An introduction to

biotechnology
Since Amgens founding in 1980, the companys focus has been on discovering, developing, and delivering novel
medicines for patients with serious illnesses. Amgens scientists are pioneers in the eld of biotechnology, delivering
treatments based on advances in cellular and molecular biology. And Amgen therapies have helped millions of people
worldwide to ght cancer, kidney disease, bone disease, rheumatoid arthritis, and other serious illnesses.
Pioneering science delivers vital medicines
In 1919, Hungarian agricultural engineer Karl Ereky foresaw a time when biology could be used
for turning raw materials into useful products. He coined the term biotechnology to describe
that merging of biology and technology.
Erekys vision has now been realized by thousands of companies and research institutions. The
growing list of biotechnology products includes medicines, medical devices, and diagnostics,
as well as more-resilient crops, biofuels, biomaterials, and pollution controls. While the eld
of biotechnology is diverse, the focus of this guide is on biotechnology medicines.
How do biotechnology medicines differ from other medicines?
A medicine is a therapeutic substance used for treating, preventing, or curing disease. The
most familiar type of medicine is a chemical compound contained in a pill, tablet, or capsule.
Examples are aspirin and other pain relievers, antibiotics, antidepressants, and blood pressure
drugs. This type of medicine is also known as a small molecule because the active ingredient
has a chemical structure and a size that are small compared with large, complex molecules
like proteins. A medicine can be made by chemists in a lab. Most medicines of this type can
be taken by mouth in solid or liquid form.
What is biotechnology?
Biotechnology medicines, often referred to as biotech medicines, are large molecules that are
similar or identical to the proteins and other complex substances that the body relies on to stay
healthy. They are too large and too intricate to make using chemistry alone. Instead, they are made
using living factoriesmicrobes or cell linesthat are genetically modied to produce the desired
molecule. A biotech medicine must be injected or infused into the body in order to protect its
complex structure from being broken down by digestion if taken by mouth.
In general, any medicine made with or derived from living organisms is considered a biotech
therapy, or biologic. A few of these therapies, such as insulin and certain vaccines, have been in
use for many decades. Most biologics were developed after the advent of genetic engineering,
which gave rise to the modern biotechnology industry in the 1970s. Amgen was one of the rst
companies to realize the new elds promise and to deliver biologics to patients.
Like pharmaceuticals, biologics cannot be prescribed to patients until their use has been
approved by regulators. For example, in the United States, the Food and Drug Administration
evaluates new medicines. In the European Union, the European Medicines Agency manages
that responsibility.
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The science of biotechnology
How does the body
make a protein?
Protein production is a multistep process that
includes transcription and translation. During
transcription, the original DNA code for a specic
protein is rewritten onto a molecule called
messenger RNA (mRNA); mRNA has nucleotides
similar to those of DNA. Each successive
grouping of three nucleotides forms a codon,
or code, for one of 20 different amino acids,
which are the building blocks of proteins.
During translation, a cell structure called a
ribosome binds to a ribbon of mRNA. Other
molecules, called transfer RNAs, assemble
a chain of amino acids that matches the
sequence of codons in the mRNA. Short
chains of amino acids are called peptides.
Long chains, called polypeptides, form proteins.
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The molecular structure of DNAthe double helix
Chromosome
DNA
Gene
Biotechnology has been used in a rudimentary form since
ancient brewers began using yeast cultures to make beer. The
breakthrough that laid the groundwork for modern biotechnology
came when the structure of DNA was discovered in the early
1950s. To understand how this insight eventually led to biotech
therapies, its helpful to have a basic understanding of DNAs
central role in health and disease.
What does DNA do?
DNA is a very long and coiled molecule found in the nucleus,
or command center, of a cell. It provides the full blueprint for the
construction and operation of a life-form, be it a microbe, a bird,
or a human. The information in DNA is stored as a code made
up of four basic building blocks, called nucleotides. The order in
which the nucleotides appear is akin to the order of the letters
that spell words and form sentences and stories. In the case of
DNA, the order of nucleotides forms different genes. Each gene
contains the instructions for a specic protein.
With a few exceptions, every cell in an organism holds a complete
copy of that organisms DNA. The genes in the DNA of a particular
cell can be either active (turned on) or inactive (turned off)
depending on the cells function and needs. Once a gene is
activated, the information it holds is used for making, or
expressing, the protein for which it codes. Many diseases
result from genes that are improperly turned on or off.
What functions do proteins control?
The amino acids that form a protein interact with each other, and
those complex interactions give each protein its own specic,
three-dimensional structure. That structure in turn determines
how a protein functions and what other molecules it impacts.
Common types of proteins are:
Enzymes, which put molecules together or break them apart.
Signaling proteins, which relay messages between cells,
and receptors, which receive signals sent via proteins from
other cells.
