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We Innovate Healthcare

Excerpt from Facets No. 22:

DNA-based medicine creating value for patients
Roche Corporate Communications, Basel
To appear in summer 2003

DNA chips: choosy fish hooks

When scientists fish in murky waters, it is not necessarily a bad
sign. After all, only rarely does nature provide clear solutions.
For example, a cell extract contains, in at most slightly presorted form, the entire inner life of thousands or even millions
of cells in the form of a generally colourless, opaque, thick
fluid. All that matters is that from such murky solutions scientists be able to draw clear conclusions. And nowadays they are
aided in this task by fishing lines whose properties would
make ordinary fishermen green with envy: fast, accurate and
capable of catching enormous numbers of different types of
fish at the same time. These fishing
Terms:
lines are known as biochips, and
Biochip: a solid substrate (e.g. glass or plasthere can be little doubt that a bright
tic) upon which biomolecules are anchored.
future awaits them. In medicine, at
DNA chip: biochip with single-stranded
least, they are in the process of turnDNA as the probe.

ing research, diagnosis and therapy

GeneChip : a widely used DNA chip develupside down.
oped by the US company Affymetrix.
Biochips are among the most imporDNA: deoxyribonucleic acid; the chemical
tant instruments used in the miniasubstance of which our genetic material
consists.
turisation and automation of biology.
In most applications their task is to
RNA: ribonucleic acid; the chemical substance of which, among other things, workrecognise and bind to specific moleing copies of genes (mRNA) consist.
cules in a solution like fishing lines
cDNA: complementary DNA; DNA transet up to catch only one kind of fish,
scribed enzymatically from RNA (mostly
but to do so with a high degree of
mRNA).
reliability. The hooks used for this
Nucleic acids: generic chemical term for
purpose are molecular probes atDNA and RNA; chain-shaped molecules
tached to a substrate surface barely
whose individual building blocks are
the size of a thumbnail. It is this surbases/nucleotides.
face that gave biochips their name: it
Oligonucleotides: short nucleic acid chains
consists of plastic or glass and is
composed of at most a dozen building blocks
similar to the silicon chips used in
(nucleotides).
the computer industry. In principle,
Genes: functional segments of our genetic
any substance that interacts with
material that serve mostly as blueprints for
the synthesis of proteins.
components of our cells can serve as
a molecular probe.
Genome: the totality of the genes of an organism.

The most important biochips at present: DNA chips

In the type of biochip that is most important at present, the molecular probe that is attached to the chip is DNA. In future,
DNA chips are likely to serve the most varied of purposes
ranging from basic research in biology through diagnosis of
disease to water ecology. Equally as varied as their potential
applications are the shape, size and method of manufacture of

DNA chips. Despite these differences, almost all DNA chips

exploit the same biological principle, that of hybridisation.
The four bases that are the building blocks of DNA always pair
with the same partner. Our genetic material therefore consists
of two strands of DNA arranged in the form of a twisted rope
ladder, or double helix. The two strands are complementary in
the sense that the sequence of one can be deduced from that of
the other. This joining together, or hybridisation, of two nucleic acid chains to form a double-stranded structure has been
exploited by biologists for decades. For example, labelled short
segments of single-stranded DNA (oligonucleotides) can be
used to search for the presence in our genome of oligonucleotides with the complementary base sequence.
DNA chips do basically the same thing. DNA fragments tethered to the chip bind to complementary base sequences in the
solution being studied. The difference is that DNA chips make
it possible to perform many such experiments at once: millions
of copies of each of several hundred thousand different oligonucleotides can now be accommodated on a chip measuring
just one square centimeter. Conversely, such a chip can be used
to search for tens of thousands of different DNA segments in a
solution and it is precisely this possibility that forms the basis
of entirely new applications in biological research and medicine.
Field of application: gene research
The most important application of DNA chips is in the search
for, and the study of, genes. In this application, as in the classical oligonucleotide experiment, short segments of DNA are
used to help identify longer genes. There are two basic ways in
which this can be done: either the genes are attached to the chip
and incubated with a solution of a labelled oligonucleotide, or
else the oligonucleotide is attached to the chip and the genes
are placed in the solution. Of these two methods, the former
was developed first, whereas the latter is used more commonly
nowadays because it permits the performance of more experiments on a single chip.
The developers of both types of chip were in any case faced
with the same two problems, namely how to get the DNA onto
the chip and how to know when two matching bases have
found each other. In both cases a variety of approaches have
been tried, and it is not yet clear which techniques will win out.
A large number of companies are currently offering competing
methods of tackling scientific tasks that are in some cases identical but in other cases different. It may be that a number of different techniques will survive.

