An introduction to

biotechnology

Pioneering science delivers vital medicines

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 field of biotechnology, delivering
treatments based on advances in cellular and molecular biology. And Amgen therapies have helped millions of people
worldwide to fight cancer, kidney disease, bone disease, rheumatoid arthritis, and other serious illnesses.

What is biotechnology?
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 field
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.

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 modified 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 first
companies to realize the new fields 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 molecular structure of DNAthe double helix

Illustration is copyrighted material of BioTech Primer, Inc., and is
reproduced herein with its permission.

The science of biotechnology

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.

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 specific,
three-dimensional structure. That structure in turn determines
how a protein functions and what other molecules it impacts.
Common types of proteins are:

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 specific protein.

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.

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

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.

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 specific
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.

Genetic engineering tools

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 specific restriction enzymes that researchers use like scissors to snip specific 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.

How does genetic engineering work?

Genetic engineering is the cornerstone of modern
biotechnology. It is based on scientific 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 modified blueprint and their own cellular machinery to
make the protein encoded by the recombinant DNA. Cells
that have recombinant DNA are known as genetically
modified or transgenic cells.
G
 enetic 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 specific 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.
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How are biotechnology medicines

discovered and developed?
The first step in treating any disease is to clarify how the

disease process. Once the picture starts to emerge, it can still

Scientists estimate there are about 8,000 therapeutic targets

disease is caused. Many questions must be answered to

take years to learn which of the changes linked to a disease

that might provide a basis for new medicines. Most are

arrive at an understanding of what is needed to pursue new

are most important. Is the change the result of the disease, or

proteins of various types, including enzymes, growth factors,

types of treatments.

is the disease the result of the change? By determining which

cell receptors, and cell-signaling molecules. Some targets

molecular defects are really behind a disease, scientists can

are present in excess during disease, so the goal is to block

How does a person get the disease?

identify the best targets for new medicines. In some cases,

their activity. This can be done by a medicine that binds to

Which cells are affected?

the best target for the disease may already be addressed

the target to prevent it from interacting with other molecules

Is the disease caused by genetic factors? If so, what

by an existing medicine, and the aim would be to develop a

in the body. In other cases, the target protein is deficient or

genes are turned on or off in the diseased cells?

new drug that offers other advantages. Often, though, drug

missing, and the goal is to enhance or replace it in order to

discovery aims to provide an entirely new type of therapy by

restore healthy function. Biotechnology has made it possible

pursuing a novel target.

to create therapies that are similar or identical to the complex

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?

The term target refers to the specific molecule in the body

The amazing complexity of human biology makes it a

In modern labs, sophisticated tools are used for shedding

that a medicine is designed to affect. For example, antibiotics

challenge to choose good targets. It can take many years

light on these questions. The tools are designed to uncover the

target specific proteins that are not found in humans but are

of research and clinical trials to learn that a new target

molecular roots of disease and pinpoint critical differences

critical to the survival of bacteria. Many cholesterol drugs

wont provide the desired results. To reduce that risk,

between healthy cells and diseased cells. Researchers often

target enzymes that the body uses to make cholesterol.

scientists try to prove the value of targets through research

use multiple approaches to create a detailed picture of the

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molecules the body relies on to remain healthy.

Selecting a target

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 scientific 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.

experiments that show the targets role in the disease

transgenic mice to the target so as to induce their immune

process. The goal is to show that the activity of the target

systems to make antibodies to that protein. The cells that

is driving the course of the disease.

produce these specific antibodies are then extracted and

manipulated to create a new cell line. The mice used in this

Selecting a drug

process are genetically modified to make human antibodies,

Once the target has been set, the next step is to identify a drug

which reduces the risk of allergic reactions in patients.

that impacts the target in the desired way. If researchers decide

to use a chemical compound, a technology called drug screening

Developing the drug

is typically used. With automated systems, scientists can rapidly

Once a promising test drug has been identified, it must go

test thousands of compounds to see which ones interfere with the

through extensive testing before it can be studied in humans.

targets activity. Potent compounds can be put through added tests

Many drug safety studies are performed using cell lines

to find a lead compound with the best potential to become a drug.

engineered to express the genes that are often responsible

for side effects. Cell line models have decreased the number

In contrast, biologics are designed using genetic engineering. If

of animals needed for testing and have helped accelerate the

the goal is to provide a missing or deficient protein, the gene for

drug development process. Some animal tests are still required

that protein is used for making a recombinant version of the

to ensure that the drug doesnt interfere with the complex

protein to give to patients. If the goal is to block the target

biological functions that are found only in higher life-forms.

protein with an antibody, one common approach is to expose

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If a test drug has no serious safety issues in preclinical studies,

A company can continue doing clinical trials on an approved

researchers can ask for regulatory permission to do clinical

medicine to see if it works under other specific conditions

trials in humans. There are three phases of clinical research,

or in other groups of patients, and additional trials may also

and a drug must meet success criteria at each phase before

be required by regulatory agencies. These are known as

moving on to the next one.

phase 4 studies.

