GENETIC DISEASE

&
MODERN MEDICINE
PRESENTED BY: MAHEEN JAMIL
 WHAT HAPPENS WHEN A GENE DOESN’T
WORK?

• If a person carries alleles that fail to code correctly

for a particular protein, the effect may be medically
insignificant e.g., blue eyes instead of brown eyes.
• It has been estimated that each of us in a carrier for
30 or more recessive disorders.
• Not all diseases are inherited e.g., cancer
 INHERITED DISEASES

• CYSTIC FIBROSIS:
• It is caused by an autosomal recessive allele; most common in young people.
• Symptoms include severe respiratory difficulties, liver, pancreatic, and digestive failure.

• Biomedical scientists recently isolated the defective gene that causes cystic fibrosis. the gene encodes a
chloride channel in the cell membrane.
• TAY-SACHS DISEASE:
• It is most common among Ashkenazic Jews.

• Tay-Sachs disease results from a failure to produce a specific enzyme, hexosaminidase a. without this
enzyme, the nervous system degenerates.
• Children with Tay-Sachs disease appear normal for their first few months, but they usually lose their eyesight
by about the age of one year, and they rarely survive more than five years.
• SICKLE CELL ANEMIA
• This disease is most common among people whose ancestors came from tropical areas of the
Mediterranean.
• In this, the carrier produces an abnormal Hb(hemoglobin) which leads to defect in red blood cells.
• DUCHENNE MUSCULAR DYSTROPHY:
• It is an x-linked recessive trait that appears in the first three years of life. muscular deterioration becomes
more and more severe as the disease progresses. victims generally die in their twenties.
• The gene associated with the disease has been isolated and cloned. it is the largest known human gene
(over a million base pairs) and encodes a protein found only in the plasma membranes of skeletal muscle
cells.
• FRAGILE-X SYNDROME:
• Most common form of inherited mental retardation.
• Not all individuals with a fragile-x chromosome are mentally retarded.
• The gene responsible for fragile-x syndrome was cloned and sequenced in 1991.
• HEMOPHILIA
• Blood does not clot normally and it is an x-linked recessive trait. the failure of the blood to clot results
from its failure to produce a protein that participates in the clotting process. some hemophiliacs are at
risk of death from even minor cuts, because they cannot stop bleeding.
• Treatment is primarily blood transfusion and the provision of a blood clotting factor.
• At the end of 1992, a blood clotting factor produced by recombinant DNA technology was approved
for general medical use.
DEALING WITH GENETIC DISEASE

• First, we must characterize the symptoms of

the disease—this is under the of the
physician.
• Epidemiologists (those who study the
frequency and distribution of diseases within
populations) often take the next steps,
tracing the disease to discover whether it
strikes most often at a particular group of
people or in a particular place.
 FINDING A DEFECTIVE GENE:

Mapping Human Chromosomes

• “the process of determining the position of specific genes on specific chromosomes and constructing a
diagram of each chromosome showing the relative position of the genes.”
• Drawbacks:
• time consuming
• moral unacceptability
 Pedigree analysis
 Somatic cell genetics
 Restriction fragment length polymorphisms
 Narrowing the search
 PEDIGREE ANALYSIS

• This process documents the transmission of a particular

genetic characteristic over two or more generations and
reveals whether the pattern is dominant or recessive.
• Human pedigrees include data on relatively few
individuals and generations
• It shows a map of relationship in a family and certain
traits.
SOMATIC CELL GENETICS

1. SOMATIC CELL HYBRIDIZATION:

• one of several new techniques used to map human genes is
somatic-cell hybridization.
• this method involves creating and analyzing hybrid cells that
contain the chromosomes of two different species, helps to
determine which chromosome houses a particular gene.

