although tnf itself was not discovered until the 1970s , a physician named william coley first noted the phenomenon of tumor necrosis at the turn of the 20th century .
the tumors of some of his cancer patients shrank after they had acquired streptococcal infections ( 1 ) .
but the inherent dangers of injecting humans with a toxic soup of bacterial endotoxins prevented coley 's observation from being converted into an antitumor therapy .
researchers , however , hoped to separate the tumor - blasting factor from the toxic mess .
lloyd old and his team at the memorial sloan kettering cancer center ( new york , ny ) finally zeroed in on serum tnf from bacterium - primed , endotoxin - challenged mice in 1975 ( 2 ) .
bruce beutler ( left ) and anthony cerami tnf was immediately included with the likes of interferon- , il-2 , and monoclonal antibodies as the next best hope in cancer treatment . by the mid-1980s
tnf therapy not only failed to shrink tumors but also caused side effects . and just across the street from sloan kettering , a group from rockefeller university headed by anthony cerami would soon publish data that would put a further damper on the tnf - as - cure idea .
his main interest was in understanding the basis of cachexia  the weight loss associated with many chronic diseases , such as cancer and tuberculosis .
in the 1970s , while testing drugs designed to rid cattle of the parasite trypanosoma , cerami noticed that the animals continued to waste away even though the parasites were dying off .
the continued weight loss was not drug induced , as parasite - infested antelopes also responded to the drug but showed no further wasting .
cachexia , cerami surmised , might be due to a host factor that was meant to fight the infection but became a threat when produced in amounts that overwhelmed the body .
cerami soon found a reliable biochemical read - out for cachexia : lipaemia , the accumulation of lipids in the blood due to the suppression of a fat - metabolizing enzyme ( 3 ) .
the hypothetical host factor , cerami realized , might be suppressing this enzyme , lipoprotein lipase ( lpl ) , thus triggering a fat storage problem and cachexia .
he and a post - doctoral associate , masanobu kawakami , tested this hypothesis in a mouse model of endotoxin - induced cachexia .
mice that were genetically susceptible to endotoxin had deficient lpl activity after an injection of bacterial lipopolysaccharide ( lps ) , whereas endotoxin - resistant mice had normal lpl activity .
serum from lps - treated sensitive mice triggered lpl suppression in normally resistant mice , suggesting the presence of the cachexia - inducing host factor in the serum .
the task of purifying this mystery protein was taken up by bruce beutler , another of cerami 's post - doctoral associate .
the team had previously found that a macrophage cell line produced copious amounts of the lpl - suppressing factor when stimulated by endotoxin ( 4 ) .
the macrophage prep was also a better starting point for protein purification compared with the messy mouse serum .
beutler then took a year to purify the protein , which the team named  cachectin .
 they published their discoveries in the journal of experimental medicine ( 5 , 6 ) .
the team 's collaborators at the scripps institute ( la jolla , ca ) , however , found that cachectin shared the same biological activity with tnf .
a comparison of cachectin 's sequence with that of the newly sequenced human tnf solidified the link .
the team added this later discovery as a footnote to their already - accepted paper ( 5 ) .
the identification of cachectin as the benign cytokine tnf created a furor in the field , especially as the other biological activities of cachectin mimicked the side effects seen in the tnf - treated cancer patients .
 everyone else was advocating for tnf to be given to patients ,  says cerami .  we wanted to get rid of it  .
his team later found that blocking tnf activity using antibodies reduced infection - induced inflammation and endotoxin - induced lethality ( 7 ) .
today , anti - tnf drugs are successfully used in the treatment of inflammatory diseases such as rheumatoid arthritis and psoriasis .
 in the early 1980s , in search of the cytokine that triggers disease- associated weight loss and lethal shock , anthony cerami and bruce beutler purified  cachectin .  they soon found out that their malevolent cytokine already had another name  
 tumor necrosis factor ( tnf)and was being lauded as a potential antitumor agent . 
The bright side
The wasting connection
A cytokine by any other name
Therapy becomes therapeutic target