Immune system proteins, such as antibodies, which defend
against disease and external threats.
Structural proteins, which give shape to cells and organs.
Given the tremendous variety of functions that proteins perform,
they are sometimes referred to as the workhorse molecules of
life. However, when key proteins are malfunctioning or missing,
the result is often disease of one type or another.
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Illustration is copyrighted material of BioTech Primer, Inc., and is
reproduced herein with its permission.
How does genetic engineering work?
Genetic engineering is the cornerstone of modern
biotechnology. It is based on scientic tools, developed
in recent decades, that enable researchers to:
Identify the gene that produces the protein of interest.
Cut the DNA sequence that contains the gene from
a sample of DNA.
Place the gene into a vector, such as a plasmid
or bacteriophage.
Use the vector to carry the gene into the DNA
of the host cells, such as Escherichia coli (E coli)
or mammalian cells grown in culture.
Induce the cells to activate the gene and produce
the desired protein.
Extract and purify the protein for therapeutic use.
When segments of DNA are cut and pasted together to form
new sequences, the result is known as recombinant DNA.
When recombinant DNA is inserted into cells, the cells use
this modied blueprint and their own cellular machinery to
make the protein encoded by the recombinant DNA. Cells
that have recombinant DNA are known as genetically
modied or transgenic cells.
Genetic engineering allows scientists to manufacture
molecules that are too complex to make with chemistry.
This has resulted in important new types of therapies,
such as therapeutic proteins. Therapeutic proteins
include those described below as well as ones that are
used to replace or augment a patients naturally occurring
proteins, especially when levels of the natural protein are
low or absent due to disease. They can be used for treating
such diseases as cancer, blood disorders, rheumatoid
arthritis, metabolic diseases, and diseases of the immune
system.
Monoclonal antibodies are a specic class of
therapeutic proteins designed to target foreign
invadersor cancer cellsby the immune system.
Therapeutic antibodies can target and inhibit proteins
and other molecules in the body that contribute to
disease.
Peptibodies are engineered proteins that have
attributes of both peptides and antibodies but that
are distinct from each.
Vaccines stimulate the immune system to provide
protection, mainly against viruses. Traditional vaccines
use weakened or killed viruses to prime the body
to attack the real virus. Biotechnology can create
recombinant vaccines based on viral genes.
These new modes of treatment give drug developers
more options in determining the best way to counteract a
disease. But biotech research and development (R&D), like
pharmaceutical R&D, is a long and demanding process with
many hurdles that must be cleared to achieve success.
To manipulate cells and DNA, scientists use tools that are borrowed from nature, including:
Restriction enzymes. These naturally occurring enzymes are used as a defense by bacteria to cut up DNA from viruses.
There are hundreds of specic restriction enzymes that researchers use like scissors to snip specic genes from DNA.
DNA ligase. This enzyme is used in nature to repair broken DNA. It can also be used to paste new genes into DNA.
Plasmids. These are circular units of DNA. They can be engineered to carry genes of interest.
Bacteriophages (also known as phages). These are viruses that infect bacteria. Bacteriophages can be engineered to
carry recombinant DNA.
Genetic engineering tools
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The first step in treating any disease is to clarify how the
disease is caused. Many questions must be answered to
arrive at an understanding of what is needed to pursue new
types of treatments.
How does a person get the disease?
Which cells are affected?
Is the disease caused by genetic factors? If so, what
genes are turned on or off in the diseased cells?
What proteins are present or absent in diseased cells
as compared with healthy cells?
If the disease is caused by an infection, how does the
infectious organism interact with the body?
In modern labs, sophisticated tools are used for shedding
light on these questions. The tools are designed to uncover the
molecular roots of disease and pinpoint critical differences
between healthy cells and diseased cells. Researchers often
use multiple approaches to create a detailed picture of the
disease process. Once the picture starts to emerge, it can still
take years to learn which of the changes linked to a disease
are most important. Is the change the result of the disease, or
is the disease the result of the change? By determining which
molecular defects are really behind a disease, scientists can
identify the best targets for new medicines. In some cases,
the best target for the disease may already be addressed
by an existing medicine, and the aim would be to develop a
new drug that offers other advantages. Often, though, drug
discovery aims to provide an entirely new type of therapy by
pursuing a novel target.
Selecting a target
The term target refers to the specic molecule in the body
that a medicine is designed to affect. For example, antibiotics
target specic proteins that are not found in humans but are
critical to the survival of bacteria. Many cholesterol drugs
target enzymes that the body uses to make cholesterol.
