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Why and how is DNA synthesis so much faster then RNA synthesis in bacteria?

Why and how is DNA synthesis so much faster then RNA synthesis in bacteria?


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DNA synthesis in E. coli is 20x faster than RNA synthesis at 1000nt/s vs 50nt/s. (Mirkin'05)

I find that perplexing since DNA polymerization has better proofreading than the RNA variety, which requires extra time as you need to backtrack, excise, and replace. Also, in bacteria there's almost no splicing, so that doesn't slow you down. And the 1000nt/s is a single replication fork. We are not talking about several replisomes together clocking 1knt per second.

Is there an explanation of this or, in the absence of evidence, hypotheses?


I wouldn't call them hypotheses, but the question is intriguing, and, as it seems to be ignored in the literature, I'll make a couple of suggestions.

  1. Perhaps it has something to do with recognition of termination signals in relation to selective pressure for speed in the two processes.

Perhaps if elongation of the RNA chain were any faster it wouldn't be able to respond to the rho-independent termination signals which are thought to be specific stem-loops in the DNA that cause the RNA polymerase to pause and fall off the DNA. The speeding RNA polymerase might disrupt the loops instead. The termination system for DNA replication may have evolved to be much more robust so as to be able to bring faster elongation to a stop. (Note: my suggestion of different 'robustness' in termination is not based on any data, it's pure speculation.)

If this were true, it would beg the question of why transcription hasn't evolved a more efficient termination system in concert with the a evolution of a smarter RNA polymerase. Perhaps the answer here is that there is no selective pressure for faster transcription - the rate is clearly sufficient to supply the needs of the cell - whereas the rate of DNA replication determines the time between cell divisions and thus the rate of growth, which is subject to selective pressure.

  1. Perhaps it has something to do with error frequency in relation to selective pressure for speed in the two processes.

First I'll make it clear that I think the proofreading argument in the question is a bit of a red herring. If the rate replication is 20x as fast as transcription, the occasional backtracking will not have much effect on the overall difference. However errors and proofreading could be involved in a different explanation.

RNA transcription does not have proof-reading. The length of RNA transcripts is such that the cell can tolerate the errors that occur. However if the speed transcription were increased it is reasonable to expect an increase in error frequency, which might be detrimental. The current rate of transcription may be a trade-off between efficiency and accuracy. Of course one can imagine a proof-reading system for transcription evolving if it were necessary, but, as discussed above, if the rate of transcription is adequate there would seem to be no selective pressure to produce.


This is because of the fact that DNA polymerase does the fast process that is 1000 nu/sec as compared to the RNA polymerase that 1000-2000nu/min because this process is done without discrimination and also DNA pol has exonuclease activity


Why and how is DNA synthesis so much faster then RNA synthesis in bacteria? - Biology

Nucleic acids are the most important macromolecules for the continuity of life. They carry the genetic blueprint of a cell and carry instructions for the functioning of the cell.

The two main types of nucleic acids are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). DNA is the genetic material found in all living organisms, ranging from single-celled bacteria to multicellular mammals. It is found in the nucleus of eukaryotes and in the organelles, chloroplasts, and mitochondria. In prokaryotes, the DNA is not enclosed in a membranous envelope.

The entire genetic content of a cell is known as its genome, and the study of genomes is genomics. In eukaryotic cells but not in prokaryotes, DNA forms a complex with histone proteins to form chromatin, the substance of eukaryotic chromosomes. A chromosome may contain tens of thousands of genes. Many genes contain the information to make protein products other genes code for RNA products. DNA controls all of the cellular activities by turning the genes “on” or “off.”

The other type of nucleic acid, RNA, is mostly involved in protein synthesis. The DNA molecules never leave the nucleus but instead use an intermediary to communicate with the rest of the cell. This intermediary is the messenger RNA (mRNA). Other types of RNA—like rRNA, tRNA, and microRNA—are involved in protein synthesis and its regulation.

DNA and RNA are made up of monomers known as nucleotides. The nucleotides combine with each other to form a polynucleotide, DNA or RNA. Each nucleotide is made up of three components: a nitrogenous base, a pentose (five-carbon) sugar, and a phosphate group (Figure 1). Each nitrogenous base in a nucleotide is attached to a sugar molecule, which is attached to one or more phosphate groups.

Figure 1. A nucleotide is made up of three components: a nitrogenous base, a pentose sugar, and one or more phosphate groups. Carbon residues in the pentose are numbered 1′ through 5′ (the prime distinguishes these residues from those in the base, which are numbered without using a prime notation). The base is attached to the 1′ position of the ribose, and the phosphate is attached to the 5′ position. When a polynucleotide is formed, the 5′ phosphate of the incoming nucleotide attaches to the 3′ hydroxyl group at the end of the growing chain. Two types of pentose are found in nucleotides, deoxyribose (found in DNA) and ribose (found in RNA). Deoxyribose is similar in structure to ribose, but it has an H instead of an OH at the 2′ position. Bases can be divided into two categories: purines and pyrimidines. Purines have a double ring structure, and pyrimidines have a single ring.

The nitrogenous bases, important components of nucleotides, are organic molecules and are so named because they contain carbon and nitrogen. They are bases because they contain an amino group that has the potential of binding an extra hydrogen, and thus, decreases the hydrogen ion concentration in its environment, making it more basic. Each nucleotide in DNA contains one of four possible nitrogenous bases: adenine (A), guanine (G) cytosine (C), and thymine (T). RNA nucleotides also contain one of four possible bases: adenine, guanine, cytosine, and uracil (U) rather than thymine.

Adenine and guanine are classified as purines. The primary structure of a purine is two carbon-nitrogen rings. Cytosine, thymine, and uracil are classified as pyrimidines which have a single carbon-nitrogen ring as their primary structure (Figure 1). Each of these basic carbon-nitrogen rings has different functional groups attached to it. In molecular biology shorthand, the nitrogenous bases are simply known by their symbols A, T, G, C, and U. DNA contains A, T, G, and C whereas RNA contains A, U, G, and C.

The pentose sugar in DNA is deoxyribose, and in RNA, the sugar is ribose (Figure 1). The difference between the sugars is the presence of the hydroxyl group on the second carbon of the ribose and hydrogen on the second carbon of the deoxyribose. The carbon atoms of the sugar molecule are numbered as 1′, 2′, 3′, 4′, and 5′ (1′ is read as “one prime”). The phosphate residue is attached to the hydroxyl group of the 5′ carbon of one sugar and the hydroxyl group of the 3′ carbon of the sugar of the next nucleotide, which forms a 5′–3′ phosphodiester linkage. The phosphodiester linkage is not formed by simple dehydration reaction like the other linkages connecting monomers in macromolecules: its formation involves the removal of two phosphate groups. A polynucleotide may have thousands of such phosphodiester linkages.

DNA Double-Helix Structure

Figure 2. DNA is an antiparallel double helix. The phosphate backbone (the curvy lines) is on the outside, and the bases are on the inside. Each base interacts with a base from the opposing strand. (credit: Jerome Walker/Dennis Myts)

DNA has a double-helix structure (Figure 2). The sugar and phosphate lie on the outside of the helix, forming the backbone of the DNA. The nitrogenous bases are stacked in the interior, like the steps of a staircase, in pairs the pairs are bound to each other by hydrogen bonds. Every base pair in the double helix is separated from the next base pair by 0.34 nm.

