ABSTRACT
In this chapter, I will trace the sequence of observations that led to the formu-
lation of the apoptosis concept and will briefly describe its aftermath.
DIFFERENTIATION OF TWO MORPHOLOGICALLY DISTINCT TYPES OF CELL DEATH IN THE LIVER
My interest in cell death began in 1962 during my PhD studies at University
College Hospital Medical School in London. My adviser, Sir Roy Cameron,
suggested that I examine the cellular processes involved in the shrinkage of liver
tissue that was known to follow obstruction of its portal venous blood supply. To
this end, I ligated the portal vein branches supplying the left and median lobes of
the liver in rats (1). These lobes shrank to about one-sixth of their original weight
during the first eight days after operation, the rest of the liver undergoing com-
pensatory enlargement. Within six hours of operation, necrosis developed in the
ischemic lobes in discrete foci around the terminal hepatic venules, i.e., down-
stream in the blood flow to the liver tissue. Typically, the necrosis affected
groups of adjoining hepatocytes and involved degeneration with loss of their
normal histological staining pattern. The necrotic cells were rapidly removed by
mononuclear phagocytes, the abundance of the phagocytes suggesting that many
of them were derived from circulating monocytes that had left the micro-
vasculature during an inflammatory response. The remaining parenchyma in
the ischemic lobes remained essentially viable, being sustained by blood from the
hepatic artery. However, as the lobes shrank, scattered single hepatocytes were
converted into small round or oval cytoplasmic masses, some of which contained
one or more specks of markedly condensed nuclear chromatin. These bodies were
taken up by Kupffer cells, the resident mononuclear phagocytes of the liver, or
occasionally by epithelial hepatocytes. Formation of the bodies clearly repre-
sented a distinctive form of cell death, which differed from necrosis in its
microscopic appearance, in affecting only scattered individual cells and in not
evoking inflammation. Importantly, very small numbers of the bodies could be
found in the livers of healthy rats.