Scientists estimate there are about 8,000 therapeutic targets
that might provide a basis for new medicines. Most are
proteins of various types, including enzymes, growth factors,
cell receptors, and cell-signaling molecules. Some targets
are present in excess during disease, so the goal is to block
their activity. This can be done by a medicine that binds to
the target to prevent it from interacting with other molecules
in the body. In other cases, the target protein is decient or
missing, and the goal is to enhance or replace it in order to
restore healthy function. Biotechnology has made it possible
to create therapies that are similar or identical to the complex
molecules the body relies on to remain healthy.
The amazing complexity of human biology makes it a
challenge to choose good targets. It can take many years
of research and clinical trials to learn that a new target
wont provide the desired results. To reduce that risk,
scientists try to prove the value of targets through research

How are biotechnology medicines
discovered and developed?
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experiments that show the targets role in the disease
process. The goal is to show that the activity of the target
is driving the course of the disease.
Selecting a drug
Once the target has been set, the next step is to identify a drug
that impacts the target in the desired way. If researchers decide
to use a chemical compound, a technology called drug screening
is typically used. With automated systems, scientists can rapidly
test thousands of compounds to see which ones interfere with the
targets activity. Potent compounds can be put through added tests
to nd a lead compound with the best potential to become a drug.
In contrast, biologics are designed using genetic engineering. If
the goal is to provide a missing or decient protein, the gene for
that protein is used for making a recombinant version of the
protein to give to patients. If the goal is to block the target
protein with an antibody, one common approach is to expose
transgenic mice to the target so as to induce their immune
systems to make antibodies to that protein. The cells that
produce these specic antibodies are then extracted and
manipulated to create a new cell line. The mice used in this
process are genetically modied to make human antibodies,
which reduces the risk of allergic reactions in patients.
Developing the drug
Once a promising test drug has been identied, it must go
through extensive testing before it can be studied in humans.
Many drug safety studies are performed using cell lines
engineered to express the genes that are often responsible
for side effects. Cell line models have decreased the number
of animals needed for testing and have helped accelerate the
drug development process. Some animal tests are still required
to ensure that the drug doesnt interfere with the complex
biological functions that are found only in higher life-forms.

Models for studying disease
The following tools help researchers gain insights into how disease develops.
Cell cultures. By growing both diseased and healthy cells in cell cultures, researchers can study differences in cellular
processes and protein expression.
Cross-species studies. Genes and proteins found in humans may also be found in other species. The functions of many
human genes have been revealed by studying parallel genes in other organisms.
Bioinformatics. The scientic community generates huge volumes of biological data daily. Bioinformatics helps organize that
data to form a clearer picture of the activity of normal and diseased cells.
Biomarkers. These are substances, often proteins, that can be used for measuring a biological function, identifying a disease
process, or determining responses to a therapy. They also can be used for diagnosis, for prognosis, and for guiding treatment.
Proteomics. Proteomics is the study of protein activity within a given cell, tissue or organism. Changes in protein activity can
shed light on the disease process and the impact of medicines under study.
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If a test drug has no serious safety issues in preclinical studies,
researchers can ask for regulatory permission to do clinical
trials in humans. There are three phases of clinical research,
and a drug must meet success criteria at each phase before
moving on to the next one.
Phase 1. Tests in 20 to 80 healthy volunteers and, sometimes,
patients. The main goals are to assess safety and tolerability
and explore how the drug behaves in the body (how long it
stays in the body, how much of the drug reaches its target, etc.).
Phase 2. Studies in about 100 to 300 patients. The goals
are to evaluate whether the drug appears effective, to further
explore its safety, and to determine the best dose.
Phase 3. Large studies involving 500 to 5,000 or more
patients, depending on the disease and the study design.
Very large trials are often needed to determine whether
a drug can prevent bad health outcomes. The goal is to
compare the effectiveness, safety, and tolerability of the
test drug with another drug or a placebo.
If the test drug shows clear benets and acceptable risks
in phase 3, the company can le an application requesting
regulatory approval to market the drug. In the United States,
the Food and Drug Administration evaluates new medicines.
In the European Union, the European Medicines Agency
manages that responsibility. Regulators review data from
all studies and decide whether the medicines benefits
outweigh any risks it may have. If the medicine is approved,
regulators may still require a plan to reduce any risk to patients.
A plan to monitor side effects in patients is also required.
A company can continue doing clinical trials on an approved
medicine to see if it works under other specic conditions
or in other groups of patients, and additional trials may also
be required by regulatory agencies. These are known as
phase 4 studies.
The whole drug development process takes 10 to 15 years
to complete on average. Very few test drugs are able to clear
all the hurdles along the way.
A key early decision in drug discovery is whether to pursue a target by using a small-molecule chemical compound or a
large-molecule biologic. Each has its advantages and disadvantages.
Small molecules can be designed to cross cell membranes and enter cells, so they can be used for targets inside cells.
Some may also cross the blood-brain barrier to treat psychiatric illness and other brain diseases. Biologics usually cannot
cross cell membranes or enter the brain. Their use is largely restricted to targets that sit on the cell surface or circulate
outside the cell.