The two strands of the helix run in opposite directions, meaning that the 5′ carbon end of one strand will face the 3′ carbon end of its matching strand. (This is referred to as antiparallel orientation and is important to DNA replication and in many nucleic acid interactions.)

Only certain types of base pairing are allowed. For example, a certain purine can only pair with a certain pyrimidine. This means A can pair with T, and G can pair with C, as shown in Figure 3. This is known as the base complementary rule. In other words, the DNA strands are complementary to each other. If the sequence of one strand is AATTGGCC, the complementary strand would have the sequence TTAACCGG. During DNA replication, each strand is copied, resulting in a daughter DNA double helix containing one parental DNA strand and a newly synthesized strand.

Practice Question

Figure 3. In a double stranded DNA molecule, the two strands run antiparallel to one another so that one strand runs 5′ to 3′ and the other 3′ to 5′. The phosphate backbone is located on the outside, and the bases are in the middle. Adenine forms hydrogen bonds (or base pairs) with thymine, and guanine base pairs with cytosine.

A mutation occurs, and cytosine is replaced with adenine. What impact do you think this will have on the DNA structure?

Ribonucleic acid, or RNA, is mainly involved in the process of protein synthesis under the direction of DNA. RNA is usually single-stranded and is made of ribonucleotides that are linked by phosphodiester bonds. A ribonucleotide in the RNA chain contains ribose (the pentose sugar), one of the four nitrogenous bases (A, U, G, and C), and the phosphate group.

There are four major types of RNA: messenger RNA (mRNA), ribosomal RNA (rRNA), transfer RNA (tRNA), and microRNA (miRNA). The first, mRNA, carries the message from DNA, which controls all of the cellular activities in a cell. If a cell requires a certain protein to be synthesized, the gene for this product is turned “on” and the messenger RNA is synthesized in the nucleus. The RNA base sequence is complementary to the coding sequence of the DNA from which it has been copied. However, in RNA, the base T is absent and U is present instead. If the DNA strand has a sequence AATTGCGC, the sequence of the complementary RNA is UUAACGCG. In the cytoplasm, the mRNA interacts with ribosomes and other cellular machinery (Figure 4).

Figure 4. A ribosome has two parts: a large subunit and a small subunit. The mRNA sits in between the two subunits. A tRNA molecule recognizes a codon on the mRNA, binds to it by complementary base pairing, and adds the correct amino acid to the growing peptide chain.

The mRNA is read in sets of three bases known as codons. Each codon codes for a single amino acid. In this way, the mRNA is read and the protein product is made. Ribosomal RNA (rRNA) is a major constituent of ribosomes on which the mRNA binds. The rRNA ensures the proper alignment of the mRNA and the ribosomes the rRNA of the ribosome also has an enzymatic activity (peptidyl transferase) and catalyzes the formation of the peptide bonds between two aligned amino acids. Transfer RNA (tRNA) is one of the smallest of the four types of RNA, usually 70–90 nucleotides long. It carries the correct amino acid to the site of protein synthesis. It is the base pairing between the tRNA and mRNA that allows for the correct amino acid to be inserted in the polypeptide chain. microRNAs are the smallest RNA molecules and their role involves the regulation of gene expression by interfering with the expression of certain mRNA messages.


What Is Rna Therapy

Are based on a novel lipid-encapsulated messenger RNA mRNA technology. A DNA or RNA vaccine has the same goal as traditional vaccines but they work slightly differently.

Small Rna Therapies For Cystic Fibrosis Cystic Fibrosis Secondary Science Scientific Articles

RNA and DNA are sometimes used as medicine.

What is rna therapy. By correcting the mistake the RNA can then be used to create the protein that the cell needs taking away the underlying cause of the disease. And if it is only a treatment that neither prevents infection nor transmission in truth it is no better than any of the other treatments floating around like IvermectionZincVit DHCQVit C HBOTozone etc. What it does is this gene therapy or medical device is setting up an autoimmune disease chronically.

In other words it is a treatment a genetic treatment that has never been used in humans before. RNA therapies that target proteins use a type of molecule known as an RNA aptamer. People take RNA and DNA for conditions such as athletic performance stomach and intestine problems immune system problems aging and.

Its anaphylaxis in the first wave. Unlike gene therapy which provides new DNA to cells RNA therapy modifies or provides ribonucleic acid RNA to patients cells. An RNA-based vaccine therefore acts as a code to instruct the body to make many copies of the virus proteinand the resulting antibodiesitself resulting in an immune response.

Evaluation of the vaccines effectiveness is outside the scope of this report. The purpose of this Evidence Advisory is to identify and summarize high-level evidence on the safety of mRNA vaccines. Such technologies would make gene therapy so much less difficult Often antivaxxers conflate RNA with DNA and vice-versa not realizing that although both molecules contain genetic information needed for a cell to make protein they are nonetheless very.

Instead of injecting a weakened form of a virus or bacteria into the body DNA and RNA vaccines use part of the virus own genes to stimulate an immune response. Unlike more traditional vaccines RNA-based vaccines are also beneficial in. How RNA therapy works Why focus on RNA therapies.

The molecule is designed to bind to a specific site on a specific protein to modulate its function. RNA interference therapeutics are based on a natural process by which RNA sequences can block the expression of DNA into protein. An article titled m6A RNA modification as a new player in R-loop regulation by the Dynamic Gene Regulation research group led by Arne Klungland at IMB was published in.

Despite the overwhelming popularity of gene-editing technologies like CRISPR new advancements in RNA therapy are poised to address some of their serious limitations. It is becoming increasingly clear that unique RNA profiles within individual cancers may play a major role in defining both the biology of the cancer and its response to therapy says Maurie Markman MD President of Medicine Science for the Cancer Treatment Centers of America CTCA. MRNA vaccines used for therapeutic purposes such as those used in cancer.

An RNA therapy is designed to correct the mistake or mutation in the RNA of someone with a genetic disease. Note the false equivalence. Its anaphylaxis allergic reaction the 2nd wave.

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The functional difference between DNA vs RNA:

The main function of DNA is storing and transferring information from one generation to another generation in a population. For that DNA replicates- becomes doubled and inherited to daughter cells.

Therefore, inherited from one generation to another.

On the other side, the function of RNA is to form a protein.

Actually, RNA collects the coding information from DNA through transcription and translates it into a chain of amino acid. (A long chain of amino acid- polypeptide chain, creates protein).

On the basis of that, another difference between both is that-

“The DNA is self-replicating while the RNA is synthesised from DNA only when it needed.”

Different types of DNA:

DNA in nature, found in five different forms- A-DNA, B-DNA, C-DNA, D-DNA and Z-DNA.

The B form DNA is found in almost all living organism and most prevalent in nature. It is a right-handed DNA with a major and minor groove. It has 10.5 base pairs per helical turn.

The A-form DNA is also right-handed but the helix is wider than the B-form DNA. It has the major and minor groove and has 11 base pairs per helical turn.

The z-form DNA is left-handed and does not have the major groove in it. It has 12 base pairs per helical turn.

The C-form DNA is very rare varients having 9.33 base pairs per helical turn. Even, the D-form is extremely rare.

