Reproductive Technology, Genetic Testing, and Gene Therapy

Advances in genetics, physiology and molecular biology allow control over many aspects of reproduction

Infertility Is a Common Problem

In the US, about 13% of all couples are infertileInfertility is a complex problem and has many causes, including physical and physiological problems with gamete formation and hormonal imbalances

Cervical problems10%Oviduct blockage Uterine problems Damaged or absent ovaries3050%40%Hormone-related ovulation problemsThe Major Causes of Female Infertility

The Major Causes of Male Infertility

Major cause of male infertilityVaricocele is the widening of the veins along the cord that holds up a man's testiclesOccurs in 15-20% of all malesSymptoms: Enlarged, twisted veins in the scrotum; Infertility; Painless testicle lump, scrotal swelling, or bulge within the scrotum.Causes: Defective valves, or compression of the vein by a nearby structure, can cause dilatation of the veins near the testis, leading to the formation of a varicocele.

Infertility Increases with Age

Assisted Reproductive Technologies (ART) Expand Childbearing Options Assisted reproductive technologies (ART)A series of methods used to help infertile couples have children

ART Requires the Obtaining of Gametes

Hormones can induce ovaries to produce many oocytes which can be collected, sorted, and frozen for future useSperm can be pooled, or retrieved through microsurgery and frozen in sperm banks

Methods of Assisted ReproductionIn vitro fertilization (IVF) Gametes are collected and fertilized in a dishThe resulting zygote is implanted in the uterus

Gamete intrafallopian transfer (GIFT) Gametes are collected and placed into a womans oviduct

Intracytoplasmic sperm injection (ICSI) An egg is fertilized by microinjection of a single sperm (for defects in sperm count or motility)

In Vitro Fertilization

Intrauterine Insemination (IUI)In intrauterine insemination (IUI), donor sperm is placed into the uterus of an ovulating woman. The sperm swim up the oviduct and fertilize the egg.

Intracytoplasmic Sperm Injection (ICSI)Injection of a single sperm into an egg. This ART procedure is known as intracytoplasmic sperm injection (ICSI).

Some Ways Gametes Can Be Combined

Artificial Insemination and Embryo Transfer1. Father is infertile. Mother is inseminated by donor and carries child.2. Mother is infertile but able to carry child. Donor egg is inseminated by father via IVF. Embryo is transferred and mother carries child.3. Mother is infertile and unable to carry child. Donor of egg is inseminated by father and carries child.4. Both parents are infertile, but mother is able to carry child. Donor egg is inseminated by sperm donor via IVF. Embryo is transferred and mother carries child.KEYSperm from fatherEgg from motherBaby born of motherSperm from donorEgg from donorBaby born of donor (Surrogate)+=+=+=+=The many ways gametes can be combined in assisted reproduction.

In Vitro Fertilization (IVF)1. Mother is fertile but unable to conceive. Egg from mother and sperm from father are combined in laboratory. Embryo is placed in mothers uterus.+=2. Mother is infertile but able to carry child. Egg from donor is combined with sperm from father and implanted in mother.3. Father is infertile and mother is fertile but unable to conceive. Egg from mother is combined with sperm from donor.4. Both parents are infertile, but mother is able to carry child. Egg and sperm from donors are combined in laboratory (also see number 4, column at left).5. Mother is infertile and unable to carry child. Egg of donor is combined with sperm from father. Embryo is transferred to donor (also see number 3, column at left).6. Both parents are fertile, but mother is unable to carry child. Egg from mother and sperm from father are combined. Embryo is transferred to donor.7. Father is infertile. Mother is fertile but unable to carry child. Egg from mother is combined with sperm from donor. Embryo is transferred to surrogate mother.KEYSperm from fatherEgg from motherBaby born of motherSperm from donorEgg from donorBaby born of donor (Surrogate)+=+=+=+=+=+=

IVF has Resulted in the Birth of Millions of ChildrenChildren born by IVF and their parents. Louise Brown, the first human born by IVF, is the redheaded woman at the bottom center of the photograph.

Gamete Intrafallopian Transfer (GIFT)Gamete intrafallopian transfer (GIFT). Eggs and sperm are collected and implanted into the fallopian tube. Fertilization occurs here, and the embryo moves down the oviduct and implants in the uterus.

