Plant Biotechnology And Drug Discovery Research Biology Essay

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Biotech is a very exciting and yet controversial industry with millions of pounds from venture capital and government funding being pumped into it coupled with public suspicion and controversy. Due to this business ethics must be engaged within the industry. This is an industry capable of promising revolutions in agriculture, healthcare and a range of industrial processes. Additionally current biotechnology ethical issues need to take into account the complexities of corporate decision making.

Current situation

Let me set the scene the year is 2011 the global world population is ever increasing no one knows earth earths human carrying capacity. The planet is undergoing global climate change of anthropogenic and natural causes. The Holocene extinction continues with many overestimating 'by the end of the century half of all species will be extinct' (willson E 2002). There is a ever increasing need and demand to feed the evergrowing global population this may not be naturally sustainable. Breakthroughs in current GM technology have brought about many scientific (fluorescent DNA marking), industrial (mineral leaching) and medical (Viagra) innovations. What does the pope branding GM technology a deadly sin mean? To my knowledge the church has always been against cloning and some other experimental or therapeutic procedures that constitute a direct assault on human dignity however this case is not clear with genetically modified organisms (GMO's). Further more the forerunner for the current pope (Giovanni Paolo II) made contradictory statements in regards to GM technology refer to table one.

For GMO's

Against GMo's

' we look with deep concern at the enormous possibilities of biological research we are not yet in a position to asses the biological disturbance that could result from indiscriminate genetic manipulation and from the unscrupulous development of new forms of plant and animal life. To say nothing of unacceptable experimentation regarding the origins of human life itself. It is evident to all that in any area as delicate as this, indifference to fundamental ethical norms, or their rejection, would lead mankind to the very brink of self destruction' (reference).

Contrastingly 8 years prior to that he said 'The advantages that come from the increase of food products and from the formation of new vegetal species for the benefit of all especially people most in need' (ref).

The popes defamation of GM technology shows he has no competency to select much less command use of GM technology in regards to a religious context of mans self destruction. Are his assumptions based on fear of the unknown or is he making a valid point, does GM technology assault mans dignity? The majority of known GM technologies are used to tackle current global issues.

Table 2. Current biotechnologies.

Biotechnology

Platforms

Pharmaceuticals/Human health

Epo, insulin, Viagra, New drugs, Biotherapies

Agri-food

GMO's Soya, quorn, GM maize aquaculture

Bioprocesses

Detergents, mineral leaching, Food & industrial enzymes

Environment and resource management

Biofuels, bioremediation

Biotools

biosensors, analytical equipment, paternity testing

Bioinformatics

Cdna cloning

How GM technologies benefit society

Currently there are global needs that biotech can help alleviate. Human carrying capacity is dynamic and uncertain governed by natural constraints and human choices concerning economics, environment, culture and demographics (Cohen 1995) of which biotechnology and science will fundamentally play a large part in management and production of resources two examples being the use of GMO' in aquacultural and agricultural practices. The former alleviating stress off unsustainable fishing activities and the latter offering food safety, stability and income in at risk area's.

Translation of the ethical matrix for GM use in food production

Wellbeing

Autonomy

Fairness

Treated organism

Wellfare

Another issue GM tech can help with is species loss. 'Humanity is rapidly destroying the habitats that are species rich with about 2/3 of all species occupying in the tropics (ref). These regions represent an invaluable source of genetic information that can be used for, industrial medical and cosmetic use. Breakthroughs in biotechnology could eventually lead to the emergence new industries in developing nations leading ultimately to a intrinsic understanding to the commercial value of their biodiversity rather than it being aimlessly destroyed and mismanaged before its value is ever understood.

The popes statements are not misplaced there are areas where concern should be placed these are area's such as biological warfare these are where stringent sanctions should be placed. None the less when there is need for specific urgent goal ethics and the concept of morality are placed on the side, for example the use of biological warfare with native north american peoples during the colonisation of america (ref)

GM ethics

The areas where ethics becomes murky will be seen with the following examples .

