Medical Issues: The Future Impact of Biotechnology on Human Factors

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Oct 22, 2013 (3 years and 11 months ago)

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Medical Issues: The Future Impact of
Biotechnology on Human Factors
Dr Steve Nicklin
DERA/DSTL Fort Halstead
Building S18, Room 72
Sevenoaks, Kent TN14 7BP
United Kingdom
Summary
Biotechnology within the military context can be defined as the the exploitation and manipulation of biological
systems to benefit overall military capability . Recent years have witnessed a massive advance in scientific
knowledge and capability mainly through the advent of molecular biology and genetic engineering techniques.
These techniques have already led to considerable military benefits in the form of new countermeasures to
chemical and biological warfare agents, novel sensors for the detection of explosives and equipment for
bioremediation and environmental clean-up. In the future it is envisaged that advances in biotechnology will
continue to provide advances particularly in the field of autonomous sensing systems and new and unique
products and materials.
Introduction
The aim of this paper is to review the past, present and future of biotechnology in the context of health, human
factors and subsequent defence applications.
The term biotechnology was coined in the early 1970s to describe industrial microbiological processes that
either, harvest the products of naturally occurring free living cells / biological system or control and exploit
their abilities within a manufacturing or process engineering context. However biotechnology is not new and is
essentially a re-branding of a product from the 1930s when efforts were being made to use agricultural
surpluses to produce plastic and hydrocarbon substrates. Examples include everything from modern brewing
and cheese making, the production of antibiotics by fermentation, microbial conversion of simple chemicals
(e.g. methanol and ammonia) into animal feed and production of fuel alcohol by fermentation.
In more recent years however biotechnology has been massively expanded through developments in genetic
engineering and molecular biology that now allows the transfer of DNA from one organism to another. This
approach provides the recipient organism with the blue prints necessary to produce an almost indefinite
number of products. It is even possible to make completely artificial genes and generate molecules previously
unknown in nature offering the almost limitless potential for the production of novel materials. Running in
parallel with developments of genetic engineering techniques modern tissue culture and fermentation systems
have also advanced significantly allowing cells and microbes to be grown under precisely controlled conditions
allowing bulk production of a range of high value materials.
Utility of Biotechnology for Human Factors and Defence
Genetic manipulation and biotechnology clearly has many commercial and practical applications, a number of
which readily lend themselves for exploitation and advancement by the military. These are summarised below
and include the production of:
Antibiotics:
Micro-organisms make a number of anti-microbial products, with the antibiotics representing the major
materials of military relevance. The major antibiotics of clinical significance include the beta-lactams e.g.
penicillin and cephalosporin, and the aminoglycoside and tetra cyclin antibiotics. All these are typical
Paper presented at the RTO HFM Specialists Meeting on Human Factors in the 21
st
Century,
held in Paris, France, 11-13 June 2001, and published in RTO-MP-077.
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secondary bacterial metabolites and whereas their industrial production is well understood the biochemistry and
genetics of their biosynthesis is less clear. Genetic manipulation and mutation methods are now being used to
manipulate the antibiotic producing organisms in order to obtain increased yields and a panel of faster acting,
broad spectrum antibiotics capable of protecting against the more difficult target organisms and organisms that
have evolved to be resistant to the normal clinically available antibiotics.
Vaccines:
A Vaccine is a biological material that induces immunity to an infectious agent. Many vaccines are in use today
and provide protection against a wide range of childhood diseases and infectious agents and are particularly
important for individuals travelling abroad. (see table 1). They are also used extensively within the veterinary
and farming community to protect pets and livestock from endemic diseases. Historically, killed organisms
were used as vaccines. Although very effective there is always the possibility that the killing process modified
/reduced the effectiveness of the vaccine by reducing antigenicity of the organism or worse that the process
failed to kill all of the organisms. Since in many instances the primary active ingredient of a killed vaccine is
the outer protein coat it became increasingly attractive to attempt to produce vaccines containing only the outer
immunogenic coat proteins. By genetic engineering, viral coat proteins can be cloned and expressed in living
non-pathogenic carrier organisms thus allowing the development of safe, effective and convenient vaccines.
Currently available genetically engineered vaccines include CMV, Hepatitis B, Measles, Rabies etc with the
list including veterinary and experimental vaccines growing year on year. As one might expect a similar range
of vaccines are also being developed to protect troops against Biological Warfare (BW) agents including
amongst others plague, anthrax and botulism toxins. However vaccination doesnt stop with controlling disease.
By using modified virus it is also possible to transfer other genetic capabilities and in the future it may also be
possible to develop vaccines that endows the user with enhanced stamina and bigger and more effective muscle
without the need for excessive training.
