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Biotechnology and Society---Part
XVII
Aftermath of genome project
We often think that when we have completed our
study of one, we know all about two, because "two" is "one and
one". We forget that we still have to make a study of "and." -
Sir Arthur Eddington (1882-1944), British astronomer and physicist.
kaRRathu kaimaNNaLavu
kallAthathulagaLavu…- avvaiyAr, Thamizh saint-poetess
 In modern times man has
explored outer space and we know quite a bit about the rest of the planets and
our Milky Way galaxy. That constitutes the macrocosm. Correspondingly, we have
also explored the inner workings of life forms from the tiniest bacteria to huge
mammals. We understand quite a significant amount of the details of life at the
microcosm level. But in both cases, what we know is minuscule compared to what
we do not know.
Genomics: With respect
to the human genome we have just begun to scratch the surface in trying to
understand the journey of ‘DNA to life’. Now that the human genome is
sequenced, let us examine what we can do with the knowledge gained, the
challenges we will face and the pitfalls against which we have to guard
ourselves and society at large. The total completed genome count is about 150.
This number is expected to double in the year 2004 and increase six-fold to
about 1,000 in 2005.
Proteomics: With the
completion of the sequencing the human genome, attention is now turned to
unravelling the nature and function of the various human proteins. The gene
sequence leads to protein sequence and protein expression. The goal of
proteomics is to identify all the proteins and understand their ranges of
expression in different cell types, as well as characterise modifications,
interactions, and structure. Once completed, the proteomics project will yield
drug targets and information on disease states and drug response. If the
disease-causing tendencies revealed through defects or deficiency of proteins
are understood, then therapies can be devised via external intervention
treatments such as gene therapy to rectify the defect.
Genomics to drugs: The
human genome sequence provides a precise chemical structure of the human
chromosomes. Any slight changes in the chemical structure cause perturbations in
biological processes. In addition, various small molecules can modulate the
individual functions of proteins. Cheminformatics (the science of interaction of
chemicals with biological targets) can then enable new drug discovery based on a
rational approach. Whether it is small molecules or functional proteins or gene
therapy, the face of medicine will be changed forever as a consequence of the
genome revolution.
The genome sequence of
Anopheles gambiae, the major mosquito carrier of the malarial parasite
Plasmodium falciparum, was reported in 2002. The genome sequence of the parasite
was also determined. The genomes of these two organisms along with that of the
human provide a triad set of data critical to understanding the stages of
malaria transmission cycle which is the first step in the fight against malaria,
a disease that takes a large toll of humanity. The emphasis is now on the
control of the life of the parasite vis-à-vis the vector (mosquito) rather than
simply on the eradication of the mosquito that has been the strategy so far. The
final punch may occur through identification of the protein targets of the
parasite and blocking them effectively to arrest the development of the
parasite. Drug resistance is bred by polymorphism (changes in base composition
of DNA) in the genome of the parasite and being able to determine where the
polymorphism occurs allows one to study and eliminate the spread the drug
resistance.
Other issues: Analysing
and understanding the human genome in conjunction with microbial and plant
genomes will enable us to (a) increase energy production (b) mitigate global
climate change (c) attempt environmental clean-up (d) produce customised drugs
to fight all kinds of genetic, infectious and lifestyle diseases and (e)
increase food production in a scenario that can be called the Blue Revolution.*
Microbes make up more than 50
per cent of the Earth’s biomass. They control the biosphere’s biochemical
cycles, soil productivity, water quality and global climate. It thus behoves us
to understand the genomic function of various microbes to be in control of our
energy and climate future. Some of the issues we face in this area are detailed
below:
Clean energy: Currently,
petroleum refineries convert crude petroleum into usable energy products using
heat and catalysis. In future, biorefineries would be able to use microbial
enzymes to convert renewable biomass into fuel ethanol. This vision can be
accelerated by understanding the plant genome and the microbial genome systems
necessary to deconstruct the plant material into simple sugars. Some
microorganisms are capable of producing hydrogen at normal biological
conditions. Again, the microbial genomics need to be investigated to make use of
this capability. Certain algae produce hydrogen from water and sunlight.
