Making babies: Genetically Correct

Zhi Hua RanThe department of Gastroenterology

Ren Ji Hospital

A Glossary of Genetics Terms

Gene: basic unit of inheritance for all living organisms

Genome: Genetic endowment of a species

Gene mapping: Determining location of genes on chromosome

Gene sequencing: Determining identity of genes from the distinctive order (sequence) of base pairs, such as A-T and G-C

Chromosome: Threadlike structure in the nuclei of plant and animal cells; it carries the linearly arranged genetic units (genes)

A Glossary of Genetics Terms

Nucleic acid: Large, chainlike molecule of phosphric acid, sugar and purine and pyrimidine bases

Marker: Gene with a known location on a chromosome

Template: Macromolecular model for another macromolecule, as in the synthesis of RNA from a DNA template

Transgenic: Organism, such as a mouse, containing experimentally transferred genetic material from another organism, such as mammal

Mutation: Abrupt change in the genotype of an organism that is not the result of recombination

A Glossary of Genetics Terms

Recombination: Formation in offspring of genetic combinations not present in parents

Genotype: The genetic constitution of an individual

Phenotype: The observable characters of an organism; the result of the way the genes are expressed

Genetic defect: Pathological changes that occur by duplication, deletion or rearrangement of DNA

Transcription: The process by which RNA is formed from DNA

Nucleotide: The structural unit of nucleic acid

A Glossary of Genetics Terms

RT-PCR: Reverse transcriptase polymerase chain reaction

Gene therapy: A technique for correcting defective genes responsible for disease development

DNA microarray: An experimental tool for obtaining high-throughp

ut gene expression data

Stem cell: have the remarkable potential to develop into many different cell types in the body. Serving as a sort of repair system for the body, they can theoretically divide without limit to replenish other cells as long as the person or animal is still alive. When a stem cell divides, each new cell has the potential to either remain a stem cell or become another type of cell with a more specialized function, such as a muscle cell, a red blood cell, or a brain cell.

Milestones of Genetics

Discover the double-helix structure of DNA---by James Watson and Francis Crick

Mapping the human genome---The Human Genome Project, completed in 2001

Create the first recombinant DNA molecule---by Paul Berg

Discover the DNA structure

1953---James Watson/Francis Crick

Double-helix structure of DNA

Biography---James Watson

Born in Chicago, April 6, 1928

His father‘s ancestors were originally of English descent

His mother‘s father was Scottish-born taylor married to a daughter of Irish immigrants who arrived in the US about 1840

Spent entire boyhood in Chicago

Biography---James Watson

Study at University of Chicago at 1943

In 1947, received a B.Sc.degree in

Zoology During these years, his boyhood interest in bird-watching had matured into a serious desire to learn genetics

His Ph.D thesis was a study of the effect of hard X-rays on bacteriophage multiplication

In 1950, received Ph.D degree in Zoology at Indiana University

Biography---James Watson

In the spring of 1951, he change his direction of his research toward the structural chemistry of nucleic acids and proteins

Met Crick at 1952, common interest in solving the DNA structure

Solved in early March, 1953---the proposal of the complementary double-helical configuration

1953~1955 at the California Institute of Technology as Senior Research Fellow in Biology 1956, Assitant Professor, Harvard Biology Department

1958, Associate Professor

1961, Professor

Biography---James Watson

1962, The Nobel Prize in Physiology or Medicine

Born on June 8, 1916 at Northampton, England

In 1937, obtained a B.Sc. In Physics at London

During the war, he worked as a scientist for the British Admiralty

Biography---Francis Crick

Left the Admiralty in 1947 to study biology

Started to learn biology in 1937, interrupted by World War Two

Joined the Medical Research Council Unit since 1949

Restarted in 1950, obtained Ph.D in 1954

Biography---Francis Crick

1962, The Nobel Prize in Physiology or Medicine

Died at 2004

Worked out the general theory of X-ray diffraction by a helix

Born on June 30, 1926, New York

Biography---Paul Berg

Best known for his development of a technique for splicing together DNA from different types of organisms.

His achievement gave scientists a tool for studying the structure of viral chromosomes and the biochemical basis of human genetic diseases.

Gained early recognition/influence when he delineated the key steps in which DNA produces proteins

Awarded the Nobel Prize for Chemistry in 1980

The Human Genome Project

Began at 1990

Draft sequence was published in 2001

Founded by US department of Energy (DOE), US National Institute of Health (NIH) in collaboration with Britains Wellcome trust

The Human Genome Project

Celera Genomics, a private company based in Maryland, is publishing its findings in Science.

Human have about 30,000 genes

A public international effort, led by the United States, is publishing its analysis of the genome in N

ature, a British journal.