Bioactive Peptides and Designer Drugs:
Numerous biologically active proteins e.g. hormones, blood products, growth factors, antibodies, enzymes, and
cytokines etc are of considerable medical importance. Historically these were collected and purified by direct
isolation from tissues, blood or body fluids. The process is complicated and increasingly expensive. By cloning
and over expressing the gene for a specific human protein in a host organism or cultured cell, large-scale
production of biologically relevant proteins is possible (see table 1). The classic example of this process being
the production of human insulin by transferring human DNA into E coli. This area of research has now been
rapidly advanced by the pharmaceutical industry keen to develop and mass-produce new drugs and high value
medicines by combining recombinant DNA technology and modern fermentation techniques. As alluded to
above early work in this area focused on industrial exploitation of biotechnology for the production of high
value and medically important natural gene products. Increasingly more recent research is directed towards the
creation of new products (the so-called designer drugs) and the precise control of specific genes. However
producing such genetic drugs is one thing, using them
in vivo
is another. Consequently much effort is also
directed towards the packaging and delivery of these products and getting them into the correct cells and
tissues.
Transgenic Organisms and Modified Foods
In addition to providing valuable drugs and medicines by microbial manipulation, genetic engineering now
allows the advent of genetically modified whole plants and animals. By introducing cloned DNA into fertilized
eggs of animals or directly into plant/animal cells grown in tissue culture, it is now possible to grow genetically
modified (GM) higher organisms. Such organisms, referred to as transgenics, hold great promise for boosting
agricultural production, improving the nutritional quality of meats and vegetables and producing a range novel
proteins and products not normally produced in the host organisms. We already see crops being developed with
genes conferring resistance to insects, pesticides, pollutants, herbicides and extremes of climate. Within a
decade or so it is expected that we will see foods that are clinically/ pharmacologically active and able to
provide increased vitamins, trace elements and even counteract various ailments such as non-insulin- dependant
diabetes, cholera, high cholesterol and hepatitis B. Moreover, research within the US Combat Feeding program
is already investigating the feasibility of producing small, high-density rations (the size of a pack of cards) that
are intended to provide a soldiers nutritional and calorific needs for a full day. It is hoped that such foods
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already termed neutraceuticals will not only provide calories but will be engineered to boost their immune
systems. It has also been suggested that in certain environments or operations, soldiers could be equipped with
emergency ration biodigesters containing immobilized enzymes or even living organisms that could convert
locally acquired materials such as grass, leaves and insects into a nutritious (if unappetizing) meal.
Environmental Biotechnology: Impact & Military Duty of Care:
Because of evolutionary selection and environmental pressures from a wide and diverse range of natural
habitats, bacteria provide a massive gene pool of capability, offering an enormous metabolic diversity. In order
to survive in hostile environments, bacteria needed to evolve genes to allow them to coexist with the toxic
elements within their immediate environment. As a consequence it is now possible to isolate genes for the
biodegradation of many hazardous chemicals and wastewater pollutants. Genetic engineering and
biotechnology is now beginning to exploit these resources for biotreatment of wastewater and contaminated
land. Examples include genes for the biodegradation of chlorinated pesticides e.g. 2,4,5-trichlorophenoxyacetic
acid (2,4.5-T), chlorobenzenes and related chlorophenolics, naphalines, toluenes, anilines and a growing list of
solvents and hydrocarbons. In brief, the desired genes are isolated from species co-existing with the pollutant of
interest and cloned into plasmids. These plasmids are then used to transfer genetic capability to other
organisms. In this way it has been possible to transfer the ability to degrade explosives/hydrocarbons between
organisms. Moreover it is perfectly possible to construct plasmids containing either single or multiple copies of
genes for the degradation of a range of different toxic chemicals or pollutants. More recently this work has been
extended to plants and trees allowing us to develop novel organisms capable of removing toxic pollutants from
a range of contaminated environments including training areas and firing ranges (Fig 1). In addition to
removing explosives contamination from the soil similar approaches have been developed to remove pollutants
from submarine atmospheres, with future application being considered for space missions. Returning to more
earthly issues biotechnology and biotreatment using mobile fermenters and processing plants are also being
developed to treat waste water/sewage generated on ships and will eventually be required for similar
applications in the battle field /war zone for processing local waste water and sewage etc.
Genetic Screening and Gene Therapy
.
