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Biotechnology:
Past, Present, And Future
Donna C. Sullivan, PhD
Division of Infectious Diseases
Univ. Mississippi Medical Center
History Of Biotechnology: Food
And Beverages
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6000 BC: Sumarian
and Babylonian beer
4000 BC: Egyptian
leavened bread,
cheese, mushroom
cultivation
At time Genesis was
written: wine
1857-1876: Pasteur
demonstrated
fermentation by
microorganisms
The Brave New World


We are at the
beginning of the
biotech century
Biotech is expanding
• Industrial &
environmental
applications
• Medical applications
• Food and agricultural
applications
Bio Mass

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Biomass already
supplies 14% of the
world’s primary
energy consumption.
On average, biomass
produces 38% of the
primary energy in
developing countries.
USA: 4% of total
energy from biomass,
around 9000
MegaWatts
GASOHOL: Are We Starving
Children to Drive Our Hummers?
US Dept. of Energy Web Page:
FAQ Looks at Myths


MYTH: Ethanol cannot be produced from
corn in large enough quantities to make a
real difference without disrupting food and
feed supplies.
FACT: Corn is only one source of
ethanol. As we develop new, costeffective methods for producing biofuels, a
significant amount of ethanol will be made
from more abundant cellulosic biomass
sources.
Sugar Sources: Why Don’t We Use
Them?
1/ Based on 2003-05 U.S. average raw sugar recovery rate of 12.26% per ton of cane and sucrose recovery from cane molasses at 41.6 pounds per ton of sugarcane.
2/ Based on 2003-05 U.S. average refined sugar recovery rate of 15.5% per ton of beets and sucrose recovery from beet molasses at 40.0 pounds per ton of sugar beets.
3/ Based on an average sucrose recovery of 49.2% per gallon of cane molasses.
Does It Have To Be That Way?
Even Iowa Wants to Know What
Is Going On
http://www.extension.iastate.edu/agdm/articles/hof/HofJan09.html
http://www.extension.iastate.edu/agdm/articles/hof/HofJan09.html
Historical Trend Ethanol And
Flex Vehicles In Brazil
US Dept. of Energy Web Page:
FAQ Looks at Myths


MYTH: More energy goes into producing
ethanol than it delivers as a fuel.
FACT: In terms of fossil
Raw Material
Energy output/
Energy input
energy, each gallon of
Wheat
1.2
ethanol produced from
Corn
1.2-1.5
Sugar beet
1.9
corn today delivers one
Sugar cane
8.3
third or more energy
(Brazil)
than is used to produce it.
US Dept. of Energy Web Page:
FAQ Looks at Myths


MYTH: Ethanol-gasoline blends can lower
fuel economy and may harm your
engine.
FACT: Ethanol blends in use today have
little impact on fuel economy or vehicle
performance.
Even if you don’t, you can
have your car converted.
Several companies provide
kits to convert gasoline
powered vehicles to FFVs.
The U.S. has Abundant
Cellulose Sources
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Corn Stover
Rice Straw
Wheat Straw
Barley Straw
Sugar Beet Tops
Alfalfa
Switch Grass
Saw Dust
Sugar cane waste
Biomass: And It Doesn’t Have To
Be Just Plants….
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Bio Mass from cattle manure,
agricultural waste, forest residue and
municipal waste.
Anaerobic digestion of livestock
wastes to give bio gas
Fertilizers as by product.
Average electricity generation of
5.5kWh per cow per day!!
Algae Tested As Fuel For Arizona
Power Plant


The algae, which grow
in racks of plastic
bags, feed on the
carbon dioxide in the
exhaust of the power
plant.
The system not only
reduces the
greenhouse gases
coming from the
power plant by 40%
but can also produce
biodiesel and animal
feedstock as a
byproduct without
competing with the
global food supply.
And It’s Not Just “Someplace
Else”….
Notice the MICROBIOLOGIST!!