The example of GeneChip

One of the most important
Common example: the GeneChip
DNA chip technologies was
developed by the CaliforOne of the most commonly used DNA chips at present is Affynian company Affymetrix. metrixs GeneChip. This is an oligonucleotide chip in which the
The name of this com- short strands of DNA are synthesised in situ, i.e. on the chip, by
panys best-known product, means of photolithography:
GeneChip, is often used

synonymously with the Such a GeneChip can be used to examine different types of DNA
solution. Commonly performed experiments include genome studterm DNA chip to refer to ies and, in particular, gene expression profiles. These are used to
any such product. (In addi- identify those genes that are actually expressed in a given cell type
tion to DNA chip and or tissue.
gene chip, other terms in- For this purpose the mRNA the working copy of genes in a cell
cluding microarray, ge- extract is transcribed into cDNA. This process is known as reverse
nome chip and gene ar- transcription, as opposed to transcription, which is the synthesis of
ray are in common use.) RNA on the basis of DNA. Precisely this can occur in a second
step, since in many experiments the cDNA that is formed is tranAffymetrix manufactures scribed back into cRNA. In one of these steps a label is introduced;
its GeneChips using the commonly used for this purpose is, for example, the molecule bioprinciple of photolithogra- tin. The cRNA (or cDNA) is then cut into smaller pieces and placed
phy, just as in the manufac- on the chip, where it hybridises with the oligonucleotides. Measture of computer chips. In urement of fluorescence then shows how much of the label is bound
at what sites on the chip and thus what quantity of the mRNA of
this technique a light interest was present in the cell extract.
source, special masks and
photosensitive
protector
molecules are used to deposit billions of oligonucleotides with (at present) up to
700,000 different base sequences alongside each other in tiny
cells (spots) on a chip (see box).
Such a GeneChip is then incubated with a solution containing
the DNA of interest, which has previously been labelled with a
fluorescent dye. Whether given oligonucleotides on the chip
have hybridised with DNA in the solution is apparent from the
positions on the chip at which fluorescent dye is present at the
end of the experiment. For this purpose the individual positions
on the chip are read with a scanner. The readings are analysed
by computer with the aid of specially developed programs.
Variety on a chip
Though GeneChips and other oligonucleotide chips are the
most commonly used type of biochip at present, a variety of
other molecules are used on biochips. In the case of DNA
chips, not only oligonucleotides and genes, but also RNA,
cDNA and even whole chromosomes can be used. Depending
on the problem to be addressed and the solution to be examined, chips can be either individually chosen or specially made.
One-off products are considerably more expensive than more
or less standard products.

In addition, many attempts are being made at present to produce protein chips with a performance similar to that of DNA
chips. As compared with Competing techniques: design and function of DNA chips
DNA, proteins are vastly
more difficult to produce in The tasks performed using DNA chips are many and varied, and the
the required quantities and design of such chips is correspondingly diverse. Affymetrixs Ge
at constant quality. Protein neChip is a commonly used DNA chip, however various other
chips are therefore still very other manufacturers are offering a variety of techniques aimed at
winning over customers. Points of difference include not just chip
expensive. Attachment to design, but also the way in which the experiments are performed
the chip is also problematic and the way in which the results are analysed.
in that many proteins need - Probe material: The most commonly used DNA chips use short
oligonucleotide chains as probes, however RNA, cDNA, genes
a great deal of freedom of
and even whole chromosomes can be attached to chips.
movement in order to func- Manufacture: DNA can be attached to chips in various ways.
tion correctly. In addition,
These include photolithography, a technique borrowed from
assessment of the diverse
the computer chip industry. Other techniques include applicainteractions that can occur
tion by pipette, dropping and electronic methods, e.g. in a
manner similar to the operation of an inkjet printer.
between proteins and other
Target molecules: The probe and target molecules are dependsubstances is difficult and
ent on each other. Depending on what type of target molecule
time-consuming.
Given,
is present on it, a chip may be suitable for the study of other
however, that proteins octypes of DNA, such as oligonucleotides, RNA, cDNA, genes,
cupy a central place in drug
chromosomes or whole genomes.
research, protein chips are - Reaction: Hybridisation is not the only reaction that can occur
on a DNA chip. DNA molecules can also be bound by ligases
regarded as an important
or via chemical or photochemical reactions. Another possibility
tool, especially in prois to combine PCR (polymerase chain reaction) with a chip.
teomics.
- Detection: Different reactions on the chip require different
Growing number of applications
-

