An intro i ntroducti duction on to biotechnology
Pioneering science delivers vital medicines Since Amgen’s ounding in 1980, the company’s ocus has been on discovering, developing, and delivering novel medicines or patients with serious illnesses. Amgen’s scientists are pioneers in the eld o biotechnology, delivering treatments based on advances in cellular and molecular biology. And Amgen therapies have helped millions o people worldwide to ght cancer, kidney disease, bone disease, rheumatoid arthritis, and other serious illnesses.
What is biotechnology? In 1919, Hungarian agricultural engineer Karl Ereky oresaw a time when biology could be used
Biotechnology medicines, oten reerred to as biotech medicines, are large molecules that are
or turning raw materials into useul products. He coined the term biotechnology to describe
similar or identical to the proteins and other complex substances that the body relies on to stay
that merging o biology and technology.
healthy. They are too large and too intricate to make using chemistry alone. Instead, they are made using living actories—microbes or cell lines—that are genetically modied to produce the desired
Ereky’s vision has now been realized by thousands o companies and research institutions. The
molecule. A biotech medicine must be injected or inused i nto the body in order to protect its
growing list o biotechnology products includes medicines, medical devices, and diagnostics,
complex structure rom being broken down by digestion i taken by mouth.
as well as more-resilient crops, biouels, biomaterials, and pollution controls. While the eld o biotechnology is diverse, the ocus o this guide is on biotechnology medicines.
In general, any medicine made with or derived rom living organisms is considered a biotech therapy, or biologic. A ew o these therapies, such as insulin and certain vaccines, have been in
How do biotechnology medicines differ from other medicines?
use or many decades. Most biologics were developed ater the advent o genetic engineering,
A medicine i s a therapeutic substance used or treating, preventing, or curing disease. The
which gave rise to the modern biotechnology industry in the 1970s. Amgen was one o the rst
most amiliar type o medicine is a chemical compound contained in a pill, tablet, or capsule.
companies to realize the new eld’s promise and to deliver biologics to patients.
Examples are aspirin and other pain relievers, antibiotics, antidepressants, and blood pressure drugs. This type o medicine is also known as a small molecule because the active ingredient
Like pharmaceuticals, biologics cannot be prescribed to patients until their use has been
has a chemical structure and a size that are small compared with large, complex molecules
approved by regulators. For example, in the United States, the Food and Drug Administration
like proteins. A medicine can be made by chemists in a lab. Most medicines o this type can
evaluates new medicines. In the European Union, the European Medicines Agency manages
be taken by mouth in solid or liquid orm.
that responsibility.
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DNA The molecular structure of DNA—the double helix Illustration is copyrighted material o BioTech Primer, Inc., and is reproduced herein with its permission.
The science of biotech biotechnology nology
How does the body make a protein? Protein production is a multistep process that includes transcription and translation. During
Biotechnology has been used in a rudimentary orm since
activated, the inormation it holds is used or making, or
transcription, the original DNA code or a specic
ancient brewers began using yeast cultures to make beer. The
“expressing,” the protein or which it codes. Many diseases
protein is rewritten onto a molecule called
breakthrough that laid the groundwork or modern biotechnology
result rom genes that are improperly turned on or o.
messenger RNA (mRNA); mRNA has nucleotides similar to those o DNA. Each successive
came when the structure o DNA was discovered in the early 1950s. To understand how this insight eventually led to biotech
What functions do proteins control?
grouping o three nucleotides orms a codon,
therapies, it’s helpul to have a basic understanding o DNA’s
The amino acids that orm a protein interact with each other, and
or code, or one o 20 dierent amino acids,
central role in health and disease.
those complex interactions give each protein its own specic,
which are the building blocks o proteins.
three-dimensional structure. That structure in turn determines What does DNA do?
how a protein unctions and what other molecules it impacts.
During translation, a cell structure called a
DNA is a very long and coiled molecule ound in the nucleus,
Common types o proteins are:
ribosome binds to a ribbon o mRNA. Other molecules, called transer RNAs, assemble
or command center, o a cell. It provides the ull blueprint or the construction and operation o a lie-orm, be it a microbe, a bird,
• Enzymes, Enzymes,whichputmole whichputmoleculestoge culestogetherorbr therorbreakthemapa eakthemapart. rt.
a chain o amino acids that matches the
or a human. The inormation in DNA is stored as a code made
• Signalingproteins,whichrelaymessagesbetweencells,
sequence o codons in the mRNA. Short
up o our basic building blocks, called nucleotides. The order in
and receptors, which receive signals sent via proteins rom
chains o amino acids are called peptides.
which the nucleotides appear is akin to the order o the letters
other cells.