Small molecules often have good specicity for their targets, but therapeutic antibodies tend to have extremely high
specicity. Most large molecules stay in the body longer, resulting in the need for less frequent dosing.
The right tool for the target
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How are biotechnology medicines made?
The manufacture of biologics is a highly demanding process.
Protein-based therapies have structures that are far larger, more
complex, and more variable than the structure of drugs based on
chemical compounds. Plus, protein-based drugs are made using
intricate living systems that require very precise conditions in order
to make consistent products. The manufacturing process consists
of the following four main steps:
1. Producing the master cell line containing the gene that makes
the desired protein
2. Growing large numbers of cells that produce the protein
3. Isolating and purifying the protein
4. Preparing the biologic for use by patients
Some biologics can be made using common bacteria, such as E coli.
Others require cell lines taken from mammals, such as hamsters.
This is because many proteins have structural features that only
mammalian cells can create. For example, certain proteins have
sugar molecules attached to them, and they dont function properly
if those sugar molecules are not present in the correct pattern.
Maintaining the right growth environment
The manufacturing process begins with cell culture, or cells grown
in the laboratory. Cells are initially placed in petri dishes or asks
containing a liquid broth with the nutrients that cells require for
growth. During the scale-up process, the cells are sequentially
transferred to larger and larger vessels, called bioreactors. Some
bioreactor tanks used in manufacturing hold 20,000 liters of cells
and growth media.
At every step of this process, it is crucial to maintain the specic
environment that cells need in order to thrive. Even subtle changes
can affect the cells and alter the proteins they produce. For
that reason, strict controls are needed to ensure the quality and
consistency of the final product. Scientists carefully monitor such
variables as temperature, pH, nutrient concentration, and oxygen
levels. They also run frequent tests to guard against contamination
from bacteria, yeast, and other microorganisms.
When the growth process is done, the desired protein is isolated
from the cells and the growth media. Various ltering technologies
are used to isolate and purify the proteins based on their size,
molecular weight, and electrical charge. The puried protein is
typically mixed with a sterile solution that can be injected or infused.
The nal steps are to ll vials or syringes with individual doses of
the nished drug and to label the vials or syringes, package them,
and make them available to physicians and patients.
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Biotechnology is still a relatively new eld with great potential for driving medical progress.
Much of that progress is likely to result from advances in personalized medicine. This new
treatment paradigm aims to ensure that patients get the therapies best suited to their specic
conditions, genetic makeups, and other health characteristics.
For example, a new discipline called pharmacogenomics seeks to determine how a patients
genetic prole affects his/her responses to particular medicines. The goal is to develop tests
that will predict which patient genetic proles are mostly likely to benet from a given medicine.
This model is sometimes called personalized medicine.
Pharmacogenomics has already changed the way clinical trials are conducted: Genetic data is
routinely collected so that researchers can determine whether different responses to a test medicine
might be explained by genetic factors. The data is kept anonymous to protect patients privacy.
Biotechnology is also revolutionizing the diagnosis of diseases caused by genetic factors. New
tests can detect changes in the DNA sequence of genes associated with disease risk and can
predict the likelihood that a patient will develop a disease. Early diagnosis is often the key to
either preventing disease or slowing disease progress through early treatment.
Advances in DNA technology are the keys to pharmacogenomics and personalized medicine.
These developments promise to result in more effective, individualized healthcare and advances
in preventive medicine.
What does the future of biotechnology therapies look like?
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Emerging treatments
Gene therapy involves inserting genes into the cells of patients to replace defective genes with
new, functional genes. The eld is still in its experimental stages but has grown greatly since the rst
clinical trial in 1990.
Stem cells are unspecialized cells that can mature into different types of functional cells. Stem
cells can be grown in a lab and guided toward the desired cell type and then surgically implanted
into patients. The goal is to replace diseased tissue with new, healthy tissue.
Nanomedicine aims to manipulate molecules and structures on an atomic scale. One example is
the experimental use of nanoshells, or metallic lenses, which convert infrared light into heat energy
to destroy cancer cells.
New drug delivery systems include microscopic particles called microspheres with holes just
large enough to dispense drugs to their targets. Microsphere therapies are available and being
investigated for the treatment of various cancers and diseases.
The practice of medicine has changed dramatically over the years through
pioneering advances in biotechnology research and innovation; and millions
of patients worldwide continue to benefit from therapeutics developed
by companies that are discovering, developing, and delivering innovative
medicines to treat grievous illnesses. As companies continue to develop
medicines that address signicant unmet needs, future innovations in
biotechnology research will bring exciting new advances to help millions
more people worldwide.
Looking ahead
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Amgen Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320-1799
www.amgen.com
Visit the biotechnology website at www.biotechnology.amgen.com