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Introduction to Biotechnology


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An introductory primer on biotechnology.

Published in: Health & Medicine

Introduction to Biotechnology

  1. 1. An introduction to biotechnology
  2. 2. Since Amgen’s founding in 1980, the company’s focus has been on discovering, developing, and delivering novelmedicines for patients with serious illnesses. Amgen’s scientists are pioneers in the field of biotechnology, deliveringtreatments based on advances in cellular and molecular biology. And Amgen therapies have helped millions of peopleworldwide to fight cancer, kidney disease, bone disease, rheumatoid arthritis, and other serious illnesses.Pioneering science delivers vital medicines
  3. 3. In 1919, Hungarian agricultural engineer Karl Ereky foresaw a time when biology could be usedfor turning raw materials into useful products. He coined the term biotechnology to describethat merging of biology and technology.Ereky’s vision has now been realized by thousands of companies and research institutions. Thegrowing list of biotechnology products includes medicines, medical devices, and diagnostics,as well as more-resilient crops, biofuels, biomaterials, and pollution controls. While the fieldof 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. Themost 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 pressuredrugs. This type of medicine is also known as a small molecule because the active ingredienthas a chemical structure and a size that are small compared with large, complex moleculeslike proteins. A medicine can be made by chemists in a lab. Most medicines of this type canbe taken by mouth in solid or liquid form.What is biotechnology?Biotechnology medicines, often referred to as biotech medicines, are large molecules that aresimilar or identical to the proteins and other complex substances that the body relies on to stayhealthy. They are too large and too intricate to make using chemistry alone. Instead, they are madeusing living factories—microbes or cell lines—that are genetically modified to produce the desiredmolecule. A biotech medicine must be injected or infused into the body in order to protect itscomplex 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 biotechtherapy, or biologic. A few of these therapies, such as insulin and certain vaccines, have been inuse 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 firstcompanies to realize the new field’s promise and to deliver biologics to patients.Like pharmaceuticals, biologics cannot be prescribed to patients until their use has beenapproved by regulators. For example, in the United States, the Food and Drug Administrationevaluates new medicines. In the European Union, the European Medicines Agency managesthat responsibility.1
  4. 4. The science of biotechnologyHow does the body make a protein?Protein production is a multistep process thatincludes transcription and translation. Duringtranscription, the original DNA code for a specificprotein is rewritten onto a molecule calledmessenger RNA (mRNA); mRNA has nucleotidessimilar to those of DNA. Each successivegrouping 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 aribosome binds to a ribbon of mRNA. Othermolecules, called transfer RNAs, assemblea chain of amino acids that matches thesequence of codons in the mRNA. Shortchains of amino acids are called peptides.Long chains, called polypeptides, form proteins.CGCGATATCGATATATCGATATCGATATCGCGATCGThe molecular structure of DNA—the double helixChromosomeDNAGeneBiotechnology has been used in a rudimentary form sinceancient brewers began using yeast cultures to make beer. Thebreakthrough that laid the groundwork for modern biotechnologycame when the structure of DNA was discovered in the early1950s. To understand how this insight eventually led to biotechtherapies, it’s helpful to have a basic understanding of DNA’scentral 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 theconstruction and operation of a life-form, be it a microbe, a bird,or a human. The information in DNA is stored as a code madeup of four basic building blocks, called nucleotides. The order inwhich the nucleotides appear is akin to the order of the lettersthat spell words and form sentences and stories. In the case ofDNA, the order of nucleotides forms different genes. Each genecontains the instructions for a specific protein.With a few exceptions, every cell in an organism holds a completecopy of that organism’s DNA. The genes in the DNA of a particularcell can be either active (turned on) or inactive (turned off)depending on the cell’s function and needs. Once a gene isactivated, the information it holds is used for making, or“expressing,” the protein for which it codes. Many diseasesresult 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, andthose complex interactions give each protein its own specific,three-dimensional structure. That structure in turn determineshow 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 fromother cells.• Immune system proteins, such as antibodies, which defendagainst 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 oflife. However, when key proteins are malfunctioning or missing,the result is often disease of one type or another.2Illustration is copyrighted material of BioTech Primer, Inc., and isreproduced herein with its permission.
