Chartres cathedral 1194-1260
Biotechnology:
Industry expectations and
Technological Evolution
Implications for the well-educated
student.
• Part 1: Industry context in Australia and
industry requirements
• Part 2: An evolutionary/generational
definition of biotechnology that captures
technological change
Part 1
Australia: Industry context 2001
•
•
•
•
190 core biotech companies
460 non-core/support companies
5,700 employees
+46% fulltime equiv. employees
1999 to 2001
Source: E &Y, 2001
Australia: Industry context 2006
•
•
•
•
•
427 core biotech companies
625 medical device companies
Biotech employment doubled 2005 to 2006
Now > 12,100 people
Operating in diverse fields
– Therapeutics, bioprospecting, livestock genetics,
molecular biology, biosensors, diagnostics, plant
biotechnology, process technology, vaccines
Source:Hopper & Thorburn Innovation Dynamics, 2007
Key features of biotechnology
• Trans-disciplinary
• Rapidly evolving and emerging fields
– Nanotech, proteomics, genomics, bioinformatics, PTGS
• A very diverse industry
• A large number of small companies
Implications for teaching
• How should we deliver our teaching,
for what seems to be a moving target?
– Content?
– Teaching methods?
• Are we delivering what industry
needs?
– Core content knowledge
– Generic skills
A Review of Biotechnology Education
& Industry Needs
in Australia:
Funded by AUTC/DEST and Carrick Institute for Learning and
Teaching in Higher Education
What did we ask?
Asked of industry
•
What 3 attributes / abilities
do you look for in graduates
when they commence employment
with your company?
ob
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35
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Attributes looked for in graduates
*
25
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Asked of industry
•
What 3 areas of technical knowledge
do you see as most important
amongst your scientists?
Technical Knowledge
Tech. Knowledge Important in Scientists
*
35
*
*
30
Responses
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Asked of industry
•
List skills requirements
most affected by these
technological developments
in your company.
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Skills Requirements most Affected by Tech. Devts.
35
30
*
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Mean Response
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Demand for generic and technical skills
*
4
3.5
3
2.5
2
1.5
1
0.5
2002
2002
2003
2004
0
Skills
Ranking of key skills by
Universities & Industry
M o le c u la r b io lo g y
O t h e r c h e m is t ry
P ro t e in c h e m is t ry
Im m u n o lo g y
C e ll a n d t is s u e c u lt u re
M ic ro b io lo g y
P ro t e o m ic s
R e g u la t o ry / Q A
U n ive rs it y In d u s t ry
1
2
3
* 11
7
5
* 3
* 15
Discordances marked with asterisks
1
2
3
4
5
6
7
8
Recommendations
• Do not dilute the chemistry
Recommendations
• Strong industry demand for certain
‘generic attributes’:
– Problem solving
– Teamwork
– Communication
– Creativity
– Enthusiasm
Recommendations
• Implications for pedagogy
– More problem based learning ??
• Core knowledge?
– More team based activities ?
– More hands-on, task based application of
core knowledge?
The future
• Students paying more
• Changing student expectations (customers)
• Changing course preferences
• Will there be sufficient numbers of science grads
to fuel the new economy?
– 23% decline in science enrolments 1989-2002
• Will there be sufficient investment to sustain
innovation in Australia?
• Will there be investment in core training in
fundamentals like chemistry?
Part 2
Evolutionary/generational definition
of biotechnology.
Part 2
• A static definition:
– Application of biological knowledge for
generation of products that are or will be valued
by society
– Value is contestable and changes over time
Part 2
• Value is contestable and changes over time
– Stage of development of the society
– Risks to which it is exposed
• people give you different definitions
Part 2
• Don’t know what biotechnology is.
– Narrow definition
• They take a lot for granted.
– health/longevity
• They don’t know he details of how their
food is produced
– Supermarket mentality/urbanisation
Taking a lot for granted
A Question
• What was average life expectancy at birth in
Western Europe in 1750?
Answer
• 33 years
Why?
