“Groundbreaking” ‘Duon’ Paper Only Continues Research From Prior Studies

There is a lot of chatter on the internets about the press release from the University of Washington about a paper published in the journal Science this week. One claim within the press release is that findings in the present study uncover a ‘hidden’ code within human DNA that scientists had no prior knowledge of. As many have written, this assumption is completely false and grossly exagerated.

After reading the paper (paywall), I can say the study does add a wealth of new information to an already known phenomenon. I recommend reading the article if one is in the molecular biology or human genetics fields. However, the press release about this study should be retracted for the amount of misleading claims raised within it.

In fact, the authors write in the final paragraph,

Our results indicate that simultaneous encoding of amino acid and regulatory information within exons is a major functional feature of complex genomes. The information architecture of the received genetic code is optimized for superimposition of additional information (3435), and this intrinsic flexibility has been extensively exploited by natural selection. Although TF binding within exons may serve multiple functional roles, our analyses above is agnostic to these roles, which may be complex (36).

Pay close attention to the parenthetical numbers within the quote. These indicate the statement is referencing a prior publication. 34 is reference to a paper from 2007 in Genome Research entitled, “The genetic code is nearly optimal for allowing additional information within protein-coding sequences.” and can be found here. 35 is a paper from 2010 also in Genome Research; “Overlapping codes within protein-coding sequences.” found here. And 36 is from Nature Genetics earlier this year entitled, “DNase I–hypersensitive exons colocalize with promoters and distal regulatory elements” found here.

A question for UW Today,

If these authors uncovered an unknown, hidden code within DNA, how could they reference earlier studies that essentially elaborated upon these same ‘secrets’?

I’ll be waiting for an answer…

Repeat after me: There is no newly discovered hidden code in DNA.

It is a very sad and unfortunate occurrence when newly released research findings are hyped and overstated. This week the University of Washington Office of News & Information released a press release embarrassingly called “Scientists discover double meaning in genetic code“. Since then, the release has been picked up by websites across the globe. In that way, the press release did its job. Unfortunately, the statements within the release along with the title have done a world of harm. I can only hope it was unintended.

The release starts by stating scientists discovered a second code hiding within DNA.

This second code contains information that changes how scientists read the instructions contained in DNA and interpret mutations to make sense of health and disease.

This ‘second code’ will not change anything scientists do regarding studying DNA. This ‘hidden second code’ has been known and studied for decades.

Since the genetic code was deciphered in the 1960s, scientists have assumed that it was used exclusively to write information about proteins. UW scientists were stunned to discover that genomes use the genetic code to write two separate languages. One describes how proteins are made, and the other instructs the cell on how genes are controlled. One language is written on top of the other, which is why the second language remained hidden for so long.

Let me rewrite this paragraph to make it factual:

Since the genetic code was deciphered in the 1950s, scientists have continued to find additional layers of complexity in the regulation of how genes are transcribed to make proteins. The current study from UW scientists have added additional knowledge to this growing field.

This is the most unfortunate part:

“For over 40 years we have assumed that DNA changes affecting the genetic code solely impact how proteins are made,” said Stamatoyannopoulos. “Now we know that this basic assumption about reading the human genome missed half of the picture. These new findings highlight that DNA is an incredibly powerful information storage device, which nature has fully exploited in unexpected ways.”

This release was written by writers in a news department as a marketing piece, but when the scientist also grossly exaggerates the findings, it is very sad. Like Emily Willingham said in Forbes, “I can only hope that Stamatoyanopoulos didn’t really say that”. Scientists have not made any such assumption and have decades of evidence to the contrary.

The study shows that changes in the DNA sequence can have two-fold consequences upon the protein made from it. It can change the amino acid sequence of the protein and change which proteins bind that help transcribe the DNA into the RNA used to create the protein. This is not new. The finding that made this study worth of the prestige of publishing into Science is the frequency of the DNA code that is used to determine which proteins bind to the DNA to create the right form of the protein. These proteins, known as transcription factors, have been known for decades and bind to a number of DNA sequences to ensure the cell creates the exact protein needed.

As is common in press releases, the last part of the piece tries to explain DNA and the language of genes. In this aspect, the release does an even worse job:

The genetic code uses a 64-letter alphabet called codons.

The genetic code uses 64 different combinations of nucleotide sets of three, called codons; most of which code for one of the twenty amino acids needed to make a protein.

I could keep going, but I’m exhausted by trying to set the record straight.