  5. 5. How does genetic engineering work?Genetic engineering is the cornerstone of modernbiotechnology. It is based on scientific tools, developedin recent decades, that enable researchers to:• Identify the gene that produces the protein of interest.• Cut the DNA sequence that contains the gene froma sample of DNA.• Place the gene into a vector, such as a plasmidor bacteriophage.• Use the vector to carry the gene into the DNAof the host cells, such as Escherichia coli (E coli)or mammalian cells grown in culture.• Induce the cells to activate the gene and producethe desired protein.• Extract and purify the protein for therapeutic use.When segments of DNA are cut and pasted together to formnew sequences, the result is known as recombinant DNA.When recombinant DNA is inserted into cells, the cells usethis modified blueprint and their own cellular machinery tomake the protein encoded by the recombinant DNA. Cellsthat have recombinant DNA are known as geneticallymodified or transgenic cells.• Genetic engineering allows scientists to manufacturemolecules that are too complex to make with chemistry.This has resulted in important new types of therapies,such as therapeutic proteins. Therapeutic proteinsinclude those described below as well as ones that areused to replace or augment a patient’s naturally occurringproteins, especially when levels of the natural protein arelow or absent due to disease. They can be used for treatingsuch diseases as cancer, blood disorders, rheumatoidarthritis, metabolic diseases, and diseases of the immunesystem. • Monoclonal antibodies are a specific class oftherapeutic proteins designed to target foreigninvaders—or cancer cells—by the immune system.Therapeutic antibodies can target and inhibit proteinsand other molecules in the body that contribute todisease. • Peptibodies are engineered proteins that haveattributes of both peptides and antibodies but thatare distinct from each. • Vaccines stimulate the immune system to provideprotection, mainly against viruses. Traditional vaccinesuse weakened or killed viruses to prime the bodyto attack the real virus. Biotechnology can createrecombinant vaccines based on viral genes.These new modes of treatment give drug developersmore options in determining the best way to counteract adisease. But biotech research and development (RD), likepharmaceutical RD, is a long and demanding process withmany 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 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 tocarry recombinant DNA.Genetic engineering tools3
  6. 6. The first step in treating any disease is to clarify how thedisease is caused. Many questions must be answered toarrive at an understanding of what is needed to pursue newtypes of treatments.• How does a person get the disease?• Which cells are affected?• Is the disease caused by genetic factors? If so, whatgenes are turned on or off in the diseased cells?• What proteins are present or absent in diseased cellsas compared with healthy cells?• If the disease is caused by an infection, how does theinfectious organism interact with the body?In modern labs, sophisticated tools are used for sheddinglight on these questions. The tools are designed to uncover themolecular roots of disease and pinpoint critical differencesbetween healthy cells and diseased cells. Researchers oftenuse multiple approaches to create a detailed picture of thedisease process. Once the picture starts to emerge, it can stilltake years to learn which of the changes linked to a diseaseare most important. Is the change the result of the disease, oris the disease the result of the change? By determining whichmolecular defects are really behind a disease, scientists canidentify the best targets for new medicines. In some cases,the best target for the disease may already be addressedby an existing medicine, and the aim would be to develop anew drug that offers other advantages. Often, though, drugdiscovery aims to provide an entirely new type of therapy bypursuing a novel target.Selecting a targetThe term target refers to the specific molecule in the bodythat a medicine is designed to affect. For example, antibioticstarget specific proteins that are not found in humans but arecritical to the survival of bacteria. Many cholesterol drugstarget enzymes that the body uses to make cholesterol.Scientists estimate there are about 8,000 therapeutic targetsthat might provide a basis for new medicines. Most areproteins of various types, including enzymes, growth factors,cell receptors, and cell-signaling molecules. Some targetsare present in excess during disease, so the goal is to blocktheir activity. This can be done by a medicine that binds tothe target to prevent it from interacting with other moleculesin the body. In other cases, the target protein is deficient ormissing, and the goal is to enhance or replace it in order torestore healthy function. Biotechnology has made it possibleto create therapies that are similar or identical to the complexmolecules the body relies on to remain healthy.The amazing complexity of human biology makes it achallenge to choose good targets. It can take many yearsof research and clinical trials to learn that a new targetwon’t 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?4
