gen module 8

antigen

Substance that stimulates production of an antibody

Seen as “foreign”

antibody

Made in response to the entry of a foreign protein Coded for by genes

Universal donor

O

Universal recipient

AB

What is RhoGAM? Who is it given to and under what conditions is it required?

Concentrated Rh+ antibodies injected into mothers 72 hours after she has RH+ babies

must be after every pregnancy (even abortions and miscarriages)

What does HLA stand for? Describe a situation when the alleles at the HLA loci are important medically.

Human leukocyte antigen

Specific alleles of the HLA-DQ and HLA-DR genes are correlated with an increased risk of developing food and pollen allergies

Greater Transplant Success if Match at HLA Loci

8.6e13 possible combinations possibl

autograft

a graft of tissue from one point to another of the same individual's body.

isograft

genetically identical people (twins)

allograft

same species

xenograft

different species (pig to human)

haplotype

array of HLA alleles on a given chr #6

Organ trafficking

When someone sells an organ

Exploiting Poor

Forced Donation

Black Market Sales

Complications from Foreign Surgery

Transplant tourism

When someone goes to another country to receive an organ illegally (that is outside the laws of that country).

What is the purpose of T cells? Where are they formed?

Originate in bone marrow

fight pathogens directly

What is the purpose of B cells? Where are they formed?

Originate in bone marrow

Release antibodies

Bruton’s disease

X-linked

T cells, but no B cells so no antibodies

SCID

Missing T and B cells

1 type is missing adenosine deaminase enzyme

• Gene therapy for ADA-deficient SCID patients

Rheumatoid Arthritis

Autoimmune disease

Attacks linings of joints mainly in hands, wrists and shoulders

Tissue becomes inflamed and joint surfaces are destroyed

Usually an immuno-suppressant drug to reduce response to the disease

HLA-DR4 allele identified in about 60% of people with the disease, but about 20% who have this allele do not have the disease

HIV and AIDS

AIDS (acquired immunodeficiency syndrome)

HIV (Human Immunodeficiency Virus) Infection/Progression:

HIV infects T cells

When T cell called on to act in immune response, the viral genes are activated, making more virus particles that attack more T cells

T cell population decreases and patients become more susceptible to infections and some types of cancers and ultimately early death

What disorder did bubble boy have

SCID

Describe the characteristics that a cell must have to be classified as a stem cell.

Ability to continue to divide continuously (immortal) in culture

Produce more cells like itself

Ability to differentiate into specialized tissues in the body

What are some goals of stem cell research? What do scientists hope to be able to do some day?

Knowledge about processes of development and differentiation may allow us to learn how heart disease, cancer, birth defects, etc develop and may help us to better treat or prevent these

Therapy: Manipulation of stem cells into specific cell types may allow physicians to repair and/or regenerate damaged tissues and organs

Drug Testing: Recreate disease in cell line and test different drugs

Types of stem cells

Embryonic Stem Cells – have potential to differentiate into many/most (Pluripotent not Totipotent) tissue types

Adult Stem Cells – more limited as to types of tissues they can become (multipotent)

What is somatic cell nuclear transfer? Describe the procedure.

How do you Get Adult Stem Cells?

Umbilical cord at delivery

Bone Marrow of adult

Some adult cells (brain, liver, skeletal muscle, dermal tissues, others)

Amniotic fluid (surrounding fetus during pregnancy)

How do you get embryonic stem cells

From blastocyst of early embryo

Inner cell mass = ESCs

Implant DNA of somatic cell into an enucleated human egg

Pluripotent

stem cells can give rise to all cell types of the body (but not the placenta).

Multipotent

can only give rise to some types

Totipotent

stem cells can give rise to any of the 220 cell types as well as placenta

Name the researchers who received a Nobel Prize in 2012 for their work on stem cells and regeneration biology. Discuss the contributions each made to this field

John B Burdon

1962 - Discovered that a specialized cell possessed all the genetic information needed to develop all cells in a mature organism

Shinya Yamanaka

2006 - Determined that the insertion of 4 genes could reprogram differentiated cells and cause them to become pluripotent stem cells

Discuss some of the controversial/ethical issues regarding stem cell research.

