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I have a presentation to do where non-biologist are attending. In order to introduce a little bit my work I have to do a quick summary on genomes. So what is a genome, a gene, an mRNA and a protein. And the best would be to have that in one figure, an easy to understand. I found this : http://dnamismatch.com/Test/wp-content/uploads/2013/07/Genes-and-genomes.png">genomes
Central dogma of molecular biology
The central dogma of molecular biology is an explanation of the flow of genetic information within a biological system. It is often stated as "DNA makes RNA, and RNA makes protein",  although this is not its original meaning. It was first stated by Francis Crick in 1957,   then published in 1958:  
The Central Dogma. This states that once "information" has passed into protein it cannot get out again. In more detail, the transfer of information from nucleic acid to nucleic acid, or from nucleic acid to protein may be possible, but transfer from protein to protein, or from protein to nucleic acid is impossible. Information means here the precise determination of sequence, either of bases in the nucleic acid or of amino acid residues in the protein.
He re-stated it in a Nature paper published in 1970: "The central dogma of molecular biology deals with the detailed residue-by-residue transfer of sequential information. It states that such information cannot be transferred back from protein to either protein or nucleic acid." 
A second version of the central dogma is popular but incorrect. This is the simplistic DNA → RNA → protein pathway published by James Watson in the first edition of The Molecular Biology of the Gene (1965). Watson's version differs from Crick's because Watson describes a two-step (DNA → RNA and RNA → protein) process as the central dogma.  While the dogma, as originally stated by Crick, remains valid today,  Watson's version does not. 
The dogma is a framework for understanding the transfer of sequence information between information-carrying biopolymers, in the most common or general case, in living organisms. There are 3 major classes of such biopolymers: DNA and RNA (both nucleic acids), and protein. There are 3 × 3 = 9 conceivable direct transfers of information that can occur between these. The dogma classes these into 3 groups of 3: three general transfers (believed to occur normally in most cells), three special transfers (known to occur, but only under specific conditions in case of some viruses or in a laboratory), and three unknown transfers (believed never to occur). The general transfers describe the normal flow of biological information: DNA can be copied to DNA (DNA replication), DNA information can be copied into mRNA (transcription), and proteins can be synthesized using the information in mRNA as a template (translation). The special transfers describe: RNA being copied from RNA (RNA replication), DNA being synthesised using an RNA template (reverse transcription), and proteins being synthesised directly from a DNA template without the use of mRNA. The unknown transfers describe: a protein being copied from a protein, synthesis of RNA using the primary structure of a protein as a template, and DNA synthesis using the primary structure of a protein as a template - these are not thought to naturally occur. 
Central Dogma of Molecular Biology (With Diagram) | Biology
The process of synthesis of proteins involves one of the central dogma of molecular biology, according to which genetic information flows from nucleic acids to proteins. It was first proposed by Crick in the year 1958. The first step of this central dogma is the synthesis of RNA from DNA. This is known as transcription. The second step involves a change of code from nucleotide sequences to amino acid sequences and is called translation.
It can be illustrated as follows:
The DNA found in organisms has two main functions – replication and phenogenesis. Phenogenesis is a mechanism by which the phenotype of an organism is produced under the control of DNA in a given environment. The environment includes external factors such as temperature, quality and quantity of light, and internal factors such as hormones and enzymes.
The phenotype of an organism is the result of various embryological and biochemical activities of its cells from the zygotic to the adult stage. All these activities involve the action of a variety of structural and functional enzymes. The enzymes perform catalytic functions causing the splitting or union of various cellular molecules. Each reaction occurs in a stepwise manner involving the conversion of one substance to another.
The various steps involve the transformation of a precursor substance to its end product which ultimately is a structural or functional phenotypic trait. The various steps constitute a biosynthetic pathway. Each step of the pathway is catalysed by a specific enzyme, which in turn is produced by a specific gene.
