What is RNA?
RNA is an acronym for "ribonucleic acid". RNA is a polymer composed of four different repeating units: Adenosine, Cytosine, Guanosine and Uridine (A, C, G, and U). One can think about RNA as a long necklace made out of four different colored beads or letters. Which beads/letters are present in what order encodes information, much like the letters that make up the words you are currently reading.
Why is RNA important?
RNA and its molecular sibling, DNA (short for "deoxyribonucleic acid") are the main information carrying molecules in all living organisms. DNA is extremely stable (amazingly, intact DNA has been isolated from frozen wooly mammoths that died more than 10,000 years!), so it is used to transmit genetic information from generation to generation. The genes carried on your chromosomes are made of DNA. Most genes (and you have over 20,000 of them!) are sets of instructions for making a structural (e.g., the collagen in your joints), catalytic (e.g., the enzyme pepsin that helps you digest food) or regulatory protein in your body. Your DNA serves as the master copy of these instructions, and so its integrity is highly guarded by your cells. When a cell needs to activate a particular set of instructions, it makes copies (transcribes) of the DNA master. The copies are made of RNA, which is much less stable than DNA. These so-called messenger RNAs (mRNAs) serve as the working set of blue prints for a gene. Messenger RNAs are shipped to the molecular factories (ribosomes) that build proteins. These factories read the blueprints and use the information to make the appropriate protein. When the cell no longer needs to make any more of that protein, the RNA blueprints are destroyed. But because the master copy in the DNA remains intact, the cell can always go back to the DNA and make more RNA copies when it needs more of the encoded protein.
So RNA is a central intermediary in the expression of genetic information. This information flow from DNA -> RNA -> protein is known as "The Central Dogma of Biology". RNA is essential for all life.
What are the different kinds of RNAs and what do they do?
In addition to the messenger RNAs discussed above that serve as the working sets of blueprints for proteins, many other types of RNA molecules have structural, catalytic and/or regulatory roles. In fact, the molecular factories that build proteins (the ribosomes) are themselves composed primarily of RNA (ribosomal or rRNA)! Other RNA molecules, called transfer RNAs (tRNAs), ferry amino acids (the building blocks for proteins) into the ribosome factories. Some RNAs are very tiny – only 20-25 beads/letters long. One set of such tiny RNAs are called microRNAs (miRNAs). These miRNAs are used by cells to regulate the number of protein molecules made from individual messenger RNAs. Thus, miRNAs provide an important braking mechanism to prevent production of too much protein. However, miRNAs do not completely turn off protein production, they only turn it down. Another class of tiny RNAs are the small interfering RNAs (siRNAs). These siRNAs can completely turn off protein production from a particular gene. They can thus "silence" the gene.
What is RNA silencing?
RNA silencing or "RNA interference" (RNAi) is the process by which protein production from a gene is turned off by a small interfering RNA (siRNA). An siRNA is a tiny RNA molecule whose sequence of beads/letters perfectly match a complementary set of beads/letters on a messenger RNA (mRNA). When a siRNA recognizes its perfect match in an mRNA, it causes cleavage and destruction of that mRNA. The siRNA emerges unharmed, so afterward it can go off in hunt of other matching mRNA molecules. Thus even if the cell keeps producing new mRNAs, the siRNA can continue to destroy each new mRNA. In this way, protein expression from the target gene is silenced.
Evolutionarily, siRNAs likely arose as a natural intracellular defense mechanism against RNA viruses. But scientists and clinicians now use them to turn off genes of their choosing. Because it is easy to design and synthesize an siRNA complementary to almost any mRNA, siRNAs are a promising and emerging therapy option for human disorders that can potentially be resolved by silencing inappropriate gene expression.
What does "RNA Therapeutics" mean?
By "RNA therapeutics", the UMMS RTI means the use of RNAs (e.g., siRNAs) as a therapeutic agents and/or the modulation of RNA-based processes with more traditional drugs (e.g., small molecules). Because RNA is central to all biological processes, there are numerous potential avenues for addressing human disorders at the RNA level. RTI researchers are currently working on many different RNA-based pathways to find new therapies for human disease.
What are other potential RNA-based or RNA-directed therapies?
Besides siRNAs, miRNAs are promising as therapeutics. As discussed above, whereas siRNAs can completely silence a gene, miRNAs tend to just turn protein production down a little. So in cases where complete shutoff of a gene is not desirable, miRNAs might be the therapeutic molecule of choice.
Although both siRNAs and miRNAs can be introduced into cells from the outside using synthetic (man-made) materials, cells can also make their own siRNAs and miRNAs from genes specially built to encode them. Inside cells, siRNA and miRNAs can be made from longer short hairpin RNAs (shRNAs). RTI scientists are currently collaborating with colleagues in the UMMS Gene Therapy Center to develop gene therapy approaches to deliver genes encoding shRNAs to specific tissues. The promise of this approach is that, instead of having to continually administer synthetic siRNAs or miRNAs, our own cells could be permanently programmed to make their own RNA therapeutics.
Another promising therapeutic avenue is to modulate RNA based processes, such as protein production by the ribosome, with small molecules. Indeed, many of the antibiotics currently in use to control bacterial infections target the bacterial ribosome. Numerous additional small molecules have been identified that modulate other steps in gene expression involving RNA. For instance, a new class of small molecules that inhibit a process called RNA splicing show promise as anti-tumor and anti-cancer agents.
For what diseases are RTI scientists and clinicians currently trying to develop therapies?
Since RNA is so central to many basic life processes, any new therapeutic approach developed by RTI researchers could potentially be applied to a wide variety of problems. The following disorders, however, constitute the current focus of RTI researchers:
Amytrophic Lateral Scleorsis (ALS, Lou Gehrig's Disease)
Frontotemporal Lobar Degeneration (FTLD)
Does RTI make any products that I can buy?
No, the UMMS RTI is a research entity only. We do not manufacture or distribute any products.
How will any new approaches developed by RTI scientists be turned into real therapies?
In the United States, any new therapy must be approved by the Food and Drug Administration (FDA). FDA approval requires extensive clinical trials to assess effectiveness and toxicity (side effects). Before a clinical trial can commence, extensive animal testing is usually required. Currently, RTI researchers and clinicians have several potential therapies in the animal testing stage.
When will these therapies become available?
Although we would all like shorten the "bench to bedside" timeline, careful development of new therapies takes time. It will likely be several years before any therapies currently in development at the RTI will be FDA-approved and available for general use. However, it will be possible to participate in clinical trials.
How can I find out about clinical trials?
A searchable database of all current clinical trials in the US can be found at http://clinicaltrials.gov. Searchable terms include the disease of interest (e.g., ALS), the trial site (e.g., Worcester, MA), the therapeutic method (e.g., siRNA), clinician's name (e.g., Dr. Robert Brown) and the sponsor/responsible party (i.e., academic institution or company).
More information about clinical trials and translational science at UMass Medical School can be found at Translating Knowledge into Clinical Practice.
Is the RTI currently recruiting any new faculty members?
Great question! Yes we are. Please see the Opportunities link on our website for more information. We are always looking for world class scientist from synthetics chemists and material science, biochemistry, genetic and molecular biology scientists to join our team.
How can I help the RTI?
There are many ways to help the RTI.
If you would like to donate money, we have many levels of giving. These include creating endowments, supporting a postdoctoral researcher, a scholarship fund, medical research, or our graduate school. For more information, please contact our Development office, and be sure to designate your gift to the RNA Therapeutics Institute. Thank you.
If you would like to donate your time, there are several ways to get involved. Please visit the volunteer opportunities link to see what you can do to be a part of the University of Massachusetts Medical School family.