Ethics field

Question

Stem Cells

Are the blastocyst extracted from stem cells morally significant,

Research Ethics

When will gene therapy be safe enough to test on humans, public policy ethics should governments use criminal law to regulate cloning.

Institutional ethics

What role do biotech companies play in the marketing of various biotechnologies e.g. is it permissible for biotech companies to sell or promote designer babies. Is it permissible for parents to use pre-implantation genetic diagnosis to create deaf babies. Another such topic for biotechnology ethics are is it correct for biotechnology companies and internet marketing companies to directly market genetic tests directly to consumers online, selling a product of unknown value to people who do not fully understand it. Additionally marketing two different genetic testing applications that would normally be thought of as a single technology. Which represents the same technology bringing about 2 different ethical questions.

Transgenic ethics

the varying impact of transgenic technologies on farmers in the developing world.

what impact does agricultural biotech companies ignoring native farmers agricultural culture have on acceptance of their products in other countries.

Is it correct for agricultural biotech companies such as Monsanto to create GM crops that make resource poor farmer dependant on them.

What danger does genetic pollution pose on native stocks

There will always be the danger of companies making fantastical claims about their technologies this will need to be vigorously policed in order to protect the industry.

In conclusion in the popes own words it is necessary that science is is always guided and accompanied by the wisdom that belongs to the permanent spiritual heritage of man. It is extremely important that ethics are considered and enforced to ensure the appropriate use of GM technologies so they can add and protect the heritage of nature & humanity for future generations. Aswell as safeguarding the industry

References

Medical Aspects of Chemical and Biological Warfare JEFFERY K. SMART, M.A

Ethical issues in the biotechnology industry: introduction to the special issue

Extinction by numbers (2000)

Ethical analysis of the use of gm fish: emerging issues for aquaculture development

Genetically modified organisms: a catholic's animadversions

The Future of Life 2002 Edward O Wilson

http://www.vatican.va/holy_father/john_paul_ii/speeches/1982/october/documents/hf_jp-ii_spe_19821023_pont-accademia-scienze_en.html

There have been reports in the media about fish genes in tomatoes and rat genes in lettuce. Are the media being responsible in their reporting?

Fish and rat genes in foods represent GM technology being used for progressive improvements in agriculture. For centuries humans have directed the evolution of plants and animals for agricultural gain. If this is the case the incorporation of animal genes into the genome of plants to produce superior variety's is too good a business opportunity to miss. However public perception plays a big part in acceptance of such products, are the media being responsible with their reporting. Firstly lets use both examples as case studies but before that lets look at a brief history of GM food. The first GM food became commercially viable in 1994 which was the Flavr Savr tomato created by Calgene which was approved by the FDA. It was engineered to ripen on the vine, stay firmer and have a longer shelf life than normal variety's. This was done using an antisense polygalacturonase gene isolated from another variety of tomatoes. However due to inefficient commercialisation the Flavr Savr was removed from shelves, irrespectively this example paved the way for the human consumption of GM food. Ever since the emergence of this transgenic tomato environmental activist have targeted GM tomatoes. With particular focus on the next 2 examples.

Case studies

GMO

Story

Outcome

Tomato (1991)

Plant technology produced GM tomatoes that expressed the arctic flounder AFP (arctic freeze protein) using the AFA1 gene that confers cold resistance in a aim to to develop tomatoes that could withstand frost and cold storage damage.

The tomatoes never materialized due to the expressed gene not producing the desired effect

Lettuce (1998)

Craig Nessler and his team at Virginia tech were able to produce GM lettuce and tobacco that were able to accumulate vitamin C within their leaves due to the incorporation rat Cdna which encodes the GLOase the terminal enzyme in the animal pathway. This was done in an attempt to produce plants with an increased nutritional value and longer shelf life as vitamin C acts as a natural preservative. This was done in an attempt to produce plants with an increased nutritional value and longer shelf life as vitamin C acts as a natural preservative.

