An_Introduction to Biotechnology

7/28/2019 An_Introduction to Biotechnology

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An introduction to

biotechnology


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Since Amgens ounding in 1980, the companys ocus has been on discovering, developing, and delivering novel

medicines or patients with serious illnesses. Amgens 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.

Pioneering science delivers vital medicines


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In 1919, Hungarian agricultural engineer Karl Ereky oresaw a time when biology could be used

or turning raw materials into useul products. He coined the term biotechnology to describe

that merging o biology and technology.

Erekys vision has now been realized by thousands o companies and research institutions. The

growing list o biotechnology products includes medicines, medical devices, and diagnostics,

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.

How do biotechnology medicines differ from other medicines?

A medicine i s a therapeutic substance used or treating, preventing, or curing disease. The

most amiliar type o 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 o 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 o this type can

be taken by mouth in solid or liquid orm.

What is biotechnology?

Biotechnology medicines, oten reerred 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 actoriesmicrobes or cell linesthat are genetically modied to produce the desired

molecule. A biotech medicine must be injected or inused into the body in order to protect its

complex structure rom being broken down by digestion i taken by mouth.

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

use or many decades. Most biologics were developed ater the advent o genetic engineering,

which gave rise to the modern biotechnology industry in the 1970s. Amgen was one o 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.1


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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 or a specic

protein is rewritten onto a molecule called

messenger RNA (mRNA); mRNA has nucleotides

similar to those o DNA. Each successive

grouping o three nucleotides orms a codon,

or code, or one o 20 dierent amino acids,

which are the building blocks o proteins.

During translation, a cell structure called a

ribosome binds to a ribbon o mRNA. Other

molecules, called transer RNAs, assemble

a chain o amino acids that matches the

sequence o codons in the mRNA. Short

chains o amino acids are called peptides.

Long chains, called polypeptides, orm proteins.

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The molecular structure of DNAthe double helix

Chromosome

DNA

Gene

Biotechnology has been used in a rudimentary orm since

ancient brewers began using yeast cultures to make beer. The

breakthrough that laid the groundwork or modern biotechnology

came when the structure o DNA was discovered in the early

1950s. To understand how this insight eventually led to biotech

therapies, its helpul to have a basic understanding o DNAs

central role in health and disease.

What does DNA do?

DNA is a very long and coiled molecule ound in the nucleus,

or command center, o a cell. It provides the ull blueprint or theconstruction and operation o a lie-orm, be it a microbe, a bird,

or a human. The inormation in DNA is stored as a code made

up o our basic building blocks, called nucleotides. The order in

which the nucleotides appear is akin to the order o the letters

that spell words and orm sentences and stories. In the case o

DNA, the order o nucleotides orms dierent genes. Each gene

contains the instructions or a specic protein.

With a ew exceptions, every cell in an organism holds a complete

copy o that organisms DNA. The genes in the DNA o a particular

cell can be either active (turned on) or inactive (turned o)

depending on the cells unction and needs. Once a gene is

activated, the inormation it holds is used or making, or

expressing, the protein or which it codes. Many diseases

result rom genes that are improperly turned on or o.

What functions do proteins control?

The amino acids that orm 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 unctions and what other molecules it impacts.

Common types o proteins are:

Enzymes,whichputmoleculestogetherorbreakthemapart.

Signalingproteins,whichrelaymessagesbetweencells,

and receptors, which receive signals sent via proteins rom

other cells.

Immunesystemproteins,suchasantibodies,whichdefend

against disease and external threats.

Structuralproteins,whichgiveshapetocellsandorgans.

Given the tremendous variety o unctions that proteins perorm,

they are sometimes reerred to as the workhorse molecules o

lie. However, when key proteins are malunctioning or missing,

the result is oten disease o one type or another.

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Illustration is copyrighted material o BioTech Primer, Inc., and is

reproduced herein with its permission.


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How does genetic engineering work?

Genetic engineering is the cornerstone o modern

biotechnology. It is based on scientic tools, developed

in recent decades, that enable researchers to:

Identifythegenethatproducestheproteinofinterest. CuttheDNAsequencethatcontainsthegenefrom

a sample o DNA.

Placethegeneintoavector,suchasaplasmid

or bacteriophage.

UsethevectortocarrythegeneintotheDNA

o the host cells, such as Escherichia coli(E coli)

or mammalian cells grown in culture.

Inducethecellstoactivatethegeneandproduce

the desired protein.

Extractandpurifytheproteinfortherapeuticuse.

When segments o DNA are cut and pasted together to orm

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.

Geneticengineeringallowsscientiststomanufacture

molecules that are too complex to make with chemistry.

This has resulted in important new types o 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 o the natural protein are

low or absent due to disease. They can be used or treating

such diseases as cancer, blood disorders, rheumatoid

arthritis, metabolic diseases, and diseases o the immune

system.

Monoclonal antibodies are a specic class o

therapeutic proteins designed to target oreign

invadersor cance r 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 o both peptides and antibodies but thatare distinct rom 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 o 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 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.