Long chains, called polypeptides, orm proteins.
that spell words and orm sentences and stories. In the case o DNA, the order o nucleotides orms dierent genes. Each gene
• Immunesystemproteins,suchasantibodies,whichdefend
against disease and external threats.
contains the instructions or a specic protein.
• Structural Structuralproteins, proteins,whichgives whichgiveshapetocells hapetocellsandorgan andorgans. s.
With a ew exceptions, every cell in an organism holds a complete
Given the tremendous variety o unctions that proteins perorm,
copy o that organism’s DNA. The genes in the DNA o a particular
they are sometimes reerred to as the workhorse molecules o
cell can be either active (turned on) or inactive (turned o)
lie. However, when key proteins are malunctioning or missing,
depending on the cell’s unction and needs. Once a gene is
the result is oten disease o one type or another.
Genetic engineering tools To manipulate cells and DNA, scientists use tools that are borrowed rom nature, including: Restriction enzymes. These naturally occurring enzymes are used as a deense by bacteria to cut up DNA rom viruses.
There are hundreds o specic restriction enzymes that researchers use like scissors to snip specic genes rom 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 o DNA. They can be engineered to carry genes o interest. Bacteriophages (also known as phages). These are viruses that inect bacteria. Bacteriophages can be engineered to
carry recombinant DNA.
How does genetic engineering work?
When recombinant DNA is inserted into cells, the cells use
invaders—or cance r cells—by the immune system.
Genetic engineering is the cornerstone o modern
this modied blueprint and their own cellular machinery to
Therapeutic antibodies can target and inhibit proteins
biotechnology. It is based on scientic tools, developed
make the protein encoded by the recombinant DNA. Cells
and other molecules in the body that contribute to
in recent decades, that enable researchers to:
that have recombinant DNA are known as genetically
disease.
modied or transgenic cells.
attributes o both peptides and antibodies but that
• Identifytheg Identifythegenethatpro enethatproducesthep ducestheproteinofinte roteinofinterest. rest. • CuttheDNAs CuttheDNAsequenceth equencethatcontainsth atcontainsthegenefrom egenefrom
a sample o DNA.
Peptibodies • P eptibodies are engineered proteins that have
• Geneticengineeringallowsscientiststomanufacture
molecules that are too complex to make with chemistry.
are distinct rom each. • Vaccines stimulate the immune system to provide
This has resulted in important new types o therapies,
protection, mainly against viruses. Traditional vaccines
such as therapeutic proteins. Therapeutic proteins
use weakened or killed viruses to prime the body
include those described below as well as ones that are
to attack the real virus. Biotechnology can create
o the host cells, such as Escherichia coli ( E coli )
used to replace or augment a patient’s naturally occurring
recombinant vaccines based on viral genes.
or mammalian cells grown in culture.
proteins, especially when levels o the natural protein are
• Placethegeneintoavector,suchasaplasmid
or bacteriophage. • Usetheve Usethevectortocarry ctortocarrythegenein thegeneintotheDNA totheDNA
• Inducethecellstoactivatethegeneandproduce
the desired protein. • Extractan Extractandpurifythe dpurifytheproteinforth proteinfortherapeutic erapeuticuse. use.
When segments o DNA are cut and pasted together to orm new sequences, the result is known as recombinant DNA.
low or absent due to disease. They can be used or treating
These new modes o treatment give drug developers
such diseases as cancer, blood disorders, rheumatoid
more options in determining the best way to counteract a
arthritis, metabolic diseases, and diseases o the immune
disease. But biotech research and development (R&D), like
system.
pharmaceutical R&D, is a long and demanding process with
• Monoclonal antibodies are a specic class o
many hurdles that must be cleared to achieve success.
therapeutic proteins designed to target oreign
How are biotec biotechnology hnology medicines discovered and developed? The irst step in treating any disease i s to clariy 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 o the changes linked to a disease
that might provide a basis or new medicines. Most are
arrive at an understanding o what is needed to pursue new
are most important. Is the change the result o the disease, or
proteins o various types, including enzymes, growth actors,
types o treatments.