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University of Georgia researchers
have developed a new technology
that promises to dramatically
increase the yield of ethanol from
readily available non-food crops,
such as Bermuda grass, switch
grass, Napier grass-and even
yard waste.
"Producing ethanol from
renewable biomass sources such
as grasses is desirable because
they are potentially available in
large quantities," said Joy
Peterson, PROFESSOR OF
MICROBIOLOGY
Columbus, Mississippi
Biodiesel in Mississippi

Multi-feed stock
• Columbus
• Greenville

Soy
• Natchez

Make your own
• Arkansas company
sells kit
BIOTECHNOLOGY AND
MEDICINE

Pharmaceuticals
• Antibiotics-most come from microbes

Biopharmaceuticals
• Monoclonal antibodies
• Vaccines
• Gene therapy

Diagnostics
Biotechnology has Revolutionized
Drug Development


Injected insulin directly supplements an insufficiency in
diabetics
Prior to 1982, insulin was primarily extracted from pig
pancreas
• 50 pigs sacrificed to produce sufficient insulin for one person for
one year
• Risk of disease transmission, shortages, immune system rejection

Use gene splicing to insert human insulin gene into
bacteria
• Plentiful supply
• No risk of animal disease transmission
• Reduced risk of immune system rejection


Traditional pharmaceutical methods involve chemical
synthesis and biological extracts and pharmaceuticals are
often indirect effectors
Biotechnology uses biological synthesis and biologics are
often direct effectors
BUILDING BIOTECHNOLOGY pp. 10-11, 36
Personalized
Medicine
People Have Been Making Decisions Based on
Biotechnology for Years: Testing for Down’s
Syndrome and sex
“Karyotyping”
Screening For Genetic Abnormalities

Fluorescent in situ
hybridization
(FISH) used to
detect:
• Extra
chromosomes
• Missing parts of
chromosomes
• DNA swapping
across different
chromosomes

Chronic
myelogenous
leukemia
• DNA exchange
between
chromosome 9
and 22
ACCATG
GTATAC
*TGGTAC
*CATATGFluorescent DNA probes
Allele Specific Oligonucleotide Analysis
(ASO)


Analyze DNA
from cells of 832-cell-stageold embryo
created by in
vitro fertilization
Allows
individuals to
select healthy
embryos before
implantation
SNPs are abundant
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Estimated that 1 SNP occurs every 10003000 bp along the DNA of every
chromosome
Over 1.4 million SNPS identified to date on
human chromosome.
When SNPs occur in a gene that codes for
a body function, a disease can result.
Pharmaceutical companies are cataloguing
the chromosomal locations of SNPs
Identifying sets of
disease genes by
microarrays
Testing Issues
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Should we test people for genetic
conditions for which no cure exists?
What are the accepted consequences if a
parent learns their unborn child has a
genetic defect?
What are the psychological consequences
of a false results that indicates that a
healthy person has a disease gene or a
gene defect?
How do we ensure privacy and
confidentiality?
Microarray for Leukemia screening
Drug delivery

Getting drug to target organs and tissue
• Oral drug to treat arthritis in knee is not very
efficient
• Drug solubility may be an issue

Microspheres
Insulin
delivered as a
powder through
an inhaler
10-9 meters
Nanomedicine
1 meter

Nanometer is one
billionth of a meter
• May be used for
delivery of small
sensors to target
sites in body
• Unclogging arteries
• Detect and destroy
cancer cells
Artificial blood

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Cell-free solutions containing molecules
that can bind and transport oxygen like
hemoglobin
Benefits
• Disease-free alternative to real blood
• Constant supply
• Universal donor type

Disadvantages
• Cannot perform all the functions of a red blood
cell-only oxygen delivery

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Source of iron
Carbon dioxide removal
A
B
A,B
Type
You Can Give Blood
To
You Can Receive
Blood From
A+
A+ AB+
A+ A- O+ O-
O+
O+ A+ B+ AB+
O+ O-
B+
B+ AB+
B+ B- O+ O-
AB+
AB+
Everyone
A-
A+ A- AB+ AB-
A- O-
84 donors
are RH+
O-
Everyone
O-
38 are O+
7 are O-
B-
B+ B- AB+ AB-
B- O-
34 are A+
6 are A-
9 are B+
2 are B-
3 are AB+
1 is AB-
AB-
AB+ AB-
AB- A- B- O-
O
Out of 100 donors . . . . .
16 donors
are RH-
Monoclonal antibodies
Gene therapy
stopped

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Delivery of therapeutic genes into the body
to correct disease conditions created by
faulty gene
How is it done?
1
2
4
3
Pharmacogenomics
Epogen – Biotech’s First
Blockbuster