DNA however, is not involved directly in the biosynthetic pathway. An intermediate molecule called mRNA is involved in the assemblage of amino acids to form enzymes. Thus, to produce a particular phenotypic trait, DNA transcribes mRNA which translates into either an enzymatic or structural protein. The groundwork for a functional relationship between genes and enzymes was laid in 1902 when Bateson reported a rare human defect known as alkaptonuria, which is inherited as a recessive trait.
Later in the year 1909, an English physician, Archibald Garrod known popularly as the father of biochemical genetics published his work in his book ‘Inborn errors of metabolism’ suggesting a relationship between genes and specific chemical reactions. But his work remained unnoticed until Beadle, Tatum and other geneticists worked on Neurospora to get a better understanding of gene action. They found that mutational change of genes can cause loss of specific enzymes. This concept was widely known as the ‘One gene one enzyme hypothesis’.
The concept of ‘one gene one enzyme’ one phenotypic effect relationship is exemplified by Neurospora crassa. The wild type or prototroph of Neurospora can live in a simple medium containing inorganic salts, a source of organic carbon and vitamin biotin. This simple medium is known as minimal medium.
Thus, the fungus has an innate capacity to synthesize all the other vitamins, amino acids and nitrogenous bases required for normal development. According to Beadle and Tatum, a gene controls a structural or functional trait through controlling the synthesis of a specific enzyme formed by the latter.
They treated the conidia of Neurospora to X rays or UV rays and obtained number of mutants called auxotrophs. These are nutritional mutants, which cannot grow on normal or minimal medium. Beadle and Tatum selected three mutants for their study.
a. Ornithine Requiring Auxotrophs:
These are unable to synthesise citrulline and arginine. They were however able to synthesise arginine if supplemented with ornithine.
b. Citrulline Requiring Auxotrophs:
These synthesise ornithine, but could not make arginine.
c. Arginine Requiring Auxotrophs:
These could synthesise both citrulline and ornithine. These would grow normally if supplemented with arginine.
The existence of these three types of mutants indicates a sequence of reactions involved in the synthesis of arginine. The work of Beadle and Tatum have been summarised in Fig. 8.
They reasoned that mutations caused defects in enzymes. One mutation produces only one defective enzyme. Beadle and Tatum were awarded the Nobel Prize for their contribution in 1958.
But ‘one gene one enzyme’ hypothesis has some limitations which are as follows:
a. All genes do not produce enzymes or their components. Some of them control other genes.
b. All proteins are not enzymes. Many proteins are made up of subunit called polypeptides, with each distinct polypeptide under the control of a gene. For example, the enzyme tryptophan synthetase of bacterium Escherichia coli consists of two separate polypeptides, A and B.
Polypeptide A is of α-type while polypeptide B is β-type. A change in any of the two genes causes inactivation of tryptophan synthetase through non-synthesis of A and B-type. Inactivation of enzyme stops the synthesis of tryptophan. Similarly, adult human haemoglobin consists of four polypeptide chains, 2a and 2b.
Each polypeptide chain is coded by a separate gene. Therefore, one gene one enzyme hypothesis was changed to ‘one gene one polypeptide’ hypothesis. According to which, a structural gene specifies the synthesis of a single polypeptide. Since the segment of DNA that codes for a polypeptide is termed as Cistron, the hypothesis is also named as one cistron one polypeptide hypothesis.
In 1970, H M Temin and D Baltimore reported the existence of an enzyme ‘RNA dependent DNA polymerase’ in certain RNA containing viruses. This enzyme could synthesise DNA from a single stranded RNA template. This process is also known as reverse transcription or teminism. The newly synthesised DNA then synthesises mRNA by transcription which in turn produces polypeptide by translation.
This enzyme gave rise to the concept of ‘central dogma reverse’ according to which the sequence of information is not necessarily from DNA to RNA to protein but can also take place from RNA to DNA.
What Is the Relationship Between Chromosomes, DNA and Genes?
Chromosomes are structures within a cell nucleus that are made up of many genes. Genes contain deoxyribonucleic acid (DNA), which contain the genetic information used to synthesize proteins.