Zygote Intrafallopian Transfer (ZIFT)Zygote intrafallopian transfer (ZIFT). Gametes are collected and fertilized by in vitro fertilization before transfer to the oviduct.

Surrogacy is another form of ARTTeresa Anderson, a surrogate mother carrying quintuplets for parents Mr. and Mrs. Gonzales.

Ethical Issues in Reproductive TechnologyUse of ART raises unresolved ethical issuesHealth risks to both parents and their offspring resulting from ARTUse of preimplantation genetic diagnosis to select siblings who are suitable tissue or organ donors for other members of the family

Use of ART Carries Risks to Parents and ChildrenRisks of ARTThreefold increase in ectopic pregnanciesMultiple births (35% in IVF)Increased risk of low birth weightIncreased risk of transmitting genetic defects to male children (in ICSI)

ANIMATION: Endometriosis and IVFTo play movie you must be in Slide Show ModePC Users: Please wait for content to load, then click to playMac Users: CLICK HERE

ABC Video: Rent a Womb? Extreme Measures to Have a Baby

Risk of Premature Birth and Increase Health Costs Following IVF(left) Risk of premature birth and low birth weight following IVF. (right) Increased costs of premature babies in the first year after birth.

Genetic Testing and Screening

Several types of testing and screeningNewborn screeningCarrier testing - done on family membersPre-natal testingPre-symptomatic or predictive testing

Diseases and Birth Defects that can be Diagnosed by Prenatal testingPrenatal testing focuses on conditions that can be corrected or treated medically.

Preimplantation Genetic Diagnosis (PGD)

Preimplantation genetic diagnosis (PGD)Removal and genetic analysis of a single cell from a 3- to 5-day old embryo Used to select embryos free of genetic disorders for implantation and developmentHas been used to select embryos tissue-matched to siblings with Fanconi anemia or leukemia to serve as transplant donors

Preimplantation Genetic Diagnosis (PGD)Removing a cell from a day 3 embryo

Removal of a Polar Body for Genetic Analysis

Reasons Cited for PGD in the USReasons for PGD at 137 fertility clinics in the United States. Three clinics reported selecting embryos with specific disabilities, including dwarfism and deafness.

Selecting ChildrenMolly Nash (right) and her brother, Adam. Mollys parents used in vitro fertilization and prenatal genetic diagnosis to avoid having another child with Fanconi anemia and to select a compatible stem-cell donor for Molly.

Genetic Testing is not Always Possible due to the Presence of Multiple Mutations for the Same DiseaseCystic Fibrosis testing for 25 mutations: diagnostic success for different ethnic groups

Exploring Genetics: The Business of Making Babies

The first successful in vitro fertilization was carried out in 1981Since that time more than 40 hospitals and clinics have openedCharges for services can run as high as $60,000IVF is estimated to be a $3-billion-per-year industryThese businesses have little government oversightThe US Food and Drug Administration (FDA) controls the regulation of sperm banks.

The Genetic Revolution: Saving Cord Blood

Umbilical cord blood contains stem cells used to treat XLP and other immune disorders

Cord blood is better for transplants than marrow; it has not been exposed to pathogens and is less likely to carry antibodies

Mothers should consider donating cord blood to a cord blood bank to save lives

ABC Video: Personalized Health Care

ABC Video: Selecting Sex Causes Controversy

Genetic Testing: Screening Embryos for Disease

Gene Therapy Promises to Correct Many DisordersGene therapy transfers a normal gene copy into target cells of individuals carrying a mutant allele

Gene therapy The transfer of cloned genes into somatic cells as a means of treating a genetic disorder

What Are the Strategies for Gene Transfer?There are several methods for transferring cloned genes into human cellsViral vectorsChemical methods used to transfer genes across cell membranesPhysical methods such as microinjection or fusion of cells with vesicles carrying cloned DNA

Using Viral Vectors for Gene TherapyThe most widely used method of gene therapy uses a virus as a vector to insert a normal copy of a gene into the white blood cells of a patient who has a genetic disorder. The normal gene becomes active, and the cells are reinserted into the affected individual, curing the genetic disorder. Because white blood cells die after a few months, the procedure has to be repeated regularly. In the future, it is hoped that transferring a normal gene into the mitotically active cells of the bone marrow will make gene therapy a one-time procedure.

