort

Dear Professor Comfort:
I have read In Search of Human Perfection with pleasure.  It is always nice to see an emotionally difficult subject handled with cool, meticulous work.  There were a couple of things that I was hoping to learn more about.

The first, as I have mentioned, is Rh incompatibility.  My own opinion is that eliminating it is the greatest accomplishment of eugenics, if by that one means reducing disease produced by genes in the newborn rather than eliminating the genes themselves.  In fact I think it is the greatest accomplishment of medicine.  I shall defend that opinion after a few numbers. 

I must pull my knowledge out of medical school, which I may have attended before you were born, so take everything with a bit of skepticism.  I believe they say “D” now rather then “Rh,” but what precisely the change means I don’t know.  Anyway I’ll have to stick with “Rh” because that is what I learned.

A chromosome in the human genome harbors a locus for the Rh alleles, of which there are two, positive and negative.  The positive allele attaches an antigen on the surface of the red blood cell; the negative does not.  The antigen is not a common one in contrast with the A antigen, which is strong and common.  If you do not have A or AB blood you probably have the antibody against the A antigen.  If you do not have the Rh negative allele you still most probably don’t have the antibody against it.  The positive is dominant, of course.  So if you are homozygous for positive or heterozygous you will have Rh positive blood.  Homozygous negative give Rh negative blood.

Before modern medicine, if an Rh negative woman married an Rh positive man of course she could have an Rh positive baby.  If the man was homozygous positive, all of her babies would be positive; otherwise half would be positive.  The first pregnancy generally went well, but at delivery the baby’s red cells usually entered the mother’s circulation sufficiently to elicit an antibody response.  The mother was now primed to attack Rh positive cells.  During the next Rh positive pregnancy maternal antibodies could cross the placenta and destroy fetal blood cells.  The antibodies against A could not do so, by the way.  In fact, if the baby was A and the mother was not, the anti A antibodies would destroy any fetal blood cells that entered the maternal circulation and destroy them so fast there was not time to mount an anti Rh response.  (I’m not sure how the B antigen fits in.)  Thus it is not true that all Rh negative women married to Rh positive men would have a problem with multiple pregnancies.  We shall ignore this protective effect, although it was important in the development of the treatment.  They take anti Rh antibodies and heat treat them so that they cannot cross the placenta.  Given at judicious times, this treated antibody prevents any maternal attack and thus the incidence of problems has dropped just about to zero. 

Back when it was still happening, and I was involved with the care of affected babies early in my career, the breaking of the fetal red blood cells released hemoglobin into the fetal circulation.  This rapidly crossed the placenta to be cleared by the mother’s liver.  But at birth the umbilical cord was cut and the remaining maternal antibodies would create a surge of hemoglobin in the newborn which the newborn’s liver could not cope with well and which was able to cross the immature blood brain barrier of the newborn and cause brain damage in the first few days of life.  Strategies like exchange transfusions and putting the infant under ultraviolet light to detoxify the hemoglobin were available but not all that good. 

As Rh positive pregnancy followed Rh positive pregnancy the wastage of fetal red blood cells could produce a significant anemia.  This could cause congestive heart failure in the fetus with the fetus swelling up, a condition called hydrops fetalis.  If that got to be too bad the baby could get stuck in the birth canal and without modern surgery the mother’s subsequent death was very unpleasant as the fetus died, decayed and the mother went septic.  I know it happened.  I have a friend it happened to except modern surgery just barely saved her.

Now for the numbers: The numbers are hard to find, but assuming that the people of Appalachia had the same incidence as the people of the Scottish borders and northern Ireland whence they hailed, the number of Rh negative women should have been 15% to 20%, let’s say 18 % of the population.  That means about 42 % of the alleles in the community were negative alleles and 58% were positive.  So, assuming random mating, the fetus of an Rh negative woman would have necessarily one Rh negative allele and a 58% chance of a positive.  58% of 18% is roughly 10% of the population being Rh positive babies born of Rh negative women.  Of course many of those would be the result of the first Rh positive pregnancy and would have no problem.  The rest were pretty much dead or brain damaged.  And people being stubborn, you might suppose that a woman who lost one baby would be a little more eager than average to have another.

In short, the idea that 5% of the population was “feebleminded” is no stretch at all.  I would guess that and a roughly equal number dead, not to mention the dead young mothers.  You see the possibility of finding fewer “feebleminded” offspring of cousins than of less related people, as Darwin’s son in fact did.  Cousins are slightly more likely to have the same blood type.  But there is a terrible problem here, which I shall address later.