Chromosomes are long strands within a cell that can contain hundreds or thousands of genes. Humans have anywhere from 20,000 to 30,000 genes. Each human cell has a pair of 23 chromosomes, which yields a total of 46 chromosomes. Genes help form traits, and more than one gene can create a certain trait. Genes sometimes contain genetic abnormalities or acquired mutations, which in turn influence how traits develop. Within genes, deoxyribonucleic acid (DNA) contains four building blocks, which are adenine, cytosine, guanine and thymine. The order of these bases shapes the genome's instructions.
Despite chromosomes having a large number of genes, those genes are arranged in a very specific sequence. Each gene has a special place within a chromosome, which is called its locus. Most cells in the human body have 23 pairs of chromosomes, with the exception of a few cells like red blood cells, egg cells and sperm. Each pair of chromosomes contains genetic information from a mother cell and a father cell. Of the 23 pairs of chromosomes within a cell, 22 are nonsex chromosomes, or autosomal chromosomes. The last pair of chromosomes contains the sex chromosomes, which are X and Y. The pairing of the sex cells determines the offspring's gender. Males have one X chromosome and one Y chromosome. The X originates from the mother, and the Y chromosome comes from the father. Females, in contrast, have two X chromosomes. One chromosome comes from the mother and the other comes from the father. Ordinarily, genes in the nonsex chromosomes can be fully expressed. Occasionally, however, problems arise wherein this is not the case. Depending on the abnormality, people can be born with or develop mild to severe developmental problems.
Abnormalities that arise in chromosomes can take several different forms. Chromosomal abnormalities can arise as a result of an abnormal number of chromosomes or when an area of the chromosome develops abnormally, such as sections that are accidentally deleted or placed in a different chromosome, which is called translocation. Having an abnormal number of chromosomes can create serious complications. Having an extra nonsex chromosome or lacking a nonsex chromosome, for example, can be fatal to a fetus. It can also cause developmental problems, such as Down syndrome, which appears in genetics as a person having three copies of chromosome 21. Large areas of chromosome that are abnormal can be due to a genetic disorder or an acquired mutation. One example of this abnormality is chronic myelogenous leukemia, which arises when part of chromosome 9 is translocated to chromosome 22.
Sometimes, people have genetic abnormalities without suffering from harmful effects. Humans have about 300 to 400 abnormal genes, but they are less likely to develop problems if one part of the affected chromosome is still normal. Disorders arise when an individual has two copies of the same abnormal genes. The likelihood of an individual developing a disorder is higher in people whose parents have genetic abnormalities than in people whose parents do not have any genetic problems.
What is the Central Dogma of Molecular Biology
The central dogma of molecular biology describes the process by which the information in genes flows into proteins: DNA → RNA → protein. DNA contains genes that code for proteins. RNA is the intermediate between DNA and proteins. It carries information in genes from the nucleus to the cytoplasm in eukaryotes. Proteins are the determinants of the structure and the function of a particular cell. A protein is composed of an amino acid sequence, which is the coding sequence of a gene. Gene expression is the process of synthesizing proteins based on the instructions in genes. The two steps of gene expression are transcription and translation.
Figure 1: Central Dogma of Molecular Biology
This is the website for “Orchestrating Single-Cell Analysis with Bioconductor”, a book that teaches users some common workflows for the analysis of single-cell RNA-seq data (scRNA-seq). This book will teach you how to make use of cutting-edge Bioconductor tools to process, analyze, visualize, and explore scRNA-seq data. Additionally, it serves as an online companion for the manuscript “Orchestrating Single-Cell Analysis with Bioconductor”.
While we focus here on scRNA-seq data, a newer technology that profiles transcriptomes at the single-cell level, many of the tools, conventions, and analysis strategies utilized throughout this book are broadly applicable to other types of assays. By learning the grammar of Bioconductor workflows, we hope to provide you a starting point for the exploration of your own data, whether it be scRNA-seq or otherwise.
This book is organized into three parts. In the Preamble, we introduce the book and dive into resources for learning R and Bioconductor (both at a beginner and developer level). Part I ends with a tutorial for a key data infrastructure, the SingleCellExperiment class, that is used throughout Bioconductor for single-cell analysis and in the subsequent section.