The purpose of the lettuce experiment was for research to discover other ways to stimulate the vitamin C production in lettuce and other plants. It was not carried out for commercial gain as Nessler said 'we realize that a plant altered by a rat gene wouldn't appeal to consumers' (Benton 2001). It is even hoped that this work will result in more acceptable ways to turn on latent vitamin production in crop plants producing functional food fruit and veg.

Both works were done to increase the efficiency of food productivity. Rats were mearly used because the gene was readily available and rodents were known natural producers of vitamin C it is a similar story with the flounder.

Despite this similar ending for both case studies, these stories continue to circulate as if any of these products were successful enough to make it into a food store. The existence of antifreeze proteins, vitamin production pathways and many other favourable traits have been for decades and have been identified in many organism's such as fungi, mammals fish and plants.

We are still at a very early stage with genetic engineering and it is just coincidence that we are using genes from the easiest sources that may be surrounded with controversy. Furtermore one key point that the media missed with the fish/tomato story is that the gene used in the experiment was actually a synthetic construct based on the genetic sequence of the flounder gene which was made in order to optimize the proper expression of the gene in the tomato. The gene in question did not physically come from a fish it was merly information copied from a fish. In conclusion to say the media need to be more responsible in their reporting would be incorrect. The nature of the media is well understood so companies, scientists and research institutes need to be more selective with the way they allow their works to be publicised. The media will always use controversy to sell papers and at times with just reason. However the potential GM technology holds is immense for example researchers from the university of california have produced salt resistant tomatoes that can be grown in uncultivatable farmland that has been damaged by poor management, remove salt accumulation from soil acting as a phytoremediator and produce commercially viable fruit unaffected by these functions. This plant is yet to be approved commercially.

References:

http://www.pbs.org/wnet/dna/pop_genetic_gallery/index.html

http://www.public.iastate.edu/~rhetoric/105H16/cofp/tmrcofp.html

the commercialisation of a tomato with a antisense polygalacturonase gene: the FLAVR SAVR tomato story. Kramer M & Redenbaugh K (1994)

http://www.reeis.usda.gov/web/crisprojectpages/190345.html

Hightower R, Baden C, Penzes E, Lund P, and Dunsmuir P. 1991. Expression of antifreeze proteins in transgenic plants. Plant Molecular Biology 17: 1013-1021.

Waiter there is a rat gene in my salad

Metabolic engineering of an alternative pathway for ascorbic acid in biosynthesis in plants

Benton N. 2001. Rat genes increase vitamin C in plants. 23: 38 SPECTRUM magazine VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY VOLUME

Expression of antifreeze proteins in transgenic plants

Transgenic technology could result in the production of toxins/ allergens from plant genes that were formerly silent. Is this a real problem, and could the regulatory framework in place prevent the approval of such crops

Transgenic technology resulting in the production of toxins and allergens is a problem. Although this technology offers increased crop production and nutritional enhancements it may come at a cost. Upon random insertions of specific DNA sequences into target genomes the modification, disruption and silencing of active genes or the activation of silent genes may occur resulting various consequences (Table 1) and ecological consequences as can be seen in the incidents in table 2.

Table 1 Table 2 ecological consequences of Transgenic agriculture

Potential unintended Consequences of transgene insertion: plant Genome

Disruption, modification or silencing of active genes

Activation of silent genes

Formation of new metabolites

Altered levels of existing metabolites

Modified metabolism

Novel fusion proteins

Production of new allergens or toxins

Increased Antibiotic resistance in marker plants

Modified genetic material transferring horizontally to humans through ingestion and other biopathways

Year

Incident

1997

Ladybirds that predated pest aphid populations feeding on BT potatoes developed reproductive difficulties.

1998

Lacewings that predated prey fed on BT maize developed longterm health defects

1999

Pollen from a not widely variety of BT corn had lethal effects on monarch butterfly larvae. Initial field tests did not express the BT toxin at high levels to threaten monarchs. However in test this toxin was discovered and that variety of BT corn was discontinued.