Climate control: The new
energy sources cited above would then contribute to reduction of atmospheric
carbon dioxide, which will have reciprocal effects on global climate change.
Carbon and nitrogen are circulated through the atmosphere, oceans, organisms and
soil mainly through microbial metabolism.
Cleaner environment:
There are so many thousands of waste sites all over the world resulting from
weapons production, energy production and chemicals production and processing.
Neutralising contaminants in situ using microbes that are native to such
environments will be made possible by understanding the genomics of such
microorganisms. Microbes can change the chemical properties and thus the
solubility of metals in water causing segregation and thus avoiding the toxicity
of such metals to animals and humans who come into contact with them. The case
of arsenic contamination in the drinking water of Bangladesh is so familiar to
invite such attempts.
The rice genome: More
than half the world’s population depends on rice** as a principal source of
calories and nutrition. The genome of this cereal grain (0.4 billion base pairs)
is now determined. The genome of Oryza sativa, subspecies indica, the most
widely cultivated in Asia, contains roughly 46,000 to 56,000 genes. Once the
genomes are completely annotated and their regulation understood, it may be
possible to alter the productivity as well as nutrition content of rice through
gene manipulation.
Challenges: The
completion of the human genome sequence entails more challenges. We now have to
understand gene regulation, non-coding DNA (known as junk DNA) and its function,
if any. We also have to understand coordination of gene expression and
evolutionary conservation of genes among organisms. It is also equally important
to correlate single nucleotide polymorphisms (SNPs) with health and disease.
Another challenge is to be able to predict disease susceptibility of individuals
based on gene sequence variation.
At the beginning of this
article we indicated we will examine the ways in which understanding the genome
will benefit humanity. Some of the benefits in the health area are: (1)
individual tailoring of drugs to suit the genetic profile of people thereby
avoiding adverse reactions of drugs which cause 100,000 unnecessary deaths a
year (2) gene therapy to cure certain incurable diseases.
We also indicated that we have
to avoid certain pitfalls. Those pitfalls concern possible tampering of the
ecology of the biosphere and causing extinction of wild species and a consequent
tilting of the natural balance of the ecosystem, whether it is the microbial
world or plant kingdom.
In addition, when genetic
testing is done on individuals we have to make sure that the genetic profile
does not get misused by employers and insurers in discriminating against certain
people in terms of jobs and availability of insurance. Society also has a
responsibility to make sure that the errant genes are not used as an excuse for
crimes and aberrant behaviour by individuals. The scientific community and
society are well aware of these and will proceed with caution on any measures
that are undertaken.
* The term Blue Revolution is
used here in the sense that the possibilities are endless akin to the blue sky,
inviting and offering hope. ** Of the 23 known Oryza species, only Oryza sativa
(Asian rice), and Oryza glaberrima (African rice) are cultivated. The two
predominant food crops come from O. sativa, L subspecies indica, and O. sativa,
L subspecies japonica. The indica species is grown largely in the tropics and
subtropics while the japonica is grown in the sub-tropics and temperate
climates.
Definitions
Bioinformatics: It is a
discipline in biotechnology which involves computerised storage and analysis of
biological data from standard gene sequence databases (such as the online
repository GenBank) to complex fuzzy logic systems in order to find comparative
patterns of gene transcription in healthy and disease states of the body.
Proteomics:
It is an area of research which seeks to define the function and
expression profiles of all proteins encoded within a given genome. It
involves separation, identification, and characterization of proteins
expressed by a cell in order to understand their functions and the
regulation of such functions. Such an understanding is useful in
various fields such as pharmacology, toxicology, bioremediation and
agriculture.
Single Nucleotide Polymorphism
(SNP pronounced ‘snip’): It is the most common type of genetic variation,
consisting of a change at a single base in a codon in a DNA molecule. These snip
markers will facilitate efforts to discover therapeutic drugs.
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