The second part, Focus Topics, begins with an overview of the framework for analysis of scRNA-seq data, with deeper dives into specific topics are presented in each subsequent chapter.
The third part, Workflows, provides primarily code detailing the analysis of various datasets throughout the book.
Finally, the Appendix highlights our contributors.
The book is written in RMarkdown with bookdown. OSCA is a collaborative effort, supported by various folks from the Bioconductor team who have contributed workflows, fixes, and improvements.
This website is free to use, and is licensed under the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License.
Transcription is the process by which the information in DNA is copied into messenger RNA (mRNA) for protein production. Transcription begins with a bundle of factors assembling at the promoter sequence on the DNA (in red). Here, two transcription factors are already bound to the promoter. Other proteins arrive, carrying the enzyme RNA polymerase (in blue). To initiate transcription, these assembled proteins require contact with activator proteins that bind to specific sequences of DNA known as enhancer regions. Once the contact is made, the RNA polymerase races along the DNA to transcribe the gene.
Duration: 1 minutes, 52 seconds
What you are about to see is DNA's most extraordinary secret&mdashhow a simple code is turned into flesh and blood. It begins with a bundle of factors assembling at the start of a gene. A gene is simply a length of DNA instructions stretching away to the left. The assembled factors trigger the first phase of the process, reading off the information that will be needed to make the protein. Everything is ready to roll: three, two, one, GO! The blue molecule racing along the DNA is reading the gene. It's unzipping the double helix, and copying one of the two strands. The yellow chain snaking out of the top is a copy of the genetic message and it's made of a close chemical cousin of DNA called RNA. The building blocks to make the RNA enter through an intake hole. They are matched to the DNA - letter by letter - to copy the As, Cs, Ts and Gs of the gene. The only difference is that in the RNA copy, the letter T is replaced with a closely related building block known as "U". You are watching this process - called transcription - in real time. It's happening right now in almost every cell in your body.
rna polymerase,dna instructions,messenger rna,central dogma,chemical cousin,intake hole,genetic message,double helix,transcription factors,flesh and blood,location code,narration,building blocks,molecule,strands,protein,animation,real time
Coronavirus genome structure and replication
In addition to the SARS coronavirus (treated separately elsewhere in this volume), the complete genome sequences of six species in the coronavirus genus of the coronavirus family [avian infectious bronchitis virus-Beaudette strain (IBV-Beaudette), bovine coronavirus-ENT strain (BCoV-ENT), human coronavirus-229E strain (HCoV-229E), murine hepatitis virus-A59 strain (MHV-A59), porcine transmissible gastroenteritis-Purdue 115 strain (TGEV-Purdue 115), and porcine epidemic diarrhea virus-CV777 strain (PEDV-CV777)] have now been reported. Their lengths range from 27,317 nt for HCoV-229E to 31,357 nt for the murine hepatitis virus-A59, establishing the coronavirus genome as the largest known among RNA viruses. The basic organization of the coronavirus genome is shared with other members of the Nidovirus order (the torovirus genus, also in the family Coronaviridae, and members of the family Arteriviridae) in that the nonstructural proteins involved in proteolytic processing, genome replication, and subgenomic mRNA synthesis (transcription) (an estimated 14-16 end products for coronaviruses) are encoded within the 5'-proximal two-thirds of the genome on gene 1 and the (mostly) structural proteins are encoded within the 3'-proximal one-third of the genome (8-9 genes for coronaviruses). Genes for the major structural proteins in all coronaviruses occur in the 5' to 3' order as S, E, M, and N. The precise strategy used by coronaviruses for genome replication is not yet known, but many features have been established. This chapter focuses on some of the known features and presents some current questions regarding genome replication strategy, the cis-acting elements necessary for genome replication [as inferred from defective interfering (DI) RNA molecules], the minimum sequence requirements for autonomous replication of an RNA replicon, and the importance of gene order in genome replication.
MRNA Technology Gave Us the First COVID-19 Vaccines. It Could Also Upend the Drug Industry
I had been staring her in the eyes, as she had ordered, but when a doctor on my other side began jabbing me with a needle, I started to turn my head. “Don’t look at it,” the first doctor said. I obeyed.