Mouse and Human Cells Can Fuse

Somatic-cell Hybridization Phenomena:
• Somatic cells (i.e., cells other than gametes) isolated from two animal species and cultured together on a suitable
medium, and fused to form a hybrid cell with two nuclei, one from each species
• After a hybrid cell forms, the two nuclei may fuse to create a nucleus containing the chromosomes of both
species.
• Mitosis in hybrid cells is sometimes abnormal due to which chromosomes of one of the species starts to
disappear. as a result, some daughter cells have nuclei containing all the chromosomes of one species and only
one or a few chromosomes of the second species (figure)
• In mouse-human hybrid cells, it is most often the human chromosomes that are lost.
2. CHROMOSOME-MEDIATED GENE TRANSFER:
• Another technique of somatic-cell genetics is chromosome-mediated
gene transfer.
• Somatic cells of a recipient species (such as a mouse) are combined with
chromosomes isolated from metaphase cells of a donor species (such as
humans).
• When recipient cells are incubated with isolated chromosomes, only
some parts of some chromosomes are taken up by the cells, and only a
small fraction of what is taken up becomes associated with the host
chromosomes of the mouse and is thus stabilized.
• Thus by observing the frequency of two loci (position of gene on a
chromosome) that are transferred together, biologists can determine the
Chromosome indicating Loci 1,2,3,4
map distance between them.
 RESTRICTION FRAGMENT LENGTH
POLYMORPHISMS

• Restriction fragment length polymorphisms are

differences in DNA sequences that serve as genetic
markers. linkage studies can be used to isolate
genes involved with diseases.
• genetic markers is a DNA sequence with a known
physical location on a chromosome. Genetic
markers can help link an inherited disease with the
responsible gene.
 NARROWING THE SEARCH

• Chromosome Walking is a suitable technique for finding a gene in a relatively small stretch of dna.
• For larger stretches, an analogous procedure called Chromosome Jumping was developed. using this
technique, scientists established a series of starting points for chromosome walks and narrowed the location
of the cystic fibrosis gene to a much smaller part of chromosome 7.
• Additional experiments narrowed the search even further. eventually the start and stop signals were located,
and ultimately the nucleotide sequence of the gene was determined.
• Locating the gene that causes a particular disease is the first step to developing an effective treatment.
 DEALING WITH A DEFECTIVE GENE

• After locating a gene related to a disease, the next thing is to know is

what the gene does—that is, what the function of the protein encoded by
the gene is.
• We can study specific gene function in laboratory animals called
“knockout mice” that are genetically engineered to contain the defective
allele. we can also try to get around the effects of a defective allele by
inserting functioning alleles into the cells of persons with the disease.
 KNOCKOUT MICE
• KNOCKOUT MICE— mice in which defective alleles have been
inserted to replace the functioning alleles, which were “knocked out.”
many of the genes studied in this fashion are associated with specific
human diseases.
• Knockout mice are now available as models for cystic fibrosis, sickle-
cell anemia, atherosclerosis, and many other human diseases.
• With knockout mice as their subjects, scientists are now able to study
human genetic diseases in ways that would be difficult or impossible
in work with humans.
• We can explore how the defective alleles lead to the expression of a
disease and we can test potential drugs and other treatments.
 GENE THERAPY
Objective:
The objective of gene therapy is to insert a new gene that will be expressed in the host. The new DNA must
be attached to a promoter that will be active in human cells.

Adenosine Deaminase (ADA):

The first federally approved gene therapy in the United States began in September 1990 on a patient
suffering from immune deficiency because the enzyme adenosine deaminase (ADA) her body produced
was defective.

Adenosine deaminase is needed for the maturation of white blood cells, and a genetic disease results when
a person is homozygous for a mutant allele for this enzyme. People without this enzyme have severe
immune system deficiencies. The wildtype gene for adenosine deaminase has been isolated and inserted
into a virus that can carry the gene into white blood cells of a patient lacking the enzyme. When these
transformed white blood cells with the wild-type gene were put back into the patient, the cells made
adenosine deaminase and the patient’s condition improved.
PROCEDURE:
a gene can’t be directly inserted into a cell. instead a carrier also known as vector
helps deliver the gene typically viruses are used because they are very good at
sneaking into the infective cells.

the infectious part of virus is removed allowing it to enter into the cells nucleus
without making patient sick.

1. isolated somatic cells from the patient are homozygous for the
defective allele
2. a copy of normal allele is inserted into viral DNA
3. infect isolated somatic cells with virus containing the wild-type DNA
4. the viral DNA carrying the normal allele is inserted into the patient’s
somatic cell chromosome
5. somatic cells containing the normal allele are cultured.

6. cultured cells are injected into the patient.

7. symptoms are relieved by expression of normal allele.
 CANCER
• The other approach to gene therapy is to insert the gene directly into cells in the body of the patient. this in vivo
approach is being attempted for various types of cancer.
• Lung cancer cells, for example, are accessible to such treatment if the dna is given as an aerosol through the
respiratory system.
• In preliminary clinical trials, people are given the therapy to see whether it has any toxicity and whether the
new gene is actually incorporated into the patients’ genomes.