Tag Archives: biochemistry

Intron Retention: a common cause for cancer

Tumor suppressor genes are normally busy keeping your cell’s growth cycle regulated, and when in good working order, prevent cells becoming malignant.  A new study finds that many cancers are caused by mutations that block the tumor suppressor gene’s effect, through a process called Intron Retention. Introns are normally removed after a gene is transcribed into RNA, but in intron retention, one is accidentally left in place.  The result can be disastrous, leading to cancer and possibly other disease.  

3d render of a DNA spirals

3d render of a DNA spirals

Introns are found in complex cells, like those of animals and plants, but not in simple cells like bacteria.  Introns are non-coding sequences, meaning that even though the intron is part of the gene, it’s DNA is not used in the gene’s instruction for making protein.   Within the gene, the introns are placed between exons – the sequences of DNA that are the actual code for protein.  A single gene may contain many introns and exons.   When a gene becomes activated, the cell transcribes the DNA into messanger-RNA (mRNA), which then leaves the cell nucleus to be translated into a protein by ribosomes in the cytoplasm.  Under normal conditions, both intron and exon DNA on the gene get transcribed into mRNA, but the intron is then cut out of the mRNA prior to leaving the cell nucleus, and so never goes on to the ribosome.  Therefore, the mature mRNA comes only from the DNA of the gene’s exons – all unwanted introns having been removed. The removal of the introns from the mRNA is called splicing, and is carried out by complex cellular machinery, composed of both protein and RNA, called the Splicosome.

 Organization of the gene into introns and exons. Splicing of the gene after transcription removes the intron sequences producing the mature mRNA.

Organization of the gene into introns and exons. Splicing of the gene after transcription removes the intron sequences producing the mature mRNA.

Splicing is an important invention of complex cells, leading to greater variation due to Alternative Splicing – different combinations of the exons used to code for the final protein.  Alternative splicing creates the potential for multiple protein product from a single gene.  For example, some proteins might use the code from all the gene’s exons, but others might use only a few exons, the others having been spliced out, leading to very different proteins with different functions.  

Getting back to Intron Retention, this is the situation when an intron escapes being spliced out, and erroneously remains in the mature mRNA.  It can happen due to a mutations at a splice site – sequence of DNA that marks where to splice – and therefore, makes the intron invisible to the Splicosome. 

The study, published in the November 2015 journal of Nature Genetics, by Hyunchul Jung at the National Research Center in Gyeonggi-do, South Korea, describes the analysis of DNA samples from 1812 patients, with a variety of different types of cancer, including breast, colon, lung, kidney, ovarian, and uterine.  After computational analysis of the tumor DNA, Jung found that 31.6% had mutations disrupting normal splicing, with one of the most common type of splicing error being Intron Retention.  

Jung also showed that the mutation disrupting the splice site doesn’t need to be one that would change the amino acid sequence of the future protein – a so called Synonymous Mutation- so might be easily overlooked as being disease causing.  In many cases, the intron contains a warning signal for the cell to destroy the mRNA before making it into protein, so that gene never gets expressed.  In a significant number of the cancers studied, Intron Retention was found to have occurred more frequently in Tumor Suppressor Genes (TSG).  TSGs are like the brakes on the cell cycle, and Intron Retention is like having bad brakes, so the cell cycle speeds out of control, leading to a malignant cell that divides uncontrollably.  As a suggestion for future research the paper states, “…intronic splice sites should be carefully considered for their potential as disease-causing variants, regardless of whether an amino acid change occurs.”  Knowledge of this mechanism of gene disruption may lead to a much better understanding of the causes of certain cancers and other diseases.

Reference Journal:

  1. Intron retention is a widespread mechanism of tumor-suppressor inactivation.  Jung H, Lee D, Lee J, Park D, Kim YJ, Park WY, Hong D, Park PJ, Lee E.  Nat Genet. 2015 Nov;47(11):1242-8. doi: 10.1038/ng.3414. Epub 2015 Oct 5.  PMID: 26437032
Side-by-side comparison of FT synthetic fuel and conventional fuel. The synthetic fuel is clear as water because of a near-absence of sulfur and aromatics.