isthediseasetheresultofthechange?Bydeterminingwhich
cell receptors, and cell-signaling molecules. Some targets
molecular deects are really behind a disease, scientists can
are present in excess during disease, so the goal is to block
• Howdoesa Howdoesapersonge persongetthediseas tthedisease? e?
identiy the best targets or new medicines. In some cases,
their activity. This can be done by a medicine that binds to
• Whichcells Whichcellsareaffected areaffected? ?
the best target or the disease may already be addressed
the target to prevent it rom interacting with other molecules
• Isthediseasecausedbygeneticfactors?Ifso,what
by an existing medicine, and the aim would be to develop a
in the body. In other cases, the target protein is decient or
genesareturnedonoroffinthediseasedcells?
new drug that oers other advantages. Oten, though, drug
missing, and the goal is to enhance or replace it in order to
discovery aims to provide an entirely new type o therapy by
restore healthy unction. Biotechnology has made it possible
pursuing a novel target.
to create therapies that are similar or identical to the complex
• Whatproteinsarepresentorabsentindiseasedcells ascomparedwithhealthycells?
molecules the body relies on to remain healthy.
• Ifthediseaseiscausedbyaninfection,howdoesthe infectiousorganisminteractwiththebody?
Selecting a target
The term target reers to the specic molecule in the body
The amazing complexity o human biology makes it a
In modern labs, sophisticated tools are used or shedding
that a medicine is designed to aect. 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 specic proteins that are not ound in humans but are
o research and clinical trials to l earn that a new target
molecular roots o disease and pinpoint critical dierences
critical to the survival o bacteria. Many cholesterol drugs
won’t provide the desired results. To To reduce that risk,
between healthy cells and diseased cells. Researchers oten
target enzymes that the body uses to make cholesterol.
scientists try to prove the value o targets through research
use multiple approaches to create a detailed picture o the
Models for studying disease The ollowing tools help researchers gain insights into how disease develops. Cell cultures. By growing both diseased and healthy cells in cell cultures, researchers can study dierences in cellular
processes and protein expression. Cross-species studies. Genes and proteins ound in humans may also be ound in other species. The unctions o many
human genes have been revealed by studying parallel genes in other organisms. Bioinformatics. The scientic community generates huge volumes volumes o biological data daily. Bioinormatics helps organize that
data to orm a clearer picture o the activity o normal and diseased cells. Biomarkers. These are substances, oten proteins, that can be used or measuring a biological unction, identiying a disease
process, or determining responses to a therapy. They also can be used or diagnosis, or prognosis, and or guiding treatment. Proteomics. Proteomics is the study o protein activity within a given cell, tissue or organism. Changes in protein activity can
shed light on the disease process and the impact o medicines under study.
experiments that show the target’s role in the disease
transgenic mice to the target so as to induce their immune
process. The goal is to show that the activity o the target
systems to make antibodies to that protein. The cells that
is driving the course o the disease.
produce these specic antibodies are then extracted and manipulated to create a new cell line. The mice used in this
Selecting a drug
process are genetically modied to make human antibodies,
Once the target has been set, the next step is to identiy a drug
which reduces the risk o allergic reactions in patients.
that impacts the target in the desired way. I 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 identied, it must go
test thousands o compounds to see which ones interere with the
through extensive testing beore it can be studied in humans.
target’s activity. activity. Potent compounds can be put through added tests
Many drug saety studies are perormed using cell lines
to nd a lead compound with the best potential to become a drug.
engineered to express the genes that are oten responsible or side eects. Cell Cell line models have decreased the number
In contrast, biologics are designed using genetic engineering. I
o animals needed or testing and have helped accelerate the
the goal is to provide a missing or decient protein, the gene or
drug development development process. Some animal tests are still required
that protein is used or making a recombinant version o the
to ensure that the drug doesn’t interere with the complex
protein to give to patients. I the goal is to block the target
biological unctions that are ound only in higher lie-orms.
protein with an antibody, one common approach is to expose
I a test drug has no serious saety issues in preclinical studies,
A company can c ontinue doing clinical tri als on an ap proved
researchers can ask or regulatory permission to do clinical
medicine to see i it works under other specic conditions
trials in humans. There are three phases o clinical research,
or in other groups o patients, and additional trials may also
and a drug must meet success criteria at each phase beore
be required by regulatory agencies. These are known as
moving on to the next one.
phase 4 studies.