This was in early August in New Orleans, where I had signed up to be a participant in the clinical trial for the Pfizer-BioNTech COVID-19 vaccine. It was a blind study, which meant I was not supposed to know whether I had gotten the placebo or the real vaccine. I asked the doctor if I would really been able to tell by looking at the syringe. “Probably not,” she answered, “but we want to be careful. This is very important to get right.”
I became a vaccine guinea pig because, in addition to wanting to be useful, I had a deep interest in the wondrous new roles now being played by RNA, the genetic material that is at the heart of new types of vaccines, cancer treatments and gene-editing tools. I was writing a book on the Berkeley biochemist Jennifer Doudna. She was a pioneer in determining the structure of RNA, which helped her and her doctoral adviser figure out how it could be the origin of all life on this planet. Then she and a colleague invented an RNA-guided gene-editing tool, which won them the 2020 Nobel Prize in Chemistry.
The tool is based on a system that bacteria use to fight viruses. Bacteria develop clustered repeated sequences in their DNA, known as CRISPRs, that can remember dangerous viruses and then deploy RNA-guided scissors to destroy them. In other words, it’s an immune system that can adapt itself to fight each new wave of viruses&mdashjust what we humans need. Now, with the recently approved Pfizer-BioNTech vaccine and a similar one from Moderna being slowly rolled out across the U.S. and Europe, RNA has been deployed to make a whole new type of vaccine that will, when it reaches enough people, change the course of the pandemic.
Up until last year, vaccines had not changed very much, at least in concept, for more than two centuries. Most have been modeled on the discovery made in 1796 by the English doctor Edward Jenner, who noticed that many milkmaids were immune to smallpox. They had all been infected by a form of pox that afflicts cows but is relatively harmless to humans, and Jenner surmised that the cowpox had given them immunity to smallpox. So he took some pus from a cowpox blister, rubbed it into scratches he made in the arm of his gardener’s 8-year-old son and then (this was in the days before bioethics panels) exposed the kid to smallpox. He didn’t become ill.
Before then, inoculations were done by giving patients a small dose of the actual smallpox virus, hoping that they would get a mild case and then be immune. Jenner’s great advance was to use a related but relatively harmless virus. Ever since, vaccinations have been based on the idea of exposing a patient to a safe facsimile of a dangerous virus or other germ. This is intended to kick the person’s adaptive immune system into gear. When it works, the body produces antibodies that will, sometimes for many years, fend off any infection if the real germ attacks.
One approach is to inject a safely weakened version of the virus. These can be good teachers, because they look very much like the real thing. The body responds by making antibodies for fighting them, and the immunity can last a lifetime. Albert Sabin used this approach for the oral polio vaccine in the 1950s, and that’s the way we now fend off measles, mumps, rubella and chicken pox.
At the same time Sabin was trying to develop a vaccine based on a weakened polio virus, Jonas Salk succeeded with a safer approach: using a killed or inactivated virus. This type of vaccine can still teach a person’s immune system how to fight off the live virus but is less likely to cause serious side effects. Two Chinese companies, Sinopharm and Sinovac, have used this approach to develop vaccines for COVID-19 that are now in limited use in China, the UAE and Indonesia.
Another traditional approach is to inject a subunit of the virus, such as one of the proteins that are on the virus’s coat. The immune system will then remember these, allowing the body to mount a quick and robust response when it encounters the actual virus. The vaccine against the hepatitis B virus, for example, works this way. Using only a fragment of the virus means that they are safer to inject into a patient and easier to produce, but they are often not as good at producing long-term immunity. The Maryland-based biotech Novavax is in late-stage clinical trials for a COVID-19 vaccine using this approach, and it is the basis for one of the two vaccines already being rolled out in Russia.
The plague year of 2020 will be remembered as the time when these traditional vaccines were supplanted by something fundamentally new: genetic vaccines, which deliver a gene or piece of genetic code into human cells. The genetic instructions then cause the cells to produce, on their own, safe components of the target virus in order to stimulate the patient’s immune system.