Different types of RNA:

mRNA: a messenger RNA encodes amino acid for creating a polypeptide chain.

tRNA: a transfer RNA helps to transfer amino acid to the site of translation henceforth, in the cytoplasm at the ribosome.

rRNA: a cytoplasmic ribosomal RNA is a component of ribosome required for protein synthesis.

Graphical illustration of the process of transcription and translation. mRNA is formed from the DNA through transcription while a chain of amino acid translated from the mRNA.

Other smaller RNAs: other smaller fragments of dsRNA called microRNA and siRNA are also present in a cell.

Several more differences:

“The alkaline condition is more favourable for a DNA henceforth, the DNA is more stable under alkaline condition while the RNA is not.”

The DNA is made up of the manor and minor groove, the minor groove doesn’t allow enzyme binding, so it is very difficult for nuclease to bind with DNA and destroy it.

Contrary to this, the RNA is single-stranded and does not have a minor groove structure, a nuclease can attack it easily and destroy it.

However, RNA break-down and re-synthesis continuously occur in a cell, faster than DNA.

“The DNA is less reactive because of the stability provided by the C-H bonds of deoxyribose while the RNA is more reactive due to the O-H bonds of ribose.”

“A genome- made up of the DNA carries some methylated DNA as well which can neither express. On the other side, none of the RNAs is methylated.”

Another important difference between DNA and RNA is the susceptibility against ultraviolet rays.

The Ultraviolet rays- UV rays are one of the common types of natural mutagens that damages our DNA.

A mutagen UV damages our DNA and causes genetic mutations. The DNA is more susceptible to UV damage while the RNA is resistant to UV, comparatively.

Graphical illustration of the major differences between DNA and RNA.

Some more…

DNA is double-stranded and longer while the RNA is shorter and single-stranded, hence the RNA migrates above DNA in a gel. If you see a smear above the DNA band in a gel, your DNA is contaminated with the RNA.

Extracting DNA is even easier than the RNA RNase presents everywhere even on our hands and on other instruments thus RNA can easily be broken down or destroyed during isolation.

An additional step of reverse transcription is required during the RNA sequencing but not in DNA sequencing. The extracted RNA is first reverse-transcribed to the cDNA and then processed for sequencing.

These are some of the Differences which you should know about DNA and RNA. Now let’s talk about similarities.


What is PCR?

Polymerase Chain Reaction (PCR) is an in vitro DNA amplification technique that is routinely performed in Molecular Biological laboratories. This method enabled the production of thousands to millions of copies of a particularly interested DNA fragment. PCR was introduced by Kary Mullis in 1980. In this technique, the interested fragment of DNA is served as the template for making copies. The enzyme called Taq polymerase is used as the DNA polymerase enzyme, and it will catalyze the synthesis of new strands of the DNA fragment. Primers that are in the PCR mixture will work as the starting points for the fragment extensions. At the end of the PCR reaction, many copies of the sample DNA can be obtained.

All the ingredients that are necessary to make copies of DNA are included in the PCR mixture. They are sample DNA, DNA polymerase (Taq polymerase), primers (forward and reverse primers), nucleotides (building blocks of DNA) and a buffer. PCR reaction is run in a PCR machine, and it should be fed with correct PCR mixture and the correct PCR program. If the reaction mixture and the program are correct, it will produce the required amount of copies of a particular section of DNA from a very small amount of DNA.

There are three major steps involved in a PCR reaction namely denaturation, primer annealing and strand extension. These three steps occur at three different temperatures. DNA exists as a double-stranded helix. Two strands are bonded by hydrogen bonds. Prior to amplification, double-stranded DNA is separated by giving a high temperature. At high temperature, double-stranded DNA denatured into single strands. Then the primers anneal with the flanking ends of the interested fragment or the gene of the DNA. Primer is a short piece of single-stranded DNA that is complementary to the ends of the target sequence. Forward and reverse primers anneal with the complementary bases at the flanking ends of the denatured sample DNA at the annealing temperature.

When primers are annealed with DNA, Taq polymerase enzyme initiates the synthesis of the new strands by adding nucleotides that are complementary to the template DNA. Taq polymerase is a heat stable enzyme that is isolated from a thermophilic bacterium called Thermus aquaticus. PCR buffer maintains the optimal conditions for the Taq polymerase action. These three stages of PCR reaction are repeated to produce the required amount of the PCR product. At each PCR reaction, the number of the DNA copy is doubling. Hence, an exponential amplification can be observed in PCR. PCR product can be observed using gel electrophoresis since it produces the visible amount of DNA on a gel and it can be purified for further studies such as sequencing etc.

Figure 01: PCR

PCR is a valuable tool in medical and biological research. Especially in forensic studies, PCR has an immense value since it can amplify DNA for studies from the tiny samples of the criminals and make forensic DNA profiles. PCR is widely used in many areas of the Molecular biology including, genotyping, gene cloning, mutation detection, DNA sequencing, DNA microarrays and paternity testing etc.


Epitranscriptomics: The new RNA code and the race to drug it

A small group of scientists studying chemical modifications on RNA ushered in the field of epitranscriptomics. Now they’re hoping it will create an entirely new way to treat cancer

By Ryan Cross, Chemical & Engineering News, Feb. 18, 2019

It’s not every day that a biotech investor stumbles across an entirely new field of science. And frankly, Carlo Rizzuto wasn’t even looking for such a thing. When Rizzuto, a partner at the venture capital firm Versant Ventures, embarked on a scouting trip to New York City in 2014, he was simply hoping to discover academic research that was ripe enough to form the basis of a biotech company.

Rizzuto had an appointment with Samie Jaffrey, an RNA scientist at Weill Cornell Medicine. RNA is often described as a cousin to DNA—the stuff that our genes are made of. One kind of RNA, called messenger RNA, acts as the intermediary code that cells use to transfer information stored in DNA into a set of instructions that cells can easily read for making proteins.

After Rizzuto rejected several of his projects, Jaffrey mentioned a relatively young line of work focused on studying chemical modifications to RNA. In 2012, his lab invented a method to map the location of methyl groups that, for some reason, cells were adding to their mRNA. It was reminiscent of another field, called epigenetics, or the study of chemical modifications made to DNA to turn genes on or off. The entirety of RNA in a cell is called the transcriptome, so Jaffrey dubbed the new field “epitranscriptomics.”

Rizzuto perked up. “This is something that we would be very interested in,” he said.Credit: Gotham TherapeuticsSamie Jaffrey, a professor of pharmacology at Weill Cornell Medicine and cofounder of Gotham Therapeutics, explains the m6A modification on RNA. Jaffrey’s lab invented a technique to map the location of m6A on RNA.

Jaffrey was hesitant. “We’re just doing basic stuff now,” he recalls explaining. His lab, and others, was still trying to figure out how this RNA modification system worked. They were building evidence suggesting that enzymes added and removed these methyl marks to control the fate of mRNA, and thus protein production, but many questions remained. Jaffrey implored: “Carlo, what disease would we be curing if we started a company around epitranscriptomics?”

“It doesn’t matter,” Rizzuto replied. “This is so central to molecular biology it has to be related to fundamental disease processes.”