Researchers have long known that genetic alterations result in disease. Mutations in one gene may cause cystic
fibrosis; in another it results in sickle cell anaemia, high blood pressure, depression, diabetes, dementia or even
schizophrenia. But it is now becoming clear that genetic differences can also occur in how well a person
absorbs, degrades and responds to various drugs. Moreover genetic variation can also render certain drugs toxic
to certain individuals. Isoniazid, an anti- Tuberculosis drug adversely affects individuals who are slow
acetylators. These individuals possess a less active form of the enzyme N-acetyltransferase, which normally
clears the drug from the body. Similarly if slow acetylators are given procainamide, a drug commonly given
after a heart attack, the recipients stand a good chance of developing a debilitating autoimmune disease. Thus
in certain individuals a drug can actually out live its therapeutic utility and actually cause more harm than good.
The gradual completion of the human genome programme is already opening up new areas of research. For
example pharmacogenetics has recently emerged as a new area of science that aims to use a systematic analysis
of genetic variation to understand idiosyncratic responses to drugs thereby enabling researchers to link
particular genetic finger prints with differences in drug responsiveness. Genetic testing of this type could help
match the right drug, treatment or vaccine at the right dose to the right soldier with out the risk of adverse
effects. In the longer term genetic screening may even be able to predict how an individual might respond to
changes in climate/environment, or how they might perform under stress. A linked area of research showing
great promise is gene therapy i.e. the use of graftable genetic elements for the treatment of genetic diseases.
Biosensors
Biotechnology also underpins the rapidly growing field of biosensing. A biosensor is a device concerned with
the detection of a specific target analyte (either biological/organic material or chemical vapour) through the use
of appropriate biological receptors. In its simplest form, a biosensor device is comprised of three main
elements; the biological receptor layer, a transducer to monitor binding effects between the receptor layer and
its species/targets of interest, and a linking layer between these two. Bioreceptors come in a range of forms
including antibodies, enzymes, olfactory binding proteins, DNA/RNA probes, synthetic ligands and cell surface
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receptors, but to name a few (Fig 2). These biomolecules have evolved with the sole purpose of binding either
firmly or reversibly to a range of target ligands in order to fulfil a specific biological or biochemical process.
Today many of these reagents find in vitro applications in a variety of sensor and detection systems. These
biomolecules allow assays to be both exquisitely sensitive and highly specific and increasingly, further
advances in modern biotechnology and molecular biology based techniques now provide a variety of
biological type reagents never seen in nature. Problems still exist, however, and considerable effort is often
required in order to get the biological molecules to behave as nature intended in an unnatural and hostile
environment. For example, spacing, positioning and orientation of antibodies and enzymes are crucial to ensure
maximum functionality and in many instances the chemists involved in coupling ligands to surfaces are more
important to the success of a sensor system that the biologist who provides the reagents.
The transducer is usually chosen for its sensitivity to changes produced when the biological receptor binds to, or
reacts with, the target material. The system is arranged to minimise or prevent false alarms. In their simplest
format biosensors may take the form of a clinical dipstick or ELISA based diagnostic kit generating a coloured
signal, the intensity of which is proportional to the analyte concentration. Others are more complex and are
designed to monitor changes in optical, electrical or mass changes and include surface plasmon resonance
(SPR) and evanescent wave (optical transducers), electrochemical or impedance cell arrangements and ISFETS
(electrical transducers), or quartz crystal microbalance and surface acoustic wave devices (mass transducers).
Biosensor research began in the 1960s with the development of glucose sensors, many of which are now
marketed as over the counter products. In a military context however, it is also particularly noteworthy that the
current in-service nerve agent detector (NAIAD) is a biosenor utilising an immobilised enzyme (acetylcholine
esterase) as the key recognition element within the sensor. Similar sensors are also under development for the
detection of pesticides, pollutants and explosives etc. Much of the current research in this field explores the
utility of other bioreceptors and in particular antibodies, as the key recognition element within various types of
sensor arrays. The research effort is currently being directed at linking receptor molecules, (which, provide the
specificity to the system), on to supporting surfaces e.g. silicon, metal, polymers, colloids etc in such a way that
the binding of a target analyte is detected in real time. Whereas these methods demonstrate the proof of
principal and the validity of the approach, it is likely that future years will witness further advances, in
particular, in the miniaturisation of the arrays through silicon based micro-nanofabrication techniques. In the
longer term other biological molecules such as enzymes and olfactory protein might replace antibodies to
provide even higher levels of specificity and sensitivity.
