Introduction 
Genetics Program 
The emergence of what is sometimes referred 
to as the "new genetics" has contributed more to 
our fundamental understanding of biology and 
medicine in the past two decades than any other 
advance in biomedical science. Not surprisingly, 
this development has come to assume a central 
place in all biological research, making it possi- 
ble to examine biological processes at a level of 
resolution that was considered quite impossible 
just 20 years ago. "Gene cloning," "recombinant 
DNA technology," "genetic engineering," and 
the "Human Genome Initiative" are phrases that 
have entered everyday language, but the possibili- 
ties they offer for major advances in biology and 
medicine have yet to be fully appreciated. Given 
the central role of genetics in modern biology 
and the current sense of excitement that the new 
genetics has generated, it is appropriate that the 
Genetics Program is by far the largest research 
program within HHMI. 
Historically, one of the first applications of 
Mendel's classic laws of inheritance was to the 
analysis of certain human diseases. In the early 
years of this century, Archibald Garrod, an En- 
glish physician, noted that a number of relatively 
rare diseases tended to occur in families, often in 
families with consanguineous marriages. The pat- 
tern of occurrence of these rare diseases followed 
Mendel's laws, discovered almost 50 years ear- 
lier. Mendel's work on inherited characteristics 
in plants was neglected for many years, but after it 
was rediscovered, around the turn of the century, 
it was quickly established that the laws of genet- 
ics are universal and govern inheritance in organ- 
isms as disparate as peas and worms, mice and 
fruit flies, bacteria and human beings. Beginning 
with Garrod, these genetic laws were applied to a 
host of inherited diseases, as it was realized that 
the genetic makeup of an individual can have a 
profound effect on his or her health and well- 
being. However, an understanding of what genes 
are and how they function had to await the discov- 
ery, in 1944, that the genetic material is DNA, 
and, in 1953 and 1961, of the double helix and 
the genetic code, respectively. 
Much of our early understanding of the action 
of genes came from experiments that took advan- 
tage of the universality of gene action by using 
simple organisms, especially bacteria and their 
viruses, as model systems. The cardinal discovery 
was the identification of deoxyribonucleic acid 
(DNA) as the fundamental chemical in which ge- 
netic information is encoded. But the finding that 
DNA has a double-stranded, mirror image struc- 
ture provided the first clear insight as to how this 
information could be replicated and passed on 
from one generation of organisms to the next (Fig- 
ures 9 and 1 0) . Understanding how the chemical 
language of DNA could be used to direct the syn- 
thesis of other cellular constituents, especially 
proteins, came with the discovery of the nature of 
the genetic code. These great advances will al- 
ways be viewed as the high watermark of the early 
molecular stage of modern genetics. 
Notwithstanding these dramatic developments 
— arguably the most important in biology since 
the publication of Darwin's On the Origin of Spe- 
cies in 1859 — the molecular details of the genes 
of higher organisms remained hidden from view 
by the enormous complexity of their genomes 
(Figure 11). Fortunately, the genes of simple or- 
ganisms were accessible, because they are rela- 
tively few in number (involving in many cases an 
assemblage of as few as 3,000 base pairs, as the 
building blocks of DNA are called) compared to 
the human genome, which probably contains 
about 3 billion base pairs. 
The problem of genetic complexity has been 
finally overcome in the past 1 0 years by the devel- 
opment of the powerful new genetic methods 
known collectively as recombinant DNA tech- 
nology. This technology allows researchers to 
isolate specific genes from complex mixtures, to 
prepare them in sufficiently large amounts that 
their entire molecular structure can be deter- 
mined, and to move them from one group of cells 
or from one organism to another, so that their 
functional properties can be identified and their 
products produced in abundance. In a number of 
cases, medically valuable products such as hu- 
man insulin, growth hormone, antihemophilic 
factor, and TPA (tissue plasminogen activator) 
have been commercially manufactured in this 
way and are now being used therapeutically. 
Most of these accomplishments depend on the 
technique commonly referred to as gene clon- 
ing. In this process a gene (for example, the hu- 
man insulin gene, which is a few thousand base 
pairs in length) is isolated from a complex mix- 
ture of human DNA fragments and transferred 
into the genetic apparatus of a much simpler or- 
ganism such as a bacterium. Since bacteria multi- 
ply very rapidly, the inserted human insulin gene 
is amplified (cloned) along with the genes of its 
simple host. It is then a relatively straightfor- 
ward process to purify the cloned gene and to 
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