In the last
decade, whole-genome sequencing efforts of microbes, plants and animals have
become a reality, making available an ever increasing pool of genetic information
about life on this planet. The most complex of these efforts, the Human Genome
Project (HGP), is now nearing completion. A "draft quality" sequence
of the human genome was published simultaneously by the government-funded HGP
and the privately funded Celera Genomics Corp. in February of 2001, with the
final, high quality sequence expected to be finished by 2004. For more information
read the Human Genome Hot Topic article.
Sequences in Progress
While work on the human genome has received the bulk of publicity, sequencing
has been proceeding apace with the genomes of a wide variety of organisms. These
include non-human vertebrates such as mice, zebrafish and pufferfish, as well
as frogs and chickens. Invertebrates such as the highly studied worm Caenorhabditis
elegans, its relative C. briggsae and Brugia malayi (the causal
agent for filariasis) are also the subject of sequencing efforts. Amongst the
microorganisms, in addition to E. coli and its relatives, the organisms
for whooping cough (Bortadella pertussis and B. parapertusis), food
borne diseases (Campylobacter botulinum jejuni, Clostridium botulinum
and Shigella dysenteriae) along with the agents for leprosy and tuberculosis
(Mycobacterium leprae and M. tuberculosis respectively) are under
intensive study along with a variety of Streptococcus species (rheumatic
fever, scarlet fever).
Government-sponsored scientists also are working to combat bioterrorism. This
research is made even more urgent by the anthrax letters found in the mail after
the September 11, 2002 terrorist attacks on the U.S. Several people died of anthrax,
many others had to take massive doses of antibiotics, and thousands more were
tested for exposure to the bacterium. As these very real events demonstrate, fast
and accurate detection of bioterrorism agents, as well as effective methods of
disease prevention and treatment, are needed to protect the American public from
bioterrorist attacks. Research currently underway to better understand the genomes
of human pathogens such as Bacillus anthracis (anthrax, multiple strains),
Yersinia pestis (plague), Variola virus (smallpox), and Clostridium
botulinum (botulism) will help scientists accomplish these goals.
Very often these genome sequencing efforts are carried out by consortia rather
than by research teams at a single institution. An example of such a collaborative
effort is the sequencing of the genome of Plasmodium falciparum, the parasitic
organism causing human malaria. Here the studies are being carried out jointly
by the Wellcome Trust Sanger Institute, (U.K.), the Institute for Genomic Research
[TIGR], (U.S.) and at Stanford University (U.S.).
The Post-Genomic Era
The full sequencing of so many genomes represents a new beginning for research
in what has been dubbed the “Post-Genomic Era.” With the completion
of the human genome now close at hand, scientists are starting to turn their attention
to how such sequence information can be utilized for the good of society.
Dissecting the genome
Certainly one overriding goal is to understand what is actually encoded by
the four-letter “alphabet” of G, A, T and C nucleotides. This is the
domain of functional genomics, a field in which scientists study the structure
of the genome, and work to decipher how its constituent parts contribute to a
healthy human being. This work has only just begun. So far, only half of the approximately
30,000 to 40,000 genes contained on the 23 pairs of human chromosomes have a known
function, and identifying the rest of the genes presents a formidable challenge.
However, genes themselves are only a small part of the genomic puzzle, making
up only about 2% of the genome sequence. Some of the other 98% is involved in
regulating gene expression, but much of this extra sequence has been dubbed “junk
DNA” because it is not clear if it is needed for anything at all. With so
little currently known, making sense of the 3 billion-letter human “book
of life” will be no easy task, and will keep geneticists around the globe
busy for years to come.
Preliminary examinations of the genome have already generated a great deal of
interest in single nucleotide polymorphisms, or SNPs. These single nucleotide
differences between individuals are believed to hold the key to many frustrating
medical questions. Why does a drug that does wonders for one patient cause such
miserable side effects in another? Why do some people develop diseases such as
cancer at a young age, while others manage to live to a ripe old age? The answers
are believed to lie at least partially in those slight differences in genetic
code that make each one of us unique, about one base in every 2,000 to 3,000.
Over one million of these SNPs have already been identified, although not all
of them are expected to be associated with disease states. Still, scientists are
hopeful that SNP analysis will someday lead to more sophisticated medications,
and aid in the diagnosis and treatment of a wide variety of ailments.