methods of detection, and hybridisation can be detected in

various ways. In addition to fluorescence, mass spectrometry,
in particular, and also conductivity and electronic methods, can
be used for detection.
Analysis: DNA chip experiments generate enormous quantities
of data that would be impossible to evaluate without computer
assistance. Of importance in this regard are not just suitably
sophisticated programs, but also automatic control of experiments, image analysis, databases, Internet links and platforms
and visualisation of results.

DNA chips have also found

broad application in drug
development. In fact, medicine is currently one of the
most important and exciting, though by no means
the only, field of application of these tiny chips. Many different variants of them are
used in almost all branches of biological science. Their outstanding feature in almost all these applications is their ability
to analyse genes rapidly and simply. The enormous quantities
of data collected in the Human Genome Project and similar undertakings form the basis for the evaluation of DNA chip experiments. When only small amounts of the DNA (or RNA) of
interest are available, it is generally still necessary to amplify
the nucleic acids first by means of PCR. These two techniques
are therefore often used in conjunction.
Now routine: basic research in biology
The first field of application of DNA chips was in basic research in biology. In this, unlike many other, fields, use of

DNA has long been routine. Since in this field the chips are often used to address new questions, basic research also leads to
the development of new techniques and opens up new fields of
application.
Among other uses in basic research, DNA chips have been and
are used to map genomes, to find genes and control elements
and to search the genomes of different organisms for points in
common. Now, however, their role has been extended far beyond these uses: now that the sequence of the human genome
is known, they are being used to investigate the tasks and functions of genes.
An important instrument for such investigations is gene expression analysis. In this, attention is focused not on the gene itself,
but on the working copies of a gene that are produced in a
given type of cell. These molecules, which are known as messenger RNA (mRNA), act as intermediaries between the genome and the life processes of the cell. Their primary role is as
blueprints for the synthesis of proteins. DNA chips now permit
rapid and simple generation of gene expression profiles in
which the activity of thousands of genes is determined simultaneously. This method, which is known as MEP (microarraybased expression profiling), can be used to answer important
questions such as: Which genes are expressed in which cells?
When and under what conditions does gene expression occur?
Which genes are active in diseases? And how is gene expression affected by administration of medicines?
The results of such experiments provide important insights into
the molecular processes that take place within cells. They also
provide evidence of the role of certain genes in the genesis,
progression and treatment of diseases. Medicine thus becomes
a new field of application of DNA chips.
A time of upheaval: DNA chips in medicine
DNA chips long ago became a standard tool for use in research
into diseases, especially as they permit analysis of almost complete genomes in a single experiment. Basic research and applied science often overlap to some extent here, however applications of DNA chips, and in particular gene expression analysis, are becoming increasingly important in all other areas of
medicine, e.g.:
- Genetic causes of disease. Our genome plays at least a contributory role in the genesis of the great majority of diseases. Discovering which genes play a role in which diseases and how genes interact in diseases requires detailed
observation of many DNA segments simultaneously a
task for which DNA chips are well suited.
- Hereditary diseases and genetic predisposition. Where disease-relevant genes are known, DNA chips can make it
possible to test patients for genetic susceptibility to the disease concerned. In complex diseases such as cancer and