Moral status of embryos and when life begins

Poor women could be exploited for eggs

Health risks from surgical removal and hormonal treatments used to extract oocytes

Discuss the historical and current state of federal regulations on stem cell research.

Federal funding is available for adult stem cell and iPS research

2001 Bush allowed federal funding for embryonic stem cell research on older but not new cell lines

2009 Obama- federal funding available on embryonic stem cell lines created after August 2001 and that NIH would be allowed to set regulations for ESC use

On July 7, 2009, NIH published guidelines for Human Stem Cell Research.

• Lines must be registered and approved for use

• Ok to use excess embryos from fertility clinics (with qualifications)

On September 21, 2009, NIH opened their website to accept requests for human embryonic stem cell line approvals for ESC lines.

December 2009: NIH approved first ESC line under new guidelines.

What genes involved in stem cells

Signal transduction genes are associated with the cell membrane. They receive signals from outside the cell and transmit these signals through receptor proteins and enzymatic reactions to cause changes inside the cell

Which organization set the current regulations for ESC funding? What are some of the new regulations?

NIH

Nuclear Reprogramming Induced Pluripotent Stem Cells (iPS)

State regulations on stem cell research

Currently, it is restricted/banned in Arkansas, Indiana, Louisiana, Michigan, North Dakota, South Dakota

Carcinoma

Solid tumor from epithelial tissue

• Body surface coverings and derivatives

• E.g. skin, breast, respiratory, colon, urinary

• 85.3% of cancer

Sarcomas

Solid tumors from embryonic mesoderm tissue • E.g. bone, cartilage, muscle, fat • 1.9% of cancers

Lymphoma

Abnormally large number of lymphocytes (type of WBC) made by spleen and lymph nodes

• E.g. Hodgkin Disease

• 5.4% of cancers

Leukemia

Abnormally large number of leukocytes (WBCs) made by bone marrow

• Common in children. Can occur in adults

• 3.4% of cancers

Anaplasia

Structure/function of cell is undifferentiated

Hyperplasia

Uncontrolled cell division Immortal and Invasive

Metastasis

Ability to move to and establish tumors at other sites in body

G1/S checkpoint

monitors for proper cell size and undamaged DNA

G2/M

holds up cycle until replication and DNA repair are complete

M checkpoint

proper spindle formation and attachment

Malignant

cancer cells invade surrounding tissue

Metastatic

cancer cells spread and establish secondary tumors in other sites in the body

Cancer genetic causes

Single gene

Polygenic (more than 1 gene)

Chromosome aberration

Mutation(s) in somatic cell or in gamete producing cell

Viruses

How is cancer multi hit?

arises over time with multiple genetic changes.

sporadic and influenced by environment

How many of cancer causing mutations are errors in replication?

2/3

Proto-oncogenes

allow “good” cells to divide

dominant acting: only 1 copy mutated to cause cancer

Mutations of what genes cause cancer

tumor suppressor genes and proto onco genes

Loss of function mutation

Complete or partial absence of protein function Recessive-acting mutations

Gain of Function mutation

Cell produces protein that is not normally present

Either new gene product or gene product in new location or at an inappropriate time in development.

Dominant-acting mutations (usually).

Example: mutation in a gene that encodes a receptor for a growth factor might cause the mutated receptor to stimulate growth in the absence of the growth factor.

Tumor suppressor genes

recessive action: both need to be mutated for cancer

examples: APC, BRCA1, CDKN2A, NF1, p53, RB

Retinoblastoma – RB Gene

40% of cases are inherited (1 mutant allele in zygote)

Normal protein responsible for regulation at G1/S checkpoint

Knudson’s Two Hit Hypothesis

both copies have to be defective in same cell to allow tumor to develop

BRCA1and BRCA2 normal action

repair double strand breaks

BRCA 1 and BRCA 2 cancers

5-10% of all breast cancers

20-25% of hereditary breast cancers

Strong family history of breast or ovarian cancer may indicate a mutation in one of these genes.

Men with these mutations Have an increased risk of breast cancer and prostate cancer.