Pharmacogenomics
The realization
that the genetic makeup can change the way individuals respond to medication has
let do a new type of drug research. In pharmacogenomics, scientists are using
genetic information to design better pharmaceuticals. It is hoped that someday,
drug treatments will be tailor-made to each individual based on genetic makeup,
taking much of the guesswork out of prescribing drugs. Allergic reactions to drugs
will be prevented, and the correct drug and proper dosage can be determined from
the individual's genetic code, rather than through the trial and error procedure
that doctors currently use. Understanding the genetic causes of disease will allow
researchers to find better drug targets and custom design drugs to impact a particular
RNA or proteins involved in the disease. An awareness of an individual's susceptibility
to specific diseases should also help the doctor and patient decide on appropriate
lifestyle changes or medical treatments to prevent disease or lessen its severity.
Of course it is this type of highly personal information that also has the greatest
potential for abuse (denying employment or health insurance to a person because
they have or may develop a disease, for instance), so finding ways to keep such
information private will be paramount.
Gene therapy
Another highly anticipated yet controversial avenue of genomics research is
gene therapy. In gene therapy, genes are inserted into a person’s cells
to correct for missing or mutated genes that cause disease. Such therapy has the
promise of someday curing conditions that are currently incurable. There are studies
underway to treat such diseases as cancer, AIDS, cystic fibrosis, hemophilia,
and diabetes. However, gene therapy is still very much in the experimental stages,
and there are many hurdles that need to be solved before it can become a standard
medical treatment.
Perhaps most pressing problem is the need for a good gene delivery system. In
other words, how can the necessary gene be safely and effectively brought to the
cells in the body that need it? Most studies currently underway utilize modified
viruses to carry the desired gene into cells. In this method, some of the viral
genome is replaced by the desired human gene, and when the virus infects the person,
the gene is delivered to the correct cell. Unfortunately, such viral carriers
can cause unwanted side effects, including strong, or even fatal, immune reactions.
To avoid such undesired responses, scientists are looking for ways to deliver
genes without the use of viruses. One intriguing idea is to use a “47th
chromosome” – a long piece of DNA that would supplement the 46 chromosomes
in each human cell. It would be large enough to carry large amounts of genetic
information, but if made properly, would evade immune system detection because
it would have all the features of human chromosomes. Much more needs to be understood
about how the human genome works, however, before scientists can confidently make
such a sophisticated gene carrier.
Genetically-modified foods and cloning
While gene therapy is still years away, our ability to manipulate DNA has already
led to the production of genetically modified organisms, or GMOs. Although farmers
and ranchers have manipulated the genes of domesticated plants and animals for
thousands of years through selective breeding programs, this new ability to insert
individual desired genes into genomes of a totally unrelated organisms has been
greeted with both enthusiasm and unease. Proponents of such technology note that
GMOs can make crops resistant to insects, pesticides, even spoilage, and will
make foods more nutritious and delicious. Opponents point out the possibility
that such foods will be harmful to human health, and that the introduction of
inappropriate genes into plants will result in “superweeds” capable
of destroying entire ecosystems. Both sides make opposing arguments regarding
the impact of these technologies on the human and economic health of countries
around the globe. But despite being dubbed “frankenfoods” by objectors,
food made from GMOs are already a part of our daily lives. Many farmers grow Monsanto’s
“Roundup Ready” pesticide-resistant soybeans, and most of the milk
consumed in this country is produced by cows injected with genetically engineered
bovine growth hormone (BGH). While the debate rages on, no clear picture has emerged
regarding the overall effect of these products on the lives of people around the
world. The impact of GMO products on global health, as well as global economies,
still needs to be more thoroughly studied.
Another aspect of genetic research is mammalian cloning, with the possibility
of clining human beings. For more informatin on this topic visit the Mammalian
Cloning Hot Topic article.
Other potential benefits of genetic research
As noted above, one feature of the post-genomic era is the increased interest
in sequencing the DNA of all types of organisms. Dozens of microbial genomes are
currently under investigation as part of the US government’s “Genomes
to Life” (GTL) program, and they harbor some surprising potential. Bioenergy
research is focused on finding microbes that can produce energy as an alternative
to foreign oil. Scientists have already identified bacteria that produce hydrogen
gas or other fuels as a by-product of their metabolism as they break down biomass.
Microbes may also be useful for toxic waste cleanup. There are strains of bacteria
that actually thrive under conditions that are highly toxic to humans, such as
in radioactive waste. Efficient decontamination of toxic materials by microbes
could save the US taxpayers millions of dollars, as well as eliminate health hazards
at toxic dump sites.