Alzheimers disease a number of genes and environmental

factors are generally involved. DNA chips can help determine a persons individual risk so that, for example, people
who are genetically predisposed to myocardial infarction
can avoid additional risk factors such as smoking, an unbalanced diet and lack of exercise.
Diagnosis. The causes of diseases can also be determined
reliably with the aid of DNA chips. For example, different
causes can often bring about the same signs and symptoms,
and if these causes are genetic in nature they can be distinguished by means of DNA chips. This is exemplified by
various types of cancer which, though also subject to external influences, almost always result from genetic defects.
Knowledge of what genetic alteration is present in a patient
can have a crucial influence on what treatment is required.
Another example of the use of DNA chips for diagnostic
purposes is in infectious diseases. Here they can be used to
identify pathogens. Examples of both these diagnostic applications of DNA chips are given below.
Therapy. Our genetic predisposition has considerable influence on the efficacy and tolerability of medicines. This is
due mostly to small differences in our genome known as
single nucleotide polymorphisms, or SNPs. DNA chips
can be used to detect these differences rapidly and reliably,
and in this way can provide doctors with crucial information to assist them in choosing the most appropriate treatment for a particular patient. Also, it is only with the aid of
such techniques that novel medicines that take account of
individual differences in the way our body reacts to drugs
can be developed. DNA chips are therefore set to play a
major role in the development of individualised medicine.

Checking up on green gene technology

DNA chips also have potential for use in consumer protection.
An example of this is in the field of green gene technology,
i.e. the use of gene technology in agriculture. The fact that in
most industrialised countries a proportion of the population
takes a sceptical view of this technology has led to the introduction of a variety of regulations including compulsory labelling. Given, however, that the vast majority of foods produced
in this way do not differ visibly from conventional products, it
is often only by means of an examination of the genome of the
plant concerned that adherence to such regulations can be effectively checked. DNA chips are well suited for use in such
tests.
Chip instead of a magnifying glass: ecology and taxonomy
Ecology is a broad field of application for DNA chips. For example, it is often necessary to distinguish between fairly

closely related animal species in a body of water in order to assess the condition of the ecosystem concerned. This is because
the presence of one species may indicate a clean, but that of the
other a polluted, environment. Up to now, this task has often
required painstaking and detailed work with a magnifying glass
or even a microscope, since many species are scarcely distinguishable from their close relatives on the basis of their appearance to the naked eye. DNA chips can make such distinctions more rapidly, more simply and above all more reliably.
This ability creates applications for DNA chips in all situations
in which closely related species need to be studied. These include ecology, taxonomy, anthropology and research into evolution.
Sure identification: forensic medicine
DNA chips could also have a bright future in forensic medicine. Prominent in this field of application is the ability of
DNA chips to detect differences between individual genomes
and thereby to identify people. This can be required for identification of victims and already plays a crucial role in the search
for and conviction of criminals. Many countries, e.g. the Netherlands, also allow their police to use the genetic profile of
people they are seeking in order to draw conclusions as to the
external appearance of the person concerned. So far this applies
mostly to determination of sex, however the discovery of more
genes could make it possible also to determine a persons hair
colour, eye colour and ethnic origin. Though at present such forensic tests are performed almost exclusively using PCR methods, DNA chips can play a useful complementary role in many
such tasks and in future may be able to perform such tasks
more rapidly and simply than PCR, thereby supplanting it in
this application.
Focus on medical applications
Examples now exist of all these fields of application of DNA
chips. In most cases commercial products are already available,
though in some applications DNA chips are still in the developmental phase. As mentioned above, most interest is focused
on basic research in biology and on medical research and drug
development. In the latter field, use of DNA chips could initiate a change of direction towards a more individualised medicine that exploits the small but significant genetic differences
that exist between people in order to develop new, more effective and safer drugs, especially for specific subpopulations.
DNA chips that provide high resolution at a low price form the
basis for the kind of rapid and simple genetic test that is essential for individualised medicine. They are thus important not
just for finding genes responsible for diseases, but also for the
development of new drugs, for correct diagnosis and for the

choice of the most appropriate treatment for the individual patient.

