Issues in Biotechnology The Way We Work With

Issues in Biotechnology: The Way We Work With Life Dr. Albert P. Kausch life edu. us Pharmaceutical Biotechnology Lecture 20 Part Ia. Emergent Technologies: Where Do Our Medicines Come From? © life_edu

Issues in Biotechnology: The Way We Work With Life Dr. Albert P. Kausch Kimberly Nelson On. Campus Live BCH 190, MIC 190, AFS 190, NRS 190, PLS 190 On. Line BCH 190 A Sweeping General Survey on Life and Biotechnology A Public Access College Course The University of Rhode Island Issues in Biotechnology: Biotechnology, Our Society and Our Future life edu. us

Issues in Biotechnology: The Way We Work With Life Dr. Albert P. Kausch life edu. us BCH 190 Section II. The Applications of Biotechnology A Sweeping General Survey on Life and Biotechnology © of The Universitylife_edu Rhode Island

Issues in Biotechnology: The Way We Work With Life Dr. Albert P. Kausch life edu. us Pharmaceutical Biotechnology Lecture 20 Part Ia. Emergent Technologies: Where Do Our Medicines Come From? © life_edu

Issues in Biotechnology: The Way We Work With Life Dr. Albert P. Kausch life edu. us Pharmaceutical Biotechnology Lecture 21 Part Ib. Emergent Technologies: DNA-Based Biotechnology and Pharmaceutical Drug Development © life_edu

Issues in Biotechnology: The Way We Work With Life Dr. Albert P. Kausch life edu. us Pharmaceutical Biotechnology Lecture 22 Part IIa. Pharmaceutical Biotechnology in the Genomics Era © life_edu

Issues in Biotechnology: The Way We Work With Life Dr. Albert P. Kausch life edu. us Pharmaceutical Biotechnology Lecture 23 Part IIb. Pharmacogenomics and Personalized Medicine © life_edu

Issues in Biotechnology: The Way We Work With Life Dr. Albert P. Kausch life edu. us Pharmaceutical Biotechnology Lecture 20 Part Ia. Emergent Technologies: Where Do Our Medicines Come From? © life_edu

The Problem of Human Suffering

The Problem of Human Suffering Plato Epicurus Socrates St. Augustine Martin Luther Thomas Aquinas Charles Templeton Albert Einstein Bertrand Russell Mark Twain John Stuart Mill Gandhi John Lennon Richard Dawkins

How many innocent Iraqi civilians have died from violent death since the beginning of the war in 2003? (A) 1 -5, 000 (B) 5 -10, 000 (C) 10 -50, 000 (D) 50 -150, 000 (E) over 5, 000

Estimates of Iraqi Civilian Deaths Table 1. Iraqi Civilian Deaths Estimates Iraq Body Count March 19, 2003 - August 22, 2008 86, 661 - 94, 558 Iraq Coalition Casualty Count April 28, 2005 - August 22, 2008 43, 099 Brookings Iraq Index May 2003 - August 14, 2008 113, 616 The Associated Press April 2005 - February 13, 2008 The Iraq Family Health Study (the “WHO study”) March 2003 - June 2006 Order Code RS 22537 Updated August 27, 2008 34, 832 dead 40, 174 wounded 151, 000 The Lancet Studies, Johns Hopkins University “Mortality after the 2003 Invasion of Iraq” March 19, 2003 - July 31, 2006 426, 369 - 793, 663 Source: Prepared by CRS with data from noted sources. The lancet studies comprise three cluster studies of violence-related mortality in Iraq that have recently been undertaken. The first two studies were both conducted by researchers from Johns Hopkins.

When do we intervene?

Is empathy uniquely human?

How do we intervene?