Then reality kicked in. Venture capital firms like Rizzuto’s aren’t in the business of funding years of basic research just to see if something like epitranscriptomics is involved in disease. “We were looking at a new paradigm for gene-expression regulation,” Rizzuto recalls, but it was too early to start a company. He and Jaffrey agreed to stay in touch.

Rizzuto’s enthusiasm in 2014 has since percolated among scientists and investors learning about epitranscriptomics. Several groups, including Jaffrey’s, have shown that the epitranscriptomic code—the number and location of chemical modifications across a cell’s RNA—is seriously out of whack in some cancers. And with basic tools in hand to read this previously hidden layer of information in cells, biotech companies are now out to alter it. Three start-ups, including one that Jaffrey and Rizzuto helped found, called Gotham Therapeutics, have launched with more than $110 million in total dedicated to epitranscriptomics drug discovery.

There was a similar reaction to epigenetics more than a decade ago, when it became clear that chemical modifications regulating genes are frequently out of whack in cancer. Companies rushed to develop drugs against proteins responsible for making, removing, and recognizing chemical modifications on genes—often referred to as the writer, eraser, and reader proteins. With the discovery of parallel writer, eraser, and reader proteins working on RNA, epitranscriptomics is looking like a promising, untapped area for drug discovery.

But there’s another parallel to epigenetics that’s less optimistic: thus far, epigenetic drugs have been a disappointment. “Epigenetics turned out to be a lot more complicated than the community originally thought,” says Chuan He, a professor of chemistry at the University of Chicago.

He, a scientific founder of the epitranscriptomics company Accent Therapeutics, has been at the forefront of developing the new study of RNA modifications and their role in disease. He, Jaffrey, and many others are confident that understanding and controlling RNA modifications will provide completely new avenues for treating disease. “What this really offers is a totally new biology,” He says. “And whenever there is a new biology emerging there are always opportunities for therapies.”

EPITRANSCRIPTOMICS, ABRIDGED

A series of discoveries and technical advancements over the past decade has spawned a new field called epitranscriptomics, the study of chemical modifications to RNA, and the proteins that write, erase, and read these modifications. In recent years, studies implicating epitranscriptomic proteins in cancer have led to the launch of three biotech companies dedicated to drugging these proteins.

May 2008: Rupert Fray shows that a methyl-adding enzyme is essential for plant development. The study inspires others to look at RNA modifications.

November 2010: Chuan He proposes new field of RNA epigenetics, suggesting that methyl modifications on RNA can be removed.

October 2011: Chuan He’s lab proves that an enzyme called FTO erases methyl modifications on RNA.

April and May 2012: The labs of Gideon Rechavi (April) and Samie Jaffrey (May) publish the first maps of RNA methyl modifications. Jaffrey coins the word “epitranscriptomics.”

October 2014: Howard Chang’s lab shows that METTL3, which adds methyl groups to RNA, is critical for embryonic stem cell development and differentiation.

June 2016: Storm Therapeutics, founded by University of Cambridge scientists Tony Kouzarides and Eric Miska, raises $16 million to drug proteins that make RNA modifications.

September and November 2017: Independent studies from Samie Jaffrey and colleagues (September) and Tony Kouzarides and colleagues (November) show that METTL3 is elevated in acute myeloid leukemia and that suppressing the enzyme forces the cancer cells to become noncancerous.

May 2018: Accent Therapeutics, cofounded by Chuan He, Howard Chang, and Robert Copeland, raises $40 million.

October 2018: Gotham Therapeutics, cofounded by Samie Jaffrey, launches with $54 million.

February 2019: Evidence builds that epitranscriptomics may be important for cancer immunotherapy. Chuan He shows that deleting a reader protein boosts the efficacy of checkpoint inhibitors in mice.

MAKING A MAP

A series of events beginning in 2008 laid the foundation for epitranscriptomics. That year, while He was studying epigenetic enzymes that remove methyl modifications from DNA, he and University of Chicago biologist Tao Pan began doubting that all these enzymes were really working on DNA as others assumed. The evidence was particularly shaky for one enzyme, called fat mass and obesity-associated protein, or FTO.

But a study coming out of the lab of plant biologist Rupert Fray at the University of Nottingham reinforced He and Pan’s suspicions that RNA modifications were underappreciated. Fray showed that plants missing a methyl-adding enzyme—similar to an enzyme called METTL3 in humans—stopped growing at a specific early stage in their development.

Scientists knew that METTL3 placed a methyl on a specific nitrogen in adenosine, one of the four building blocks of RNA. This modified building block is called N 6 -methyladenosine, or m6A for short. Beyond m6A, chemists had cataloged some 150 different chemical modifications to RNA in bacteria, plants, and animals. If He could find an enzyme that removed the methyl groups, it would suggest that there was an undiscovered RNA control system in cells, analogous to epigenetic controls in DNA.

In 2010, He coined the phrase “RNA epigenetics” in a commentary that outlined his ideas (Nat. Chem. Biol., DOI: 10.1038/nchembio.482). A year later, He and Pan published evidence showing that the FTO enzyme was an eraser—it removed the methyl modifications made by METTL3 (Nat. Chem. Biol. 2011, DOI: 10.1038/nchembio.687).

METTL3 and FTO are both enzymes, which means they should be pretty straightforward to inhibit with small-molecule drugs. That notion would later be frequently cited by the new epitranscriptomics companies, although it would be several years still before these enzymes were connected to disease.

At first, the significance of these enzymes was lost on many researchers. At Weill Cornell, however, Jaffrey immediately recognized that He’s study was part of a new field that was about to explode. His lab had been working on a method to detect and map m6A across a cell’s mRNA. Jaffrey had also seen Fray’s work on m6A in plants and thought that if the modifications existed in humans, they must be doing something important in us too.

At the time, methods for studying m6A were rudimentary. Researchers could detect the presence of m6A in ground-up globs of mRNA run through common chemistry lab techniques like chromatography or mass spectrometry. “But you had no idea which mRNAs were being modified,” Jaffrey says. No one knew if all mRNA had some m6A or if the methyl modifications were found on only certain transcripts, he adds. “And frankly, it wasn’t even terribly clear that m6A levels changed.”This is so central to molecular biology it has to be related to fundamental disease processes.Carlo Rizzuto, partner, Versant Ventures

So Jaffrey and Kate Meyer, a postdoc in his lab, developed a technique to figure out which mRNAs contained these modifications. They used commercially available antibodies that attach to m6A to fish out fragments of human mRNA for sequencing (Cell 2012, DOI: 10.1016/j.cell.2012.05.003).

That technique allowed the creation of the first map of m6A. The results were stunning. “We thought that m6A was going to be all over the place, kind of random,” Jaffrey says. Instead, the researchers saw that methyl marks tended to cluster near an area called the stop codon, and only on certain mRNA transcripts. “It was so specific, it just knocked our socks off.”

An even closer inspection revealed that many of the mRNAs containing m6A were linked to differentiation and development, the same functions that were affected in Fray’s stunted plant embryos. “We were amazed,” Jaffrey says.

In April 2012, while Jaffrey and Meyer were waiting for their m6A paper to publish, another group, led by Gideon Rechavi at Tel Aviv University, published its own paper on the use of antibodies to map m6A in mouse and human cells (Nature 2012, DOI: 10.1038/nature11112). “It was met with a lot of skepticism,” says Dan Dominissini, the PhD student in Rechavi’s lab who led the project. “People didn’t get why it was important. It took a year to publish.”