For SARS-CoV-2&mdashthe virus that causes COVID-19&mdashthe target component is its spike protein, which studs the outer envelope of the virus and enables it to infiltrate human cells. One method for doing this is by inserting the desired gene, using a technique known as recombinant DNA, into a harmless virus that can deliver the gene into human cells. To make a COVID vaccine, a gene that contains instructions for building part of a coronavirus spike protein is edited into the DNA of a weakened virus like an adenovirus, which can cause the common cold. The idea is that the re-engineered adenovirus will worm its way into human cells, where the new gene will cause the cells to make lots of these spike proteins. As a result, the person’s immune system will be primed to respond rapidly if the real coronavirus strikes.
This approach led to one of the earliest COVID vaccine candidates, developed at the aptly named Jenner Institute of the University of Oxford. Scientists there engineered the spike-protein gene into an adenovirus that causes the common cold in chimpanzees, but is relatively harmless in humans.
The lead researcher at Oxford is Sarah Gilbert. She worked on developing a vaccine for Middle East respiratory syndrome (MERS) using the same chimp adenovirus. That epidemic waned before her vaccine could be deployed, but it gave her a head start when COVID-19 struck. She already knew that the chimp adenovirus had successfully delivered into humans the gene for the spike protein of MERS. As soon as the Chinese published the genetic sequence of the new coronavirus in January 2020, she began engineering its spike-protein gene into the chimp virus, waking each day at 4 a.m.
Her 21-year-old triplets, all of whom were studying biochemistry, volunteered to be early testers, getting the vaccine and seeing if they developed the desired antibodies. (They did.) Trials in monkeys conducted at a Montana primate center in March also produced promising results.
Bill Gates, whose foundation provided much of the funding, pushed Oxford to team up with a major company that could test, manufacture and distribute the vaccine. So Oxford forged a partnership with AstraZeneca, the British-Swedish pharmaceutical company. Unfortunately, the clinical trials turned out to be sloppy, with the wrong doses given to some participants, which led to delays. Britain authorized it for emergency use at the end of December, and the U.S. is likely to do so in the next two months.
Johnson & Johnson is testing a similar vaccine that uses a human adenovirus, rather than a chimpanzee one, as the delivery mechanism to carry a gene that codes for making part of the spike protein. It’s a method that has shown promise in the past, but it could have the disadvantage that humans who have already been exposed to that adenovirus may have some immunity to it. Results from its clinical trial are expected later this month.
In addition, two other vaccines based on genetically engineered adenoviruses are now in limited distribution: one made by CanSino Biologics and being used on the military in China and another named Sputnik V from the Russian ministry of health.
There is another way to get genetic material into a human cell and cause it to produce the components of a dangerous virus, such as the spike proteins, that can stimulate the immune system. Instead of engineering the gene for the component into an adenovirus, you can simply inject the genetic code for the component into humans as DNA or RNA.
Let’s start with DNA vaccines. Researchers at Inovio Pharmaceuticals and a handful of other companies in 2020 created a little circle of DNA that coded for parts of the coronavirus spike protein. The idea was that if it could get inside the nucleus of a cell, the DNA could very efficiently churn out instructions for the production of the spike-protein parts, which serve to train the immune system to react to the real thing.
The big challenge facing a DNA vaccine is delivery. How can you get the little ring of DNA not only into a human cell but into the nucleus of the cell? Injecting a lot of the DNA vaccine into a patient’s arm will cause some of the DNA to get into cells, but it’s not very efficient.
Some of the developers of DNA vaccines, including Inovio, tried to facilitate the delivery into human cells through a method called electroporation, which delivers electrical shock pulses to the patient at the site of the injection. That opens pores in the cell membranes and allows the DNA to get in. The electric pulse guns have lots of tiny needles and are unnerving to behold. It’s not hard to see why this technique is unpopular, especially with those on the receiving end. So far, no easy and reliable delivery mechanism has been developed for getting DNA vaccines into the nucleus of human cells.