Erythropoietin (EPO) is a hormone that increases red blood
cell proliferation
• Used to treat anemia
• Reduces need for blood transfusions

Development timeline
•
•
•
•
Initially purified from 2,500 quarts of human urine in 1976
Patents filed in 1984
Efficacy demonstrated in 1986
Approved for HIV patients in 1990 – 14 years after first
purification!
• Expanded approvals thereafter

Developed by Amgen
• CEO is a former US Navy nuclear-submarine chief engineer
• Prior science training: High-school biology, college chemistry
Cloned Biopharmaceuticals
PRODUCT
APPROVED USE
Insulin
Diabetes
Human growth hormone
Growth deficiency
 Interferon
Cancer, viral infections
Hepatitis B Vaccine
HBV prevention
Tissue Plasminogen activator
Cardiovascular disease
Erythropoietin
Anemia
Interleukin-2
Cancer
Xenotransplantation
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Transplanting organs from one species
into another
May someday become an alternative to
human-to-human transplantation
• 1984 baboon heart transplanted into a 12year-old human girl

Girl died after 3 weeks as a result of organ rejection
• Can be avoided by matching immune system
of donor and acceptor

Major histocompatibility complex
• Human leucocyte antigen (HLA) present on all of our
cells
Pigs genetically engineered to lack a sugar-producing gene that
causes human bodies to reject pig organs
Tracy, a transgenic sheep,
1999

Her milk produced
a human protein
called alpha
antitrypsin, a
potential treatment
for the disease
cystic fibrosis.
More Than One Kind of Cloning
Environmental Biotechnology
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Waste water and
sewage treatment
• Safe drinking water
• Acceptable sewage
disposal
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Landfill technologies
Composting
Bioremediation
Bioleaching
Bioleaching To Solubilize Elements
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Bioleaching costs 33-50% less than
direct smelting
Commercially important metals
• Copper (10% of total production in US)
• Uranium
(4000 tons/year in US)
• Others
(zinc, cobalt, lead)
At The Table
Calgene’s Flavr Savr Tomato
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Most tomatoes are gas-ripened
•
•
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Vine-ripened tomatoes sell for a
premium
•
•
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•
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Tastier than gas-ripened tomatoes
Cost more to deliver to market, have
shorter shelf-lives
Polygluconase enzyme was
associated with ripening in 1984
•
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Picked while green to prevent damage
during shipping
Sprayed with ethylene to ‘ripen’ prior to
sale
Result is bright red but tasteless tomatoes
Highly expressed in red tomatoes, absent
in green tomatoes
Calgene set out to reduce expression of
polygluconase to delay ripening
Produce tomatoes that can be
transported like gas-ripened
tomatoes but are worthy of vineripened prices
Can compete with vine-ripened
tomatoes because of greater
durability and longer shelf-life
BUILDING BIOTECHNOLOGY p. 326
Path to Development
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Isolate PG gene and generate antisense
tomatoes
Develop assay for ripening
• Flavr Savr tomatoes spoiled slower than wild
tomatoes at room temperature
• 1 lb weight and timer to measure firmness

Field test
• Flavr Savr tomatoes ripened as fast as wild
tomatoes, rotted slower
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File Patents
Solicit FDA Approval
• Demonstrate that Flavr Savr tomatoes do not
pose a health risk
Market Launch
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Taste of Flavr Savr tomatoes not as
good as competing premiums
• Flavr Savr gene was not introduced
into premium tomato varieties

Flavr Savr tomatoes could not
withstand shipping
• Firmer than vine-ripened, but not as
durable as green tomatoes

General lack of expertise in the freshtomato business
• Product pulled from market