Gene Therapy Showed Early PromiseThe only successful gene therapy has been in a very few cases of severe combined immunodeficiency disease (SCID) There have been a number of recent failures and at least two deaths that has resulted in a loss of confidence for gene therapyTwo children had the vector virus settle into a gene that controls cell division & develop leukemia.

Numbers of Gene Therapy Trials

Ethical Issues Related to Gene Therapy

Somatic gene therapy The only form of gene therapy used to dateGene transfer to somatic target cellsInvolves a single target tissue treating only one personDone to correct a genetic disorder, using established ethical and medical guidelines

Ethical Issues Related to Gene TherapyThese types of gene therapy are not yet in use mainly due to unresolved ethical issuesGerm-line gene therapy Gene transfer to gametes or the cells that produce them Transfers a gene to all cells in the next generation, including germ cells

Enhancement gene therapy Gene transfer to enhance traits such as intelligence and athletic ability rather than to treat a genetic disorder

Gene Doping: Athletics and Enhancement Gene Therapy

Athletes have been suspended from competitions for using erythropoietin (EPO), a hormone that increases production of red blood cells to enhance athletic performance

Repoxygen, a form of gene therapy which results in increased synthesis and release of erythropoietin, may be impossible to detect

The use of EPO (erythropoietin), a hormone that increases red blood cell production to enhance athletic performance, is banned. There is controversy over using gene therapy to transfer the gene for EPO, which would be undetectable.

BBC Video: Bone Marrow as a New Source for the Creation of Sperm

Genetic Counseling Assesses Reproductive Risks

Genetic counseling involves developing an accurate assessment of a family history to determine the risk of genetic disease

Genetic counseling A process of communication that deals with the occurrence or risk that a genetic disorder will occur in a family

What Genetic Counselors Do

Counselors help people understandMedical facts, diagnosis, and treatmentHow heredity contributes to the disorder and risk of having children with the disorderAlternatives for dealing with the risk of recurrenceWays to adjust to the disorder

Who are Genetic Counselors?Genetic counselors have specialized graduate training in medical genetics, psychology, and counseling

uses the information from pedigree construction, medical records, and genetic testing

Why Do People Seek Genetic Counseling?

Counseling is recommended forWomen who are or may be pregnant after age 35Couples who have a child with a genetic defectCouples seeking information about genetic defects that are common in their ethnic groupCouples who are close blood relativesIndividuals at risk through jobs or lifestyleWomen who have had multiple miscarriagesThose concerned that they may have an inherited disorder or birth defect

How Does Genetic Counseling Work?Prenatal screening and cytogenetic or biochemical tests can be used along with pedigree analysis to determine risk Decisions about whether to have additional children, to undergo abortion, or even to marry are always left to those being counseledGenetic counseling educates individuals and families about genetic disorders and helps them make decisions about reproductive choices

ANIMATION: Genetic counselingAnalyzing pedigreesTo play movie you must be in Slide Show ModePC Users: Please wait for content to load, then click to playMac Users: CLICK HERE

*The major causes of female infertility.Varicocele is the widening of the veins along the cord that holds up a man's testicles. Symptoms: Enlarged, twisted veins in the scrotum; Infertility; Painless testicle lump, scrotal swelling, or bulge within the scrotum. Defective valves, or compression of the vein by a nearby structure, can cause dilatation of the veins near the testis, leading to the formation of a varicocele. They occur in 15-20% of all males

**Each drop of fluid in this Petri dish contains a single human egg ready for fertilization.**The many ways gametes can be combined in assisted reproduction.*The many ways gametes can be combined in assisted reproduction.**Figure 16.10Teresa Anderson, a surrogate mother carrying quintuplets for parents Mr. and Mrs. Gonzales.***Removal of a single cell from a day-3 embryo for genetic analysis by preimplantation genetic diagnosis (PGD).*******In a genetic counseling session, the counselor uses the information from pedigree construction, medical records, and genetic testing to educate and inform a couple about their risks for genetic disorders.*