Biotechnology: history, economics and the Cartesian division' Implications for the welleducated stud

1
Chartres cathedral 1194-1260
2
Biotechnology Industry expectations
andTechnological EvolutionImplications for
the well-educated student.
3

• Part 1 Industry context in Australia and
  industry requirements
• Part 2 An evolutionary/generational definition
  of biotechnology that captures technological
  change

4
Part 1
5
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
6
Australia Industry context 2006

• 427 core biotech companies
• 625 medical device companies
• Biotech employment doubled 2005 to 2006
• Now gt 12,100 people
• Operating in diverse fields
• Therapeutics, bioprospecting, livestock genetics,
  molecular biology, biosensors, diagnostics, plant
  biotechnology, process technology, vaccines

SourceHopper Thorburn Innovation Dynamics, 2007
7
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

8
Implications for teaching

• How should we deliver our teaching, for what
  seems to be a moving target?
• Content?
• Teaching methods?

9

• Are we delivering what industry needs?
• Core content knowledge
• Generic skills

10
A Review of Biotechnology Education Industry
Needs in Australia Funded by AUTC/DEST and
Carrick Institute for Learning and Teaching in
Higher Education
11
What did we ask?
12
Asked of industry

• What 3 attributes / abilities do you
  look for in graduates when they commence
  employment with your company?

13



14
Asked of industry

• What 3 areas of technical knowledge do you
  see as most important amongst your
  scientists?

15
Technical Knowledge



16
Asked of industry

• List skills requirements most affected
  by these technological developments in
  your company.

17

18





2002 2004
19
Ranking of key skills by Universities Industry
U
n
i
v
e
r
s
i
t
y
I
n
d
u
s
t
r
y
M
o
l
e
c
u
l
a
r

b
i
o
l
o
g
y
1
1
O
t
h
e
r

c
h
e
m
i
s
t
r
y
2
2
P
r
o
t
e
i
n

c
h
e
m
i
s
t
r
y
3
3
I
m
m
u
n
o
l
o
g
y
1
1
4

C
e
l
l

a
n
d

t
i
s
s
u
e

c
u
l
t
u
r
e
7
5
M
i
c
r
o
b
i
o
l
o
g
y
5
6
P
r
o
t
e
o
m
i
c
s
3
7


R
e
g
u
l
a
t
o
r
y
/
Q
A
1
5
8
Discordances marked with asterisks
20
Recommendations

• Do not dilute the chemistry

21
Recommendations

• Strong industry demand for certain generic
  attributes
• Problem solving
• Teamwork
• Communication
• Creativity
• Enthusiasm

22
Recommendations

• Implications for pedagogy
• More problem based learning ??
• Core knowledge?
• More team based activities ?
• More hands-on, task based application of core
  knowledge?

23
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?

24
Part 2
Evolutionary/generational definition of
biotechnology.
25
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

26
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

27
Part 2

• Dont know what biotechnology is.
• Narrow definition
• They take a lot for granted.
• health/longevity
• They dont know he details of how their food is
  produced
• Supermarket mentality/urbanisation

28
Taking a lot for granted
29
A Question

• What was average life expectancy at birth in
  Western Europe in 1750?

30
Answer

• 33 years

31
Why?

• No vaccines
• No antisepsis
• No antibiotics
• No analgaesia
• No knowledge of germ theory

32
The Plague Doctor, Venice, 17th Century Courtesy
Omnia, Lido de Venezia
33
Year ??
34
Year 1796
35
Definition of biotechnology

• An evolutionary/generational definition is best.

36
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 (!)

37
First generation
Bacillus
Hanseniaspora
Pichia membranifasciens
Microorganisms in fermentation and flavour
formation of cocoa to make chocolate
Saccharomyces cerevisiae
38
First generation
Microorganisms per gram during fermentation of
cocoa to make chocolate
39
First generation
40
Yeast cells (dividing) Amarna 1550-1070
BC Courtesy Delwen Samuel, Kings College, London
41
Pitted Starch granules, evidence of malting.
Tomb, Deir el Medina
Courtesy Delwen Samuel, Kings College, London
42
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

43
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)

44

• They bear little physical resemblance to their
  wild ancestors

Fig.1 Wild varieties of potato from the Americas
45
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

46
The products of these methods have led to crop
characteristics (phenotypes) as different as
Great Danes and Chihuahuas.
47
Fig. 3 Selected chili variety
Fig.2 Wild chili variety
48
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

49
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.

50

• 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

51
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

52
Medical biotechnology

• Vaccines
• Clean water

53
Milestones

• Ancient to modern biotechnology

54
Jenner (1796)

• Smallpox vaccination

55
Semmelweis (1847)

• Recognised cause of puerperal fever and
  post-natal death in maternity wards
• Did not yet know about germ origin of disease

56
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

57
Miescher (1871)

• Isolated DNA from the nucleus of thymus cells

58
Miescher (1871)

• Isolated DNA from the nucleus of thymus cells
• Died of tuberculosis,
• Aged 51
• (possibly from unpasteurised milk)

59
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.

60
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.
61
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.

62
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
63
(No Transcript)
64
Do students know who this is?
65
Watson, Crick, Franklin Wilkins, 1953
66
Salk and Sabin,1955
http//www-micro.msb.le.ac.uk/tutorials/polio/ilun
g.mov
67
Køhler and Milstein (1975)

• Monoclonal antibody technology
• Immortal cells producing a single antibody of
  defined specificity in unlimited amounts

68
First monoclonal antibodies for diagnostics, 1982
69
Cohen and Boyer, 1973

• First recombinant DNA experiments

70
Recombinant human insulin, 1982

• Human insulin produced in E.coli
• Previously had been purified from pig pancreas

71
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

72
Polymerase chain reaction (1983)
Kari Mullis
http//www.youtube.com/watch?vIqgFyPdVc4Y
73

• The combination of monoclonal antibody technology
  with human genome project
• A new therapeutic drug discovery paradigm

74
New drug development paradigm made possible by
the Human GenomeProject, for development of
therapeutic monoclonal antibodies.
75
Humanized Antibodies

• The biological age for therapeutics and
  diagnostics

76

• Magic Bullets
• 1980s 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)

77
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)

78
eg Cancer Cells
79
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 !
80
Murine (0 Human)
Chimeric (67 Human)
Humanised (90 Human)
Fully Human (100 Human)
81
Chimeric Antibodies
Allows specificity Allows effector
functions Decreases HAMA but can get HACA
82
Humanised Antibodies
Allows specificity Allows effector functions Less
immunogenic
83

• 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

84
Monoclonal Antibody based therapeutics
85
Success stories

• Rituxan (Chimeric Mab)
• Effective against refractory non- Hodgkins
  lymphoma
• Well tolerated (few side effects)
• Herceptin
• Genotype dependant
• metastatic breast cancer (Her-2 positive)

86
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

87
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

88
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

89
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.

90
Infectious disease diagnostics

• Comparison of engineered antibody versus serum
  for Srub typhus test
• Jones Barnard, 2007 (in press)

91
Cancer therapeutic

• Characteristic surface antigens
• CMRF 44
• CD 83
• Make humanised antibodies that bind to these

92
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

93
Antibody formatsnatural and engineered
94
Antibody formatsnatural and engineered
95

• Shark single chain antibodies

96
Chartres cathedral 1194-1260
97

• A transdisciplinary synthesis of
• mathematical
• technical
• artistic skill

98

• Renaissance grew out of a transdisciplinary
  synthesis of
• mathematical
• technical
• artistic skill
• for a social purpose

99
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.

100

• Paradoxically consistent with expressed demands
  of industry

101
Thankyou