Introduction 
determine the sequence of nucleotides that en- 
codes the relevant genetic instructions. 
One of the most important developments to 
emerge from gene cloning and sequencing is 
that they permit geneticists to determine exactly 
how a gene may have been altered (genetic alter- 
ations of this kind are called mutations) to pro- 
duce an inherited disease. While a majority of the 
investigators in the HHMI Genetics Program are 
directing their efforts toward understanding the 
principles that govern the action of genes, a large 
and growing number are trying to identify the 
mutations responsible for some of the esti- 
mated 4,000 human genetic defects. Among the 
genes being studied are those responsible for 
muscular dystrophy, cystic fibrosis, several forms 
of hemoglobinopathy, chronic granulomatous 
disease, phenylketonuria, polyposis coli, neu- 
rofibromatosis, osteogenesis imperfecta, and he- 
mophilia. Most of the genes responsible for these 
diseases have already been cloned and their 
structures determined; in this way the precise mo- 
lecular effects of the mutations that cause the dis- 
orders are now being determined. Information 
that has been derived in this way is being used in 
several ways. For example, in some cases it is be- 
ing used to counsel affected families about the 
risks they face in having additional children; in 
others it is being used to develop tests that are 
critical for prenatal diagnosis, and, in the case of 
hemophilia and chronic granulomatous disease, 
it is already being used to provide appropriate 
therapy. Information about some of these genes 
and their protein products has also told us a great 
deal about the role of the relevant proteins in 
development (e.g., the protein dystrophin, 
which is normally found in muscle but is missing 
in most cases of muscular dystrophy) or about the 
mechanisms required for normal function (e.g., 
in the lungs and pancreas in cystic fibrosis, or for 
the mechanisms of blood clotting in hemo- 
philia). It is the continuous interplay between 
the development of new basic knowledge and its 
application to the understanding of human dis- 
ease that is so dramatically informing modern 
medicine. 
The execution of a genetic program in a cell 
obviously cannot be left to chance. To bring 
about an ordered series of changes in a develop- 
mental or metabolic process, each genetic in- 
struction must be activated at a specific time, and 
the product of the gene must be produced in a 
specific amount commensurate with the needs of 
the organism. As was pointed out in the section 
on cell biology, different sets of genes are ex- 
pressed in each cell type so, for example, those 
expressed in muscle cells are likely to be quite 
different from those expressed in skin cells or in 
bone. Since with few exceptions (one of which 
will be discussed in the section on immunology) 
each cell contains the same genetic information, 
there must be some mechanism or mechanisms 
that insure that the appropriate genes are being 
expressed in each cell type. The processes that 
govern these crucial steps are generally referred 
to as gene regulation. 
Once again, the study of inherited human dis- 
eases has revealed mutations that can disrupt 
those regulatory programs. For example, it is now 
known that certain inherited anemias are brought 
about by specific mutations that affect the regula- 
tory apparatus of the genes that encode the red 
blood cell protein, hemoglobin (Figure 12). An 
even larger number of examples could be cited 
from work on simpler organisms to show how 
powerful this mutational analysis has been for 
our understanding of genetic regulation. How- 
ever, it will suffice to say here that the work of a 
considerable number of HHMI investigators has 
this as its primary theme. 
As discussed in the section on cell biology and 
regulation, genetic information is usually con- 
veyed through a series of steps from the nucleus 
of the cell to the surrounding cytoplasm, where it 
is decoded or translated to form the protein prod- 
ucts that execute the relevant genetic program. 
This process involves making many copies of the 
gene, in the closely related chemical, RNA. The 
process of copying a gene from DNA into RNA is 
called transcription. This is one of the key 
points at which the flow of genetic information 
can be regulated. Genes that are not scheduled 
for expression in a particular cell type are not 
transcribed; while still present, they remain si- 
lent and ineffective. 
Since it plays such a central role in regulating 
the expression of genetic information, it is not 
surprising that the study of transcription is one of 
the most active areas in modern genetic research 
(Figure 13). Investigators have taken two success- 
ful approaches in an effort to understand this pro- 
cess. One involves the study of mutations that 
disrupt regulation in a variety of organisms. The 
other is biochemical and involves isolating spe- 
cific proteins that are parts of the transcription 
machinery and then determining their mode of 
action at a molecular level. The ultimate goals of 
both approaches are to provide a complete ac- 