Flavr Savr tomatoes had marginal
added value; could not be sold at a
profit
U.S. Labeling Policy for
Food Biotechnology
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FDA safety standards
are consistent for all
foods.
A label disclosure
would be required if ..
• Allergens were present in
the food
• Levels of naturally
occurring toxins had
increased.
• Nutrient composition or
profile had been changed
from its traditional
counterpart
Labeling Laws?
Roundup Ready® Soybean First
Crop Plant Produced By Monsanto
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Today, over 90% of
the soybean crop in
the USA consists of
Roundup Ready®
plants.
Two thirds of the
cotton and a quarter
of the corn crop are
Roundup Ready®
plants.
Roundup Ready Corn 2
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Roundup agricultural
herbicides have been on
the market for 30 years.
Glyphosate is the active
ingredient in Roundup,
chances of weed resistance
less likely than other
chemistries.
After nine years of
commercial use in the US,
only two weeds have been
confirmed resistant to
glyphosate in Roundup
Ready cropping areas.
The List Keeps Growing
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Insect resistant cotton
– Bt toxin kills the
cotton boll worm
Insect resistant corn –
Bt toxin kills the
European corn borer
Herbicide resistant
crops
• Soybean, corn, canola,
sugarbeet, lettuce,
strawberry, alfalfa,
potato, wheat
Next Generation of Ag Biotech
Products
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Golden Rice –
increased Vitamin A
content (but not
without controversy)
Turfgrass – herbicide
resistance; slower
growing (=reduced
mowing)
Bio Steel – spider silk
expressed in goats;
used to make softbody bullet proof
vests (Nexia)
Products In The Pipeline
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Tomatoes enriched with
flavonols
Soybean and canola oils
with higher levels of vitamin
E
Vitamin-enriched rice
Decaffeinated coffee
Bananas to deliver a
hepatitis vaccine
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Benefits of biotechnology – Better food
Oranges resistant
to citrus canker
Disease-resistant
sweet potatoes
Pest- and diseaseresistant cassava
Disease-resistant
bananas
Potatoes to protect
against cholera, E. coli
and Norwalk virus
Apples to protect
against RSV
More Than 50 Biotech Food
Products Have Been Approved For
Commercial Use In The US
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Canola
Corn
Cotton
Papaya
Potato
Products on the market
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Soybeans
Squash
Sugar beets
Sweet corn
Tomato
US Crops of Genetically
Modified Organisms
http://www.ers.usda.gov/Data/BiotechCrops/
HT=herbicide-tolerant
Genetically Modified Animals

Genetically
modified sheep
grow bigger and
faster, produce
double the amount
of milk, can grow
more wool, but
require more care.
Tracy (1990-1997): Transgenic
Ewe

Genetically
modified so that
her milk produced
a human protein
called alpha
antitrypsin, a
potential treatment
for the disease
cystic fibrosis.
GTC Biotherapeutics
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Pharmaceutical
product derived from
transgenic goats
modified to produce
therapeutic proteins in
their milk.
The product, ATryn
(an antithrombrin)
received regulatory
approval in the EU in
2006 and in the U.S.
in 2008.
Domesticated Farm Animals Are Being Used
To Produce Pharmaceutical Products

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Sheep
• alpha1 anti trypsin
deficiency leads to
emphysema
• CFTR treatment of cystic
fibrosis
• tissue plasminogen activator treatment of thrombosis
• factor VIII, IX -treatment of
hemophilia
• Fibrinogen -treatment of
wound healing
Pig

tissue plasminogen activator treatment of thrombosis

factor VIII, IX -treatment of
hemophilia
•
Goat
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•
human protein C -treatment of
thrombosis
antithrombin 3 -treatment of
thrombosis
glutamic acid decarboxylase-treatment
of type 1 diabetes
Pro542 -treatment of HIV
Cow
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alpha-lactalbumin-anti-infection
factor VIII-treatment of hemophilia
Fibrinogen-wound healing
collagen I, collagen II-tissue repair,
treatment of rheumatoid arthritis
Lactoferrin-treatment of GI tract
infection, treatment of infectious
arthritis
human serum albumin-maintains blood
volume
The SCID-hu Mouse
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Animal model for
the study of
HIV/AIDS
Destroy the
mouse’s normal
immune system
Reconstitute with
human immune
cells (essentially a
bone marrow
transplant)
Transgenic Animals
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
Transgenic Atlantic
salmon (bottom)
overexpressing a
growth hormone (GH)
gene display rapidly
accelerated rates of
growth compared to
wild strains and
nontransgenic
domestic strains (top).
GH salmon weigh an
average of nearly 10
times more than
nontransgenic strains.
By 2025, there will
be another 2 billion
mouths to feed
— United Nations
Population Fund
Developed world
(EU, U.S., Japan)
– Population: 1 billion
– Income: $5,000+
Developing world
(Asia, Latin America)
– Population: 4.2 billion
– Income: $400 - $5,000
Impoverished areas
(Africa)
– Population: 800 million
– Income: <$400
More food
will be needed to
feed a growing
global middle class
Benefits of biotechnology – More food
Farmers will need to at least
double production over the
next 25 years to meet
increased demand.
— Consultative Group
on International
Agricultural Research
Without an increase in farm
productivity, an additional 4
billion acres of arable land will
need to come under the plow
by 2050. — C.S. Prakash, founder and
president of the nonprofit
AgBioWorld Foundation
WORLD PRODUCTIVITY
Forests and woodlands 44.3%
Grassland
9.7%
Cultivated land
5.9%
Desert and semi-desert
1.5%
Freshwater
3.2%
Oceans
35.4%
Benefits of biotechnology – More food
And In Case You Think Green
Technology Is Only For Tree
Huggers In Oregon or
Arizona…..
TVA’s First Solar Power Array In
Mississippi