  7. 7. experiments that show the target’s role in the diseaseprocess. The goal is to show that the activity of the targetis driving the course of the disease.Selecting a drugOnce the target has been set, the next step is to identify a drugthat impacts the target in the desired way. If researchers decideto use a chemical compound, a technology called drug screeningis typically used. With automated systems, scientists can rapidlytest thousands of compounds to see which ones interfere with thetarget’s activity. Potent compounds can be put through added teststo find a lead compound with the best potential to become a drug.In contrast, biologics are designed using genetic engineering. Ifthe goal is to provide a missing or deficient protein, the gene forthat protein is used for making a recombinant version of theprotein to give to patients. If the goal is to block the targetprotein with an antibody, one common approach is to exposetransgenic mice to the target so as to induce their immunesystems to make antibodies to that protein. The cells thatproduce these specific antibodies are then extracted andmanipulated to create a new cell line. The mice used in thisprocess are genetically modified to make human antibodies,which reduces the risk of allergic reactions in patients.Developing the drugOnce a promising test drug has been identified, it must gothrough extensive testing before it can be studied in humans.Many drug safety studies are performed using cell linesengineered to express the genes that are often responsiblefor side effects. Cell line models have decreased the numberof animals needed for testing and have helped accelerate thedrug development process. Some animal tests are still requiredto ensure that the drug doesn’t interfere with the complexbiological functions that are found only in higher life-forms.Models for studying diseaseThe 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 cellularprocesses and protein expression.Cross-species studies. Genes and proteins found in humans may also be found in other species. The functions of manyhuman 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 thatdata 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 diseaseprocess, 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 canshed light on the disease process and the impact of medicines under study.5
  8. 8. If a test drug has no serious safety issues in preclinical studies,researchers can ask for regulatory permission to do clinicaltrials in humans. There are three phases of clinical research,and a drug must meet success criteria at each phase beforemoving 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 tolerabilityand explore how the drug behaves in the body (how long itstays in the body, how much of the drug reaches its target, etc.).Phase 2. Studies in about 100 to 300 patients. The goalsare to evaluate whether the drug appears effective, to furtherexplore its safety, and to determine the best dose.Phase 3. Large studies involving 500 to 5,000 or morepatients, depending on the disease and the study design.Very large trials are often needed to determine whethera drug can prevent bad health outcomes. The goal is tocompare the effectiveness, safety, and tolerability of thetest drug with another drug or a placebo.If the test drug shows clear benefits and acceptable risksin phase 3, the company can file an application requestingregulatory approval to market the drug. In the United States,the Food and Drug Administration evaluates new medicines.In the European Union, the European Medicines Agencymanages that responsibility. Regulators review data fromall studies and decide whether the medicine’s benefitsoutweigh 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 approvedmedicine to see if it works under other specific conditionsor in other groups of patients, and additional trials may alsobe required by regulatory agencies. These are known asphase 4 studies.The whole drug development process takes 10 to 15 yearsto complete on average. Very few test drugs are able to clearall 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 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 for targets inside cells.Some may also cross the blood-brain barrier to treat psychiatric illness and other brain diseases. Biologics usually cannotcross cell membranes or enter the brain. Their use is largely restricted to targets that sit on the cell surface or circulateoutside the cell.Small molecules often have good specificity for their targets, but therapeutic antibodies tend to have extremely highspecificity. Most large molecules stay in the body longer, resulting in the need for less frequent dosing.The right tool for the target6