Imagine that again you are standing on a train platform. A train is coming down the track and you can again see the conductor through the window, frantically waving his arms and indicating that there are no brakes. When you look down the tracks, you see five men working where the abuts the end of the tracks and that they will be crushed by the incoming train. You quickly notice that there is a lever, which if you throw it, will divert the train to another track, saving the lives of the five men. However, there is a man working on that track who will certainly be killed. You Decide: (A) to throw the lever (B) not to throw the lever (C) that this is not my problem (D) stand watch (E) turn and walk away 40 35 30 25 20 15 10 5 0 1 2 3 4 5

Imagine that again you are standing on the same train platform. The same train is coming again and you can again see the conductor through the window, frantically waving and indicating that there are no brakes, and again when you look down the tracks, and you see five men working, who will be crushed by the incoming train. This time however, there is no lever to divert the train, but there is a very large man next to you reading a newspaper, unaware of the situation. You are not large enough to stop the train, but he is. If you push him, or drop kick him, onto the tracks his body will stop the train, saving the five men. You Decide: (A) to push him (B) not to push him (C) that this is not my problem (D) stand watch (E) turn and walk away 30 25 20 15 10 5 0 1 2 3 4 5

Imagine that again you are standing on the same train platform. The same train is coming again and you can again see the conductor through the window, frantically waving and indicating that there are no brakes, and again when you look down the tracks, and you see five men working, who will be crushed by the incoming train. This time however, there is no lever to divert the train, but there is a very large man next to you reading a newspaper, unaware of the situation. You are not large enough to stop the train, but he is. If you push him, or drop kick him, onto the tracks you will stop the train, saving the five men. You happen to know that he is a Nobel Prize Laureate. You Decide: (A) to push him (B) not to push him (C) that this is not my problem (D) stand watch (E) turn and walk away 30 25 20 15 10 5 0 1 2 3 4 5

Imagine that again you are standing on the same train platform. The same train is coming again and you can again see the conductor through the window, frantically waving and indicating that there are no brakes, and again when you look down the tracks, and you see five men working, who will be crushed by the incoming train. This time however, there is no lever to divert the train, but there is a very large man next to you reading a newspaper, unaware of the situation. You are not large enough to stop the train, but he is. If you push him, or drop kick him, onto the tracks you will stop the train, saving the five men, one of whom is your father. You happen to know that he is a convicted pedophile. You Decide: (A) to push him (B) not to push him (C) that this is not my problem (D) stand watch (E) turn and walk away 40 35 30 25 20 15 10 5 0 1 2 3 4 5

How do we intervene?

Pharmaceutical Biotechnology What is it? • Where do our Medicines come from? • History • Alternative Therapies and Science • How is DNA-based biotechnology used in current pharmaceutical drug development improvement? • Small Molecule Drug Design • Vaccine Development and Production • Recombinant DNA Drugs • How is it done? • What are the goals? • What as been done so far? • What is in the future? • What are the controversies and concerns?

Drugs and Medicine

The Anthropology of Medicinals A History of Pharmacy • Where did our early ‘drugs’ come from? • How do animals ‘know’ which plants to eat to alleviate unpleasant symptoms? • Did humans acquire knowledge through observation and experimentation? • Herbal Medicinal Botanicals

Wild Medicinals Animals self-medicate: Many mammals (including gorillas, chimps, and elephants) as well as certain indigenous tribes, eat clay rich soils that contain essential minerals, but also bind plant toxins and stop diarrhea. Kaolinite clay Kaopectate Animals partake in certain stimulating refreshments: • Coffee is reputed to have been discovered 1500 yrs ago when a goatherd noticed his goats became excessively energetic after feeding on red berries of a small shrub • Ancient Peruvian Indians observed that their lamas chewed coca leaves when carrying heavy loads on long journeys, and took up the habit themselves

Humans not the only animals to enjoy behavioral modification through ingestion of plant, fungal and microbial based compounds Animals and birds have a strong predilection for alcohol which they obtain from fermented fruit They often are observed to over indulge, despite the associated risks (accidents and predation), perhaps because alcohol is rich in calories and a stress reducer

Pharmacy is the health profession that links the health sciences with the chemical sciences and it is charged with ensuring the safe and effective use of pharmaceutical drugs. The word derives from the Greek: φάρμακον (pharmakon), meaning “drug” or “medicine. ”

