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									    Making babies:
   Genetically Correct

           Zhi Hua Ran
The 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
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-
throughput 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

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

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

                         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 in
        During these years, his boyhood interest
        in bird-watching had matured into a
        serious desire to learn genetics
        In 1950, received Ph.D degree in
        Zoology at Indiana University
        His Ph.D thesis was a study of the effect
        of hard X-rays on bacteriophage
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
         Solved in early March, 1953---the
         proposal of the complementary
         double-helical configuration
Biography---James Watson

        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
        1962, The Nobel Prize in Physiology
        or Medicine
Biography---Francis Crick

         Born on June 8, 1916 at
         Northampton, England
         In 1937, obtained a B.Sc. In Physics
         at London
         Started to learn biology in 1937,
         interrupted by World War Two
         During the war, he worked as a
         scientist for the British Admiralty
         Left the Admiralty in 1947 to study
Biography---Francis Crick

         Joined the Medical Research Council
         Unit since 1949

         Restarted in 1950, obtained Ph.D in
         Worked out the general theory of X-
         ray diffraction by a helix

         1962, The Nobel Prize in Physiology
         or Medicine
         Died at 2004
             Biography---Paul Berg
Born on June 30, 1926, New York
Gained early recognition/influence when he
delineated the key steps in which DNA
produces proteins
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
Awarded the Nobel Prize for Chemistry in
The Human Genome Project

   Began at 1990

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

   Draft sequence was published in 2001
       The Human Genome Project

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

                             A public international effort, led by the United
                             States, is publishing its analysis of the genome in
                             Nature, a British journal.

Human have about 30,000 genes

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

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

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

  Since then, IVF has exploded in populatiry, accournts 1% of all
  birth, 115,000 in total in US
        In Vitro Fertilization---history

The first “test-tube “ baby
Louise Brown born in England
in July 25, 11:47 PM, 1978

                     25 y

                                      With parents
In Vitro Fertilization---history
                               Dr. Patrick Steptoe

        At birth

     Oldham General Hospital
                               Dr. Robert Edwards
            In Vitro Fertilization
Phase 1:
           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

           The last injection given is that of human chorionic
           gonadotropin (hCG), the hormone normally produced during
                  In Vitro Fertilization
Phase 2:

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

           The entire procedure usually takes
           8-20 mins
             In Vitro Fertilization
Phase 3:
           The third phase involves fertilization of the eggs
ICSI---Intracytoplasmic sperm

     1                          3

                   In Vitro Fertilization
Phase 4:
                 Phase four is the actual embryo replacement

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

 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 Analysis
Prenatal 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 Analysis
Heterozygosity testing for recessive disease could only be attempted for
eugenic purposes

                                                             Gregor Mendel

                                Mendel‘s law of independent assortment

                                Mendel‘s law of segregation
   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

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

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

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.
         Ethical challenges

Bypassing the natrual method of conception

Creating life in the laboratory
Fertilizing more embryos than will be needed

Discarding excess embryos

Unnatural environment for embryos
Contributes to overpopulation
        Ethical challenges

Potential to creat embryos for medical purposes

Potential to select embryos

Potential to modify embryos
Potential to modify embryos

  Alteration of genetic traits:
  Beauty/handsome, longevity, healthy
Potential to select embryos

  A girl or boy, you pick?
Ethical challenges

        We can test for lots of
        things, the question is,
             should we?

                --- Dr. Mark Hughes

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