2007

Byproducts such as pollen and detritus from BT corn resistant to lepidoptern pests widely planted throughout midwestern united states entered the natural water system. Resulting in consumption, storage and transport by non target organism's causing reduced growth and increased mortality of non target insects and other ecosystem damage.

Although the examples seen have not caused any human problems for these incident to occur there is real problem. Globally there are 23 countries reporting commercial GM crops 60% of US processed foods include undisclosed GM ingredients (ref). The future generation of GM crops will likely include varieties with improved nutritional properties, if global regulatory assessments are not improved there is a possibility of unpredictable effects not revealed by the traditional profiling approach occurring in humans. Traditionally GMO's are assessed generally by having the knowledge of the place the transgenic DNA insertion, the function of the inserted trait and its involvement in metabolic pathways. The problem is other effects are often unpredictable due to limited knowledge of gene to gene interactions and gene regulation. GM food may be engineered to contain pesticidal substances in which proteins from non food sources are sometimes incorporated whose allergic potential and toxicity is presently unknown resulting in products that pose at least a possibility of serious allergic reactions in some consumers. Due to these products not lending themselves to traditional methods of risk assessment. E.G. toxicity assessments involving exposing lab animals to high levels of isolated chemicals and complex mixtures of chemicals such as novel GM foods that cannot be administered to test animals the conventional way. The modern criteria for assessing GMO's is comparing the composition of the GMO with a traditionally bred counterpart. This resulted in the substantial equivalent doctrine that forms the backbone of the US assessment model formed by the Reagan administration in 1986. (ref) (Table 3).

Table 3 comparison of traditional assessment and new suggested GMO assessment

Analysis

screens

Limitations

Comparison of chemical composition of GMO's with normal plant

Similarity and differences in between transgenic crops and normal crops.

The occurrence of unknown natural toxins and anti-nutrients in GMO with no history and availability of adequate detection methods

Targeted Chemical analysis of key nutrients & toxicants typical for the plant variety

Agronomical, morphological characteristics to identify secondary effects of genetic modifications.

Transcript profiling, proteomics & metabolics integrated with bioinformatics

Potential physiological, cyclical, developmental or environmental changes in the GMO at different cellular integration levels, at the genome level during gene expression & protein translation and the level of metabolic pathways

N/A

The regulatory framework in place currently cannot stop the approval of such crops as seen the examples in table 1 particularly in the US with the substantial equivalent doctrine where regulations subject GM food products to no greater scrutiny than unmodified products. It is a different case in the EU where they take a precautionary approach manufacturers are required to demonstrate the safety of GM crops and food products before they are marketed and are required to label foods before they are sold. Furthermore before a GMO can be marketed the European food and safety

authority must assess its safety through an extensive risk assessment and evaluation process that is open to public input and does not include any shortcut mechanisms. Additionally all products containing more than 0.9% of GM material must be labelled and all GM products must be traceable through information networks that track GM products. After high profile food scares the EU illegally suspended authorisation of any new GMO's for environmental release in 1998 according to the WTO resulting in the US filling a complaint to the WTO.

In conclusion the way forward is for the creation of regional bodies or laws that unify and apply appropriate regulations that will lead to the development of GM crops with long term potential to ensure safety and security.

References:

Food, health and biotechnology

Linking transcript profiles to metabolites and metabolic pathways: a systems biology approach to transgene risk assessment. *Kiambi DK, Fortin M, Stromvick M (2008)

Toxins in transgenic crop byproducts may affect headwater stream ecosytems (2007)

Calling the tunes on transgenic crop: the case for regulatory harmony (2008)

Genetic engineering and substantial equivalence (2004)

Preferences for Processes: The Process/Product Distinction and the Regulation of Consumer Choice Douglas A. Kysar Source: Harvard Law Review, Vol. 118, No. 2 (Dec., 2004), pp. 525-642 Published by: The Harvard Law Review Association

Discuss the concept of 'rational drug design'. Has it been successful or not? Provide examples where possible.