Synthetic fuels could eliminate U.S. crude oil addiction and hamper carbon emissions

Over the past few years, a series of papers looked on how the United States could benefit by switching from crude oil to alternative synthetic fuels. Their findings show that, given the current economic environment where oil prices have simply skyrocketed, synthetic fuels are more advantageous compared to crude oil from a number of perspectives, including environmental.

Synthetic oils are chemical processed hydrocarbons made from various feedstock like coal, natural gas and non-food crops. The resulting products include fuels, waxes and lubricants normally made from crude oil. Actually plants can produce gasoline, diesel and aviation fuels at competitive prices, depending on the price of crude oil and the type of feedstock used to create the synthetic fuel, all with the same or similar performances of those derived from crude oil.

This means that motor vehicles can run without issues on synthetic fuels without the need for complicated addons or new specifically designed engines, like ethanol, a biofuel, requires.

Lowering greenhouse gas emissions with synthetic fuels

Side-by-side comparison of FT synthetic fuel and conventional fuel. The synthetic fuel is clear as water because of a near-absence of sulfur and aromatics.

Side-by-side comparison of FT synthetic fuel and conventional fuel. The synthetic fuel is clear as water because of a near-absence of sulfur and aromatics. (c) Wikimedia Commons

Because refineries, extraction facilities and non-edible crops would have to be integrated in a newly build infrastructure, an enormous social and economic impact could potentially unfold. Millions of jobs would open and the country wouldn’t have to import oil or resort to unorthodox extraction methods (see wars). Moreover, since  plants absorb carbon dioxide to grow, the United States could cut vehicle greenhouse emissions by as much as 50 percent in the next several decades using non-food crops to create liquid fuels, the researchers said.

“The goal is to produce sufficient fuel and also to cut CO2 emissions, or the equivalent, by 50 percent,” said  Christodoulos Floudas, a professor of chemical and biological engineering at Princeton, who led the research. “The question was not only can it be done, but also can it be done in an economically attractive way. The answer is affirmative in both cases.”

Synthetic fuels make for an important chapterof a white paper recently produced by the American Institute of Chemical Engineers (AIChE) and authored by Vern Weekman, one of Floudas’ co-researchers.

“Right now we are going down so many energy paths,” said June Wispelwey, the institute’s director and a 1981 Princeton alumna. “There are ways for the system to be more integrated and much more efficient

The struggles that come with transitioning to synthetic fuels

The main synthetic fuel production method employed today is the Fischer-Tropsch process, first developed in the 1920s in Germany out of the need to convert coal into liquid fuels. The process involves heat and a complicated chemistry to create gasoline and other liquid fuels from high-carbon feedstock ranging from coal to switchgrass, a native North American grass common to the Great Plains.

“This is an opportunity to create a new economy,” Floudas said. “The amount of petroleum the U.S. imports is very high. What is the price of that? What other resources to do we have? And what can we do about it?”

If synthetic fuels hold so many benefits, why isn’t the US or other countries in the world use them at a mass scale? As with all things – cost. Experts estimate that an investment of $1.1 trillion would be required for a synthetic fuel infrastructure to be developed. Also, an expected 30 to 40 years transition period would have to pass before the U.S. would be capable of fully embracing synthetic fuels.

Why not start now? This is exactly what the researchers are striving for, and the white paper published by the AIChE is particularly addressed to key national planning agencies like the national academies, the Department of Energy, the Environmental Protection Agency, the Defense Department.

“Even including the capital costs, synthetic fuels can still be profitable,” said Richard Baliban, a chemical and biological engineering graduate student who graduated in 2012 and was the lead author on several of the team’s papers. “As long as crude oil is between $60 and $100 per barrel, these processes are competitive depending on the feedstock,” he said.

