Cancer and Genetic Modification of 
Biologic Control 
Philip Leder, M.D. — Senior Investigator 
Dr. Leder is also John Emory Andrus Professor in the Department of Genetics at Harvard Medical School. 
He received his M.D. degree from Harvard Medical School. He has also received three honorary D.Sc. de- 
grees. Dr. Leder held several positions at the NIH before returning to Harvard. His many honors include 
the Albert Lasker Medical Research Award, the National Medal of Science, and the Heinekin Prize awarded 
by the Royal Netherlands Academy of Arts and Sciences. He is a member of the National Academy of Sciences. 
THE growth of cells within an organism is far 
too delicate and important a process to be left 
to chance. Rather, as with all biologic processes, 
it is subject to a stringent set of rules that are 
programmed into the genetic makeup of the or- 
ganism. Genes form the basis for controlling 
growth within an organism, setting the parame- 
ters that allow the liver to take the shape it does 
or the kidney to assume its particular size and 
function. Genes establish the rules that ensure 
that an organ grows in an orderly fashion and 
reaches a prescribed and limited size. Growth 
can thus proceed so far but no farther, attaining a 
programmed equilibrium compatible with life. 
Cancer as a Disease of Genes 
Cancer is a profound disorder of cell growth. 
The delicate balance established by a genetically 
encoded program is overturned. Instead of reach- 
ing an equilibrium, a cancer cell no longer re- 
sponds to signals that would limit its ability to 
divide. It is out of control, and its unlimited 
growth has profoundly dangerous consequences 
for the organism. 
Over the past decade or so, it has become in- 
creasingly clear that many cancers can be ac- 
counted for, at least in part, by damage occurring 
to genes that encode the rules for control of cell 
growth. Genetic damage, or mutation, can inacti- 
vate a gene or cause it to function at the wrong 
time or at the wrong place or, indeed, even cause 
it to make the wrong product. The set of genes 
whose damage (or mutation) can give rise to 
cancer are often just those genes that normally 
regulate cell growth. Geneticists refer to the dam- 
aged genes that contribute to the development of 
malignancy as oncogenes (from the Greek ovKoa, 
or tumor) . 
Transgenic Mice and the Genetic Basis 
of Cancer 
For some time my colleagues and I have been 
interested in genes that control cell growth and, 
in particular, the control processes that operate 
in the living organism. Our work has been consid- 
erably advanced by the technique of introducing 
active oncogenes into the hereditary makeup of 
special strains of laboratory mice. These "trans- 
genic" mice carry oncogenes created in the labo- 
ratory, pass these cancer-causing genes on to off- 
spring, and therewith transmit a strong tendency 
to develop cancer. Thus, in many ways, trans- 
genic mice become useful models of human ma- 
lignancy. For example, we have designed specific 
mice that develop cancer of the breast and others 
that develop cancer of the blood cells — specific 
leukemias and lymphomas. These experiments 
have taught us that some cancers can be caused by 
certain specific oncogenes and that many, but not 
necessarily all, cancers are the result of a collabo- 
ration between two or more oncogenes. This sug- 
gests that cancer is often a "multihit" process, a 
process that requires several activating events. 
Host Defenses Against Cancer 
Although transgenic mice are very useful in ana- 
lyzing the action of oncogenes, they are also use- 
ful in exploring the host defense mechanism that 
can be mobilized to prevent the development and 
spread of cancer. The immune system is one of 
the organism's chief instruments against the 
spread of infectious disease and for the rejection 
of foreign tissues. For example, the body's im- 
mune system must be neutralized to accomplish 
effective heart or kidney transplants. The role 
that the immune system plays in tumor rejection 
is at best poorly understood, but important recent 
discoveries in the field of immunology indicate 
that the immune response is regulated by an array 
of hormone-like agents called lymphokines. 
These are released by cells of the immune system 
to influence the growth and development of 
other cells. They can act as growth factors signal- 
ing target cells to divide, or they can trigger ge- 
netic programs that cause a target cell to change, 
mature, or even assume a new function. 
We are particularly interested in how lympho- 
kines influence the host's response to cancer. In 
the course of this work, we have focused on the 
action of two particularly interesting lympho- 
kines, IL-4 and IL-7. (These biologic response- 
modifying agents are frequently given the name 
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