Introduction

Drugs are essential for the treatment and prevention of disease they work by interacting and altering receptor activity beneficially to human health. Ideal drugs are always in great demand. To meet this challenge of producing ideal drugs rational drug design is used. The traditional way of producing drugs is challenging, expensive and time consuming. Many current drugs have been discovered by chance observations, the scientific analysis of folk medicines or by noting side effects of other drugs.

What is rational drug design

Rational drug design is the 'development of small molecules with desired properties for targets, biomolecules, who's functional roles in cellular processes and 3D structural information are known' (soma et al 2009)'.

taken from rational drug design URL http://www.scribd.com/doc/9628595/Rational-Drug-Design-by-Bernd-WendtEMBL

Rational drug design can also be defined as 'the development of small molecules with predefined properties for targets, whose cellular functions and structural information may be known or unknown. Knowledge of unknown targets may obtained through analysis of global gene expression data samples treated and untreated with a drug using computational tools such as bioinformatics and gene expression tools. This results in the selection of compounds most likely to interact with target receptors being tested in the laboratory and the production of new generations of effective drugs. Basically rational drug design is Computer Aided Drug Design (CADD).

Examples

Rational drug design is very new but it has been successful in producing novel drugs. The first example we will look at viagra it was designed based of the structure of a known ligand. In 1985 Pfizer scientists aimed to find new drugs for the treatment of angina & high blood pressure. They targeted the enzyme phosphodiesterase, which would lead to an increase in the amount of available cGMP, resulting in vasodilation. Using new chemical entities designed based on the structure of cGMP, as such molecules would be expected to block the enzyme's active site. the most promising compound Sildenafil citrate was submitted for clinical trials.

No serious side effects were found in the phase I clinical trials and the testing progressed to phase II trials in patients with severe angina. The results were disappointing. However, further phase I trials carried out at the same time with high doses of the drug revealed frequent erections in the male participants. The research team switched direction and tested the drug as a possible treatment for impotence.

In the first trial, in 1994, ten out of the 12 patients reported an improvement in erectile function. Further trials were carried out on a larger sample, and again about 90 per cent of the patients reported an improvement. The drug was finally licensed in 1998 and is currently the best selling generic drug on the market The price of Pfizer's Viagra has doubled since it was launched with Price of Viagra Rising by 108%; 100 Pills Now Cost $1,400.

Drug

Target

Illness

History

outcome

Zanamivir (Relenza ®)

Neuraminidase

Influenza type A & B

discovered in 1989 by Victorian College of Pharmacy, Monash University scientists in collaboration with the Commonwealth Scientific and Industrial Research Organisation and Glaxomith. the first of the neuraminidase inhibitors. its discovery was funded by Australian biotechnology company Biota program to develop antiviral agents through rational drug design. Done by analysing of the structure of influenza neuraminidase, by X-ray crystallography.Computational chemistry techniques were used in addition to The software GRID from Molecular Discovery

Inhibits the Neuramindase protein which plays a critical role in the influenza replication cycle. Inhibiting influenza replication. Currently one of the main antivirals recommended for influenza pandemics. This drug has side effects

Dorzolamide Trusopt®

carbonic anhydrase

glaucoma

First human therapeutic drug produced by rational design

Blocks carbonic anhydrase decreasing intraocular pressure. This reduces the risk of nerve damage and loss of vision that is caused by increased intraocular pressure in patients with glaucoma.

Raltegravir MK-0518,

(Isentress®)

integrase

HIV

The first of the integrase inhibitors received approval by the FDA in 2007. rationally designed to interact with viral protease, the enzyme that splits up the viral proteins and allows them to assemble properly.

Inhibits integration of viral genetic material into human chromosomes. Surpressing viral occurance

Imatinib

bcr-abl protein

Various cancers

Imatinib was developed by rational drug design. After the Philadelphia chromosome mutation and defective bcr-abl protein were discovered. chemical libraries were screened to find a drug that would inhibit that bcr-abl. With high-throughput screening, they identified 2-phenylaminopyrimidine. Whuch was tested and modified by the introduction of methyl and benzamide groups to give it enhanced binding properties, resulting in imatinib,

Gleevec received FDA approval in May 2001.

inhibits a number of tyrosine kinase enzymes. It occupies the TK active site, leading to a decrease in activity.

