1. Genetic Disorders and Gene Therapy
Contemporary Issue – Genetic Disorders and Gene Therapy
Lesson Goals
To understand the nature of genetic diseases.
To differentiate between chromosomal and single gene diseases.
To understand the nature of Down Syndrome and diagnostic methods to detect it.
To understand the important points of heredity including dominant and recessive alleles.
To understand how to predict heredity using a Punnett square.
To understand the nature and heritability of Huntington Disease, Cystic Fibrosis, and Sickle Cell Disease.
To understand the nature of genetic testing and it’s future application to diagnose diseases and the probability of getting genetic diseases.
To understand the nature of gene therapy and it’s future application to cure diseases.
Key Terms;
chromosome chromosomal disease meiosis nondisjunction Down syndrome karyotype amniocentesis autosomal disease gene allele dominant recessive co-dominant widow’s peak genotype phenotype Huntington disease cystic fibrosis sickle cell disease

2. Overview of Lesson Genetic diseases Gene Therapy Chromosomal
Single gene
Gene Therapy
What is it?
How is it done?
Advance Organizer
This lesson will begin with the basics of genetic diseases distinguishing between chromosomal diseases and single gene diseases. Emphasis will be given to patterns of heredity and how to work basic genetic crosses.
The second portion of the lesson will cover genetic testing and discuss how scientists can now identify the presence of genetic diseases using their knowledge of the human genome and proteomics.
The third portion of the lesson will deal with how scientists are learning to treat genetic diseases with gene therapy in which healthy genes are “inserted” into the body of people with genetic diseases.

3. Chromosomal Diseases
Gametes have abnormal chromosome numbers and mutations
Offspring inherit extra chromosome or are missing a chromosome
Caused by problems with meiosis
Main Idea(s) of This Slide -
There are two types of genetic diseases discussed in this lesson; Chromosomal and Single Gene.
In chromosomal disease, there is an odd number of chromosomes present in the gametes that form the zygote. In normal gametes, there are 23 chromosomes resulting in a zygote with 46 chromosomes after the egg and sperm fuse. For a chromosomal disease to occur, a problem must occur during the meiotic division that forms either the egg or the sperm cell. During meiosis, the chromosomes of a diploid cell (with 46 chromosomes) line up and split to opposite sides of the cell. The resulting gametes from this type of division have only 23 chromosomes. When nondisjunction occurs, two of the chromosomes fail to separate and some of the resulting gametes have one extra copy of a chromosome and others are missing one chromosome entirely. When these gametes are joined with another gamete from the other parent, the resulting zygote has either 45 or 47 chromosomes. This results in developmental abnormalities because the DNA instructions for protein synthesis are flawed.

4. Nondisjunction of chromosomes during meiosis
Main Idea(s) of This Slide -
This diagram shows how nondisjunction can occur during meiosis. Note how some of the resulting gametes have an extra chromosome (n+1) while others are missing the chromosome entirely (n-1).
Based on: Brooks/Cole – Thomson Learning

5. Characteristics of a child with Down Syndrome
-wide, rounded face equal length fingers
-Lower cognitive ability webbed neck
-enlarged tongue
Main Idea(s) of This Slide -
Down Syndrome is a chromosomal disease that results from the presence of an extra chromosome #21. People affected by Down Syndrome have 3 copies of chromosome #21 in each of their cell’s nuclei. Down Syndrome is characterized by a wide, round face, mental retardation, and an enlarged tongue (causing speech difficulty). A karyotype is a visual display of the chromosomes from a cell and can be used to identify if Down Syndrome is present.
Normal female karyotype with 46 chromosomes
Down syndrome karyotype with an extra chromosome 21
Based on: Mader, S., Inquiry Into Life, McGraw-Hill

6. Overview of Lesson Genetic diseases Gene Therapy Chromosomal
Single gene
Gene Therapy
Process
Vectors
Main Idea(s) of This Slide -
In a single gene disease, there is a correct number of chromosomes, but one of the chromosomes contains a gene that is responsible for the disease.

7. Important Points about Inheritance
Genes have different forms, called
alleles
Each trait is controlled by effects of
two alleles
Some alleles are:
dominant/recessive
other alleles are co-dominant
Main Idea(s) of This Slide -
Genes usually have different forms (expressions) called alleles. For example, the gene for hairline has a dominant allele (that results in Widow’s peak) and a recessive allele (that causes the hairline to be straight). Generally speaking, traits are controlled by the expression of one or both of the alleles found on the two chromosomes which contain the gene (one chromosome originating from the egg and the other from the sperm). Some alleles are dominant over other alleles and if they are present, their expression will be seen instead of the other allele which is termed recessive. Other alleles are co-dominant and if present will be expressed as a blend of the two alleles. Expression of traits will be determined based upon which alleles are present on the chromosomes.