The problem was researchers still hadn’t established a clear link between these RNA modifications and disease, or even basic human biology. Moreover, the field wouldn’t have its name of epitranscriptomics for another three weeks, when Jaffrey and Meyer’s paper describing their m6A-mapping technique was published online in May 2012. Although Jaffrey had been scooped, the back-to-back publications put epitranscriptomics on the radar. The field was poised to explode.

Editing the epitranscriptomic code

The most common RNA modification is N 6 -methyladenosine (m6A), which is made when a protein complex containing the “writer” enzyme METTL3 adds a methyl group to adenosine. Two different “eraser” enzymes, called ALKBH5 and FTO, can remove a methyl group to turn m6A back into adenosine.Credit: ALKBH5, FTO, and METTL3-METTL14 protein images created with the Protein Data Bank, NGL Viewer

SEARCHING FOR DISEASE

In Chicago, He was positioning his lab as the forefront of epitranscriptomics research. His group discovered that an enzyme called ALKBH5, like FTO, erased methyl marks on RNA, turning m6A back into adenosine. Yet even by 2014, two years after the m6A-mapping methods were published, epitranscriptomics wasn’t getting the recognition, or funding, that He thought it deserved. “People thought it was cute,” He says. “But biologists were not convinced of its significance.”

Epitranscriptomics was now a hot topic. As studies began bubbling up exploring the role of RNA modifications, particularly m6A, in a variety of cells and species, investors started putting money into the field. In June 2016, a British start-up called Storm Therapeutics raised $16 million and became the first company dedicated to tackling the new RNA epigenetics.

Although Storm was several years in the making, it wasn’t clear what diseases the company would be curing. Two University of Cambridge scientists, Tony Kouzarides and Eric Miska, began discussing the idea for the company back in 2012, when they had published work on obscure enzymes that chemically modify microRNAs, which regulate the function of other RNAs.

Although the enzymes were linked to cancer, at least in cells growing in a dish, the microRNA studies went largely unnoticed. Kouzarides and Miska thought more undiscovered links between RNA modifications and cancer must exist, but it took a few years to find investors willing to bet on their hypothesis. “I don’t think that there was a huge amount of actual data it was just the belief that there must be,” Storm’s CEO, Keith Blundy, says. “The idea that all of these chemical modifications on RNA weren’t dysregulated or mutated or changed in cancer was almost unthinkable.”

That belief, which echoes the sentiment that Versant Ventures’ Rizzuto expressed in Jaffrey’s office in 2014, was about to be validated. In the second half of 2016, studies began linking reader and writer proteins to cancer. Jaffrey saw the evidence firsthand in an ongoing study he was conducting in blood cancer. The implications for drug discovery were becoming clear. He reached out to Rizzuto. It was time to move forward.

ANNOTATIONS IN THE BLOOD

The common thread running through epitranscriptomics research was its link to cell differentiation and development. Chang’s and Rechavi’s stem cell studies on m6A gave several research labs—including He’s, Jaffrey’s, and Kouzarides’s—the idea to look at the role of these RNA modifications in a deadly blood cancer called acute myeloid leukemia.

Leukemia is essentially a disease of dysfunctional differentiation. Healthy people’s bones are filled with hematopoietic stem cells that produce white blood cells. In leukemia, these stem cells go haywire. They proliferate and displace other blood cells because they can’t differentiate, or mature, into normal white blood cells.

In December 2016, He’s lab, together with several collaborators, showed that tissue samples taken from people with certain kinds of acute myeloid leukemia displayed high levels of the enzyme FTO—which, five years earlier, He had discovered is an m6A eraser (Cancer Cell 2016, DOI: 10.1016/j.ccell.2016.11.017). A few months later, with a different set of collaborators, He showed that levels of the methyl-removing enzyme ALKBH5 were elevated in glioblastoma stem cells (Cancer Cell 2017, DOI: 10.1016/j.ccell.2017.02.013).Credit: Journal of the American Chemical SocietyA surface (mesh) structure of an RNA duplex (sticks) with the methyl modification of m6A (balls).

At the beginning of 2017, Lasky, the Column Group investor, reached out to He. Now that epitranscriptomic enzymes were tied to cancer, Lasky’s firm wanted to start a drug company to control RNA modifications. With the new cancer data in hand, He felt that the time was right.

The investors also knew about a publication in the works from Jaffrey and leukemia expert Michael Kharas at Memorial Sloan Kettering Cancer Center. The Column Group and Versant Ventures worked together for a time to begin forming a single epitranscriptomics company with several of the academic leaders. During the summer of 2017 however, the different players split into two camps. The Column Group brought on He and Chang as academic cofounders of Accent Therapeutics. Versant Ventures named Jaffrey the academic founder of Gotham Therapeutics.

While Accent and Gotham were still in stealth mode, Jaffrey published a study showing that genetic mutations led to fixed, elevated levels of METTL3 in acute myeloid leukemia, keeping white blood cells from forming. By reducing METTL3 levels, leukemia cells could be coaxed into undergoing differentiation to become noncancerous cells that eventually die (Nat. Med. 2017, DOI: 10.1038/nm.4416). “It was remarkable because we didn’t even need complete inhibition of METTL3,” Jaffrey says.

Two months later, Kouzarides’s lab at the University of Cambridge published similar results, with additional details on what METTL3 was doing in these cells (Nature 2017, DOI: 10.1038/nature24678). In leukemia, elevated METTL3 encouraged the production of proteins linked to cancer. “It is feeding the cell the very proteins that are driving tumorigenesis,” Gotham CEO Lee Babiss says.

Epitranscriptomics now had drug targets, diseases, and high-profile studies. After recruiting additional investors, Accent launched with $40 million in May 2018, and Gotham launched with $54 million in October. Storm Therapeutics is in the process of raising approximately $65 million for its second round of cash from investors. Although none of these companies will name their targets or first diseases they will attempt to treat, conversations with the companies’ CEOs suggest that developing inhibitors of METTL3 is a goal for all three.

Drug designers have a lot of experience inhibiting enzymes, making METTL3 an attractive first target. But its activity may not be straightforward, says Yunsun Nam, a biophysicist at the University of Texas Southwestern Medical Center. METTL3 grabs the methyl group it adds to RNA from S-adenosylmethionine (SAM), a molecule used by several other enzymes. Companies’ compounds will need to avoid inhibiting these other enzymes as well, she explains.

Nam thinks a workaround could be targeting a protein called METTL14, which is attached to METTL3 as part of a larger m6A-writing complex. “METTL3 and METTL14 are very dependent on each other for stability,” she says.

Even if the companies can develop selective METTL3 inhibitors, it’s unclear how many people would benefit from them. While the leukemia studies by Jaffrey and Kouzarides showed that m6A levels are too high, He’s leukemia and glioblastoma studies showed the opposite, that m6A levels are too low. Other studies have suggested more contradictory results—including that m6A levels may be too high in glioblastoma. In other words, when developing therapies, it will be crucial to know the epitranscriptomic state of one’s cancer cells. Otherwise, giving the wrong person a METTL3 inhibitor might make things worse.