Autonomous Sensors
Ultimately the merger of biosensors with micro/nanoelectronics will provide the future generation of smart
sensors. Moreover it is also likely that by combining these approaches with biocompatible materials and
suitable telemetry it will eventually prove possible to attach or implant sensors into individuals. These sensors
could be designed to be capable of not only providing physiological outputs (e.g. cardiovascular / respiratory
parameters and body temperature) but also sense and report on other parameters e.g. stress and may even be
able to warn against the threat of infection. Similarly by incorporating therapeutic elements within such devices
they may also be able to release agents to directly into the tissues /blood to improve wound healing and/or
counter stress, infection, nerve agents etc. There are also designs to investigate the utility of devices referred to
as transdermal nutrient delivery systems (TNDSs), these systems are intended to deliver nutrients/water into
soldiers during times of intense conflict/confinement when they are unable to take in food or water normally.
Tissue replacement and Biomimetics
As early as 1965 researchers at the University of California LA demonstrated that new bone growth could be
seeded in animals that received a powdered bone implant. This observation lead to the isolation and cloning
of a family of proteins known as bone morphogenic proteins (BMPs) . Various clinical trials are now underway
to test the ability of these agents to promote bone growth in accident victims. Encouraging growth in vivo is
one thing but growing replacement tissues or even organs in vitro is a significantly more complex task since
tissues that are more than a few mm thick need capillaries to grow into them in order to supply nutrients. This is
also being addressed through modern tissue culture techniques which in combination with genetically
engineered growth factors now allows us to culture and grow human skin (suitable for skin grafting) within the
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laboratory. In future we also anticipate the production of replacement bone and collagen for use in
reconstructive surgery. However despite these major advances in tissue engineering the construction or
replacement of fully functional organs remains many years away. Others believe that by developing and
engineering materials based on nature /natural products through biomimetics it will also be possible to develop
a whole range of novel and improved man-made materials, including biopolymers and fabrics. For example one
could envisage a second skin like material being worn next to the skin containing artificial capillary nets
capable of absorbing and neutralising toxins, with enzymes to degrade nerve agents, and even clotting agents to
facilitate wound healing. In an ideal world the fabric, would change colour to blend with the environment,
generate electricity through body movement and be edible!
Issues and Concerns
Despite the undoubted promises offered by biotechnology and genetic engineering, developing useful products
is still an enormous and often expensive undertaking. Other than the technological problems of correctly
cloning and expressing the gene of interest, the cost of purifying the products and subsequent matters such as
clinical trials and government approval must also be considered. As with any new product intended for human
consumption all new GE products intended for human or veterinary use must pass extensive clinical trials.
For example human insulin produced by recombinant DNA technology had to pass strict trials in human
volunteers despite the fact that the microbially produced insulin was shown to be identical to protein made by
humans. In addition public perception and concerns over Genetically Modified Organisms entering the food
chain need to be respected and treated with due care and diligence. Conversely, we should not underestimate the
power and potential threat posed by biotechnology and the harm that it can do if purposely abused. Many
countries including potential aggressors already posses all the skills and knowledge they require to develop
biotech weapons. Whether these be overt attacks with biological agents and toxins or more subtle attacks via
ecological, environmental or economic means, the gen(i)e now is out of the bottle and can never be put back!
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Table 1 Medicinal Products Produced by Recombinant DNA Techniques
Gene Product
Activity
Vaccines
Rabies Short Term Protection from Disease
Measles Long term Protection from Disease
Cytomegalovirus Prevention of Infection
Hepatitis B Protection from serum Hepatitis
PA Proteins Protects against Anthrax
F1/V Protects against Plague
Etc....
Blood Products
Factors VII, VIII, IX Facilitates Blood Clotting
Erythropoietin Stimulates Erythrocyte Production
Tissue Plasminogen Activator Clot Buster
Urokinase Facilitates Blood Clotting
Bone Morphogenic Protein Stimulates Bone Growth
Enzymes Range of Bio-Catalytic Agents
Etc....
Immunomodulatory Agents
Alpha-Interferon Immunmodulator
Beta-Interferon Immunmodulator
Colony Stimulating Factor Stimulatory Agent
Lysozyme Reduces Inflammation
Tumour Necrosis Factor Attacks Tumours
Interleukins Immunostimulatory agents
Cytokines Cell Activation Proteins
Etc...
Hormones
Insulin Treats Diabetes
Epidermal Growth Hormone Speeds Wound Healing
Nerve Growth Factor Promotes Nerve Growth
Etc.....
NB ! New Human and Veterinary Products are Emerging
Continually
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Fig1
Worlds First Genetically Engineered  Explosive Degrading Plant
Fig 2
Schematic representation of a biosensor with some of the different options for the transducer
and biological receptors.
Analyte (target or its emission)
Receptors ( )
Antibody
Enzyme
Olfactory receptors
DNA/RNA probes
Synthetic Peptides
Optical (SPR/evanescent wave)
Transducer
Electrical (ISFETS, Porous silicon)
Acoustic (SAW, QCM)
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