Genetic engineering tools

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The irst step in treating any disease i s to clariy how the

disease is caused. Many questions must be answered to

arrive at an understanding o what is needed to pursue new

types o treatments.

Howdoesapersongetthedisease?

Whichcellsareaffected?

Isthediseasecausedbygeneticfactors?Ifso,what

genesareturnedonoroffinthediseasedcells?

Whatproteinsarepresentorabsentindiseasedcells

ascomparedwithhealthycells?

Ifthediseaseiscausedbyaninfection,howdoesthe

infectiousorganisminteractwiththebody?

In modern labs, sophisticated tools are used or shedding

light on these questions. The tools are designed to uncover themolecular roots o disease and pinpoint critical dierences

between healthy cells and diseased cells. Researchers oten

use multiple approaches to create a detailed picture o the

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

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

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

isthediseasetheresultofthechange?Bydeterminingwhich

molecular deects are really behind a disease, scientists can

identiy the best targets or new medicines. In some cases,

the best target or the disease may already be addressed

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

new drug that oers other advantages. Oten, though, drug

discovery aims to provide an entirely new type o therapy by

pursuing a novel target.

Selecting a target

The term targetreers to the specic molecule in the body

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

target specic proteins that are not ound in humans but arecritical to the survival o 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 or new medicines. Most are

proteins o various types, including enzymes, growth actors,

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 rom 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 unction. 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 o human biology makes it a

challenge to choose good targets. It can take many years

o research and clinical trials to l earn that a new targetwont provide the desired results. To reduce that risk,

scientists try to prove the value o 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 o the target

is driving the course o the disease.

Selecting a drug

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

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

to use a chemical compound, a technology called drug screening

is typically used. With automated systems, scientists can rapidly

test thousands o compounds to see which ones interere 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. I

the goal is to provide a missing or decient protein, the gene or

that protein is used or making a recombinant version o theprotein to give to patients. I 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 o allergic reactions in patients.

Developing the drug

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

through extensive testing beore it can be studied in humans.

Many drug saety studies are perormed using cell lines

engineered to express the genes that are oten responsible

or side eects. Cell line models have decreased the number

o animals needed or testing and have helped accelerate the

drug development process. Some animal tests are still required

to ensure that the drug doesnt interere with the complexbiological unctions that are ound only in higher lie-orms.

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 manyhuman genes have been revealed by studying parallel genes in other organisms.

Bioinformatics. The scientic community generates huge 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.

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I a test drug has no serious saety issues in preclinical studies,

researchers can ask or regulatory permission to do clinical

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

and a drug must meet success criteria at each phase beore

moving on to the next one.

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

patients. The main goals are to assess saety and tolerability

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

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.

I the test drug shows clear benets and acceptable risksin 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 rom

all studies and decide whether the medicines beneits

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

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

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

A company can continue doing clinical tri als on an approved

medicine to see i it works under other specic conditions

or in other groups o 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 ew 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 smal l-molecule chemical compound or alarge-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 or 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 surace or circulate

outside the cell.

Small molecules oten have good specicity or their targets, but therapeutic antibodies tend to have extremely high

specicity. Most large molecules stay in the body longer, resulting in the need or less requent dosing.

The right tool for the target

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How are biotechnologymedicines made?

The manuacture o biologics is a highly demanding process.

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

complex, and more variable than the structure o 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 manuacturing process consists

o the ollowing our main steps:

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

the desired protein

2. Growing large numbers o cells that produce the protein

3. Isolating and puriying the protein

4. Preparing the biologic or use by patients

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

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

This is because many proteins have structural eatures that only

mammalian cells can create. For example, certain proteins have

sugar molecules attached to them, and they dont unction properly

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

Maintaining the right growth environment

The manuacturing process begins with cell culture, or cells grown

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

containing a liquid broth with the nutrients that cells require or

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

transerred to larger and larger vessels, called bioreactors. Some

bioreactor tanks used in manuacturing hold 20,000 liters o cells

and growth media.

At every step o this process, i t is crucial to maintain the specic

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

can aect the cells and alter the proteins they produce. For

that reason, strict controls are needed to ensure the quality and

consistency o the inal product. Scientists careully monitor such

variables as temperature, pH, nutrient concentration, and oxygen

levels. They also run requent tests to guard against contaminationrom bacteria, yeast, and other microorganisms.

When the growth process is done, the desired protein is i solated

rom the cells and the growth media. Various ltering technologies

are used to isolate and puriy 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 inused.

The nal steps are to ll vials or syringes with individual doses o

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 or driving medical progress.

Much o that progress is likely to result rom 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 aects his/her responses to particular medicines. The goal is to develop tests

that will predict which patient genetic proles are mostly likely to benet rom 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 dierent responses to a test medicine

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

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

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

either preventing disease or slowing disease progress through early treatment.

Advances in DNA technology a re the keys to pharmacogenomics and personalized medicine.

These developments promise to result in more eective, 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 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 cellsare 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.

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.

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

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An_Introduction to Biotechnology