Cancer and Genetic Modification 
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. 
degrees. Dr. Leder held several positions at 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 in an organism is far too 
delicate a process to be left to chance. 
Rather, as with all biologic processes, it is subject 
to a very stringent set of rules that are pro- 
grammed into the makeup of the organism. The 
basis for the control of growth is genetic. The 
genes set the parameters that allow, say, the liver 
to take the shape it does or the kidney to assume 
its particular size and function. Genes establish 
the rules whereby an organ grows in an orderly 
fashion and reaches a prescribed and limited size. 
Thus growth can 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, the 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 in the wrong place or, indeed, even cause 
it to make the wrong product. The set of genes 
whose mutation can give rise to cancer is often 
just those that normally regulate cell growth. Ge- 
neticists refer to the damaged genes that contrib- 
ute to the development of malignancy as onco- 
genes (from the Greek ovkoc, 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. Our 
work has been considerably advanced by the tech- 
nique of introducing active oncogenes into the 
hereditary makeup of special strains of laboratory 
mice. Called "transgenic," such mice carry on- 
cogenes created in the laboratory, pass on these 
cancer-causing genes to offspring, and therewith 
transmit a strong tendency to develop cancer. 
Thus, in many ways, transgenic mice become use- 
ful models of human malignancy. 
For example, we have designed specific mice 
that develop cancer of the breast and others that 
develop cancer of the blood cells — specific leu- 
kemias and lymphomas. Some of these mice even 
develop benign prostatic hypertrophy, a condi- 
tion that aff^ects up to 85 percent of men by the 
eighth decade of life. These experiments have 
taught us that certain cancers can be caused by 
specific oncogenes and that many, but not neces- 
sarily all, cancers are the result of a collaboration 
between two or more oncogenes. This suggests 
that cancer is often a "multihit" process, one that 
requires several activating events. 
A Binary System for Activating 
and Silencing Transgenes 
During the past year we have extended the 
power of transgenic technology by creating a sys- 
tem that gives us much better control over the 
transgene we have introduced. For example, we 
often introduce genes that dramatically increase 
the incidence of certain cancers in our mice. 
Cancers obviously influence the ability of our an- 
imals to pass their genes on to succeeding genera- 
tions, as such genes often preclude survival. To 
overcome this problem and to assure that no 
more cancer-prone mice are produced than we 
need for our experiments, we have designed a 
binary system in which "target" genes can be 
held in an inactive state in one line of mice and 
become active only when the mice are bred to a 
second line that carries an "activator" gene. The 
system is suggestive of epoxy cement that is held 
in two tubes, the contents of which must be 
mixed to become functional. 
The binary system has the further advantage 
that it can be "multiplexed," or used in a variety 
of combinations, such that a target can be one of 
many different transgenes that is in turn com- 
bined with one or more activator genes. For exam- 
ple, the activators could specify expression of a 
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