Chartres cathedral 1194-1260. Biotechnology: Industry expectations and Technological Evolution Implications for the well-educated student.

Chartres cathedral 1194-1260

Biotechnology: Industry expectations andTechnological 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

• Trans-disciplinary• Rapidly evolving and emerging fields

– Nanotech, proteomics, genomics, bioinformatics, PTGS

• A very diverse industry • A large number of small companies

Key features of biotechnology

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

– Teaching methods?

Implications for teaching

• 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?

0

5

10

15

20

25

30

35

Responses

Scientific and technical skillEnthusiasm/willingness to learn

Prob solving/crit thinking/creativity

Interpersonal skills/teamwork

Miscellaneous

Communication skillsExperience/track record

Academic resultsIndependence

Honesty

Attributes

Attributes looked for in graduates

* **

Asked of industry

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

Technical Knowledge

0

5

10

15

20

25

30

35

Responses

Molecular biologyOther chemistry

Protein chemistry

Other

Immunology

Cell and tissue culture

BioinformaticsMicrobiology

ProteomicsRegulatory/QA

Area of Technical Knowledge

Tech. Knowledge Important in Scientists

* **

Asked of industry

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

0

5

10

15

20

25

30

35

Responses

Protein chem/chem.Molecular biology

Bioinformatics

Other

Computer/ITRegulatory/QA

Ferment'n/eng./process dev.Multiskilled/x-discipline flex'ty

Tissue culture/cell biologyDrug dev./pharma. devel.

Monoclonal antibody/immun'y

Sales/marketing/comm'n

Nanotechnology

Environmental BiotechDiagnostics/mol/ pathDevelopmental biologyAutomation/robotics/HTS

Mass spectrometry

Skills

Skills Requirements most Affected by Tech. Devts.

*

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

Mean Response

Problem Solving

Team Work

Oral Communication Written Communication

Info retrieval/ Analysis Information Technology Research Methodology

IP in Biotech

Bus. Issues in Biotech Reg's on manuf. & use

Skills

Demand for generic and technical skills

2002

2003

2002

2004

* * ** *

Ranking of key skills by Universities & Industry

U n ive rs it y In d u s t ryM o le c u la r b io lo g y 1 1O t h e r c h e m is t ry 2 2P ro t e in c h e m is t ry 3 3Im m u n o lo g y 1 1 4C e ll a n d t is s u e c u lt u re 7 5M ic ro b io lo g y 5 6P ro t e o m ic s 3 7R e g u la t o ry / Q A 1 5 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 CenturyCourtesy 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

Microorganisms in fermentation and flavour formation of cocoa to make chocolate

BacillusHanseniaspora Pichia membranifasciens

Saccharomyces cerevisiae

First generation

Microorganisms per gram during fermentation of cocoa to make chocolate

First generation

Yeast cells (dividing) Amarna 1550-1070 BCCourtesy 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

• Hybridization • Disease resistance• Increased yield

• Crosses with wild relations– Some do not breed true so it is

necessary for farmers to repurchase seeds

Development of modern varieties

– how was it done?

The products of these methods have led to crop characteristics (phenotypes) as different as Great Danes and Chihuahuas.

Fig. 3 Selected chili variety Fig.2 Wild 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

• 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.

Benefits

• 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)

http://www.youtube.com/watch?v=IqgFyPdVc4YKari Mullis

• 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 GenomeProject, for development of therapeutic monoclonal antibodies.

Humanized Antibodies

The biological age for therapeutics and diagnostics

““Magic Bullets”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)

•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)

The Immune SystemThe Immune System

eg Cancer Cells

Producing Monoclonal AntibodiesProducing 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(0% Human)

Chimeric(67% Human)

Humanised(90% Human)

Fully Human (100% Human)

Chimeric AntibodiesChimeric Antibodies

V C V C

Mouse Antibody Gene Human Antibody Gene

V

V

C

C

Express

Clone mouseVariable region

Clone humanConstant region

Ligate

Allows specificityAllows effector functionsDecreases HAMAbut can get HACA

Humanised AntibodiesHumanised Antibodies

Allows specificityAllows effector functionsLess immunogenic

Fully Human AntibodiesFully Human Antibodies

•Xenomouse (Abgenix) – entire Ab-gene repertoire in mousereplaced with the human equivalent

•Mouse produces antibodies which are 100% human•Specificity easily achieved•Effector functions active•Not immunogenic•Fast and easy production

PRODUCT DEVELOPER/MARKETER

APPROVAL DATE

TYPE TARGET DISORDER

Orthoclone OKT3 (muromonab-CD3)

Ortho Biotech / Johnson & Johnson

1986 Murine CD3 antigen on T lymphocytes

Acute transplantrejection

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

Monoclonal Antibody based therapeutics

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 formatsnatural and engineered

Antibody formatsnatural 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