Phase 1. Test Testss 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 saety and tolerability
to complete on average. Very ew 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 o the drug reaches its target, etc.). Phase 2. Studies in about 100 to 300 patients. The goals
are to evaluate whether the drug appears eective, to urther explore its saety, 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 oten needed to determine whether a drug can prevent bad health outcomes. The goal is to compare the eectiveness, saety, and tolerability o the test drug with another drug or a placebo.
The right tool for the target
I the test drug shows clear benets and acceptable risks
A key early decision in drug discovery is whether to pursue a target b y using a smal l-molecule chemic al compound or a
in phase 3, the company can le 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 or 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 rom
cross cell membranes or enter the brain. Their use is largely restricted to targets that sit on the cell surace or circulate
all studies and decide whether the medicine’s beneits
outside the cell.
outweigh any risks it may have. I the medicine is approved, regulators may still require a plan to reduce any risk to patients.
Small molecules oten have good specicity or their targets, but therapeutic antibodies tend to have extremely high
A plan to monitor side eects in patients patients is also required.
specicity. Most large molecules stay in the body longer, resulting in the need or less requent dosing.
How are biotech biotechnology nology medicines medicines made? The manuacture o biologics is a highly demanding process.
containing a liquid broth with the nutrients that cells require or
Protein-based therapies have structures that are ar larger, more
growth. During the scale-up process, the cells are sequentially
complex, and more variable than the structure o drugs based on
transerred to larger and larger vessels, called bioreactors. Some
chemical compounds. Plus, protein-based drugs are made using
bioreactor tanks used in manuacturing hold 20,000 liters o cells
intricate living systems that require very precise conditions in order
and growth media.
to make consistent products. The manuacturing process consists o the ollowing our main steps:
At every step o this process, i t is crucial to maintain the specic environment environm ent 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 aect the cells and alter the proteins they produce. produce. For that reason, strict controls are needed to ensure the quality and
2. Growing large numbers o cells that produce the protein
consistenc consi stencyy o the inal product. Scientists careully monitor such
3. Isolating and puriying the protein
variables as temperature, pH, nutrient concentration, and oxygen
4. Preparing the biologic or use by patients
levels. They also run requent tests to guard against contamination rom bacteria, yeast, and other microorganisms.
Some biologics can be made using common bacteria, such as E coli . Others require cell lines taken rom mammals, such as hamsters.
When the growth process is done, the desired protein is i solated
This is because many proteins have structural eatures that only
rom the cells and the growth media. Various ltering technologies
mammalian cells can create. For example, certain proteins have
are used to isolate and puriy the proteins based on their size,
sugar molecules attached to them, and they don’t unction properly
molecular weight, and electrical charge. The puried protein is
i those sugar molecules are not present in the correct pattern.
typically mixed with a sterile solution that can be injected or inused. The nal steps are to ll vials or syringes with individual doses o
Maintaining the right growth environment
the nished drug and to label the vials or syringes, package them,
The manuacturing 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 fasks
What does the future of biotechnology therapies look like? Biotechnology is still a relatively new eld with great potential or driving medical progress.
routinely collected so that researchers can determine whether dierent responses to a test medicine
Much o that progress is likely to result rom advances in personalized medicine. This new
might be explained by genetic actors. The data is kept anonymous to protect patients’ privacy.
treatment paradigm aims to ensure that patients get the therapies best suited to their specic conditions, genetic makeups, and other health characteristics.
Biotechnology is also revolutionizing the diagnosis o diseases caused by genetic actors. New tests can detect changes in the DNA sequence o genes associated with disease risk and can
For example, a new discipline called pharmacogenomics seeks to determine how a patient’s
predict the likelihood that a patient will develop a disease. Early diagnosis is oten the key to
genetic prole aects 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 proles are mostly likely to benet rom a given medicine. This model is sometimes called personalized medicine.
Advances in D NA technology a re the keys to p harmacogenomics and personalized medi cine. These developments promise to result in more eective, individualized healthcare and advances
Pharmacogenomics has already changed the way clinical trials are conducted: Genetic data is
in preventive medicine.
Emerging treatments Gene therapy involves inserting genes into the cells o patients to replace deective genes with
new, unctional 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 dierent types o unctional 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 o nanoshells, or metallic lenses, which convert inrared 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 or the treatment o various cancers and diseases.
Looking ahead The practice o medicine has changed dramatically over the years through pioneering advances in biotechnology research and innovation; and millions o patients worldwide continue to beneit rom 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, uture 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 www.biotechnology.amgen.com