The paper was published in the AIChE Journal.

[source Princeton]

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Biochemical reactions that maintain an erection uncovered

For decades now, scientists have known what are the biochemical reactions that trigger a penile erection, however not those that actually maintain it. In a breakthrough, physicians at Johns Hopkins Medicine have finally uncovered the exact biochemical chain of events involved in the process. The findings will hopefully lead to novel medical treatment for patients suffering from erectile dysfunctions – a big step towards developing erection pills to cure erectile dysfunction.

mouseIn a 1992 study published in the journal Science,  Arthur Burnett, M.D., professor of urology at Johns Hopkins Medicine, along with his Johns Hopkins co-author, Solomon S. Snyder, M.D., professor of neuroscience, showed that nitric oxide is produced in penile tissue, and demonstrated its role  as a key neurotransmitter responsible for triggering erections.

Twenty years later, the same Burnett leads the study whose findings have finally uncovered the mechanics that allow an erection to be maintained. By studying mice, Burnett and colleagues found that complex positive feedback loop in the penile nerves that triggers waves of nitric oxide are the culprit. Thus, after the initial release of nitric oxide, a cascade of chemicals help sustain the nerve impulses which maintain an erection, originating from brain and from physical stimulation.

“We’ve closed a gap in our knowledge,” says Arthur Burnett, M.D., professor of urology at Johns Hopkins Medicine and the senior author of the study article. “We knew that the release of the chemical nitric oxide, a neurotransmitter that is produced in nerve tissue, triggers an erection by relaxing muscles that allow blood to fill the penis. We thought that was just the initial stimulus. In our research, we wanted to understand what happens next to enable that erection to be maintained.”

Thing is, at the basic erectile biological level, we’re in the same frame as mice. Don’t think that over too much. Anyway, with this basic biological information now at hand, it may be possible to develop new medical approaches to help men with erection problems caused by such factors as diabetes, vascular disease or nerve damage from surgical procedures.

“Now, 20 years later, we know that nitric oxide is not just a blip here or there, but instead it initiates a cyclic system that continues to produce waves of the neurotransmitter from the penile nerves,” says Burnett.

In their research thus far, the scientists found an agent which stimulate the pumping of the newly covered chemical – forskolin, an herbal compound that has been used before to relax muscle and widen heart vessels. It seems forskolin also ramps up nerves and can help keep nitric oxide flowing to maintain an erection.

The findings will be reported in this week’s edition of the journal Proceedings of the National Academy of Sciences (PNAS).


[source

Major advance in computational chemistry: Designer Enzymes

designer enzymesIn what is a great leap for science, scientists from UCLA and the University of Washington have succeeded in creating “designer enzymes,” a major milestone in computational chemistry and protein engineering. The two groups were led by UCLA’s chemistry professor Kendall Houk and Washington’s biochemist David Baker.

Designer enzymes will have applications for defense against biological warfare, by deactivating pathogenic biological agents, and for creating more effective medications, according to Houk. The results seem very promising and scientists are pleased.

“The design of new enzymes for reactions not normally catalyzed in nature is finally feasible,” Houk said. “The goal of our research is to use computational methods to design the arrangement of groups inside a protein to cause any desired reaction to occur.”

“Enzymes are such potent catalysts; we want to harness that catalytic ability,” said research co-author Jason DeChancie, an advanced UCLA chemistry graduate student working with Houk’s group. “We want to design enzymes for reactions that naturally occurring enzymes don’t do. There are limits on the reactions that natural enzymes carry out, compared with what we can dream up that enzymes can potentially do.”

Combining chemistry, mathematics and physics is no kid’s play but it’s the result of years and years of hard work and colaborations from many scientists from many fields. In the paper they’ve published in Nature they reported that they have successfully created designer enzymes for a chemical reaction known as the Kemp elimination, a non-natural chemical transformation in which hydrogen is pulled off a carbon atom.