Chapter Outlines

Chapter 9      The History of Medicine, Clinical Trials, Gene Therapy and Xenotransplantation

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9.1 Why is the History of Medicine Important?
  • Humans strive to improve health through the use of medicines and medical procedures.
  • Advancements occur after more risky procedures:
    • 1952 open heart surgery by Dr. Wilfred Bigelow.
    • 1984 Baby Fae receives baboon heart.
    • 1990 Ashanti De Silva and ADA gene therapy
    • 1999 Jesse Gelsinger and OTC gene therapy
History of Medicine and Medical Research
  • Biblical times: nutrition and diet
  • Ancient Chinese herbalists
  • Shushruta: anatomy and surgery
  • Hippocrates 460 B.C.: disease descriptions
  • Galen: experimental physiology
  • Leonardo da Vinci: anatomical drawings
  • Vesalius: medical textbook, anatomy (dissecting human cadavers)
  • Ignaz Semmelweis: handwashing
  • Edward Jenner: smallpox vaccine
  • Louis Pasteur
  • Robert Koch
Female pioneers in medicine
  • Elizabeth Blackwell, Emily Jennings Stowe
Insulin and Penicillin: Great Medical Breakthroughs in the 20th Century
  • Instrumental in driving clinical research forward.
  • Macleod, Banting: insulin experiments and diabetic dogs.
  • Best and Collip: first human trials of insulin.
  • Penicillin saved the lives of many wounded soldiers in WWII
    • Discovered by Fleming
    • Florey and Chain: first human clinical trials
9.2 Clinical Trials Today
  • Today is the golden age of medical research.
Gene Therapy
  • The introduction of genes into a person's cells to replace or compensate for defective genes in a person's body responsible for a disease or medical problem.
  • The "good" genes may be delivered by a customized vector such as a virus.
The Number of Gene Therapy Trials Approved Worldwide High Profile Gene Therapy Cases Resulting in Gene Therapy Setbacks
  • 1999, Jesse Gelsinger died of immunological complications after being injected with a modified adenovirus that carried an ornithine transcarbamylase (OTC) gene.
  • 2003, the FDA halted 27 gene therapy trials using retroviruses after a second child developed leukemia after being treated for X-SCID.
  • 2007, Jolee Mohr died after receiving a modified adeno-associated virus that contain a gene that encodes the co-receptor for TNF-a to treat rheumatoid arthritis.
Gene Delivery by Viruses: The Key to Gene Delivery
  • Modified viruses can be targeted to deliver genes to the correct population of cells.
  • Viruses are engineered so that they cannot replicate and destroy or harm cells of the patient.
  • Sometimes the patient may get sick (as in the case of Jesse Gelsinger) and the patient may mount an immune response against the viral vector, preventing treatments from working.
Hallmarks of a Good Gene Therapy Virus Vector
  • Targets the appropriate cells.
  • Integrates the correct gene into the cell's nuclear DNA.
  • Transcribes and translates the correct gene product so that the gene product can function properly.
  • Causes no toxic or harmful affects related to the gene delivery vehicle.
Two Ways to Deliver the Viral Vector to the Patient's Cells
  • In vivo therapy: the patient's body is directly injected with the modified gene therapy vector.
  • Ex vivo therapy: the patient's cells are removed, grown in culture dishes in the laboratory, incubated with the viral vector to introduce the genes, then transplanted back into the patient.
Most Popular Viral Vectors Used in Gene Therapy Trials
  • Retroviruses
  • Adenoviruses
  • Adeno-associated virus
  • Herpes simplex virus
  • Vaccinia
Gene Delivery without Viruses
  • Use of plasmid or "naked DNA."
  • Plasmid delivery is less efficient than viral delivery.
  • The DNA is complexed with liposomes or other chemical polymers or physical energy is applied.
    • Electroporation
    • Pressure mediated delivery
    • Ultrasound
    • Laser
    • Magnetic fields
    • Ballistic delivery
List of the Majority of the Types of Genes Being Used in Clinical Trials Today
  • Specific antigens (involved in immune modulation)
  • Cytokines
  • Tumor suppressors
  • Receptors
  • DNA replication inhibitors
  • Cell protection/drug resistance
  • Deficiency (compensation for defective genes)
  • Growth factors
  • Suicide (induce apoptosis)
Smaller % of Clinical Trials Involve Transferring Other Types of Genes
  • Hormones
  • Adhesion molecules
  • Porins
  • Ion channels
  • Transporters
  • Ribozymes
  • Gene silencers (siRNA)
  • Transcription factors
9.3 Xenotransplantation
  • Any procedure that involves the use of live cells, tissues, and organs from a nonhuman animal source, transplant or implanted into humans or used for clinical ex vivo perfusion.
  • Xenotransplantation does not include nonliving animal products such as pig insulin or pig heart valves.
History of Organ Transplants
  • French surgeon Alexis Carrel (1873-1944)
    • Perfected blood vessel suturing in 1902.
  • Repairing blood vessels meant the possibility of replacing sick with healthy organs.
  • Carrel and Guthrie published 28 papers on re-transplanting or transplanting arteries, veins, kidneys, ovaries, thyroid glands and a thigh on animals, especially dogs.
    • Problems with organ rejection observed as early as 1907.
Human-to-Human Organ Transplants
  • 1911, U.S. earliest account: "Dr. Hammond Gives Patient New Kidney."
  • Most medical historians credit the first human-to-human kidney transplant performed in 1933 in Russia by Dr. S. Voronoff.
  • 1954 First successful organ (kidney) transplant between identical twins performed by Dr. Joseph Murphy at Brigham and Women's Hospital in Boston.
Organ Rejection
  • 1960 Nobel Prize in Physiology or Medicine
    • Sir Peter Medawar and Sir Frank Burnet
    • Research on immune tolerance (e.g. skin graft acceptance and rejection)
9.4 Organ Need, Supply and Demand
  • Waiting lists drive the need for more organs.
  • 25% of patients die while waiting for an organ.
Xenotransplantation Molecular Roadblocks and Immunological Hurdles (Organ Rejection)
Xenotransplantation and Safety
  • Xenozoonosis: disease transmitted from an animal to a human recipient after transplantation of an animal organ.
  • Viruses or other microbes can lurk in the animal's organs.
  • Pig viruses of concern: porcine endogenous retroviruses (PERVs).
  • Porcine herpesviruses
  • Porcine circoviruses

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