Another medical application of DNA chips is their use in infectious diseases. In this application attention is focused not just
on the genes of the patient, but more specifically on those of
the pathogens. Many viruses (e.g. HIV), in particular, along
with various other kinds of pathogen, develop resistance to important drugs extraordinarily rapidly via mutations in their genome. DNA chips can be used to examine the genome of such
pathogens rapidly and reliably so that treatment that is optimal
for the individual patient can be chosen.
Leading the way in medicine: DNA chips in AIDS
One of the earliest examples of the use of DNA chips in medicine is in the treatment of AIDS. Human immunodeficiency virus (HIV), the pathogen of this disease, has an extraordinary
ability to undergo change. Each of the small number of components of the virus can change so radically from one generation to the next that drugs rapidly become quite ineffective
against the virus. In order to keep the virus in check despite
this drug resistance, infected people have to take combinations
of various drugs. For a long time the only way of finding out
which variant of the virus was present and therefore which
drugs would be effective in a given patient was by trial and
error.
The year 1996 saw the introduction of a DNA chip-based test
by means of which the variants of a certain HIV gene present
in an individual could be detected and drug resistances could
accordingly be predicted. The intention was to make it possible
for doctors to prescribe drugs which they knew to be effective
against the HIV variant present in the individual patient,
thereby avoiding a lengthy period of trial and error. As it
turned out, this chip did not find a place in medical practice,
and in fact sequencing by means of PCR has now become the
most important method used for this kind of molecular diagnosis. Nevertheless, in the past few years more chips have been
developed to support AIDS therapy. These are designed to examine as many as possible of the important regions of the viral
genome and thus to make the test applicable to other categories
of drug. In future they could play at least an important complementary role to PCR in this application.
DNA chips designed to identify viruses are also being developed for other infectious diseases. An example is the hepatitis
C virus, which occurs in at least six different variants, each of
which requires a different form of treatment. DNA chips could
here again, along with PCR become the most important
means of distinguishing between these variants. A more recent
development is a DNA chip to detect human papillomavirus
(HPV). The two dozen variants of this virus cause genital
warts, which are generally similar to the more familiar com-

mon wart and are similarly harmless. Nevertheless, three of the

twenty or more variants of HPV can cause cervical cancer in
women. Precise identification of the particular variant present
in affected women is therefore of great importance. Up to now
the condition of the neck of the Policing life and death: p53
womb has been assessed by
means of a diagnostic smear so The tumour suppressor gene p53 is one of the most important genes
that any altered tissue can be involved in the development of cancer. Its gene product (P53, writremoved. In extreme cases the ten with a capital P) plays a central role in the growth and division
entire uterus needs to be re- of somatic cells. It is active especially when genetic damage is
in the cell, but it can also be activated by external signals. It
moved. A DNA chip now present
is known to have at least three functions:
makes it possible to identify
of the cell cycle. Cells divide in a regular pattern of
papillomavirus present in the 1. Control
events known as the cell cycle. If the genetic material of a cell
patients blood and thus to esis damaged, P53 holds the cycle in the G1 phase a sort of
timate the risk of cancer more
resting phase in order to permit repair of the DNA. The signal for this is transmitted via a number of proteins including
precisely. Women at high risk
P21.
can thus adjust their family
2. Apoptosis. If the damage to a cells DNA is too great, P53
planning to their increased risk.
induces the cell to commit suicide. This process, known as
Important application: cancer
diagnosis

apoptosis, stops occurring in cancer cells, with the result that

they replicate in an uncontrolled fashion. P53 appears to be
able to initiate apoptosis in various ways, including induction
of the bax gene.
DNA repair. There is considerable evidence that P53 not only
allows the cell time to repair its DNA, but also plays an active
role in this process. Here again, it acts indirectly via p21 and
other genes, however certain properties of P53 suggest that it
also plays a direct role in the repair process.

The ability of DNA chips to 3.