Proteomics
Having
the genomic sequence of an organism represents an enormous achievement, but
the important thing is to be able to understand just what the sequence can provide
in terms of biological function. In fact, having the genome sequence is generally
the very first step (though a crucial one) in understanding gene function and
regulation. Many scientists feel that the next step is to study the proteins
encoded by all those genes. In proteomics, researchers study how organisms use
their genes, by examining the proteins that cells actually make. Each organism
expresses genetic information in a very specific way, which varies over time,
and from tissue to tissue. Some protein-encoding genes are heavily utilized,
while others are used only for short bursts of time. Thus, even though the genome
of an organism does not change, the proteome, or set of proteins found within
a cell at any given time, can vary greatly. Thus, the proteins expressed by
a liver cell are very different from the proteins expressed by a brain cell,
which are different again from proteins expressed in the cells of a developing
embryo.
With
proteomics, scientists hope to gain a better understanding of how genetic information
is translated into the growth and function of active, living cells. To provide
just one example, while the sequence of the genome of the worm Caenorhabditis
elegans (representing about 20,000 genes) was determined in 1998, less than
10% of those genes have been the subject of functional analyses using classical
biochemical and genetic techniques. Only very recently have high throughput DNA
microarray (Gene Chip) methods been employed to establish gene expression and
patterns of coregulation (see Kim 2001). It is the immensity of the data sets
deriving from genomic studies that places such a heavy emphasis on high throughput,
multidimensional analysis (see Gifford, 2001).
Conclusion
Genomic research, of the human genome and the genomes of many other organisms,
is sure to bring advances in medicine and human health, energy production, toxic
waste cleanup, and more. Certainly, many of these goals will not reach fruition
for years, and some of the research being done is highly controversial. Still,
the genie is out of the bottle, and how we deal with our newfound knowledge will
be as much a test of our humanity as anything we have done in the past.
In the last
decade, whole-genome sequencing efforts of microbes, plants and animals have
become a reality, making available an ever increasing pool of genetic information
about life on this planet. The most complex of these efforts, the Human Genome
Project (HGP), is now nearing completion. A "draft quality" sequence
of the human genome was published simultaneously by the government-funded HGP
and the privately funded Celera Genomics Corp. in February of 2001, with the
final, high quality sequence expected to be finished by 2004. For more information
read the Human Genome Hot Topic article.
The realization
that the genetic makeup can change the way individuals respond to medication has
let do a new type of drug research. In pharmacogenomics, scientists are using
genetic information to design better pharmaceuticals. It is hoped that someday,
drug treatments will be tailor-made to each individual based on genetic makeup,
taking much of the guesswork out of prescribing drugs. Allergic reactions to drugs
will be prevented, and the correct drug and proper dosage can be determined from
the individual's genetic code, rather than through the trial and error procedure
that doctors currently use. Understanding the genetic causes of disease will allow
researchers to find better drug targets and custom design drugs to impact a particular
RNA or proteins involved in the disease. An awareness of an individual's susceptibility
to specific diseases should also help the doctor and patient decide on appropriate
lifestyle changes or medical treatments to prevent disease or lessen its severity.
Of course it is this type of highly personal information that also has the greatest
potential for abuse (denying employment or health insurance to a person because
they have or may develop a disease, for instance), so finding ways to keep such
information private will be paramount. 
Having
the genomic sequence of an organism represents an enormous achievement, but
the important thing is to be able to understand just what the sequence can provide
in terms of biological function. In fact, having the genome sequence is generally
the very first step (though a crucial one) in understanding gene function and
regulation. Many scientists feel that the next step is to study the proteins
encoded by all those genes. In proteomics, researchers study how organisms use
their genes, by examining the proteins that cells actually make. Each organism
expresses genetic information in a very specific way, which varies over time,
and from tissue to tissue. Some protein-encoding genes are heavily utilized,
while others are used only for short bursts of time. Thus, even though the genome
of an organism does not change, the proteome, or set of proteins found within
a cell at any given time, can vary greatly. Thus, the proteins expressed by
a liver cell are very different from the proteins expressed by a brain cell,
which are different again from proteins expressed in the cells of a developing
embryo. 
With
proteomics, scientists hope to gain a better understanding of how genetic information
is translated into the growth and function of active, living cells. To provide
just one example, while the sequence of the genome of the worm Caenorhabditis
elegans (representing about 20,000 genes) was determined in 1998, less than
10% of those genes have been the subject of functional analyses using classical
biochemical and genetic techniques. Only very recently have high throughput DNA
microarray (Gene Chip) methods been employed to establish gene expression and
patterns of coregulation (see Kim 2001). It is the immensity of the data sets
deriving from genomic studies that places such a heavy emphasis on high throughput,
multidimensional analysis (see Gifford, 2001).