•
•
•
•
•
No vaccines
No antisepsis
No antibiotics
No analgaesia
No knowledge of germ theory
The Plague Doctor, Venice, 17th Century
Courtesy Omnia, Lido de Venezia
Year ??
Year 1796
Definition of biotechnology
• An evolutionary/generational definition is
best.
First generation
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•
•
•
•
Plant breeding
Collection of herbs for medicine
Animal breeding
Bread making
Wine, beer, sake (Saccaromyces cerevisieae;
Actinomyces, Leuconostoc)
• Fermented food products
–
–
–
–
Yoghurt
Cheese
Soy
Chocolate (!)
First generation
Bacillus
Hanseniaspora
Pichia membranifasciens
Microorganisms in fermentation and
flavour formation of cocoa
to make chocolate
Saccharomyces cerevisiae
First generation
Microorganisms per gram during
fermentation of cocoa
to make chocolate
First generation
Yeast cells (dividing) Amarna 1550-1070 BC
Courtesy Delwen Samuel, King’s College, London
Pitted Starch granules, evidence of malting. Tomb, Deir el Medina
Courtesy Delwen Samuel, King’s College, London
Historical facts:
Humans have always guided evolution of
crops!
•A very small sample of wild plants were
chosen and domesticated
•More than 10,000 years of genetic
selection
Historical facts …..cont
• Crops strains and genes have
moved around the globe for
centuries
• All crops we grow today were
once wild plants but no crop
would survive in the wild
anymore (without human
support)
• They bear little
physical resemblance
to their wild ancestors
Fig.1 Wild varieties of
potato from the Americas
Improving on crop plants
Development of modern varieties
– how was it done?
• Hybridization
• Disease resistance
• Increased yield
• Crosses with wild relations
– Some do not breed true so it is
necessary for farmers to repurchase
seeds
The products of these methods have led to crop
characteristics (phenotypes) as different as Great
Danes and Chihuahuas.
Fig.2 Wild chili variety
Fig. 3 Selected chili variety
Modern methods of crop
improvement:
•Are relatively more precise and predictable
•Transfer a few genes into crop plants in contrast to
random shuffling of older approaches
•Can determine exactly where the genes have been
inserted (Polymerase chain reaction)
•Can measure the effect on all proteins in the plant
•Mass spectrometry
•HPLC
Benefits
• Decreased pesticide usage
• Decreased fuel consumption
• Decreased crop losses to pests and disease
– Papaya anecdote (Hawaii)
• Increased nutrient efficiency
– nitrogen fixing cereals
– Vitamins
• Increased crop yields.
•
•
•
•
GM crops
220 million acres under GM crops in 2005
1/3 in developing countries
In India and Australia , 70% reduction in
organochlorine and organophosphorous
pesticides
Medical biotechnology
•
•
•
•
•
•
•
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Massive reduction in disease burden since 1945
Eradication of smallpox
Eradication of polio in developed nations
Whooping cough
Diptheria
Tetanus
Cholera
Perinatal morality
Medical biotechnology
• Vaccines
• Clean water
Milestones
Ancient to modern biotechnology
Jenner (1796)
• Smallpox vaccination
Semmelweis (1847)
• Recognised cause of
puerperal fever and
post-natal death in
maternity wards
• Did not yet know
about “germ” origin of
disease
John Snow (1854)
• Showed the connection
between contaminated
water and cholera
• Used a Voronoi diagram
to pinpoint the culprit
water pump
– Application of maths to
biology
• The importance of a clean
water supply
Miescher (1871)
• Isolated DNA from the
nucleus of thymus
cells
Miescher (1871)
• Isolated DNA from the
nucleus of thymus
cells
• Died of tuberculosis,
Aged 51
(possibly from
unpasteurised milk)
Koch (1878)
• In 1878 Koch discovered that
microbes cause wounds to go
septic
• Big breakthrough came when
he decided to stain microbes
with dye, enabling him to
photograph them under a
microscope.
• Using this method he was able
to prove that every disease was
caused by a different germ. He
identified the microbes that
caused tuberculosis in 1882 and
cholera in 1883.