detect all the variants of a
number of genes simultaneously could make them an important instrument for the in- Because of its central role in the control of cell growth and division,
vestigation, diagnosis and p53 is an important target for cancer therapies. Attempts have been
treatment of cancer. The first made, for example, to restore the function of altered P53 and to
synthesis of this protein.
products designed for use in stimulate
The latter objective can be achieved, for example, via the mdm2
this field have already been gene, which together with p53 participates in an autoregulatory
used successfully, and a large loop: P53 stimulates formation of Mdm2, which in turn inhibits
number of new chips are now P53. In healthy cells this cycle stops excessive amounts of P53
in the developmental phase. It from preventing normal division of cells. If the function of p53 is
but not abolished, by genetic changes, drugs that act
is becoming increasingly clear impaired,
against Mdm2 may be useful, since in such cases more P53 is rethat use of DNA chips could quired in order to keep cells under control.
greatly improve the survival The decision as to whether such a drug will be useful therefore
chances of patients with many depends on the genetic profile of the patient concerned. Techniques
types of cancer, since it permits that can identify each of the variants of p53 and of its genetic envimore precise adaptation of ronment are therefore an important precondition for specific, rap
treatment to factors influencing idly-acting and effective therapy. The p53 GeneChip offers this
On this chip are several thousand short DNA segments
the disease in the individual pa- possibility.
with which the p53 gene variants can be identified. The illustration
tient. However, successful use below shows the fluorescence pattern that results from such a test.
in this application presupposes
the availability of more specific
treatment options.
When a tumour arises, the body increasingly loses control over
the ability of the affected cells to undergo cell division. The
cells change, the affected tissue starts to grow in an uncontrolled way and measures taken by the body to check the
growth of the cells become less and less effective. Ultimately

the cancer cells break away from their tissue of origin to form
metastases, i.e. secondary growths in other parts of the body.
For the process to advance to this stage, a whole series of control mechanisms have to be switched off, and this occurs
mostly via changes in certain genes. Almost a hundred such
oncogenes are now known and new ones are still being discovered. The products of these genes generally occupy important positions in signalling pathways that regulate cell growth
and division. Just as important a role, however, is played by
genes with the opposite effect, i.e. genes whose function is to
limit cell proliferation. Malfunction or complete loss of such
tumour suppressor genes opens the way to the development
of cancer.
The forces of law and order in cells
The most important tumour suppressor is the protein P53. This
molecule polices the growth of cells and can even force cells to
commit suicide if their genetic material is too severely damaged (see box). The importance of this protein for cancer therapy is apparent from the fact that its function is disturbed in
more than half of all human cancers. A whole series of drugs
work by attempting to restore correct functioning of this tumour suppressor. Depending on the reason why P53 is no
longer functioning correctly, different drugs may be required.
Therefore, if the best treatment for a patient is to be found
quickly, the genetic variants present in that patient must be ascertained. And that task can be made easier with the aid of a
specially designed DNA chip.
Chips designed to detect many other oncogenes and tumour
suppressor genes are being developed at present, and some are
already on the market. The aim of all such developments is to
draw a genetic profile of the patient so as to assist doctors in
the task of deciding which form of treatment is likely to be of
benefit, and which not, in that particular patient. And this applies not just to the choice of the right drug: since in many
cases there is no sure means of determining how dangerous a
particular ulcer is, many unnecessary operations are performed,
while conversely many ulcers adjudged to be harmless are later
found to be malignant. In these situations DNA chips can considerably increase the accuracy of diagnosis.
Use in preventive medicine
In fact, DNA chips can help not just when an ulcer has already
been found. Cancer arises mostly as a result of an accumulation
over decades of mutations that occur either randomly or as a
result of radiation or toxins. Nevertheless, the likelihood of developing a certain type of cancer differs between individuals
even between individuals whose lifestyle and environmental
circumstances are identical because each individual has in-