8. Hairline Traits Allele for Widow’s Peak is dominant
A person with WW or Ww
will have Widow’s Peak
Allele for Straight Hairline
is recessive
A person with ww will have
a Straight Hairline
Main Idea(s) of This Slide -
Hairline is an example of a specific trait that has two different expressions (alleles)
Widow’s Peak is a expression seen in the person shown at the top of this slide. The alternate trait is a straight hairline as seen in the lower portion of the slide. In this case, widow’s peak is a dominant trait and if the allele is present in either of the chromosomes, the result will be a widow’s peak hairline. In order for a person to have the straight hairline, they must have the recessive trait on both of their chromosomes.

9. Genotype vs. Phenotype Genotype refers to the alleles
Phenotype refers to the appearance
Example: Genotype - Phenotype
WW - person has a widow’s peak
Ww - person has a widow’s peak
ww - person has a straight hair line
Main Idea(s) of This Slide -
Genotype is a term that refers to which alleles are found on the chromosomes (WW, Ww, or ww). Phenotype is a term that refers to which expression is seen because of the alleles (widow’s peak or straight hairline).

10. Genetics & Human Diseases
About 4,000 human diseases are thought to be inherited.
Scientists are making good progress figuring out where genes are located on chromosomes.
Genetic diseases are caused by mutations, or incorrect sequences, in the normal form of the gene.
Main Idea(s) of This Slide -
Genetic testing involves looking at the genes that code for certain traits. If certain alleles are found that cause diseases, scientists can identify whether a person will have the disease or carry the trait for the disease. There are currently tests for of the diseases that are thought to be inherited. Scientists can identify the “faulty” alleles on the chromosomes very early in development either from cells taken through amniocentesis or by testing cells from embryos intended for implantation through in-vitro fertilization.

11. Huntington’s Disease
Results in a loss of muscle control and mental function.
The symptoms usually do not appear until after 30 years old.
1 in 10,000 people.
Main Idea(s) of This Slide -
Huntington Disease is a neuromuscular genetic disease that is caused by a dominant allele. Huntington Disease is characterized by loss of psychomotor control (usually in adulthood). This particular disease is especially problematic because people do not know they are affected until after they have reached their reproductive years and have quite possibly passed on the trait to their offspring. In this case the alleles will be “H” = Huntington disease and “h” = normal neuromuscular physiology.
Caused by a dominant allele

12. Cystic Fibrosis Mucus in bronchi is thick,
interfering with lung function
1 in 25 are carriers
One of the first disorders to be actively studied for gene therapy.
Most lethal autosomal recessive disorder in U.S.
Main Idea(s) of This Slide -
Cystic fibrosis is a disease of the respiratory system in which there is excessive production of mucus in the brochi of the lungs causing breathing difficulty. It is caused by a recessive allele. In this case (n) will be used to identify the recessive gene for cystic fibrosis while (N) will be used to identify the Normal gene for proper mucus production (no cystic fibrosis). Because cystic fibrosis is caused by a recessive gene, both chromosomes must have the recessive allele in order for the trait to be expressed (nn). If only one chromosome has the recessive allele (Nn), then the person will be a carrier of the trait and can pass it on to their offspring, but will not have the disease.

13. Sickle Cell Disease- recessive allele
Red blood cells are sickle shaped, issues with circulation causing anemia and pain
Main Idea(s) of This Slide -
Sickle cell disease is a disease in which the hemoglobin of red blood cells is irregularly shaped causing sickle shaped red blood cells and problems with circulation. The normal allele for proper hemoglobin production is designated (N) for normal. The alternate allele for sickle cell hemoglobin is designated (n) for Sickle. If a person has both alleles that are normal (NN) he will have normally functioning red blood cells and will not have sickle cell disease or sickle cell trait. If the person has both alleles for sickle cell (nn) then he will have sickle cell disease. If the person has one of each allele (Nn), then he will have sickle cell trait but will be phenotypically normal.
Background Information for Teachers
Sickle Cell Trait and Malaria
Having one allele for sickle cell hemoglobin can actually be beneficial to some people.
Malaria is caused by a protozoan parasite called Plasmodium that invades red blood cells and destroys hemoglobin molecules. Plasmodium cannot survive as easily in sickle cell red blood cells and so a person who has sickle cell trait is actually more resistant to this infection than a person who does not have sickle cell trait.
It is interesting to point out to students that sickle cell disease and sickle cell trait is much more common in certain ethnic groups who originate from areas in the world where malaria is a problem (ie. African Americans). In a later lesson malaria will be discussed and it is good to tie that lesson back to this one.
Based on: Harvard Family Health Guide, 1999

