to produce red cells. That is the hormone ery- 

 thropoietin (14). It's possible that this mutation 

 is affecting the cells that have committed them- 

 selves to erythropoietic differentiation but have 

 not actually begun to synthesize hemoglobin, and 

 that what it does is to decrease the ability of 

 these cells to respond to erythropoietin. This is 

 one possible hypothesis - that they do not respond 

 normally to erythropoietin, so they are late in 

 initiating hemoglobin synthesis. 



Now, if this view is correct, the defect in 

 mice of genotype f/f is manifested at a stage 

 prior to the initiation of hemoglobin synthesis. 

 Apparently, here is a case of a cell being al- 

 ready committed to erythropoietic differentia- 

 tion, since the defect appears to be specific for 

 that pathway; and yet the defect is manifested 

 at a stage prior to the synthesis of hemoglobin. 

 It seems that there must be a whole set of con- 

 trols of early differentiation which act well be- 

 fore the cell actually begins to differentiate to 

 synthesize hemoglobin. Thus, these controls 

 may have nothing to do with regulation of the 

 stable messengers or ribosomes involved in 

 hemoglobin synthesis, since they're acting at 

 stages much earlier than that. One would like 

 to know whether or not this type of early dif- 

 ferentiation involves a different means of regu- 

 lation. 



GROSS: Why do you think that kind of 

 regulatory process would involve things other 

 than ribosomes and messenger and what's your 

 suggestion for the other things? 



TILL: Simple prejudice. I have no evidence 

 whatsoever. 



GROSS: I've heard other people make that 

 statement. It would be very nice if one knew 

 about these things. However if you want to make 

 hypotheses that one can test about what makes 

 a cell decide to do something, you have to use 

 things that you know about. 



TILL: Let me take a possible example. 

 There is a system in the mouse which regulates 

 whether or not a transplant will grow, if you 

 take it from one inbred strain to another. It's 

 the histocompatibility system. There are sev- 

 eral genes that have been mapped that are con- 

 cerned with this. The principal one is the H-2 

 locus. This is a complex locus but apparently 

 one of its functions is to control the synthesis 

 of an antigen on the surface of the cell. This 

 antigen is what the new host reacts to if you 

 transplant the cells into an unrelated host. Since 

 such transplantations of cells do not occur in 

 nature, one may ask: What is the normal func- 

 tion of the surface antigen, if any? One sugges- 



tion which has been made is that the real func- 

 tion of the H-2 locus is a regulatory function in 

 the normal animal (15). If so, the antigen we 

 detect when we transplant cells from one animal 

 to another is part of a normal regulatory sys- 

 tem. This antigen is known to be on the cell 

 surface and it's possible that cell surfaces are 

 what are involved in regulation of this level. 



GROSS: I'm still afraid that it is just a 

 matter of principle which is under discussion. 

 It's entirely conceivable that cell surfaces do 

 differ dramatically from one differentiation path 

 to another, and that if they do differ, they differ 

 because their macromolecular content is dif- 

 ferent. If they have different proteins, then the 

 initial event still has to arise in the genome. 



TILL: I think there is a misunderstanding 

 here. I'm certainly not suggesting that all the 

 recent work on the mechanisms of regulation 

 of protein synthesis is incorrect, nor that there 

 is some new system of protein synthesis that 

 has nothing to do with messengers or ribo- 

 somes. It is possible that the initial stages in 

 the regiilation of the proliferation and dif- 

 ferentiation of erythropoietic cells may have 

 nothing directly to do with the production of 

 messenger for the synthesis of hemoglobin. 

 The synthesis of hemoglobin may represent 

 a very late stage in the differentiation process. 

 If so, then perhaps studies of the control of 

 the formation of messenger for the synthesis 

 of hemoglobin by cells may tell one relatively 

 little about the very early steps of differentia- 

 tion. The initiation of hemglobin synthesis may 

 be just one byproduct of other events which 

 took place long before, in the history of the 

 progenitors of those cells. 



POLLARD: Have you done any fractiona- 

 tion at all of the cells at this stage where ery- 

 thropoietin might take over? 



TILL: No. A number of people are doing 

 this, though. 



POLLARD: If it's the surface that you're 

 talking about, then this is a place where a lot 

 of material is located. 



TILL: Oh yes, I think one could get at this 

 experimentally. 



EPEL: Can you transfer these cells to 

 other parts of the body? Do they go any other 

 place and proliferate? 



TILL: Yes, the cells that we put into ir- 

 radiated recipients seem to proliferate in any 

 place where hemopoietic cells should pro- 

 liferate. 



PAPACONSTANTINOU: Do these others 

 show the same composition that you get in the 

 spleen? 



73 