There are a large number of TK enzymes in the body, including the insulin receptor. Imatinib is specific for the TK domain in abl (the Abelson proto-oncogene), c-kit and PDGF-R (platelet-derived growth factor receptor).

made the cover of TIME magazine as the "magic bullet" to cure cancer.

References:

Rational drug design 2009

Brankston et al (2009) Transmission of influenza A in human beings http://infection.thelancet.com Vol 7 April 2007

rational drug design http://genome.wellcome.ac.uk/doc_WTD020912.html

http://www.bentham.org/cpd/contabs/cpd13-34.htm

Viagra price http://industry.bnet.com/pharma/10004198/price-of-viagra-has-risen-98-since-launch-100-pills-now-cost-1400/

relenza http://www.biota.com.au/?page=1021002&subpage=1021104

Grid http://www.moldiscovery.com/soft_grid.php

Dorzolamide: development and clinical application of a topical carbonic anhydrase inhibitor.

Pfeiffer N.

Savarino A (December 2006). "A historical sketch of the discovery and development of HIV-1 integrase inhibitors". Expert Opin Investig Drugs 15 (12): 1507-22. doi:10.1517/13543784.15.12.1507. PMID 17107277.

Druker BJ, Lydon NB. Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest 2000;105:3-7. PMID 10619854

http://www.sciencedaily.com/releases/2009/12/091206162946.htm

Aspirin is arguably one of the, if not the best designed drugs currently available today. Describe its uses in particular related to its biological activity. Why has it been so successful?

What is aspirin

Aspirin is a non steroidal anti-inflammatory drug that has potent mechanisms of actions. It acts as an analgesic, antipyretic and anti-inflammatory properties. It is regarded as one of the most important drugs of last century. It originates from the bioactive compound Acetylsalicylic acid which is a derivative which of Salicylic acid from the bark of the willow tree (Salix spp, Salix alba).

Table 1. Aspirin history timeline

3000BC

Sumerian stone tablet from the Third Dynasty Ur prescribing willow-tree based medical remedies. (Mackowiak 2005)

1500BC

Egyptian The Ebers papyrus found prescribing willow leaves for fever and swelling (Mackowiak 2005)

400BC

Greek Hippocrates prescribes bark & willow leaves for fever and pain relief (pawar et al 1998)

1838AD

Salicylic acid was isolated from the glycoside salicin and identified as the bioactive compound of willow bark

1853AD

Acetylsalicylic acid first synthesized by mixing Salicylic acid with acetic acid

1894AD

Felix Hoffman at Bayer synthesizes it into a table powder form and prescribes it to treat his fathers rheumatoid arthritis

1899AD

Acetylsalicylic acid patented by Bayer as Aspirin. It is so popular its trade name become its generic name

1920AD

Used to treat symptoms of lumbago, rhematism and neuralgia

1971AD

Anti-inflammatory mechanisms of aspirin recognized by the inhibition of prostaglandin synthesis. Inhibition of cyclo-oxygenase(COX)

1980AD

Two forms of COX identified:

COX-1, constitutive

COX-2, induced at sites of inflammation

1988AD

FDA approves apspirin for reducing the risk of recurrent myocardial infarctions, reducing the symptoms of angina and prevention of transient ischemic attacks

1992AD onwards

X-ray structures of COX-1 and COX-2 available

Rational drug design of selective COX-2 inhibitors begins based on knowledge of aspirins activity. Companies Merck along with Pfizer-Pharmacia, DuPont and Taisho race to produce a drug.