Can genetic test

p53

Chromosome 17

G1/S checkpoint

Colon, lung, breast, brain cancers

found in altered form in 50% of human tumors

The fork in the road: if DNA is damaged, p53 delays cell division until damage is repaired or programs cell to die

Haploinsufficiency

Individuals can still be affected even if they have one normal allele.

bloom syndrome

bloom syndrome

defective DNA helicase enzyme that is important in repairing double stranded breaks of DNA

mutated gene causes cancer even in heterozygotes

burkitts lymphoma

Abnormal function of B cells

Reciprocal translocation between chromosomes 8 and 14 places c-myc (oncogene) next to enhancer

enhancer leads to abnormally high function of c-myc gene

Chronic Myelogenous Leukemia

Fatal, uncontrolled replication of myeloid stem cells

90% of patients have the Philadelphia chromosome

Reciprocal translocation involving chromosomes 9 and 22 places 2 oncogenes near each other

ABL oncogene

Epstein-Barr Virus

linked to Burkitt's lymphoma

Infects B cells of the immune system

• Hepatitis B Virus

liver cancer

Human Papilloma Virus

cervical cancer

Pancreatic cancer

4th leading cause of cancer death even though only about 37,000 new cases occur each year.

Palladin gene

causes pancreatic cancer

codes for a cytoskeleton protein that is important in maintaining cell shape.

Cells that metastasize generally have poor cytoskeleton structure causing them to detach from the tumor mass easily

Clonal Evolution

Over time, tumor cells acquire more mutations that allow them to be progressively more aggressive in proliferation.

Defective Nucleotide Excision Repair for pyrimidine dimers

Xeroderma pigmentosum

High risk of skin cancer since many pyrimidine dimers do not get repaired

Defective Mismatch Repair

Colorectal, endometrial, stomach cancers

Defective Double Strand Break Repair

BRCA1 BRCA2

Role of Telomere Length in Cancer

Normally, telomerase works in germline cells, but not in somatic cells: allows somatic cells to die, be replaced, etc.

Tumor cells often have telomerase expression, which is thought to contribute to the “immortality” of cancer cells.

Chromosome Segregation

Cancer cells often have abnormal karyotypes

Vascularization

Angiogenesis (growth of new blood vessels) is important to tumor progression

Growth factors and other proteins involved in angiogenesis are often overexpressed in tumor cell

Angiogenesis inhibitors may be inactivated or underexpressed

Metastasis is the cause of death in 90% of human cancer cases

International Cancer Genome Consortium

To obtain a comprehensive description of genomic, transcriptomic and epigenomic changes in 50 different tumor types and/or subtypes which are of clinical and societal importance across the globe

Cancer genome atlas

a collaboration between the National Cancer Institute (NCI) and National Human Genome Research Institute (NHGRI), has generated comprehensive, multi-dimensional maps of the key genomic changes in 33 types of cancers

Tests/screenings for Cancer

Regular breast exams

Mammograms

Colonoscopies

PSA Test (prostate cancer)

Somatic Recombination in B Cells

Germ line DNA (chr. 22) Processed to mature B cell DNA

Different cells that put the same regions together in processing do it slightly differently: Junctional Diversity

Pre-mRNA is processed causing additional segments to be removed

High frequency of Somatic Mutations (~2%) in the variable region of the DNA is also common

Allergies

The tendency to develop an allergy seems to be inherited (twin studies

Specific alleles of the HLA-DQ and HLA-DR genes are correlated with an increased risk of developing food and pollen allergies

HLA

death rate of people waiting for organs

20 per day in US

Types of Organs and Tissues Transplanted

Cornea Transplants

Kidney Transplant

Liver Transplants

Heart Transplants

Heart-Lung Transplants

Bone transplants

Diamond Blackfan Anemia

RBC not produced properly due to bad protein in ribosomes

Anemia, higher frequency of some cancers, higher frequency of congenital disorders like cleft palate and abnormal limb development

National Organ Transplant Act – 1984

Organ Procurement and Transplant Network established to promote fairness in allocating organs

Factors considered include

• Medical urgency

• Blood type, tissue and size match

• Time on wait list

• Proximity to organ

Compensation for Organ Donation

Financial compensation for live kidney donors

Compensation by placing a living relative at a higher priority for organs if a dead primary relative donates

Compensate family of deceased person for allowing the deceased organs to be used for transplant