Pasteur (1885)
• Rhabies vaccine
• Pasteurisation
Joseph Meister came to Pasteur after being bitten by a rabid dog.
Pasteur treated him with a rabies vaccine,
The rabies virus would not be identified for another half a century.
Ehrlich (1891)
• Paul Ehrlich proposes
that antibodies are
responsible for immunity.
He shows that antibodies
form against the plant
toxins ricin and abrin.
With Metchnikoff,
Ehrlich is jointly
awarded the Nobel Prize
in Medicine or
Physiology in 1908.
Fleming (1928), Florey, Chain,
Heatley (1940s)
Everyone knows that
Alexander Fleming
discovered penicillin by
accident in 1928.
Penicillium notatum
It was largely due to the technical ingenuity
of one man that enough penicillin was
produced for the first hospital tests.
That man was Norman Heatley
Do students know who this is?
Watson, Crick, Franklin &
Wilkins, 1953
Salk and Sabin,1955
http://www-micro.msb.le.ac.uk/tutorials/polio/ilung.mov
Køhler and Milstein (1975)
• Monoclonal antibody
technology
• Immortal cells
producing a single
antibody of defined
specificity in
unlimited amounts
First monoclonal antibodies for
diagnostics, 1982
Cohen and Boyer, 1973
• First recombinant
DNA experiments
Recombinant human insulin,
1982
• Human insulin
produced in E.coli
• Previously had been
purified from pig
pancreas
Recombinant therapeutics since
1982
• Many since 1982
– Protropin (human growth hormone) 1985
– Combivax (Hep B vaccine) 1986
– Pulmozyme (CF treatment) 1993
– Rituximab 1997
– Herceptin 1998
• Several hundred in clinical trial
Polymerase chain reaction (1983)
Kari Mullis
http://www.youtube.com/watch?v=IqgFyPdVc4Y
• The combination of monoclonal antibody
technology with human genome project
• A new therapeutic drug discovery paradigm
New drug development paradigm made possible by the Human Genome
Project, for development of therapeutic monoclonal antibodies.
Humanized Antibodies
The biological age for therapeutics
and diagnostics
“Magic Bullets”
•1980’s – much excitement and money invested
•But, clinical trials failed (except for orthoclone)– much
money lost
•Because the MAbs were mouse-derived – immunogenic
(Human Anti-Mouse Antibodies)
-Eliminates therapeutic antibody from system
-Effector functions less effective(eg. complement
activation).
•Genetically engineer to make the MAbs appear more
human (humanisation)
The Immune System
•B-lymphocytes express antibody (Each cell specific)
•Foreign antigen enters body (eg Bacteria or Virus)
•Binds to specific B-cell, prompting maturation
•B-cell produces large quantities of antibody
•Antigen-Antibody binding triggers other components of
immune system
•Subsequent infection – faster clearance (immunity)
eg Cancer Cells
Producing Monoclonal Antibodies
A mouse will recognise a human protein as
foreign.
Injecting human antigen will stimulate
increased production of B-cells producing
antibody against the antigen.
B-cells can be immortalised by fusion with
a myeloma cell and the specific hybridoma
cell purified.
Limitless supply of specific antibody !
Murine
Chimeric
(0% Human)
(67% Human)
Humanised
Fully Human
(90% Human)
(100% Human)
Chimeric Antibodies
V
C
V
Mouse Antibody Gene
C
Human Antibody Gene
Clone human
Constant region
Clone mouse
Variable region
V
C
Ligate
V
C
Express
Allows specificity
Allows effector functions
Decreases HAMA
but can get HACA
Humanised Antibodies
Allows specificity
Allows effector functions
Less immunogenic
Fully Human Antibodies
•Xenomouse (Abgenix) – entire Ab-gene repertoire in mouse
replaced with the human equivalent
•Mouse produces antibodies which are 100% human
•Specificity easily achieved
•Effector functions active
•Not immunogenic
•Fast and easy production
Monoclonal Antibody based therapeutics
PRODUCT
DEVELOPER/
MARKETER
APPROVAL
DATE
TYPE
TARGET
DISORDER
Orthoclone OKT3
(muromonab-CD3)
Ortho Biotech /
Johnson & Johnson
1986
Murine
CD3 antigen on
T lymphocytes
Acute
transplant
rejection
ReoPro (abciximab)
Centocor/
Eli Lilly & Co.