Genetic differences between any two people are relatively small

The Human Genome Project---more powerful tools

Durg development, customizing drugs to individual genetic profiles

Earlier diagnosis of disease

In Vitro Fertilization---history

The technique was developed in the UK by Dr. Patrick Steptoe and Robert Edwards

First “test tube“ baby: In UK, Louise Brown (July,1978

The first in US: Elizabeth Carr by Dr. Howard and GS Jones (1981)

Second “test tube“ baby: In India, Kanupriya Agarwal by Dr. Mukhopadhyay (Oct, 1978)

Since then, IVF has exploded in populatiry, accournts 1% of all birth, 115,000 in total in US

The first “test-tube “ baby

In Vitro Fertilization---history

Louise Brown born in England in July 25, 11:47 PM, 1978

25 y

1y

With parents

In Vitro Fertilization---history

Oldham General Hospital

Dr. Patrick Steptoe

Dr. Robert Edwards

At birth

In Vitro Fertilization

The first phase consists of stimulating the ovary with hormones injected, in order to cause several eggs to mature

Normally, only one egg matures per menstrual cycle, so additional hormones are usually required to prevent the body from negatively to this excess of eggs

Phase 1:

The last injection given is that of human chorionic gonadotropin (hCG), the hormone normally produced during pregnancy

In Vitro Fertilization

The second phase, that of egg retrieval, occurs about 34-36 hours after the hCG injection

The entire procedure usually takes8-20 mins

Phase 2:

In Vitro Fertilization

The third phase involves fertilization of the eggs

Phase 3:

ICSI---Intracytoplasmic sperm injection

1

2

3

In Vitro Fertilization

Phase four is the actual embryo replacement

A pregnancy test usually is done 12-14 days after retrieval

Phase 4:

2 Cell embryo 4 Cell embryo 8 Cells embryo

Thumbing through the encyclopedia of life

Technology often drives science, science drives medicine, and medicine is always pushing society

in to ethical corners

Dr. Mark Hughes

Prenatal Genetic Analysis

One of the ethically most problematic applications of genetics

If detected in the fetus, are incurable, may lead to selective abortion

Prenatal diagnosis of genetic traits typically can only provide information to assist the prospective parents in their decision making whether to carry the pregnancy to term or to terminate it

Prenatal Genetic Analysis

It requires both a medical indication and informed conset of the parents

Parents have a right to refuse medically indicated prenatal diagnosis even if there is a high risk for fetal condition that is incompatible with life

There are a few genetic traits (such as gender) are accessible to prenatal diagnosis today but unrelated to health

Prenatal Genetic AnalysisPrenatal diagnosis is carried out only to give parents and physicians information about the health of the fetus

The use of prenatal diagnosis for paternity testing, except in cases of rape or incest, or for gender selection, apart from sex-linked disorders, is not acceptable

WHO 1998

Prenatal Genetic AnalysisHeterozygosity testing for recessive disease could only be attempted for eugenic purposes

Gregor Mendel 1822~1884

Mendel‘s law of independent assortment孟德儿独立分配定律

Mendel‘s law of segregation孟德儿分离定律

Novel parameters for prenatal selection--- gene testing

Carrier screening, which involves indentifying unaffected individuals who carry one copy of a gene for a disease that requires two copies for the diasese to be expressed

Preimplantation genetic diagnosis (screening Embryos for disease)

Newbone screening

Presymptomatic testing for predicting developing adult-onset disorders such as Huntington‘s disease

Presymptomatic testing for estimating the risk of developing adult-onset cancers and Alzheimer‘s disease

Confirmational diagnosis of a symptomatic individual

Forensic/identity testing

Gene testing---HD

Huntington‘s disease (HD):Usually midlife onset; progressive, lethal, degenerative neurological disease

Caused by a single abnormal gene

An autosomal dominant disorder

Gene testing---SMA

One of the neuromuscular diseases. Muscles weaken and waste away (atrophy) due to degeneration of motor neurones which are nerve cells in the spinal cord

Gene was located Proximal portion of the long arm of chromosome 5 , 1990

Gene testing--- Fanconi Syndrome

A disorder in which the proximal renal tubules of the kidney do not properly reabsorb electrolytes and nutrients back into the body

Excessive drinking, urination and glucose in the urine

Muscle wasting, acidosis and poor condition will also occur

Pre-implantation diagnosis

Single cell analysis

Technology: RT-PCR

Technology --- RT-PCR

Electrophoresis

DNA microarray

Gene therapy

A normal gene may be inserted into a nonspecific location within the genome to replace a nonfunctional gene. This approach is most common

An abnormal gene could be swapped for a normal gene through homologous recombination

The abnormal gene could be repaired through selective reverse mutation, which returns the gene to its normal function

The regulation of a particular gene could be altered

Dr. Mark Hughes

A Professor and Director of Molecular Medicine and Genetics at Wayne State University and Director of the Genomics Center Hub for the State of Michigan's Life Sciences Corridor.

His work has centered on understanding gene expression in the early human embryo

He pioneered the field of PGD for couples at very high reproductive genetic risk and offers this technology in conjunction with IVF Centers in the U.S. and Canada.

Bypassing the natrual method of conception

Discarding excess embryos

Contributes to overpopulation

Ethical challenges

Creating life in the laboratory

Fertilizing more embryos than will be needed

Unnatural environment for embryos

Potential to select embryos

Potential to modify embryos

Ethical challenges

Potential to creat embryos for medical purposes

Alteration of genetic traits:Beauty/handsome, longevity, healthy

Potential to modify embryos

A girl or boy, you pick?

Potential to select embryos

We can test for lots of things, the question is,

should we?

--- Dr. Mark Hughes

Ethical challenges