That leads us to the molecule that has proven victorious in the COVID vaccine race and deserves the title of TIME magazine’s Molecule of the Year: RNA. Its sibling DNA is more famous. But like many famous siblings, DNA doesn’t do much work. It mainly stays bunkered down in the nucleus of our cells, protecting the information it encodes. RNA, on the other hand, actually goes out and gets things done. The genes encoded by our DNA are transcribed into snippets of RNA that venture out from the nucleus of our cells into the protein-manufacturing region. There, this messenger RNA (mRNA) oversees the assembly of the specified protein. In other words, instead of just sitting at home curating information, it makes real products.
Scientists including Sydney Brenner at Cambridge and James Watson at Harvard first identified and isolated mRNA molecules in 1961. But it was hard to harness them to do our bidding, because the body’s immune system often destroyed the mRNA that researchers engineered and attempted to introduce into the body. Then in 2005, a pair of researchers at the University of Pennsylvania, Katalin Kariko and Drew Weissman, showed how to tweak a synthetic mRNA molecule so it could get into human cells without being attacked by the body’s immune system.
When the COVID-19 pandemic hit a year ago, two innovative young pharmaceutical companies decided to try to harness this role played by messenger RNA: the German company BioNTech, which formed a partnership with the U.S. company Pfizer and Moderna, based in Cambridge, Mass. Their mission was to engineer messenger RNA carrying the code letters to make part of the coronavirus spike protein&mdasha string that begins CCUCGGCGGGCA … &mdashand to deploy it in human cells.
BioNTech was founded in 2008 by the husband-and-wife team of Ugur Sahin and Ozlem Tureci, who met when they were training to be doctors in Germany in the early 1990s. Both were from Turkish immigrant families, and they shared a passion for medical research, so much so that they spent part of their wedding day working in the lab. They founded BioNTech with the goal of creating therapies that stimulate the immune system to fight cancerous cells. It also soon became a leader in devising medicines that use mRNA in vaccines against viruses.
In January 2020, Sahin read an article in the medical journal Lancet about a new coronavirus in China. After discussing it with his wife over breakfast, he sent an email to the other members of the BioNTech board saying that it was wrong to believe that this virus would come and go as easily as MERS and SARS. “This time it is different,” he told them.
BioNTech launched a crash project to devise a vaccine based on RNA sequences, which Sahin was able to write within days, that would cause human cells to make versions of the coronavirus’s spike protein. Once it looked promising, Sahin called Kathrin Jansen, the head of vaccine research and development at Pfizer. The two companies had been working together since 2018 to develop flu vaccines using mRNA technology, and he asked her whether Pfizer would want to enter a similar partnership for a COVID vaccine. “I was just about to call you and propose the same thing,” Jansen replied. The deal was signed in March.
By then, a similar mRNA vaccine was being developed by Moderna, a much smaller company with only 800 employees. Its chair and co-founder, Noubar Afeyan, a Beirut-born Armenian who immigrated to the U.S., had become fascinated by mRNA in 2010, when he heard a pitch from a group of Harvard and MIT researchers. Together they formed Moderna, which initially focused on using mRNA to try to develop personalized cancer treatments, but soon began experimenting with using the technique to make vaccines against viruses.
In January 2020, Afeyan took one of his daughters to a restaurant near his office in Cambridge to celebrate her birthday. In the middle of the meal, he got an urgent text message from the CEO of his company, Stéphane Bancel, in Switzerland. So he rushed outside in the freezing temperature, forgetting to grab his coat, to call him back.
Bancel said that he wanted to launch a project to use mRNA to attempt a vaccine against the new coronavirus. At that point, Moderna had more than 20 drugs in development but none had even reached the final stage of clinical trials. Nevertheless, Afeyan instantly authorized him to start work. “Don’t worry about the board,” he said. “Just get moving.” Lacking Pfizer’s resources, Moderna had to depend on funding from the U.S. government. Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases, was supportive. “Go for it,” he declared. “Whatever it costs, don’t worry about it.”