1994
Chimeric
Clotting receptor
Blood clots in
cardiac
procedures
Rituxan (rituximab)
DEC Pharmaceuticals/
Genentech/Roche
1997
Chimeric
CD20 receptor
on B
lymphocytes
Non-Hodgkin's
lymphoma
Zenapax (daclizumab)
Protein Design Labs/Roche
1997
Humanized
Interleukin-2
receptor on
activated T-cells
Acute rejection
of transplanted
kidneys
Herceptin (trastuzumab)
Genentech/Roche
1998
Humanized
HER2 growth
factor receptor
Breast cancers
Remicade (inflixibmab)
Centocor/Schering-Plough
1998
Chimeric
Tumor necrosis
factor
Rheumatoid
arthritis and
Crohn's disease
Simulect (basiliximab)
Novartis
1998
Chimeric
Interleukin-2
receptor on
activated T-cells
Acute rejection
of transplanted
kidneys
Synagis (palivizumab)
Medlmmune
1998
Humanized
F protein of
respiratory
syncytial virus
RSV infection
in children
Mylotarg (gemtuzumab)
Celltech/
Wyeth-Ayerst
2000
Humanized
CD33 antigen on
leukemia cells
myeloid
leukemia
Campath
(alemtuzumab)
Millennium
Pharmaceuticals/Schering
AG
2001
Humanized
CD52 antigen on
B and T
lymphocytes
B cell chronic
lymphocytic
leukemia
Success stories
• Rituxan (Chimeric Mab)
– Effective against refractory non- Hodgkin’s
lymphoma
– Well tolerated (few side effects)
• Herceptin
– Genotype dependant
– metastatic breast cancer (Her-2 positive)
Infectious disease therapeutics
• Infantile RSV (respiratory syncitial virus)
– Humanized MAb (Medi-493)
• Medimmune
• Hepatitis B
– Human Mab (Ostavir)
• Novartis/Protein Design Lab
• HIV
– Humanized Mab (Pro 542)
• Progenics/Genzyme
Infectious disease diagnostics
• Shortage of positive control sera limits our
ability to produce diagnostic tests
– Particularly difficult to source early postinfection sera (IgM)
• Need for reliable supply of control reagents
for diagnostic tests
Infectious disease diagnostics
• Serum positive controls are difficult to source for:
– Diseases of children
– Bordatella pertussus (whooping cough)
– Rare diseases
– Rocky mountain spotted fever
– Dangerous diseases
– Dengue fever
– West Nile fever
– Q fever
Infectious disease diagnostics
• With humanized or chimeric antibodies it
will be possible to have a reliable source of
positive control reagents for these diseases.
• Longer term therapeutic reagents for these
diseases.
Infectious disease diagnostics
• Comparison of engineered antibody versus serum for Srub typhus test
– Jones & Barnard, 2007 (in press)
Cancer therapeutic
• Characteristic surface
antigens
– CMRF 44
– CD 83
• Make humanised
antibodies that bind to
these
Cancer therapeutic
• Graft versus host disease
– Haemopoietic stem cell graft
– Aim: depletion of dendritic cells
• Prostate cancer therapy
– Purification of dendritic cells
– Use the cells to treat prostate cancer
Antibody formats
natural and engineered
Antibody formats
natural and engineered
• Shark single chain
antibodies
Chartres cathedral 1194-1260
• A transdisciplinary synthesis of
– mathematical
– technical
– artistic skill
• Renaissance grew out of a
transdisciplinary synthesis of
– mathematical
– technical
– artistic skill
– for a social purpose
Biotechnology is
transdisciplinary
• Need graduates who can:
– have core technical skills
• chemistry
• mathematical skills
– problem solving skills
– can mediate a dialogue between disciplines and
value systems to build a structure with a social
purpose.
• Paradoxically consistent with expressed
demands of industry
Thankyou