“That’s a possibility,” Robert Copeland, the president and chief scientific officer of Accent, acknowledges. The challenge for Accent and other companies will be to figure out which subset of people with leukemia would benefit from a METTL3 inhibitor, to lower m6A levels, and which would benefit from an FTO inhibitor, to raise m6A levels, Copeland explains. “If the pendulum swings too much one way or too much the other way, you can cause disease.”Credit: Accent TherapeuticsRobert Copeland, president and chief scientific officer of Accent Therapeutics

EPI-EXPANSION

Although the leaders of Accent, Gotham, and Storm are being secretive about their strategies, they all hint that the potential scope of epitranscriptomics drug discovery is much bigger than just targeting METTL3.

In addition to the m6A erasers, a growing body of work is uncovering the importance of the m6A readers. Earlier this month, He’s lab showed that an m6A reader protein called YTHDF1 is an important control switch in the immune system and that inhibiting it might dramatically boost the efficacy of existing checkpoint inhibitors, a popular class of cancer immunotherapy (Nature 2019, DOI: 10.1038/s41586-019-0916-x). “I think a lot of immunotherapy companies will jump into epitranscriptomics once they read the paper,” He says.

And this isn’t the first known link between epitranscriptomics and immunotherapy, Accent’s Copeland says. His firm has been studying an enzyme called ADAR1—which stands for adenosine deaminase acting on RNA—that modifies adenosine bases in RNA. Studies from academic labs show that some tumors depend on ADAR1 in ways that normal cells do not. One study suggests that blocking ADAR1 could make certain drug-resistant cancers vulnerable to checkpoint inhibitors (Nature 2018, DOI: 10.1038/s41586-018-0768-9).

Other labs entering the fray are uncovering new proteins that read, write, and erase RNA modifications, with links to additional types of cancer and other diseases. The scope of epitranscriptomics could be enormous. “That’s what excites us about the field,” says Blundy, Storm’s CEO. “There are many, many RNA pathways that are regulated through modifications.”

The discoveries aren’t all coming smoothly, however. For example, Jaffrey claims that the main target of the eraser enzyme FTO isn’t actually m6A but a slightly different modification, called m6Am. Others disagree. “There is still some debate, but that is the normal trajectory for a field, especially in the early days,” Jaffrey says.

The field also still has technical hurdles. “Right now the methods to map and detect m6A are crude,” Jaffrey admits. Existing methods require large sample sizes and are ineffective at quantifying how m6A levels change over time on particular mRNA transcripts. His lab is now working on ways to better quantify m6A to diagnose or predict diseases in the clinic. Such tools will be critical for recruiting the right people into clinical studies testing inhibitors of epitranscriptomic proteins.

Another issue is the lack of publicly available small-molecule inhibitors for studying epitranscriptomic proteins. “We don’t even have an inhibitor for research,” says Dominissini, who has also developed new RNA-modification-mapping techniques and now runs his own epitranscriptomics lab at Tel Aviv University. Right now, researchers have to use genetic techniques to remove or block production of writer, eraser, and reader proteins, but what the field really needs are simple small molecules to test the hypotheses that these proteins will make good drug targets, he says. Of course, that’s what the companies are working on.

A similar lack of compounds stalled epigenetics drug discovery more than a decade ago. Pioneers in the epitranscriptomics field are unfazed by these parallels. “I don’t think there is a relationship between the success or failure of an epigenetics drug to an epitranscriptomics drug,” Jaffrey says.

The scientists and companies in the field are running full speed ahead. Hundreds of labs have cited papers from Dominissini, He, and Jaffrey, and all can point to several ongoing studies investigating the role of RNA modifications in other diseases. “It reflects how fast people jumped into the field,” He says. “Epitranscriptomics is booming.”


How Synthetic Biology Can Help the Environment

Most environmental science is focused on how to turn back the clock, not push it forward, says Ben Bostick, a geochemist at Lamont-Doherty Earth Observatory. “We think about how we can roll back our footprint, and not so much about how can we make our footprint bigger in a positive way,” he said. “But there are many examples of synthetic biology that I think actually have a lot of potential in the environment. Think of how we can help our environment just by doing things like improving the materials we make using synthetic biology.”

Synthetic biology (synbio) is the construction of biological components, such as enzymes and cells, or functions and organisms that don’t exist in nature, or their redesign to perform new functions. Synthetic biologists identify gene sequences that give organisms certain traits, create them chemically in a lab, then insert them into other microorganisms, like E. coli, so that they produce the desired proteins, characteristics or functions.

Since 2011, when I wrote a general introduction to synbio, the field has grown rapidly.

One reason for this is the development of the gene editing tool CRISPR-Cas9, first used in 2013, that locates, cuts and replaces DNA at specific locations. Another reason is how easy it has become to use the Registry of Standard Biological Parts, which catalogs over 20,000 genetic parts or BioBricks that can be ordered and used to create new synthetic organisms or systems.

In 2018, investors poured $3.8 billion and governments around the world invested $50 million into synbio companies. By 2022, the global market for synbio applications is projected to be $13.9 billion. But synthetic biology is still controversial because it involves altering nature and its potential and risks are not completely understood.

Bostick, who works on remediating arsenic contamination of groundwater by stimulating natural bacteria to produce substances that arsenic sticks to, explained that, in fact, the entire biological community that works on organisms alters biological systems all the time, but don’t change genetic material or organisms. Scientists delete enzymes, insert new ones, and change different things in order to understand the natural world “Those are standard techniques now but they’re done mechanistically,” he said. “If you want to see how a protein works, what do you do? You actually change it—that’s exactly how we have studied our environment. They are synthetic and they are biological alterations but they’re just not done with the purpose that defines synthetic biology.” Synbio is more controversial because its purpose is to build artificial biological systems that don’t already exist in the natural world.

Nevertheless, synthetic biology is producing some potential solutions to our most intractable environmental problems. Here are some examples.

Dealing with pollution

Microbes have been used to sense, identify and quantify environmental pollutants for decades. Now synthesized microbial biosensors are able to target specific toxins such as arsenic, cadmium, mercury, nitrogen, ammonium, nitrate, phosphorus and heavy metals, and respond in a variety of ways. They can be engineered to generate an electrochemical, thermal, acoustic or bioluminescent signal when encountering the designated pollutant.

CRISPR was used to give fruit flies red fluorescent eyes. Photo: NICHD

Some microbes can decontaminate soil or water naturally. Synthesizing certain proteins and transferring them to these bacteria can improve their ability to bind to or degrade heavy metals or radionuclides. One soil bacterium was given new regulatory circuits that direct it to consume industrial chemicals as food. Researchers in Scotland are engineering bacteria to convert heavy metals to metallic nanoparticles, which are used in medicine, industry and fuels.

CustoMem in the UK uses synthetic biology to create a granular material that attracts and sticks to micropollutants such as pesticides, pharmaceuticals, and certain chemicals in wastewater. And Australian researchers are attempting to create a multicellular structure they call a “synthetic jellyfish” that could be released after a toxic spill to break down the contaminants.

