February 7, 2010

Luciano A. Marrafinni
Department of Biochemistry
Molecular Biology and Cell Biology
Northwestern University
2205 Tech Drive Evanston, IL 60208

Dear Luciano Marrafinni:

I have read your article (Self Versus Non-Self Discrimination During CRISPR RnA-directed Immunity, Luciano A. Marrafinni and Erik J. Southeimer NATURE vol. 463 no. 7280 January 28, 2010 page 568) and find it intriguing.  My own interest is in human fertility and in particular how it is affected by the matching up of normal genetic variation. 

It is known, but not widely known, that among humans and most other animals fertility is strongly related to kinship.  Until you get into the zone of inbreeding, which appears to mean effectively a couple more closely related than second cousins (I oversimplify) the nearer the genetic match the more offspring, or at least the more in the second generation.  This appears to be true out to perhaps seventh or eighth cousins, by which time fertility levels off below replacement levels. 

I should be surprised if you are not surprised to have me say that.  As I said, this is not widely understood.  But the proof and references are on the enclosed DVD, and I hope you will take a look. 

Humans and archaea are about as unrelated as living things get to be, so if anybody has the right to say, “That’s not my field,” I suppose it would be you.  And by rights I should not trouble you except for one small thing.  First let me quote part of the second sentence of your introduction.  “Clustered, regularly spaced … loci protect bacteria and archaea from invasion … through a genetic interference pathway.”  That genetic interference has, of course, been discovered by you.

The thing is this.  As the DVD shows, I developed a computer model that reproduces with remarkable fidelity the relationship between fertility and shared DNA in humans and other animals.  My program models a population and its genes and follows it over a number of generations, reading out the total number of offspring each generation.  It is very successful in demonstrating that a population gets into trouble if the random mating pool is too large.

It makes sense.  As a crude example, consider a kind of shorebird living where there are abundant fish and abundant shellfish, to neither of which it is quite optimized.  The selective pressure is both to accumulate genetic changes that improve fishing and changes that improve shellfishing.  But these are likely to be different mutations.  The population cannot do both at once.  Given a large number or opportunities and pressures, the species may become fit for nothing at all.  The obvious solution is to limit population sizes, at least the size of the mating circles, and let some evolve one way and others another way.  Thus an ovum among this population is under pressure to exclude sperm that do not match its own DNA closely, just like your archaea. 

But while my computer model follows the rules of genetics and is a good model, it is a little unappealing.  Because the self-recognition it employs is not what you would expect from control mechanisms or gene interactions.  When I go there I cannot make a good model.  Instead the mechanism appears to be segments of regularly spaced loci.  That is what got my attention. 

There is another issue.  Fertility is falling worldwide and is particularly low in highly developed societies.  This is as you would expect.  They have a lot of genetic diversity.  Societies in which mating choice is a member of the same small village or band have very high birth rates.  But this what you might call urban infertility can often be corrected by directly injecting sperm into the ovum.  A viable pregnancy can be established where it could not if the sperm were left on its own.  In all likelihood the problem is with the sperm.  For some reason it lacks oomph. 

And that reason is pretty much beyond me.  What can go wrong with a sperm genetically?  It is haploid.  It only has one set of chromosomes.  There is no opportunity for mismatch.  Perhaps the mismatch is between one part of its genome and another, but that is not the way my computer sees it.  Perhaps the problem lies in the system that produces the sperm, and I would guess that this is the important one.

But just possibly the problem is with the egg’s own defenses.  It may be that the ovum somehow senses non-self and will not cooperate.  After all, in humans particularly it is a terribly expensive investment to establish a pregnancy and raise a child.  If that child is not going to do well, it is better to call it off at the egg-sperm interaction, at least in terms of long term fertility and welfare of the species. 

In pursuing this issue of fertility and gene pool size, I have established a website NoBabies.net where I post information as it comes in and ideas as they occur.  I have the fond hope that the experts I cite and write to will respond so I can post their wisdom for the world, but apparently time pressures prevent this. 

So if you are interested, if you have anything further to offer or I can be of assistance in any way, please do get in touch;


M. Linton Herbert MD

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