Tracking Genes That Cause Human Disease 
Francis S. Collins, M.D., Ph.D. — Investigator 
Dr. Collins is also Professor of Internal Medicine and Human Genetics at the University of Michigan Med- 
ical School. He received his Ph.D. degree in physical chemistry from Yale University and his M.D. degree 
from the University of North Carolina. After completing his internship and residency in internal medicine 
at the North Carolina Memorial Hospital, he went on to a fellowship in human genetics at Yale. This year 
he received the Gairdner Foundation's International Award and shared the National Neurofibromatosis 
Foundation's Friedrich von Recklinghausen Award. 
THE theme of our laboratory is the study of 
human genetic disease at the molecular 
level. Our goal is to identify genes involved in 
specific genetic disorders, to define their struc- 
ture and function, to understand the control of 
their expression, and to use this information to 
develop potential nev^ therapies. 
The most recent edition of Mendelian Inheri- 
tance in Man lists over 4,000 genetic disorders. 
In the majority of these, the normal function of 
the gene involved is not known. The identifica- 
tion of disease-causing genes without knowledge 
of their protein product or its normal role is a 
major endeavor in our research. 
Only recently has it become possible to iden- 
tify such genes, and the process is still laborious. 
First the gene must be mapped to a specific hu- 
man chromosome, using a process known as link- 
age analysis. This involves identification of fami- 
lies with the disorder and analysis of DNA from 
these families with a panel of probes from all 
parts of the human genome. The probes are used 
to establish the chromosomal location of a DNA 
sequence that may have been inherited in associa- 
tion with a disease gene that will probably lie 
close to it. Such sequences, or "markers," can 
pinpoint the chromosome on which the disease 
gene resides. Additional probes from that chro- 
mosome can then be tested to identify markers 
that are even closer. It is often possible to narrow 
the responsible region to about 1 percent of a 
particular chromosome. Although this is a major 
achievement, such a region may yet contain 30 to 
50 genes, only one of which is responsible for the 
disease. Thus additional refinements must be 
made before candidates for the responsible gene 
can be identified. 
A major development in the past year has been 
the successful cloning of the gene for von Reck- 
linghausen neurofibromatosis (NFl), a common 
genetic disorder (sometimes incorrectly referred 
to as the Elephant Man disease) . Using techniques 
of chromosome jumping and yeast artificial chro- 
mosomes, we were able to identify on chromo- 
some 17 a large gene that harbors unmistakable 
mutations in patients with NFl. Analysis of the 
gene reveals that it is similar in interesting ways 
to other genes in humans (and even in yeast) . It 
probably participates in the suppression of unreg- 
ulated cell growth by interaction with another 
class of cancer-related genes (the ras genes). 
These developments will make it possible to de- 
fine in precise terms the basic defect in NFl. In 
the relatively near future, this gene discovery will 
lead to improvements in diagnosis; in the longer 
term it offers the promise of improved therapy for 
this devastating disease. 
In the previous year, as part of a collaborative 
effort with investigators at the Hospital for Sick 
Children in Toronto, we were successful in iden- 
tifying the gene for cystic fibrosis (CF), a com- 
mon severe genetic disease characterized by lung 
infections, pancreatic insufficiency, and an ele- 
vation in sweat chloride. Additional investiga- 
tions of this gene, denoted CFTR (cystic fibrosis 
transmembrane conductance regulator) , has pro- 
ceeded on many fronts this year. 
WTiile one mutation (called AF508) is respon- 
sible for about 75 percent of CF chromosomes in 
the United States, we and others have identified 
numerous mutations in the CFTR gene in other 
individuals with the disease. We are also studying 
the regulation of the gene — trying to determine 
why it is expressed in some tissues (such as lungs 
and pancreas) but not at all in others (such as 
brain) . It also appears that the gene is capable of 
producing more than one protein by a phenome- 
non referred to as alternative splicing. 
Importantly, we have succeeded in transferring 
a normal version of the CFTR gene into CF cells 
growing in laboratory culture, and have shown 
that the defect is corrected. These results, 
achieved in collaboration with James Wilson 
(HHMI, University of Michigan) and Ray Frizzell 
(University of Alabama) , can be thought of as the 
first step toward a gene therapy for CF. 
The Huntington disease (HD) gene has been 
localized by a collaborative group, which in- 
cludes our laboratory. It is now known to lie in a 
region near the tip of the short arm of chromo- 
some 4, within an interval of approximately 2 
million base pairs. Using chromosome jumping 
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