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
Located on the campus of
the University of
Mississippi in Oxford.
The solar photovoltaic (PV)
system is built right next
to the concession stand at
Blackburn-McMurray
Outdoor Intramural Sports
Complex.
The entire system can
produce about 51,500
kilowatt-hours of electricity
a year; that’s equal to 343
blocks of electricity for
Green Power Switch
customers.
TVA’s Second Solar Power Array In
Mississippi



Located on the
campus of
Mississippi State
University in
Starkville.
Built as a canopy to
cover a sidewalk
between the new
Landscape
Architecture Building
and the AmmermanHearnsberger Pilot
Food Processing Lab.
System can produce
about 26,300
kilowatt-hours of
electricity
Thank You.
Questions?
Comments?
Four crops accounted for nearly all of
the global biotech crop area in 2002
Soybeans
62%
Corn
21%
Cotton
Canola
12%
5%
Source: International Service for the Acquisition of Agri-biotech Applications
Products on the market
Four countries accounted for 99
percent* of the global biotech crop area
in 2002
United States
66%
Argentina
Canada
China
23%
6%
4%
*Australia, Bulgaria, Colombia, Germany, Honduras, India, Indonesia, Mexico, Romania, South
Africa, Spain and Uruguay accounted for the remaining 1 percent of biotech crop acres.
Source: International Service for the Acquisition of Agri-biotech Applications
Products on the market
WORLD PRIMARY PRODUCTIVITY
Net Productivity
Forests and woodlands
44.3%
Grassland
9.7%
Cultivated land
5.9%
Desert and semi-desert
1.5%
Freshwater
3.2%
Oceans
35.4%
Cargill-Dow: Blair, Nebraska



Using corn derived
dextrose feedstock
Co-located near
Cargill’s corn wet
mill
Can produce over
140,000 tons per
year of polylactide
(PLA) polymers for
fibers and plastic
packaging
$300 Million Capital Investment
19 months from ground breaking to prime product
10 years to develop technology, know-how, and
receptive market
Pharmaceuticals from Plants
COMPOUND
USE
 Vinblastin/vicristine
Leukemia
 Ajmalicine
Circulatory
 Digitalis
Cardiovascular
 Quinine
Malaria
 Codeine
Sedative
 Pyrethrins
Insecticides
Economically Important
Therapeutic Agents
COMPOUND
ORGANISM
ACTIVITY
Bactracin
Bacillus sp.
Cephalosporium sp.
Acremonium sp.
Antibacterial
Penicillium sp.
Streptomyces sp.
Streptomyces sp.
Aspergillus sp.
Streptomyces sp
Streptococcus sp
Antibacterial
Cephalosporin
Chloramphenicol
Penicillin G
Streptomycin
Tetracycline
Fumagillin
Natamycin
Nisin
Antibacterial
Antibacterial
Antibacterial
Antibacterial
Amoebicidall
Food preservative
Food preservative
Monoclonal Antibodies






Cancer diagnosis and therapy
Diagnosis of pregnancy
Diagnosis of infectious diseases
Prevention of immune rejection of
organs implants
Purification of industrial products
Detection of trace molecules,
organisms
DEFINE THE PROBLEM,
DESIGN A CURE