herited a certain pattern of genetic changes. Knowledge of this

genetic predisposition can therefore be very important: people
who have inherited an increased risk of developing skin cancer,
for example, should be more rigorous than others about avoiding exposure to sunlight and should undergo regular medical
checkups. In future it will probably be possible to test for many
such predispositions using DNA chips. Disease prevention is
thus another potential application of this technology.
First pharmacogenomic product: the P450 chip
From the discipline of pharmacogenomics comes another current example of successful use of a DNA chip. This area of research is concerned with the interactions between our genes
and drugs. It is based above all on the observation that the effectiveness of drugs varies greatly and that in some individuals
drugs have dangerous side effects. Most such differences in reaction to drugs are at least partially due to differences in our
genes. If the genetic causes of such differences can be ascertained, treatment can be adjusted accordingly. It may even be
possible to develop special drugs for people with certain genetic characteristics. Such drugs would be expected to act more
specifically and thus be safer and more effective.
Cytochrome P450, for example, is important for the efficacy
and tolerability of many drugs. This is a family of enzymes
whose task it is to render water-insoluble substances including many drugs water-soluble. Above all, molecules are prepared for excretion from the body in this way (see also separate
article on pharmacogenomics). As the function of cytochrome
P450 enzymes varies from person to person, drugs are broken
down more rapidly in some individuals than in others and their
action in the body varies accordingly.
At least 50 separate genes and
New diagnostic tool: the P450 chip
hundreds of gene variants are
now known to code for this family of enzymes, and recently it
has become possible to test for
the most important variants of
two important members of this
group of genes by means of a
DNA chip. The AmpliChip
CYP450, which was developed
jointly by the healthcare comThe AmpliChip CYP450 arrived on the
pany Roche and Affymetrix,
market in 2003. The scientific basis of this
manufacturer of the GeneChip,
chip is formed by pharmacogenomic data on
is one of the first medical prodthe influence of the cytochrome P450 gene
ucts developed on the basis of
family on the efficacy and tolerability of
drugs. The AmpliChip CYP450 is able to
pharmacogenomic knowledge to
identify the most important variants of two
become commercially available.
important members of this group of genes.
The basis for the development of
this product is knowledge of the

influence of cytochrome P450 on the metabolism of drugs.

Among other potential applications, it is planned to use this
DNA chip to select suitable patients for the early phases of
drug development. The chip also has a potential role in relation
to drugs that are already on the market, since it can be used, for
example, to determine which drug works best in which patient
and at what dose.
Outlook: use of DNA chips for diagnosis
As in the case of their use in relation to cytochrome P450,
DNA chips will in future find uses in many areas of diagnosis
namely wherever genes play a role in the genesis or development of a disease. Four such areas can be identified:
- the metabolism i.e. the absorption, conversion and breakdown of drugs; the genes of the cytochrome P450 family
of enzymes fall into this category;
- the action of different genotypes in cancer, i.e. the genetic
changes that play a role in cancer; the variants of p53 fall
into this category;
- a group of genes that play a role in the reaction of the body
to infection;
- genes that influence individual susceptibility to pathogens;
the extremely rare cases in which a gene variant can prevent HIV infection are a well known example of this.
In all these areas DNA chips can permit precise diagnosis of
the genetic basis of a disease. With increasing knowledge of
the genes concerned and of the molecular basis of disease, such
chips will in future contribute to earlier detection, more effective treatment and possibly even prevention of diseases.
Before this prospect can become reality, however, a number of
obstacles have to be overcome. For one thing, the vast majority
of presently available DNA chip-based tests are too expensive
for routine use. Also, the potential for individual further development of the method, for example in public or private research institutes, is severely limited by patents. Furthermore,
the method still suffers from technical difficulties such as the
question of whether the RNA used as a marker is measurable
with a sufficient degree of accuracy in blood, the test liquid
that has generally been employed to date. This is a precondition for what appears at present to be the most promising medical application of DNA chips, namely gene expression analysis.
It is nevertheless to be expected that in the next few years DNA
chips will assume an important role in general, and especially
in medicine. In particular, the possibility they offer of testing a
patients genome for specific characteristics forms an important basis for individualised medicine.

Works consulted and literature for further reading:

Erlich, Henry: Diagnostic applications of genomics. Talk given
at Roche R&D Media Day, Munich/Penzberg, April 2002
Certa, Ulrich et al.: Biosensors in biomedical research: development and applications of gene chips. Chimia 53 (1999) 5761
F. Hoffmann-La Roche Ltd: Gene chips reveal HIV mutants,
cancer factors, and memory processes. Roche Facets, 2000
Sinclair, Bob: Everythings great when it sits on a chip. The
Scientist 13[11]:18, 1999
Baron, Diethard: Genomics und Proteomics mit Gen-Chips und
Protein-Arrays. Pharmazeutische Zeitung 31/2001
DNA Microarray Website of Leming, Shi:
http://www.gene-chips.com/
Affymetrix Website: http://www.affymetrix.com
InformationsSekretariat Biotechnologie Website: Genexpressionsanalyse
http://www.i-s-b.org/wissen/broschuere/chip.htm
Bioweb.ch Website: DNA-Chips vereinfachen Genomanalyse. 1999. http://www.bioweb.ch/de/dossiers/03/04