Pharmaceutical Giants: Market Leaders in Terms of Sales Company Rank 1 Pfizer 2 GSK 3 Novartis 4 Sanofi-Aventis 5 Astra. Zeneca 6 Hoffmann 7 J&J 8 Merck & Co. 9 Abbott 10 Eli Lilly & Co 11 Amgen 12 Wyeth 13 Teva 14 Bayer 15 Takeda Sales ($M) Based/Headquartered 43, 363 36, 506 35, 642 32, 516 30, 336 29, 425 26, 191 19, 466 19, 140 15, 794 15, 682 15, 274 15, 660 13, 819 United States United Kingdom Switzerland France United Kingdom Switzerland United States United States Israel Germany Japan

Who Regulates Drug Safety? Origin of the FDA

Origin of the FDA History of the FDA The Food and Drug Administration is the oldest comprehensive consumer protection agency in the U. S. federal government. Its origins can be traced back to the appointment of Lewis Caleb Beck in the Patent Office around 1848 to carry out chemical analyses of agricultural products, a function that the newly created Department of Agriculture inherited in 1862. Although it was not known by its present name until 1930, FDA’s modern regulatory functions began with the passage of the 1906 Pure Food and Drugs Act, a law a quarter-century in the making that prohibited interstate commerce in adulterated and misbranded food and drugs. Harvey Washington Wiley, Chief Chemist of the Bureau of Chemistry Harvey Washington Wiley, Head in the Department of Agriculture, had been the of the Division of Chemistry of the driving force behind this law and headed its U. S. Department of Agriculture, enforcement in the early years, providing basic predecessor of the FDA, in 1899 elements of protection that consumers had never with his technical staff known before that time.

History of Drug Regulation • In 1902 The US BIOLOGICS CONTROL ACT is passed to ensure purity and safety of serums, vaccines, and similar products used to prevent or treat diseases in humans. • In 1962 THALIDOMIDE, a new sleeping pill, was found to have caused birth defects in thousands of babies born in western Europe. News reports on the role of Dr. Frances Kelsey, FDA medical officer, in keeping the drug off the U. S. market, arouse public support for stronger drug regulation.

Significant Dates in U. S. Food and Drug Law History 1820 Eleven physicians meet in Washington, D. C. establish the U. S. Pharmacopeia, the first compendium of standard drugs for the United States. 1862 Lincoln appoints Charles M. Wetherill, to serve in the new Dept of Ag. the predecessor of the Food and Drug Administration. 1883 Dr. Harvey W. Wiley Father of the Pure Food and Drugs Act. 1902 The Biologics Control Act is passed to ensure purity and safety of serums, vaccines, and similar products used to prevent or treat diseases in humans. 1906 The original Food and Drugs Act prohibits interstate commerce in misbranded and adulterated foods, drinks and drugs. The Meat Inspection Act is passed the same day. 1907 First Certified Color Regulations. 1927 Food, Drug, and Insecticide Administration. 1938 The Federal Food, Drug and Cosmetic (FDC) Act of 1938. 1939 First Food Standards issued. 1950 Alberty Food Products Co. v. U. S. , directions for use on a drug label must include purpose for the drug. Worthless remedies cannot escape the law by not stating the condition it is supposed to treat.

Significant Dates in U. S. Food and Drug Law History 1954 Miller Pesticide Amendment sets safety limits for pesticide residues on raw agricultural commodities. 1958 Food Additives Amendment requires new food additives safety; Delaney proviso prohibits any food additive shown to induce cancer in humans or animals. 1962 Thalidomide, a new sleeping pill, is found to have caused birth defects in thousands of babies born in western Europe; arouses public support for stronger drug regulation. Kefauver-Harris Drug Amendments passed to ensure drug efficacy and greater drug safety. 1965 Drug Abuse Control Amendments are enacted to deal with problems caused by abuse of depressants, stimulants and hallucinogens. 1968 FDA Bureau of Drug Abuse Control. 1970 The Comprehensive Drug Abuse Prevention and Control Act replaces previous laws and categorizes drugs based on abuse and addiction potential compared to their therapeutic value. 1985 AIDS test for blood approved by FDA. 1992 Nutrition facts, basic per-serving nutritional information, are required on foods under the Nutrition Labeling and Education Act.