Nanobiopsy: the beauty in the very small is a big deal

The ability to study the living without destroying it has been the goal of many scientists for decades. A new article in ACS Nano has paved the road towards noninvasive cellular-level examination. The only true way to study cellular dynamics is to study a single cell over time (temporally). The reason for this is the heterogeneous nature of any cell culture because no two cells are identical spatially and temporally. Each individual cell has its own set of experiences that has generated its current molecular inventory, ie. RNA molecules, metabolites, proteins, sugars, lipids, etc. Studying a community of cells gives rise to noise that makes finding significant differences incredibly difficult.

In the article entitled Compartmental Genomics in Living Cells Revealed by Single-Cell Nanobiopsy, the authors used a kind of microscopy called scanning ion conductance microscopy, or SICM, that allows for continuous sampling of a single cell over time. The authors used a nanopipette as part of the SICM and combined this with sensitive sequencing techniques resulting in a high resolution look at what genes are being expressed over time into RNA molecules. Furthermore, this technique was used to study the genomic information of individual mitochondria within a single cell without also studying the nuclear material. In other words, this new technique has resulted in the ability to not only study cellular dynamics, but go beyond that and study subcellular dynamics.

This breakthrough will have impacts across many fields from cancer biology to improving climate models.

Paolo Actis, Michelle M. Maalouf, Hyunsung John Kim, Akshar Lohith, Boaz Vilozny, R. Adam Seger, & Nader Pourmand (2013). Compartmental Genomics in Living Cells Revealed by Single-Cell Nanobiopsy ACS Nano DOI: 10.1021/nn405097u

American Renaisscience: Bioengineering stem cells for targeted drug delivery

The field of stem cell research promises to deliver truly amazing medical breakthroughs in the coming decades. However, the fundamental research needed must first provide the proof-of-principle necessary for private industry to take note. That is happening according to a recent article published in the journal Blood. Researchers at Brigham and Women’s HospitalHarvard‘s Stem Cell Institute, in collaboration with MIT and Mass General have successfully reprogrammed a type of connective tissue stem cell line, known as mesenchymal stem cells, to produce specific surface proteins and the anti-inflammatory molecule interleukin-10.

To accomplish this, researchers injected a modified form of messenger RNA, the blueprint for protein synthesis in cells. The modified stem cells were injected into mice. Once in the mouse bloodstream, the stem cells successfully targeted sites of inflammation and reduced swelling.

This approach is promising because it targets the site in need of therapeutics and can deliver the needed drug at a level high enough to provide results. This approach is attracting attention from large pharmaceutical companies because of the capability to target the disease site itself.

Reference

Oren Levy, Weian Zhao, Luke J. Mortensen, Sarah LeBlanc, Kyle Tsang, Moyu Fu, Joseph A. Phillips, Vinay Sagar, Priya Anandakumaran, Jessica Ngai, Cheryl H. Cui, Peter Eimon, Matthew Angel, Charles P. Lin, Mehmet Fatih Yanik, & Jeffrey M. Karp (2013). mRNA-engineered mesenchymal stem cells for targeted delivery of interleukin-10 to sites of inflammation Blood DOI: 10.1182/blood-2013-04-495119
 

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Living at the Boiling Point: What we can learn from extreme heat-loving microbes

Thanks to the decreasing costs of sequencing genomic DNA, finding novel microorganisms that add to our understanding of metabolism in myriad environments is becoming common place. Not only are we learning about the diversity of life in extreme environments, like heat, cold, pressure, and altitude, but we are also learning what life on other planets may be like. With each additional genome added into ‘the cloud’, our synthetic biology toolbox gets a little bit bigger and our ability to manipulate tiny organisms to produce novel compounds is possible. Enter the “rushing fireball”.

Pyrococcus furiosus is an archeal species that thrives near deep-sea thermal vents where temperatures are between 90 and 100 degrees Celsius (or 194 to 212 degrees F). P. furiosus can grow at temperatures as low as 70 degrees C (158 deg F). To live in such conditions, this organism’s proteins must be tolerant to what we would consider harsh conditions. This organism’s ambient conditions makes wild-type proteins well-suited for industrial processes where temperatures are near boiling.

So far, P. furiosus has been utilized to produce 3-hydroxypropionic acid, a common industrial chemical used to make various products including acrylics. The kicker is that these cells were wired to make this chemical from atmospheric carbon dioxide. It is not crazy to think of what other useful products can be produced by P. furiosus with small modifications within the genome; products like ethanol or butanol as biofuels.