14. Sickle cell disease (sickle cell anemia)
Codominant disorder found in African Americans.
1 in 400 African Americans
Can be fatal.
Possible cure: bone-marrow transplants
The sickle cell trait can prevent Malaria

15. Hemophilia
A disorder in which a person’s blood does not clot properly.
It is a recessive sex-linked, X-chromosome disorder.
1 in 10,000 males born are afflicted.
“Royalty Disease”

16. Adenoside Deaminase (ADA) Deficiency
ADA-deficient persons are affected by severe immunodeficiency, with recurrent infections that might be life-threatening.
First disease approved for gene therapy.
Autosomal recessive disorder.
The drug exists but is very expensive, needs to be injected in vein for life.

17. Overview of Lesson Genetic diseases Gene Therapy Chromosomal
Single gene
Gene Therapy
What is it?
How is it done?
Advanced Organizer
This portion of the lesson will finish up discussing gene therapy. In gene therapy, the genetic disease may be “cured” by inserting a gene with the “healthy” allele.

18. What is Gene Therapy?
Gene therapy is a treatment or cure for disorders caused by mutated genes.
It involves adding a normally functioning copy of the gene(s) to enough affected cells to restore normal function.
Gene therapy is a treatment or cure for diseases caused by defective genes.

19. What is Gene Therapy
Germline gene therapy would be the permanent transfer of a gene into sperm or egg cells.
Future generations would be “cured”.
Somatic cell (body cell) gene therapy is ideally only the transfer of genes to the affected cells.

20. Gene Therapy Successes
Although no gene therapies have been approved by the FDA for sale, some diseases have been experimentally successful:
Melanoma (skin cancer)
Severe Combined Immunodeficiencies
Hereditary Blindness
Sickle Cell Anemia

21. How is it done? Viral Vector Carrying Healthy Gene
Cell with mutated gene(s)
Vector inserts healthy gene into cell
New gene in the cell along with original genes
Functional proteins are created from the therapeutic gene causing the cell to return to a normal state.

22. Gene Therapy
To design and carry out a gene therapy treatment, a researcher must:
Identify the gene(s) responsible for the disorder.
Make copies of the normal gene.
Insert the copies into vectors.
“Infect” the affected cells with the vectors.
Activate the gene so that transcription and translation take place.

23. Viruses as Vectors Replicate by inserting their DNA into a host cell
Gene therapy can use this to insert genes that encode for a desired protein to create the desired trait
Four different types
Adenovirus
Adeno-Associated Virus (AAV)
Retrovirus
Herpes Simplex Virus (HSV)

25. Vector Advantages and Disadvantages
Adenovirus
Infects many cell types
Does not integrate into host genome and can be lost.
Retrovirus
Integrates into host genome and cannot be lost
Integrates into host genome and can cause cancer
Adeno-Associated Virus (AAV)
Difficult to work with.
Herpes Simplex Virus (HSV)
DNA stays in nucleus without integrating into host genome.
Only infects cells of the nervous system.

26. Gene Therapy Disappointments
In 1999 a boy died due to an immune response to an adenovirus gene therapy vector.
Four children have developed cancer due to a retrovirus gene therapy vector

27. My Research: Building a better Vector
Adenovirus shell delivers genes
HSV-like virus protein tethers DNA to chromosome to keep genes in cell without integration
Instead of giving a drug to fight a disease, you give a cell a healthy or protective gene.
An adenovirus shell is very efficient at delivering DNA to a cell.
An Epstein-Barr virus is very efficient at keeping its DNA inside the cells it infects without causing problems in the infected cells.

28. Your Goals:
Learn more about gene therapy by completing a becoming a SPACE DOCTOR!
Gene Therapy Vector Engineering Project.
First groups to complete the Space Doctor activity gets to chose from the genetic diseases we talked about today.
Use what you have learned and the Vector Toolbox to choose the best vector for treating the disease.

29. Tomorrow
Learn about the techniques used to genetically engineer gene therapy vectors.
Gene Therapy Vector Engineering Project.
Use paper models to simulate the process of engineering your gene therapy vector.