It took Bancel and his Moderna team only two days to create the RNA sequences that would produce the spike protein, and 41 days later, it shipped the first box of vials to the National Institutes of Health to begin early trials. Afeyan keeps a picture of that box on his cell phone.
An mRNA vaccine has certain advantages over a DNA vaccine, which has to use a re-engineered virus or other delivery mechanism to make it through the membrane that protects the nucleus of a cell. The RNA does not need to get into the nucleus. It simply needs to be delivered into the more-accessible outer region of cells, the cytoplasm, which is where proteins are constructed.
The Pfizer-BioNTech and Moderna vaccines do so by encapsulating the mRNA in tiny oily capsules, known as lipid nanoparticles. Moderna had been working for 10 years to improve its nanoparticles. This gave it one advantage over Pfizer-BioNTech: its particles were more stable and did not have to be stored at extremely low temperatures.
By November, the results of the Pfizer-BioNTech and Moderna late-stage trials came back with resounding findings: both vaccines were more than 90% effective. A few weeks later, with COVID-19 once again surging throughout much of the world, they received emergency authorization from the U.S. Food and Drug Administration and became the vanguard of the biotech effort to beat back the pandemic.
The ability to code messenger RNA to do our bidding will transform medicine. As with the COVID vaccines, we can instruct mRNA to cause our cells to make antigens&mdashmolecules that stimulate our immune system&mdashthat could protect us against many viruses, bacteria, or other pathogens that cause infectious disease. In addition, mRNA could in the future be used, as BioNTech and Moderna are pioneering, to fight cancer. Harnessing a process called immunotherapy, the mRNA can be coded to produce molecules that will cause the body’s immune system to identify and kill cancer cells.
RNA can also be engineered, as Jennifer Doudna and others discovered, to target genes for editing. Using the CRISPR system adapted from bacteria, RNA can guide scissors-like enzymes to specific sequences of DNA in order to eliminate or edit a gene. This technique has already been used in trials to cure sickle cell anemia. Now it is also being used in the war against COVID. Doudna and others have created RNA-guided enzymes that can directly detect SARS-CoV-2 and eventually could be used to destroy it.
More controversially, CRISPR could be used to create “designer babies” with inheritable genetic changes. In 2018, a young Chinese doctor used CRISPR to engineer twin girls so they did not have the receptor for the virus that causes AIDS. There was an immediate outburst of awe and then shock. The doctor was denounced, and there were calls for an international moratorium on inheritable gene edits. But in the wake of the pandemic, RNA-guided genetic editing to make our species less receptive to viruses may someday begin to seem more acceptable.
Throughout human history, we have been subjected to wave after wave of viral and bacterial plagues. One of the earliest known was the Babylon flu epidemic around 1200 B.C. The plague of Athens in 429 B.C. killed close to 100,000 people, the Antonine plague in the 2nd century killed 5 million, the plague of Justinian in the 6th century killed 50 million, and the Black Death of the 14th century took almost 200 million lives, close to half of Europe’s population.
The COVID-19 pandemic that killed more than 1.8 million people in 2020 will not be the final plague. However, thanks to the new RNA technology, our defenses against most future plagues are likely to be immensely faster and more effective. As new viruses come along, or as the current coronavirus mutates, researchers can quickly recode a vaccine’s mRNA to target the new threats. “It was a bad day for viruses,” Moderna’s chair Afeyan says about the Sunday when he got the first word of his company’s clinical trial results. “There was a sudden shift in the evolutionary balance between what human technology can do and what viruses can do. We may never have a pandemic again.”
The invention of easily reprogrammable RNA vaccines was a lightning-fast triumph of human ingenuity, but it was based on decades of curiosity-driven research into one of the most fundamental aspects of life on planet earth: how genes are transcribed into RNA that tell cells what proteins to assemble. Likewise, CRISPR gene-editing technology came from understanding the way that bacteria use snippets of RNA to guide enzymes to destroy viruses. Great inventions come from understanding basic science. Nature is beautiful that way.
Isaacson, a former editor of TIME, is the author of The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race, to be published in March. After the Pfizer vaccine was approved, he opted to remain in the clinical trial and has not yet been “unblinded.”