nathan , as an oncology fellow , knew well that white blood cells fought infections . 
this was an experiment repeated in front of us all the time ,  he says : chemotherapy lowered his patients ' white blood cells and increased their risk of infections .
mackaness had shown that macrophage activation did not depend on direct contact with t cells ( 1 ) , suggesting the possibility of a secreted factor .
when nathan tested the supernatant from activated t cells , he saw that it did indeed induce macrophage activation ( 2 ) .
nathan got a rough idea of the molecular weight ( 3 ) , but that was  the best anyone could do ,  he says .
protein separation methods were primitive , and cloned proteins and monoclonal antibodies would only become available a decade later .
henry murray , one of nathan 's collaborators , sums up the feeling of frustration :  we were all nibbling at the edges of the same problem .  nathan therefore changed tack to take a closer look at the activated macrophages .
short - lived neutrophils were known to produce hydrogen peroxide , and nathan found the same was true of longer - lived activated macrophages ( 4 ) . unlike previous signs of macrophage activation  increased spreading , phagocytosis , and glucose metabolism this so - called  respiratory burst 
ifn had been on the cover of time magazine , and recombinant murine ifn was found to induce macrophages to kill tumor cells ( 5 ) .
nathan , now a faculty member in zanvil cohn 's  macrophage factory  at rockefeller university ( new york , ny ) , thought ifn might also activate macrophages to kill intracellular parasites .
consistent with this idea , ifn was made by antigen - stimulated t cells and was associated with defense from infection .
now the respiratory burst gave nathan an assay , berish rubin ( down the street at the new york blood center ) supplied an ifn monoclonal antibody , and a phone call to genentech yielded recombinant ifn. in a seminal paper published in the journal of experimental medicine in 1983 , nathan was thus able to show that depleting ifn from unpurified t cell supernatants decreased the respiratory burst activity and the killing of intracellular protozoa in human macrophages . adding back recombinant ifn into this mix restored macrophage activation ( 6 ) .
i had an assay , a hunch , a history of purifying proteins that did this , and the serendipity of meeting with people nearby who had the antibody . 
nathan next showed that ifn worked in people . injecting recombinant ifn directly into cutaneous lesions of lepromatous leprosy patients induced macrophage infiltration , hydrogen peroxide production , and killing of the causative pathogen , mycobacterium leprae ( 7 ) . in the 1990s ,
the macrophages of children with ifn receptor deficiencies were shown to be defective in killing mycobacteria ( 8) .
tracing the pathway from t cells to macrophages to bacteria started , for nathan , in 1967 , and he says  we still haven't finished making the molecular links . 
 t cells tell macrophages when to start making the toxic soup of lysosomal enzymes , reactive oxygen species , and nitric oxide that destroys intracellular pathogens . in 1983 
 , carl nathan proved that this start signal comes in the form of the secreted cytokine ifn. 
The elusive eluate
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