  9. 9. How are biotechnology medicines made?The manufacture of biologics is a highly demanding process.Protein-based therapies have structures that are far larger, morecomplex, and more variable than the structure of drugs based onchemical compounds. Plus, protein-based drugs are made usingintricate living systems that require very precise conditions in orderto make consistent products. The manufacturing process consistsof the following four main steps:1. Producing the master cell line containing the gene that makesthe desired protein2. Growing large numbers of cells that produce the protein3. Isolating and purifying the protein4. Preparing the biologic for use by patientsSome 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 onlymammalian cells can create. For example, certain proteins havesugar molecules attached to them, and they don’t function properlyif those sugar molecules are not present in the correct pattern.Maintaining the right growth environmentThe manufacturing process begins with cell culture, or cells grownin the laboratory. Cells are initially placed in petri dishes or flaskscontaining a liquid broth with the nutrients that cells require forgrowth. During the scale-up process, the cells are sequentiallytransferred to larger and larger vessels, called bioreactors. Somebioreactor tanks used in manufacturing hold 20,000 liters of cellsand growth media.At every step of this process, it is crucial to maintain the specificenvironment that cells need in order to thrive. Even subtle changescan affect the cells and alter the proteins they produce. Forthat reason, strict controls are needed to ensure the quality andconsistency of the final product. Scientists carefully monitor suchvariables as temperature, pH, nutrient concentration, and oxygenlevels. They also run frequent tests to guard against contaminationfrom bacteria, yeast, and other microorganisms.When the growth process is done, the desired protein is isolatedfrom the cells and the growth media. Various filtering technologiesare used to isolate and purify the proteins based on their size,molecular weight, and electrical charge. The purified protein istypically mixed with a sterile solution that can be injected or infused.The final steps are to fill vials or syringes with individual doses ofthe finished drug and to label the vials or syringes, package them,and make them available to physicians and patients.7
  10. 10. Biotechnology is still a relatively new field with great potential for driving medical progress.Much of that progress is likely to result from advances in personalized medicine. This newtreatment paradigm aims to ensure that patients get the therapies best suited to their specificconditions, genetic makeups, and other health characteristics.For example, a new discipline called pharmacogenomics seeks to determine how a patient’sgenetic profile affects his/her responses to particular medicines. The goal is to develop teststhat will predict which patient genetic profiles are mostly likely to benefit from a given medicine.This model is sometimes called personalized medicine.Pharmacogenomics has already changed the way clinical trials are conducted: Genetic data isroutinely collected so that researchers can determine whether different responses to a test medicinemight 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. Newtests can detect changes in the DNA sequence of genes associated with disease risk and canpredict the likelihood that a patient will develop a disease. Early diagnosis is often the key toeither 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 advancesin preventive medicine.What does the future of biotechnology therapies look like?8
  11. 11. Emerging treatmentsGene therapy involves inserting genes into the cells of patients to replace defective genes withnew, functional genes. The field is still in its experimental stages but has grown greatly since the firstclinical trial in 1990.Stem cells are unspecialized cells that can mature into different types of functional cells. Stemcells can be grown in a lab and guided toward the desired cell type and then surgically implantedinto 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 isthe experimental use of nanoshells, or metallic lenses, which convert infrared light into heat energyto destroy cancer cells.New drug delivery systems include microscopic particles called microspheres with holes justlarge enough to dispense drugs to their targets. Microsphere therapies are available and beinginvestigated for the treatment of various cancers and diseases.The practice of medicine has changed dramatically over the years throughpioneering advances in biotechnology research and innovation; and millionsof patients worldwide continue to benefit from therapeutics developedby companies that are discovering, developing, and delivering innovativemedicines to treat grievous illnesses. As companies continue to developmedicines that address significant unmet needs, future innovations inbiotechnology research will bring exciting new advances to help millionsmore people worldwide.Looking ahead9
  12. 12. Amgen Inc.One Amgen Center DriveThousand Oaks, CA 91320-1799www.amgen.comVisit the biotechnology website at