© life_edu Lecture 20 Part Ia. Emergent Technologies: Where Do Our Medicines Come From? Issues in...

Lecture 20

Part Ia. Emergent Technologies: Where Do Our Medicines Come From?

Issues in Biotechnology:The Way We Work With Life

Dr. Albert P. Kausch

life edu.us

Pharmaceutical Biotechnology

Issues in Biotechnology:Biotechnology, Our Society and Our Future

OnCampus LiveOnCampus LiveBCH 190, MIC 190, AFS 190, NRS 190, PLS 190BCH 190, MIC 190, AFS 190, NRS 190, PLS 190

OnLine BCH 190OnLine BCH 190

A Sweeping General Survey on Life and BiotechnologyA Public Access College Course

The University of Rhode Island

Kimberly Nelson

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A Sweeping General Survey on Life and Biotechnology

The University of Rhode Island

life edu.us

BCH 190BCH 190 Section II.

The Applications of Biotechnology

Lecture 20

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Lecture 21

Part Ib. Emergent Technologies: DNA-Based Biotechnology and

Pharmaceutical Drug Development

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Lecture 22

Part IIa. Pharmaceutical Biotechnology in the Genomics Era

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Lecture 23

Part IIb. Pharmacogenomics and Personalized Medicine

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Lecture 20

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The Problem of Human Suffering

Plato Albert EinsteinEpicurus Bertrand RussellSocrates Mark TwainSt. Augustine John Stuart MillMartin Luther GandhiThomas Aquinas John LennonCharles Templeton 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 5,000.000

Estimates of Iraqi Civilian Deaths Table 1. Iraqi Civilian Deaths Estimates

Iraq Body CountMarch 19, 2003 - August 22, 2008 86,661 - 94,558

Iraq Coalition Casualty CountApril 28, 2005 - August 22, 2008 43,099

Brookings Iraq IndexMay 2003 - August 14, 2008 113,616

The Associated PressApril 2005 - February 13, 2008 34,832 dead

40,174 woundedThe Iraq Family Health Study (the “WHO study”)

March 2003 - June 2006 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 beenundertaken. The first two studies were both conducted by researchers from Johns Hopkins.

Order Code RS22537Updated August 27, 2008

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 and watch(E) turn and walk away

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 and watch(E) turn and walk away

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:

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:

How do we intervene?

• 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?

Pharmaceutical Biotechnology What is it?

Drugs and MedicineDrugs and Medicine

• 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

The Anthropology of Medicinals

A History of Pharmacy

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

Wild Medicinals

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.”

Pharmacy

Company Sales ($M) Based/Headquartered

1 Pfizer 43,363 United States2 GSK 36,506 United Kingdom3 Novartis 36,506 Switzerland4 Sanofi-Aventis 35,642 France5 AstraZeneca 32,516 United Kingdom6 Hoffmann 30,336 Switzerland7 J&J 29,425 United States8 Merck & Co. 26,191 United States9 Abbott 19,466 United States10 Eli Lilly & Co 19,140 United States11 Amgen 15,794 United States12 Wyeth 15,682 United States13 Teva 15,274 Israel14 Bayer 15,660 Germany15 Takeda 13,819 Japan

Pharmaceutical Giants: Market Leaders in Terms of Sales

Origin of the FDA

Who Regulates Drug Safety?

Origin of the FDA

Harvey Washington Wiley, Head of the Division of Chemistry of the U.S. Department of Agriculture,

predecessor of the FDA, in 1899

with his technical staff

History of the FDAThe 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 in the Department of Agriculture, had been the driving force behind this law and headed its enforcement in the early years, providing basic elements of protection that consumers had never 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 ona drug label must include purpose for the drug. Worthless remedies cannot escape the law by not stating the conditionit is supposed to treat.

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.

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 BioShield 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 TherapiesAlternative Therapies

Herbal MedicineHomeopathyChiropracticDNA ActivationEtc.

NaturopathyOsteopathyAnthroposophical Medicine Holistic MedicineEtc.

Alternative TherapiesAlternative TherapiesIn 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”

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

Many of today’s well accepted drugs were derived from plants

Traditional Herbals (Chinese) have credence and have beenderived from thousands of years experimentation

Many of natural sources (marine) are still untapped

Most alternative therapies are not regulated (warning!)

How Can We Determine if Alternative Therapies work?

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

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

A question of:A question of:

• Efficacy Efficacy (do they actually work?)(do they actually work?)

• Reductionist thinking Reductionist thinking (this herb is (this herb is forfor that disease) that disease)

• Absence of Science-based resultsAbsence of Science-based results• Absence of RegulationAbsence of Regulation• Absence of AccountabilityAbsence of Accountability

• NEED FOR EVIDENCE BASED STUDIESNEED FOR EVIDENCE BASED STUDIES

Can KILL!!!

The History of The Pharmaceutical Drug Discovery “Pipeline”

Small Molecule Drug DesignSmall Molecule Drug Design

Designing small molecules to fit Designing small molecules to fit specific protein sitesspecific protein sites

Combinatorial chemistryCombinatorial 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

VastlyVastlydecreasing decreasing the timethe timefor new drugfor new drugdiscovery anddiscovery anddevelopmentdevelopment

Now small Now small molecule molecule design meetsdesign meetsthe genomicthe genomiceraera

The Role of PharmacogenomicsThe Role of Pharmacogenomics

Small Molecule Drug DesignSmall Molecule Drug Design

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

PharmacogenomicsPharmacogenomics

The Role of PharmacogenomicsThe Role of PharmacogenomicsPharmacogenomics is the study of how an individual’s genetic

inheritance affects the body’s response to drugs

Personalized Medicine:Personalized Medicine: Based on patients Based on patients’’ DNA sequence DNA sequenceSequencing and analysis of the human genome’s six billion base pairs

Drug MetabolismDrug Metabolism: Based on individual genomics: Based on individual genomics A drug that might be good for you might not do anything for A drug that might be good for you might not do anything for someone elsesomeone else A drug that might be good for someone else might kill youA drug that might be good for someone else might kill you

Disease PredispositionDisease Predisposition

Disease DiagnosisDisease Diagnosis

See more on this in the next lecture…

• Brown’s List of Human Universals

• Behavior is a Biological Construct

• Molecular evidence for behavioral diseasesDepressionBi-polar disorderADHD

Schizophrenia

Genes and BehaviorGenes and Behavior

Drugs and BehaviorDrugs and Behavior

SSRIsProzac and the Placebo Effect

St. John’s Wort

Illegal Drugs

MarijuanaEcstasyHeroineCocaineCrackMeth

Drugs of AbuseAlcohol Club Drugs Cocaine Fentanyl Heroin Inhalants LSD (Acid) Marijuana MDMA (Ecstasy) Methamphetamine PCP/Phencyclidine Prescription Medications Steroids (Anabolic) Tobacco Addiction (Nicotine)

Legal DrugsPrescription Drugs

Foods and Supplements

CoffeeChocolateTeaAlcoholSugarSupplements

‘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” “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

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