1998/99AD

Celebrex and Rofecoxib Vioxx approved by FDA for osteoarthritis and rheumatoid arthritis

what are aspirins mechanisms of action

Prostaglandin inhibition

Aspirin works by inhibiting the action of enzyme cyclo-oxygenase (COX). COX mediates prostaglandin and thromboxane production by catalyzing synthesis reactions from arachidonic acid :

The bis-oxygenation of arachindonate to prostaglandin PGG2.

This is followed by reduction to PGH2 in a peroxidase reaction.

Prostaglandins are unsaturated fatty acids produced by virtually of cells of the body. They are cellular invivo chemical messengers responsible for activating physiological responses to events such as injuries resulting in blood clotting and sensitization of nerve endings to pain. They exist to serve for a variety of physiological functions.

Functions of prostoglandins

Secreted by the hypothalamus in response to infection as a response to infection causing a rise in body temperature

Secreted by cells in response to cellular damage resulting in inflammation, production of pain, and fever. White blood cells flood to the site to try to minimize tissue destruction

Secreted by the stomach to regulate stomach acid and protective stomach mucus lining

Secreted when a blood vessel is damaged (the prostaglandin thromboxane) stimulating constriction and clotting of platelets in areas of damage.

involved with the induction of labor and other reproductive processes. PGE2 causes uterine contractions and has been used to induce labor

increase blood flow in kidneys,

promote constriction of bronchi associated with asthma

Aspirin suppresses the functions of the enzymes COX1 and COX2, which usually appear after injury and other stimuli. These enzymes catalyse various types of prostoglandin production within these sites of stimuli resulting in pain and inflammation. Inhibition of COX2 is responsible for the therapeutic effects of reducing inflammation, fever and pain. Inhibition of COX1 is responsible for reducing the risk of blood clots, heart attacks and stomach irritations associated with aspirin usage (table 3)

Thromboxane inhibition

Aspirins antithrombotic action is caused by the 'irreversible inhibition of arachidonic cyclo-oxygenase activity in platelets which reduces the extent of thromboxane A2 (TXA2) formation and consequently the aggregation ability of platelets. Aspirin affects the balance between protacyclin which is made by the blood vessel walls and TXA2 which is released from platelets' (Pawar et al 1998).

image from Pawer et al 1998

Why has it been so successful

Aspirin has been so successful mainly because of it's ability to inhibit prostaglandins and consequently reducing problems associated with prostaglandins inflammation and fever was the main therapeutic value of aspirin. However as understanding of aspirin's properties is growing, its therapeutic applications have widened (Table 3).

Table 3. Therapeutic uses of aspirin

Uses

Biological activity

Mild to severe pain reduction by itself & combined with other drugs

Treating Rheumatic fever

Treating Rheumatic arthritis & other

inflammatory joint conditions

Inhibition of platelet aggregation

Treatment of angina

prevention of strokes and ministrokes

Treatment and prevention of heart attacks

treatment of pericarditis (inflammation of

the pericardium )

treatment of coronary artery disease

Colorectal cancer

Cancer prevention

Treatment of dementia

It treats a number of underlying issues furthermore its mechanisms of action have the inspired rational drug design of new generations of COX inhibitors such as Celebrax and Vioxx. Both of which were released in 1999 both making the 2001 list of drugs by top 10 sells beating viagra. Both drugs were referred to as super aspirins they broadly work by selectively inhibiting COX2 whilst inhibiting COX1. aspirin is currently still being trailed on people with other health conditions not mentioned in table 3 Aspirin will make news headlines again. Its use throughout the ancient world as a folk remedy and its present day highly successful commercial form gives homage to its properties and future potential.

References:

Philip A. Mackowiak, MD What We Do When We Suppress Fever 2005

Sunny Y. Auyang From experience to design - The science behind Aspirin

Pawer et al Aspirin the novel antiplatlet drug

Asprin uses http://www.aspirin-foundation.com/uses/index.html

Prostaglandins http://www.elmhurst.edu/~chm/vchembook/555prostagland.html

Aspirin http://www.medicalnewstoday.com/articles/161255.php

How close are we to having GM cows that produce chocolate milk? Describe the technological and ethical implications for this.

