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?
 Attributes looked for in graduates
35
*
30 *
*
25
20
15
Responses
10
5
0
Honesty

Miscellaneous Independence
Academic results
Communication skills
Experience/track record
Scientific and technical skill
Interpersonal skills/teamwork
Enthusiasm/willingness to learn
Prob solving/crit thinking/creativity

Attributes
 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
25
*
20
15
Responses
10
5
0

Other

Immunology Proteomics
Microbiology Regulatory/QA
Bioinformatics
Other chemistry
Molecular biology Protein chemistry
Cell and tissue culture
Area of Technical Knowledge
 Asked of industry

• List skills requirements

most affected by these
technological developments
in your company.
 Skills Requirements most Affected by Tech. Devts.

35
30
*
25
20
15
Responses
10
5
0

Other

Computer/IT
Bioinformatics
Regulatory/QA
Molecular biology Nanotechnology
Protein chem/chem. Mass spectrometry
Diagnostics/mol/
Environmental Biotechpath
Developmental biology
Drug Sales/marketing/comm'n
dev./pharma. devel. Automation/robotics/HTS
Tissue culture/cell biology
Ferment'n/eng./process dev.
Multiskilled/x-discipline
Monoclonalflex'ty
antibody/immun'y
Skills
 Demand for generic and technical skills

4.5
** *
* *
4
3.5
3
2.5

2
1.5
1 2002
2002
Mean
0.5 Response
2003
2004
0

Team Work IP in Biotech

Problem Solving
Oral Communication
Info retrieval/ Analysis
Information
Written Communication Research
Technology Bus. Issues
Methodology in Biotech
Reg's on manuf. & use

Skills
 Ranking of key skills by
Universities & Industry
U n ive rs it y In d u s t ry
M o le c u la r b io lo g y 1 1
O t h e r c h e m is t ry 2 2
P ro t e in c h e m is t ry 3 3
Im m u n o lo g y * 11 4
C e ll a n d t is s u e c u lt u re 7 5
M ic ro b io lo g y 5 6
P ro t e o m ic s * 3 7
R e g u la t o ry / Q A * 15 8
Discordances marked with asterisks
 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
• 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 Saccharomyces cerevisiae
to make chocolate
 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
• 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 C

Mouse Antibody Gene Human Antibody Gene

Clone mouse Clone human

Variable region Constant region

V C

Ligate

V C Allows specificity
Allows effector functions
Decreases HAMA
Express 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/ APPROVAL TYPE TARGET DISORDER

MARKETER DATE

Orthoclone OKT3 Ortho Biotech / 1986 Murine CD3 antigen on Acute

(muromonab-CD3) Johnson & Johnson T lymphocytes transplant
rejection
ReoPro (abciximab) Centocor/ 1994 Chimeric Clotting receptor Blood clots in
Eli Lilly & Co. cardiac
procedures
Rituxan (rituximab) DEC Pharmaceuticals/ 1997 Chimeric CD20 receptor Non-Hodgkin's
Genentech/Roche on B lymphoma
lymphocytes
Zenapax (daclizumab) Protein Design Labs/Roche 1997 Humanized Interleukin-2 Acute rejection
receptor on of transplanted
activated T-cells kidneys
Herceptin (trastuzumab) Genentech/Roche 1998 Humanized HER2 growth Breast cancers
factor receptor

Remicade (inflixibmab) Centocor/Schering-Plough 1998 Chimeric Tumor necrosis Rheumatoid

factor arthritis and
Crohn's disease

Simulect (basiliximab) Novartis 1998 Chimeric Interleukin-2 Acute rejection

receptor on of transplanted
activated T-cells kidneys
Synagis (palivizumab) Medlmmune 1998 Humanized F protein of RSV infection
respiratory in children
syncytial virus
Mylotarg (gemtuzumab) Celltech/ 2000 Humanized CD33 antigen on myeloid
Wyeth-Ayerst leukemia cells leukemia

Campath Millennium 2001 Humanized CD52 antigen on B cell chronic

(alemtuzumab) Pharmaceuticals/Schering B and T lymphocytic
AG lymphocytes 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 post-
infection 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