Significant Dates in U. S. Food and Drug Law History 1995 FDA declares cigarettes to be drug delivery devices. 2002 The Best Pharmaceuticals for Children Act improves safety and efficacy of patented and off-patent medicines for children. 2004 Project Bio. Shield Act of 2004 FDA to expedite countermeasures to chemical, biological, and nuclear agents that may be used in a terrorist attack against the US. 2005 Food Allergy Labeling and Consumer Protection Act requires the labeling of any food that, account for the vast majority of food allergies: peanuts, soybeans, cow’s milk, eggs, fish, crustacean shellfish, tree nuts, and wheat. 2009 President Obama signs the Family Smoking Prevention and Tobacco Control Act into law. 2010 FDA Center for Tobacco Products established. FDA announced a ban on cigarettes with flavors characterizing fruit, candy, or clove.

Alternative Therapies

Alternative Therapies Herbal Medicine Homeopathy Chiropractic DNA Activation Etc. Naturopathy Osteopathy Anthroposophical Medicine Holistic Medicine Etc.

Alternative Therapies In 2011, 60 million Americans had used one or more complementary or alternative therapies to address health issues The research found that those having used alternative medicine tended to have higher education or report poorer health status The majority of alternative medicine users appear to be doing so largely because: “they find these healthcare alternatives to be more congruent with their own values, beliefs, and philosophical orientations toward health and life”

Alternative Therapies A majority of alternative medicine use was in conjunction with standard medical treatments Approximately 4. 4 percent of those studied used alternative medicine as a replacement for conventional medicine Popularity linked to low level of scientific literacy among the public at large

Alternative Therapies Many of today’s well accepted drugs were derived from plants Traditional Herbals (Chinese) have credence and have been derived from thousands of years experimentation Many of natural sources (marine) are still untapped Most alternative therapies are not regulated (warning!)

Alternative Therapies How Can We Determine if Alternative Therapies work?

Echinacea had no effect on the duration or severity of the cold

Alternative Therapies Seek a Balanced view You are an experiment of one data point There are good reasons to use ‘purified’ medicines Life expectancy is up world wide in past 100 yrs

Alternative Therapies A question of: • Efficacy (do they actually work? ) • Reductionist thinking (this herb is for that disease) • Absence of Science-based results • Absence of Regulation • Absence of Accountability • NEED FOR EVIDENCE BASED STUDIES

Alternative Therapies Can KILL!!!

Pharmaceutical Biotechnology What is it? • Where do our Medicines come from? • History • Alternative Therapies and Science • How is DNA-based biotechnology used in current pharmaceutical drug development improvement? • Small Molecule Drug Design • Vaccine Development and Production • Recombinant DNA Drugs • How is it done? • What are the goals? • What as been done so far? • What is in the future? • What are the controversies and concerns?

The History of The Pharmaceutical Drug Discovery “Pipeline”

Small Molecule Drug Design

Small Molecule Drug Designing small molecules to fit specific protein sites

Combinatorial chemistry Historical Perspective: Combinatorial chemistry, also known as test-tube evolution or applied molecular evolution, owes its origins to the arrival of the principles of molecular evolution almost 30 years ago, when RNA evolution experiments and theories on the self-organization of biopolymers suggested how it was possible to “evolve” by iteration successive generations of biopolymers from previous generations, with different properties

Vastly decreasing the time for new drug discovery and development Now small molecule design meets the genomic era

Small Molecule Drug Design The Role of Pharmacogenomics

Pharmacogenomics is the branch of pharmacology which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms (SNPs) with a drug’s efficacy or toxicity

The Role of Pharmacogenomics is the study of how an individual’s genetic inheritance affects the body’s response to drugs Personalized Medicine: Based on patients’ DNA sequence Sequencing and analysis of the human genome’s six billion base pairs Drug Metabolism: Based on individual genomics A drug that might be good for you might not do anything for someone else A drug that might be good for someone else might kill you Disease Predisposition Disease Diagnosis See more on this in the next lecture…