How close are we to have GM cows that produce chocolate milk

Is it possible to produce GM cows that produce chocolate milk? I'm sure one day it will be possible, but would it be commercially efficient and furthermore what kind of ethical implications will it have. It is not so farfetched to believe that we can produce such animals. In 2002 Biotech company Nexia inc. produced GM goats that could make spider silk proteins in their milk for the application of Biosteel TM. Biosteel is a recombinant form of dragline spider silk, with a tensile strength greater than steel and 25 percent lighter than synthetic, petroleum-based polymers. It is projected to represent $150 to $450 million in annual earnings (exclusive of military and other industrial applications). (Persal 2005). In 2003 scientist from biotech company Agresearch were the first able to produce cloned cows that could overexpress milk proteins B-casien and K-casien by 20% using nuclear transfer technology. This milk would enhance and reduce milk processing efficiency.

what are the technical implications

However making chocolate milk producing GM cow is not so simple, the aformentioned examples were done by the insertion of one or two genes. The production of chocolate would require the incorporation of a plethora of genes. Chocolate is not composed of one thing for example genes would have to be incorporated to make the milk sweet as well as make the milk taste like cocoa. Furthermore the taste of chocolate does not just occur naturally it undergoes processing in which cocoa is fermented resulting in the chocolate taste. In this process there are a multitude of chemical reactions that occur that are mediated by select micro-organisms, these genes would have to be incorporated aswell. Now let us suppose we are able to do all this, will the blending of chocolate be done invivo or invitro. How would the taste be refined, most likely blending would have to be done invitro to refine the taste and add whatever constituents needed.

The most efficient way of producing chocolate cows would be by using nuclear transfer technology (fig 1)

table 1 Basic example of the the GM chocolate cow process

genes are isolated from cocoa and sugar cane, these genes are cloned and mammalian regulatory attachment sequences are made and modified into a cow embryo this embryo is then transferred into a surrogate mother

Table 2 Technical Benefits of Nuclear transfer

Production of viable females that can express the required traits in their milk

100% chance of transgenic cow production

Production of repeated founder herds of livestock (from transgenic donor females)

Once an optimal transgenic line has been produced multiple animals can be produced from the donor.

Copies can be propagated and stored in culture by companies such as genetic savings and clones.

However before this can be done efficiently stable ES cell lines must be developed. Additionally advancements in gene targeting need to occur in order to have the ability to modify and select populations of cells of specific genotypes and phenotypes before embryonic reconstruction. To produce our cows with specific traits. Furthermore most importantly there will need to be improvements in nuclear transfer technology to overcome the problems of pre- peri and post natal deaths and development defects ( Dave 2000). eg of the Agresearch cows out of the 126 modified embryos, 11 cows survived to maturity with only 9 expressing increased Casein production.

what are the ethical implications

Ethical implications

Human safety, will this milk be safe for consumption. The Agresearch team did stress the

need to further test their milk to establish it's safety.

What impact will these incorporated genes have on the animal and product made from it. Will silent genes be activated that might cause things like cancer.

Milk from genetically modified cows will definitely stir up a lot of controversy and opposition.

Is the welfare of these genetically created cows an issue as they would have to be kept in specialised environments fed specialised feed similar to commercial diaries. What would their life expectancy be? It will not be economically viable to have these cows dying early.

What would the patents be on these animals what impact would it have on free exchange of scientific research?

In conclusion one of the main ethical implications would be what would the public perception of such a product be. If such a product was made, it would have to undergo years of rigourous testing like aspartic acid did just before it was approved. Furthermore it would have to have some kind of advantage over traditional chocolate milk i.e. Superior taste & cheaper more efficient production costs. The failure of this product would cause a serious blow to the whole biotech industry. We are very far away from GM cows being able produce even a single constituent of chocolate milk. Nuclear transfer technology efficiency must be improved. This will most likely never happen as chocolate production is a complex process and consumers preferences differ in order to make it economically viable. There might be a chocolate tasting biologically produced imitation but not chocolate milk

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