Pyrococcus furiosus, bacteria, archea, illustration, microbiology
My illustration of Pyrococcus furiosus

Reference

Keller, M., Schut, G. J., Lipscomb, G. L., Menon, A., Iwuchukwu, I., Leuko, T., Thorgersen, M. P., Nixon, W. J., Hawkins, A., Kelly, R. M. and Adams, M. W. W. (2013) “Exploiting microbial hyperthermophilicity to produce an industrial chemical using hydrogen and carbon dioxide”Proc. Natl. Acad. Sci. U.S.A. (in press).

How do bacteria make decisions? Part 4: Getting the message

chemical structure of cyclic diguanylate (Cycl...
chemical structure of cyclic diguanylate (Cyclic di-GMP; c-di-GMP; 3′,5′-Cyclic diguanylic acid; 5GP-5GP) (Photo credit: Wikipedia)

Welcome to part 4 of how bacteria make decisions. Parts 1 and 2 dealt with chemotaxis. Part 3 was a look at two component signaling systems. This part will deal with my favorite aspect of bacterial decisions for several reasons. Second messengers are common from bacteria to humans. The major second messenger we all learn about in biochemistry class is cyclic AMP (cAMP). However, bacteria use several nucleotides as second messengers. Many are used as determinants in the decision making process, but one of the most recently discovered (and personal favorite) is cyclic-di-GMP, or c-di-GMP.

Bacteria are constantly processing signals both inside and outside their cell membranes. Hard to believe that one of the most abundant response molecules was only discovered in the late 1980s while researching how a certain species, Acetobacter xylinum now known as Gluconacetobacter xylinus, produced cellulose. Almost by accident, the Benziman lab discovered the enzyme responsible for cellulose production (cellulose synthase) was regulated by a nucleotide, later found to be c-di-GMP. Since that discovery, c-di-GMP has become a hot topic among microbiologists and immunologists due to the decisions bacteria make as the level of c-di-GMP increases within the cell. As I learned it, the concentration of c-di-GMP had predictable outcomes on the decisions of bacteria: high levels leads to loss of motility, increase in biofilm formation, changes in cell morphology, and increase in cell-cell communication. When low levels of c-di-GMP are present, the cell decides to move around (motility), become resistant to heavy metals, and, most importantly, becomes virulent. For example, Vibrio cholerae, the bad guy responsible for cholera, only decides to move around and produce cholera toxin when c-di-GMP levels are low in the cell. If levels increase, V. cholerae will produce biofilms via extracellular polysaccharide (EPS) production.

You might be asking yourself what controls the c-di-GMP levels of a bacterial cell. The initial discovery in the Benziman lab also found the enzymes/proteins that were responsible for making and breaking the second messenger. The long (and short) names are; for making c-di-GMP from 2 GTP molecules, diguanylate cyclases (DGCs aka GGDEF proteins) and degradation by phosphodiesterases (PDEs aka EAL proteins). GGDEF and EAL proteins are so called due to important amino acids necessary for their functions, GGDEF is glycine, glycine, aspartate, glutamate, phenylalanine, and EAL is glutamate, alanine, leucine. These enzymatic activities are usually controlled by regulatory protein domains common in bacteria (and humans). Signals from the environment (internal or external) can trigger changes in enzyme activity of GGDEFs and EALs thus changing the cellular concentration of c-di-GMP. This mechanism is well understood after 30 years of research. However, what happens next is still essentially unknown.

Cyclic-di-GMP levels rise within a bacterial cell. Now what? It was known early on that c-di-GMP itself could then interact with GGDEFs to inhibit activity. But what other proteins interact with c-di-GMP and help these bacteria decide to make major lifestyle changes? It wasn’t until 2006 that bioinformaticians predicted c-di-GMP binding to a protein, or protein domain. PilZ, an obscure protein of unknown function but necessary for Type IV pili motility, was hypothesized to bind c-di-GMP. By the end of 2007, this prediction was verified and PilZ domain proteins were the first shown linking c-di-GMP to downstream proteins in pathways, or circus rings.

Transitioning from a free swimming/moving cell to life in a biofilm community is a major lifestyle change for bacteria. This decision takes commitment which is initiated by a small molecule. In the next installment, we will get to the heart of current research.

English: Crystal structure of diguanylate cycl...
English: Crystal structure of diguanylate cyclase PleD in complex with c-di-GMP from Caulobacter crecentus (Photo credit: Wikipedia)
bacterial second messenger, cyclic-di-GMP, bacteria, microbiology
My interpretation of c-di-GMP as created by Divvr web app.