Genes and Behavior • Brown’s List of Human Universals • Behavior is a Biological Construct • Molecular evidence for behavioral diseases Depression Bi-polar disorder ADHD Schizophrenia

Drugs and Behavior

Drugs and Behavior SSRIs Prozac and the Placebo Effect St. John’s Wort

Drugs and Behavior Illegal Drugs Marijuana Ecstasy Heroine Cocaine Crack Meth Prescription Drugs of Abuse Foods and Alcohol Supplements Club Drugs Cocaine Coffee Fentanyl Chocolate Heroin Tea Inhalants Alcohol LSD (Acid) Sugar Marijuana Supplements MDMA (Ecstasy) Methamphetamine Legal Drugs PCP/Phencyclidine Prescription Medications Steroids (Anabolic) Tobacco Addiction (Nicotine)

Drugs and Behavior ‘This is your brain on drugs’

If you knew your genome, and it revealed that you have a genetic recessive genes for schizophrenia (you do not have the disease) and your spouse has the same diagnosis, would you want a prenatal screen for your children? (A) yes (B) no (C) uncertain

What Are The Emerging Technologies That Will Impact Pharma R&D

“Bench to Bedside” Takes ~$1 billion and up 12 Years with a 1: 5000 Rate of Success

Pharmaceutical Companies invest significant $ amounts in R&D Free market strongly selects for drug targets, not health or efficacy

1. An approximate time and cost from “Bench to Bedside” for the development of a new pharmaceutical product would be in the range of: (A) 1 -5 yrs and $10 million (B) 12 -15 yrs and over 1, 000 million (C) 3 -7 yrs and 100 million (D) 3 -7 yrs and $20 million (E) 1 -5 yrs and $500 million

2. Alternative therapies, such as herbal medicines, DNA Activation, and homeopathy have all raised suspicion and scientific concerns because: (A) they are not regulated by the FDA (B) they have not been rigorously tested in clinical trials (C) they active ingredient(s) or mode(s) of action have not been elucidated or determined in peer-reviewed scientific publications (D) their results are highly variable (E) all of answers are correct

3. Pharmacy is the health profession that links the health sciences with the chemical sciences and: (A) is a relatively new profession developed with the advent of synthetic insulin (B) produce compounds that cannot be rigorously tested in clinical trials (C) it is charged with ensuring the safe and effective use of pharmaceutical drugs (D) therefore cannot be regulated by the FDA (E) all of answers are correct

4. Personalized Medicine: (A) is what is in your medicine chest at home (B) is based on individual genomes indicating appropriate drug prescriptions and diagnostics of disease susceptibilities (C) is an alternative therapy allowing patients their right of choice for their own treatment (D) is part of the Obama Health Care Bill of 2010 requiring health care and pharmaceuticals for all people regardless of income (E) is individualized hands on health care required now for all end of life patients

5. Pharmacy is the health profession that links the health sciences with the chemical sciences and it is charged with ensuring the safe and effective use of pharmaceutical drugs. The word Pharmacy derives from the Greek: φάρμακον (pharmakon), meaning: (A) from the Farm (B) “drug” or “medicine” (C) wild plant derivatives (D) deep biology (E) wonder cure

6. The FDA is: (A) The Facts on Drugs Administration (B) The Facts and Defense Administration (C) The Food and Drug Administration (D) The Food and Defense Act (E) The Finance on Drugs Act

7. Alternative therapies including; Herbal Medicine, Homeopathy, Chiropractic Medicine, DNA Activation, Naturopathy, Osteopathy, Anthroposophical Medicine and Holistic Medicine often lack extensive evidence based studies for support raising questions about: (A) their efficacy (do they actually work? ) (B) reductionist thinking (i. e. this herb is for that disease) (C) their absence of science-based results (D) their absence of regulation and accountability (E) all of the factors shown apply to our questions about alternative therapies