Phase 1. Tests in 20 to 80 healthy volunteers and, sometimes,

The whole drug development process takes 10 to 15 years

patients. The main goals are to assess safety and tolerability

to complete on average. Very few test drugs are able to clear

and explore how the drug behaves in the body (how long it

all the hurdles along the way.

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.

The right tool for the target

If the test drug shows clear benefits and acceptable risks

A key early decision in drug discovery is whether to pursue a target by using a small-molecule chemical compound or a

in phase 3, the company can file an application requesting

large-molecule biologic. Each has its advantages and disadvantages.

regulatory approval to market the drug. In the United States,

the Food and Drug Administration evaluates new medicines.

Small molecules can be designed to cross cell membranes and enter cells, so they can be used for targets inside cells.

In the European Union, the European Medicines Agency

Some may also cross the blood-brain barrier to treat psychiatric illness and other brain diseases. Biologics usually cannot

manages that responsibility. Regulators review data from

cross cell membranes or enter the brain. Their use is largely restricted to targets that sit on the cell surface or circulate

all studies and decide whether the medicines benefits

outside the cell.

outweigh any risks it may have. If the medicine is approved,

regulators may still require a plan to reduce any risk to patients.

Small molecules often have good specificity for their targets, but therapeutic antibodies tend to have extremely high

A plan to monitor side effects in patients is also required.

specificity. Most large molecules stay in the body longer, resulting in the need for less frequent dosing.

How are biotechnology medicines made?

The manufacture of biologics is a highly demanding process.

containing a liquid broth with the nutrients that cells require for

Protein-based therapies have structures that are far larger, more

growth. During the scale-up process, the cells are sequentially

complex, and more variable than the structure of drugs based on

transferred to larger and larger vessels, called bioreactors. Some

chemical compounds. Plus, protein-based drugs are made using

bioreactor tanks used in manufacturing hold 20,000 liters of cells

intricate living systems that require very precise conditions in order

and growth media.

to make consistent products. The manufacturing process consists

of the following four main steps:

At every step of this process, it is crucial to maintain the specific

environment that cells need in order to thrive. Even subtle changes

1. Producing the master cell line containing the gene that makes
the desired protein

can affect the cells and alter the proteins they produce. For
that reason, strict controls are needed to ensure the quality and

2. Growing large numbers of cells that produce the protein

consistency of the final product. Scientists carefully monitor such

3. Isolating and purifying the protein

variables as temperature, pH, nutrient concentration, and oxygen

4. Preparing the biologic for use by patients

levels. They also run frequent tests to guard against contamination

from bacteria, yeast, and other microorganisms.

Some biologics can be made using common bacteria, such as E coli.

Others require cell lines taken from mammals, such as hamsters.

When the growth process is done, the desired protein is isolated

This is because many proteins have structural features that only

from the cells and the growth media. Various filtering technologies

mammalian cells can create. For example, certain proteins have

are used to isolate and purify the proteins based on their size,

sugar molecules attached to them, and they dont function properly

molecular weight, and electrical charge. The purified protein is

if those sugar molecules are not present in the correct pattern.

typically mixed with a sterile solution that can be injected or infused.

The final steps are to fill vials or syringes with individual doses of

Maintaining the right growth environment

the finished drug and to label the vials or syringes, package them,

The manufacturing process begins with cell culture, or cells grown

and make them available to physicians and patients.

in the laboratory. Cells are initially placed in petri dishes or flasks

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What does the future of biotechnology therapies look like?

Biotechnology is still a relatively new field with great potential for driving medical progress.

routinely collected so that researchers can determine whether different responses to a test medicine

Much of that progress is likely to result from advances in personalized medicine. This new

might be explained by genetic factors. The data is kept anonymous to protect patients privacy.

treatment paradigm aims to ensure that patients get the therapies best suited to their specific
conditions, genetic makeups, and other health characteristics.

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

For example, a new discipline called pharmacogenomics seeks to determine how a patients

predict the likelihood that a patient will develop a disease. Early diagnosis is often the key to

genetic profile affects his/her responses to particular medicines. The goal is to develop tests

either preventing disease or slowing disease progress through early treatment.

that will predict which patient genetic profiles are mostly likely to benefit from a given medicine.
This model is sometimes called personalized medicine.

Advances in DNA technology are the keys to pharmacogenomics and personalized medicine.
These developments promise to result in more effective, individualized healthcare and advances

Pharmacogenomics has already changed the way clinical trials are conducted: Genetic data is
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in preventive medicine.

Emerging treatments
Gene therapy involves inserting genes into the cells of patients to replace defective genes with
new, functional genes. The field is still in its experimental stages but has grown greatly since the first
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.

Looking ahead
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 significant unmet needs, future innovations in
biotechnology research will bring exciting new advances to help millions
more people worldwide.

Amgen Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320-1799
www.amgen.com

Visit the biotechnology website at www.biotechnology.amgen.com