In a paper published April 26th in mSystems, a team of researchers led by microbiologists at Oregon State University, in Corvallis, describe a successful trial of a new method of identifying the carbon uptake of specific marine bacterioplankton taxa. The technique uses proteomics – the large-scale study of proteins – to observe directly the metabolic processes of communities of microorganisms.
Oregon State microbiologist Ryan Mueller, senior author on the paper, says the technique illuminates the carbon uptake process at three levels. “It shows how much is being used, by which microbes, and how they’re using it to produce new proteins,” he says. “It provides information about which organisms are taking up different substrates.”
Marine bacterioplankton play a critical role in the carbon cycle. They recycle chemicals and decompose carbon-rich material like dissolved free amino acids (DFAA), which can result from many processes including lysing cells or phytoplankton bloom die-offs. Bacterioplankton process half of the organic carbon fixed by phytoplankton and other microbes through photosynthesis, but not all microbial communities have the same uptake rates. Linking particular taxa to metabolic responses has been an open question in the field for decades.
The researchers tested their new method, called proteomic stable isotopic probing, or proteomic-SIP, on eight seawater samples, including six collected from the ocean at Monterey Bay, California, and two from Newport, Oregon. To those samples they added DFAAs enriched with the isotope carbon-13. Using high-resolution mass spectrometry, they extracted and analyzed proteins from the samples – half of the samples after 15 hours, and the other half after 32 hours. They used software developed by researchers at Oak Ridge National Laboratory, in Tennessee, to analyze the proteomics data.
As medical professionals search for new ways to personalize diagnosis and treatment of disease, RPB-supported researchers at the University of Iowa have already put into practice what may be the next big step in precision medicine: personalized proteomics.
Proteomics is the large-scale analysis of all the proteins in a cell type, tissue type, or organism. In contrast to genomics, which shows how genetic differences can indicate a person’s potential for developing a disease over a lifetime, proteomics takes a real-time snapshot of a patient’s protein profile during the disease. Doctors can use this information to tailor diagnosis and initiate treatment, sometimes long before a conventional diagnosis even begins to home in on a cause.
“Proteomics allows us to create a precision molecular diagnosis that’s totally personalized for the patient,” says Vinit Mahajan, M.D., Ph.D., UI clinical assistant professor of ophthalmology and visual sciences, and recipient of a 2011 RPB Career Development Award.
Mahajan’s lab recently used proteomics to devise a successful treatment strategy for a patient with uveitis, a potentially blinding eye disease that can have many causes, making it particularly difficult to diagnose and treat effectively. The team’s findings are described in a paper published in the Feb. 11 issue of the journal JAMA Ophthalmology.
Learn more: The Future of Precision Medicine
After a decade-long $3 billion international effort, scientists heralded the 2001 completion of the human genome as a moon landing achievement for biology and the key to finally solving intractable diseases like cancer.
But it turns out this was only the end of the beginning, with a much greater complexity to life revealed by the roughly 20,000 genes found within the human genome. For one, most diseases are incredibly complex, with very few caused by a single gene mutation. Rather, the more accurate picture is many acting genes acting in concert, with the routes to disease looking like public transit or subway maps.
Since then, efforts such as the modENCODE project – a $57 million multi-center initiative funded by the National Human Genome Research Institute (NHGRI) – have been aimed at identifying all the genome elements that can turn on and off genes.
Now, an international scientific team, led by Arizona State University professor and Biodesign Institute researcher Marco Mangone, has added a new worldwide resource with the first library built for researchers to explore genes’ deep and hidden messages. The paper was published in BMC Genomics (http://www.biomedcentral.com/1471-2164/16/1036, DOI 10.1186/s12864-015-2238-1).
The end of the message
“If the genome is considered the blueprint of the cell, proteins are the really bricks and mortars,” said Josh LaBaer, director of the Virginia Piper Center for Personalized Diagnostics, which aims to undercover the telltale early warning signs of disease from a systematic study of all of the proteins in the human body, a field called proteomics.
But to make proteins, first the DNA genomic information must be transcribed with complete fidelity, chemical letter by letter into an intermediary molecule, called messenger RNA, or mRNA. In what is known as the central dogma of biology, DNA makes RNA, which makes protein.
Marco Mangone, a core faculty member in LaBaer’s center, has devoted his career to looking at a peculiar region found at the ends of the mRNA sequence information, called untranslated elements, or UTRs. As the name suggests, these regions do not go on to make protein, but stresses Mangone: “They have to be there for a reason.”
Mangone’s raison d’etre is to understand the function of every UTR in the human body, called the 3’UTRome (3′ indicates a location at the end of the mRNA).
And so he and his team have painstakingly put together the first and largest human 3?UTRome library in the world. It is made up of 1,461 human 3?UTRs to date (representing about 10 percent of genome), and freely available to the worldwide scientific community to explore all aspects of biology, gene regulation and disease.
Shooting the messenger
Sophocles first wrote in his Greek civil war play “Antigone“: “no one loves the messenger who brings bad news.” And when all roads led to ancient Rome, and messengers were sent about delivering the news, a revolutionary change occurred in communications tactics: killing the messenger to prevent the communication from taking place.
Mangone, a native Italian who did his doctoral studies in Rome, has harkened back to this strategy when examining the role of the 3’UTRome. His lab uses standard molecular biology and bioinformatics tools to study the production, function and disease contributions of UTRs and their role in governing gene expression. He pioneered this work in a simple animal, the worm C. elegans, and now, in the new BMC paper, toward human genomics.
Why would this elaborate system be in place? Based on numerous studies, the role of the 3’UTRome is complicated, but one major theme that has emerged is to prevent the mRNA message from ever being delivered, or in biology terms, ever translated into protein.
Small RNAs, called micro RNAs (miRNAs), work to pair with a UTR to block translation, killing the message, and thus, silencing a gene. Uncovering the interplay between miRNA and their specific UTRs have become a hot area in biology, and big business.
Big pharma, big future
These gene silencers have become all the rage in the pharmaceutical industry. So much so, that the global miRNA research market was valued at nearly $295.1 million in 2011 and is expected to reach $763 million by 2017.
It’s become big business because of their potential as therapeutics for the treatment of some severe diseases, including cancer and genetic disorders, by introducing specific miRNAs into diseased cells to silence the defective gene.
A broad portfolio of miRNA pathway drug candidates have been developed, some already in Phase II clinical trials, showing promising clinical data in different areas of medicine, such as cancer, HCV infection, and cardiovascular diseases.