Preserving biodiversity

Scientists are using synthetic biology to make American chestnut trees more resilient to a deadly fungus. Photo: Joe Blowe

American chestnut trees dominated the East Coast of the U.S. until 1876, when a fungus carried on imported chestnut seeds devastated them, leaving less than one percent by 1950. To make blight-resistant trees, scientists have inserted a wheat gene into chestnut embryos, enabling them to make an enzyme that detoxifies the fungus. This chestnut tree is likely to become the first genetically modified organism to be released into the wild once it is approved by the Department of Agriculture, the Food and Drug Administration (FDA) and the Environmental Protection Agency (EPA).

Revive & Restore, an organization that uses genetic techniques to preserve biodiversity, is attempting to rescue the endangered black-footed ferret, which is susceptible to sylvatic plague. Because the domestic ferret is not, scientists are studying the possibility of finding the genes that give the domestic ferret resistance and editing them into the black-footed ferret’s genome. The research will begin with cell cultures in the lab.

Gene drives are mechanisms that spread a desired genetic trait through a population to control invasive species. A gene drive was recently under consideration to control the golden mussel, which has invaded South American and Latin American waters. After identifying the genes related to reproduction and infertility in golden mussels, scientists proposed using CRISPR-Cas9 to edit the mussel’s genome to make the females infertile. The genetically modified mussels would then be bred with wild mussels in the lab, creating modified embryos that could be released into the wild to spread infertility throughout the population. A gene drive to eliminate mosquitoes that carry malaria has worked in the lab, but no engineered gene drive has been tried in the field as yet.

This soil crust contains cyanobacteria, algae, fungi and lichens. Photo: brew books

Some scientists are also working on modifying coral genomes to give them more resistance to warming ocean temperatures, pollution and ocean acidification. Others have proposed modifying the genes of cyanobacteria that affect moisture in the soil crust of semi-desert ecosystems so that the soil retains more water and more vegetation can grow.

Feeding the world

With the world population expected to hit 10 billion by 2050, global demand for food could increase by 59 to 98 percent. Climate change impacts—higher temperatures, extreme weather, drought, increasing levels of carbon dioxide and sea level rise—are jeopardizing the quantity and quality of our food supplies.

Researchers at the University of California, San Diego discovered that when plants encounter dry conditions, they release a hormone that closes the plant’s pores in order to retain water, slows its growth and keeps the seeds dormant. That hormone is expensive to synthesize, however, so scientists worked with synthetically developed receptors in tomato plants that responded in a similar water-conserving fashion to a commonly used fungicide instead, making the plants more resilient to drought.

The Salk Institute’s scientists have identified the genes that encourage a plant’s root system to grow deeper into the soil. They plan to engineer genetic pathways to prompt deeper roots, which will enable crop plants to resist stress, sequester more carbon and enrich the soil.

Microbes that live with legumes give them the ability to convert nitrogen from the atmosphere into nutrients the plant needs to grow. However, because other plants cannot naturally assimilate nitrogen, farmers have traditionally used chemical fertilizers. The production of fertilizer, made mainly from fossil fuels, results in greenhouse gas emissions and eutrophication. As an alternative, Pivot Bio, a California company, engineered the genes of a microbe that lives on the roots of corn, wheat and rice plants to enable the microbe to pull nitrogen out of the air and feed it to a plant in exchange for nutrients. In field tests, its nitrogen-producing microbe for corn yielded 7.7 bushels per acre more than chemically fertilized fields.

Agriculture, including raising livestock, is responsible for about 8 percent of U.S. greenhouse gas emissions. Genetically modified microbes are being used to produce food that is more sustainable, ethical and potentially healthier. Motif Ingredients is developing alternative protein ingredients without animal agriculture. It uses engineered microbes to produce food proteins that can be tailored to mimic flavors or textures similar to those found in beef and dairy.

The Impossible Burger. Photo: Dale Cruse

Impossible Foods’ plant-based burger contains synthesized heme, the iron-containing molecule found in animals and plants that gives meat its bloody flavor. To make it, scientists added a plant gene to yeast, which, after fermentation, produced large quantities of the heme protein. Impossible Burger uses 75 percent less water and 95 percent less land than a regular beef burger, and produces 87 percent fewer greenhouse gas emissions.

As the demand for seafood grows globally (fishing stocks are already 90 percent overfished), so does the need for fishmeal, the protein pellets made of ground up small fish and grain that feed farmed fish as well as livestock. California-based NovoNutrients uses CO2 from industrial emissions to feed lab-created bacteria, which then produce protein similar to the amino acids fish get by eating smaller fish the bacteria replace the fishmeal, providing the fish with protein and other nutrients.

Creating greener products

Burning fossil fuels for energy accounted for 94 percent of total U.S. anthropogenic CO2 emissions in 2016, so a lot of research is aimed at creating better biofuels that don’t compete with food production, soil nutrients or space. The latest generation of biofuels focuses on engineered microalgae, which have high fat and carbohydrate content, grow rapidly and are relatively robust. Altering their metabolic pathways enables them to photosynthesize more efficiently, produce more oil, absorb more carbon, and be hardier so that their numbers can be scaled up.

The National Renewable Energy Lab is studying microalgae for biofuels
Photo: DOE

LanzaTech in Illinois identified an organism that naturally makes ethanol from industrial waste gases. After the company engineered it with “pathways” from other organisms to improve its performance, the organism is able to produce unique molecules for valuable chemicals and fuels. LanzaTech’s first commercial plant in China has produced over seven million gallons of ethanol from steel mill emissions that can be converted into jet fuel and other products.

165 million tons of plastic have trashed the oceans, with almost 9 million more tons being added each year. Synbio could provide a solution to this pollution problem, both by degrading plastic and replacing it.

In 2016, researchers in Japan identified two enzymes in a bacterium that enable it to feed on and degrade PET plastic, the kind used for water bottles and food containers. Since then, researchers around the world have been analyzing how the enzymes break down the plastic and trying to improve their ability to do so.

California-based Newlight Technologies is using a specially developed microorganism-based biocatalyst (similar to an enzyme) to turn waste gas captured from air into a bioplastic. The biocatalyst pulls carbon out of methane or carbon dioxide from farms, water treatment plants, landfills, or energy facilities, then combines it with hydrogen and oxygen to synthesize a biopolymer material. The biopolymer, called AirCarbon, can replace plastic in furniture and packaging.

Lignin is a key component of plants that, like other types of biomass, could be used for renewable fuels and chemicals. Since very few bacteria and fungi can break it down naturally, scientists have been trying for years to develop an efficient way of doing so. Now some have engineered a naturally occurring enzyme to break it down, which could eventually make it possible to use lignin for nylon, bioplastics and even carbon fiber.

The manufacturing of complex electronic devices requires toxic, rare, and non-renewable substances, and generates over 50 million tons of e-waste each year. Simon Vecchioni, who recently defended his PhD in biomedical engineering at Columbia University, is using synthetic biology to produce DNA nanowires and networks as an alternative to silicon device technology.

Vecchioni ordered synthesized DNA from a company, used it to create his own custom BioBrick—a circular piece of DNA—and inserted it into the bacterium E.coli, which created copies of the DNA. He then cut out a part of the DNA and inserted a silver ion into it, turning the DNA into a conductor of electricity. His next challenge is to turn the DNA nanowires into a network. The DNA nanowires may one day replace wires made of valuable metals such as gold, silver (which Vecchioni only uses at the atomic scale), platinum and iridium, and their ability to “self-assemble” could eliminate the use of the toxic processing chemicals used to etch silicon.

