ACHIEVEMENTS OF Dr.
Mario Renato Capecchi
THE 1996 KYOTO PRIZE LAUREATE
IN
BASIC SCIENCES
Fields Selected: Life Sciences (Molecular Biology,
Cell Biology, Neurobiology)
With his success on breeding mice in which targeted genes were
inactivated, referred to as "knock-out" mice, Dr. Mario
Renato
Capecchi established a new avenue for researching how genes work.
His method of research has since been used widely around the
world and benefited immensely such branches of life sciences as
biology, medicine and agriculture.
Whether we are addressing microorganisms or highly developed
forms of life, it is most desirable and meaningful to obtain
samples with mutant genes which have been inactivated and observe
their behaviors. while it is relatively easy to amass a large
population of mutagenized microorganisms and select the desired
samples, it would be unthinkable to take a similar measure with
higher life forms, especially vertebrate animals.
Dr. Capecchi opened a new way by realizing what was once
considered only a dream, that is to obtain individual vertebrate
animals with selected mutations in targeted genes. This made it
possible to research various phenomena of the genesis of
individual life forms, hereditary diseases, carcinoma and immune
responses, body functions and diseases caused by genetic
malfunctions. Furthermore, his achievements opened limitless
possibilities for applied research, including livestock breed
improvement.
It had been believed that when DNA molecules are introduced
into
an animal cell, they would enter various parts of the existing
nuclear DNA and only a minute percentage would recombine at the
matching locations. Dr. Capecchi initially studied this
phenomenon carefully and discovered that such homologous
recombination occurs with a frequency of about once in every
thousand to ten thousand nonhomologous recombination. He then
proceeded to devise a method for increasing the frequency of
homologous recombination while eliminating those cells in which
nonhomologous recombination had occurred. In this way, it became
possible to replace any gene in the cells of higher animals with
a gene with desired mutations. Referred to as "gene
targeting"
this technique enabled medicine and biology to freely generate
and study cells with genetic mutations of special interest.
Dr. Capecchi, with this gene targeting technique, further went
on to establish a method for efficiently producing
"knock-out"
mice in which targeted genes are inactivated. Embryonic stem
cells (ES cells) can be cultivated in vitro and returned to the
foster mice for pups. By creating ES cells through gene
targeting and implanting back into mice where they were allowed
to develop to term, Dr. Capecchi was able to obtain the mutant
mice and clarified the morphogenesis related genetic functioning
such as anterior-posterior axis determination of the fetal
period, and discovered that such genetic functions occur only at
limited locations during limited periods of development. This
methodology is being extended to new important areas of genetic
research and is contributing greatly to the continuous unveiling
of the functions played by genes.
The practical applications of "knock-out" mice have
opened new
broad areas of research in embryology and helped elucidate the
genetic functions of vertebrate animals in such areas as the
study of receptor functions and signal transmission, and cellular
formation analysis. Presently, in the field of medical research,
those techniques are actively being used to produce disease-model
animals in order to investigate the molecular pathology of
hereditary disease and develop genetic therapy techniques. It
would not be an overstatement to say that many of the fruitful
areas of research which comprise taday's life science have been
made possible by Dr. Capecchi's work.