Compare cancer.  A 60 year old is treated and cured and lives in perfect health to die of something else at age 70.  That would be a good result.  You have saved a seventh of a life, which would be a wonderful thing, although it would not be the most exciting seventh.  Prevent one case of Rh incompatibility and you have saved a whole life of health.  To have the same effect as preventing Rh incompatibility you would have to cure 70% of the population from cancer.  That just isn’t happening.  The same holds true for heart disease.  That is why I say the conquest of Rh incompatibility is the most glorious triumph of all medicine, possibly of all civilization.  It turned life (among those of us from Africa and Europe and anywhere that has a significant Rh negative presence) from a nightmare to something a rational person might be able to endure. 

And yet it is unsung.  Some brilliant medical historian (wink, wink, nudge, nudge) needs to get the facts clear and write a book. 

Notice, by the way, that the usual eugenic approach is flawed.  Since the prevalence of the two alleles is about even, and since eliminating one brain damaged person from the gene pool eliminates one positive allele and one negative allele, there is no change in gene frequency.  All those sterilized feebleminded folks, it was all in vain. 

Once the disease was fairly well understood laws were passed (I’m not quite sure when and by whom) that prevented Rh negative women from marrying Rh positive men.  That’s not quite fair.  Either also prohibit Rh positive women from marrying Rh positive men to balance it, or if you want to maximize freedom, take A (and maybe B) status into account.  Alas I am not even sure how the law read or if, in fact, that was the case.  That’s why we have good historians.  Another advantage of prohibiting marrying across the Rh divide is that over several generations the vast majority of the Rh positive people, and all the Rh negative people, will be homozygous.  Were we to lose our high tech civilization, the program could continue.  Firstborns of the Rh positive population would be considered Rh positive.  If incompatibility showed up (and it’s not that hard to spot) the mother would be told, “Sorry, you married the wrong guy.  You need to leave him and go marry over there.” 

There is also an even less palatable low tech approach.  Don’t worry about the feebleminded; they don’t compete well anyway.  Assuming that the prevalence of the Rh negative allele is low, the real threat is that normal first child.  To drive a low incidence of Rh negative toward zero you must sacrifice the firstborn.  I don’t recommend that, but don’t think it never happened.  Remember Abraham and Isaac.  In fact my brother (a better Bible scholar than I) says the requirement of killing the first born is still there in scripture. 

I think you handled the difficult topic of racism and eugenics quite well, but my impression is that the question of inbreeding is also a eugenic issue.  It’s thought to be very bad.  The prejudice can be traced back centuries before Darwin.  The Catholic Church forbad marrying cousins for an absurd distance out on the family tree.  And of course the prejudice is still very strong, I might say viscous.

And that is the second thing I was looking for.  Why?  In fact if you want to have a lot of grandchildren, marry a third cousin.  Instead of raving on, I’ll give you some references and a link:
On the Regulation of Populations of Mammals, Birds, Fish and Insects, Richard M. Sibly, Daniel Barker, Michael C. Denham, Jim Hope and Mark Pagel SCIENCE vol. 309 July 22, 2005 page 609

An Association between Kinship and Fertility of Human Couples Agnar Helgason et al. SCIENCE vol. 329 no. 5864 February 8, 2008 page 813 – 816

Human Fertility Increases with marital radius. Rodrigo Labourian and Antonio Amorim.  GENETICS volume 178 January 2008 page 603

Comment on “An Association Between the Kinship and Fertility of Human Couples,” Rodrigo Labouriau and António Amorim SCIENCE vol. 322, page 1634b December 12, 2008

If you want more, I have it.

My interest in this has expanded to fill my whole life.  Nations are dying for lack of babies.  It may be too late to reverse the thing, but if it can be reversed the only way to survive is for countries with low birth rates to develop a strong preference for those third cousin marriages.  (Kissing cousins, we used to say in the South.)  My success rate in stirring up anything like that has been about zero.  Well I for one would rather go down swinging.

And that brings up the issue I promised, the terrible cost of reducing Rh incompatibility by marrying cousins.  If you do that, you’re going to have a lot of children, and if incompatibility emerges (and you’re too stubborn to divorce) the tragedy of the death of the mother becomes a more serious risk. 

Thank you.


M. Linton Herbert MD 

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