“A technology for fabricating nanoscale electrical circuits could transform the electronics industry. Bacteria are microscale factories, and DNA is a biodegradeable material,” he said. “If we are successful, we can hope to produce clean, cheap, renewable electronics for consumer use.”

The production of cement (a key ingredient of concrete) is responsible for about eight percent of global greenhouse gas emissions because of the energy needed to mine, transport and prepare the raw materials. bioMASON in North Carolina provides an alternative by placing sand in molds and injecting it with bacteria, which are then fed calcium ions in water. The ions create a calcium carbonate shell with the bacteria’s cell walls, causing the particles to stick together. A brick grows in three to five days. bioMASON’s bricks can be customized to glow in the dark, absorb pollution, or change color when wet.

Dressing more sustainably

Fast fashion has a disastrous impact on the environment because of its dyes and fabric finishes, fossil fuel use and microfiber pollution. About three-fourths of the water used for dyeing ends up as toxic wastewater, and over 60 percent of textiles are made from polyester and other fossil fuel-based fibers that shed microfibers when washed, polluting our waters.

Textile mill in Bangladesh Photo: NYU Stern BHR

French company Pili synthesizes enzymes that can be tailored to produce different colors, then integrates them into bacteria. The bacteria are then able to create pigments. Pili’s dye is produced without petroleum products or chemicals, and uses one-fifth the water of regular dyes.

Spider silk, considered one of nature’s strongest materials, is elastic, durable and soft. Bolt Threads, based in San Francisco, studied spider DNA to figure out what gives spider silk its special characteristics, then engineered genes accordingly and put them into yeast, which, after fermentation, produce large quantities of liquid silk proteins. The silk protein is then spun into fibers, which can be made into renewable Microsilk.

The risks of synbio

In the U.S., synbio chemicals and pharmaceuticals are mainly regulated by the Toxic Substances Control Act of 1976. Other synbio commercial products and applications are regulated by the EPA, Department of Agriculture, and the FDA. But do these agencies have the capacity and effectiveness to monitor synthetic biology as fast as it’s developing and changing?

As some syn bio applications are starting to move out of the lab, there are worries about its potential environmental risks. If an engineered organism, such as those used in gene drives, is released into nature, could it prove more successful than existing species in an ecosystem and spread unchecked?

Bostick noted that each synthetic biology project today is usually focused on one very specific modification. “It’s adding or altering a single enzyme, possibly putting in a series of enzymes so that it can do one thing,” he said. “Very seldom do you tweak the rest of the organism, so it’s not critical to the success of the organism and it’s not likely to run rampant. From a scientific standpoint, it’s hard to change more than one thing.”

Moreover, according to Vecchioni, most synbio research is being done by student groups through iGEM’s International Genetically Engineered Machine Competition, and every iGEM project must have a safety component—some way to turn off the gene or regulate it if it gets out.

Another concern is that the creation or modification of organisms could be used to create a disease for the purpose of bioterrorism. Vecchioni explained that the FBI is on the lookout for this. “They walk in nicely and say ‘hi, we’re watching,’” he said. “They also go to conferences and just make sure people are being smart about it.” He added that DNA synthesis companies are also on alert. “They have a library of known dangerous pieces of DNA, so if you try to order something that is known to create disease in any organism, the FBI will come knocking on your door.”

A more recent concern is that research institutes have begun setting up biofoundries, facilities that rely heavily on automation and artificial intelligence (AI) to enhance and accelerate their biotechnology capabilities. Jim Thomas, co-executive director of the ETC Group, which monitors emerging technologies, is concerned about the tens of thousands of organisms that AI is being used to create. “It raises a real safety question because if you have something go wrong, you potentially don’t understand why it went wrong,” said Thomas. “With AI it’s a bit of a black box.” He noted that most experts agree that there has to be a process for monitoring and assessing new developments in synbio.

Despite the potential risks of synbio, its potential benefits for the planet are huge. And as our environment is battered by the impacts of climate change and human activity, we need to explore all options. “We need every possible solution to even remotely get to the magnitude of change that we need to improve our world,” said Bostick.


Faster by an order of magnitude

Making mRNA vaccines means manufacturing RNA, a very complex process that requires several highly purified ingredients. First, you must be able to manufacture DNA plasmids—the templates upon which the RNA is built.

“This step is roughly as complex as creating a whole vaccine in the first place,” Simone says with a laugh. “The good news is that DNA plasmid manufacturing is already well-established. And once you have the DNA templates, that’s when incredible speed starts knocking on your door.”

To understand just how much faster this approach is, you need to understand the normal pace of viral vaccine production. To begin manufacture of a viral vaccine, you need lots of animal cells, each one infected with a weakened (or dead) virus.

For some vaccines, like the one against yellow fever, these cell cultures are grown in chicken eggs (LOTS of chicken eggs). For others, like the vaccine against meningitis A, the cells are grown in a fermenter (picture a giant, stainless steel pressure-cooker).

In Vietnam, a lab technician at the Institute of Vaccines and Medical Biologicals inspects eggs that will be used for vaccine manufacturing. Photo: PATH/Matthew Dakin.

Simone says that “even with modern fermentation equipment, reaching adequate biomass to begin manufacture of a viral vaccine takes about four to six weeks. Once underway, each growth and production cycle might take a week. An mRNA vaccine is synthesized in a matter of minutes.”

The incredible difference in speed is owed to the fact that viral vaccines rely on animal cell biology while RNA manufacturing is a cell-free, biochemical process performed with synthetic enzymes.

Which brings us to the other highly purified ingredients required for RNA manufacturing: chemically derived ribonucleotides. These are the little building blocks (you might know them as G, A, U, C) that RNA polymerase synthesizes to create the desired strand of mRNA.


Chapter 21 – Genetic Basis of Development

2. Describe the natural function of restriction enzymes.

3. Describe how restriction enzymes and gel electrophoresis are used to isolate DNA fragments.

4. Explain how the creation of sticky ends by restriction enzymes is useful in producing a recombinant DNA molecule.

5. Outline the procedures for producing plasmid and phage vectors.

6. Explain how vectors are used in recombinant DNA technology.

7. List and describe the two major sources of genes for cloning.

8. Describe the function of reverse transcriptase in retroviruses and explain how they are useful in recombinant DNA technology.

9. Describe how “genes of interest” can be identified with the use of a probe.

10. Explain the importance of DNA synthesis and sequencing to modern studies of eukaryotic genomes.

11. Describe how bacteria can be induced to produce eukaryotic gene products.

12. List some advantages for using yeast in the production of gene products.

13. List and describe four complementary approaches used to map the human genome.

14. Explain how RFLP analysis and PCR can be applied to the Human Genome Project.

15. Describe how recombinant DNA technology can have medical applications such as diagnosis of genetic disease, development of gene therapy, vaccine production, and development of pharmaceutical products.

16. Describe how gene manipulation has practical applications for agriculture.

17. Describe how plant genes can be manipulated using the Ti plasmid carried by Agrobacterium as a vector.

18. Explain how foreign DNA may be transferred into monocotyledonous plants.

19. Describe how recombinant DNA studies and the biotechnology industry are regulated with regards to safety and policy matters.


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