Breakthroughs in medicine have increased substantially over the last hundred years, and most would agree that the introduction of antibiotics in 1942 has been one of the largest milestones in the history of medicine thus far. The success in treating bacterial infection has only accentuated the glaring lack of progress in developing effective therapeutics for those other enemies of the immune system, viruses. But Dr. Todd Rider and his team at MIT have dropped a bombshell with their announcement of a new broad spectrum antiviral therapeutic, DRACO, which appears not only to cure the common cold, but to halt or prevent infections by all known viruses.
Before talking specifically about this exciting news, let us first review viral biology and why viral infections have been so difficult to treat.
As you may recall from your early education, a virus particle, or virion, consists of DNA or RNA surrounded only by a protein coat (i.e., naked virus) or, occasionally, a protein coat and a lipid membrane (i.e., enveloped virus). Viruses have no organelles or metabolism and do not reproduce on their own, so they cannot function without using the cellular machinery of a host (bacteria, plant, or animal).
Viruses can be found all throughout our environment and are easily picked up and transferred to areas where they may enter our bodies, usually through the nose, mouth, or breaks in the skin. Once inside the host, the virus particle finds a host cell to infect so it can reproduce.
There are two ways that viruses reproduce. The first way is by attaching to the host cell and entering it or injecting viral DNA/RNA into the cell. This causes the host cell to make copies of the viral DNA and translate that DNA to make viral proteins. The host cell assembles new viruses and releases them when the cells break apart and die, or it buds the new viruses off, which preserves the host cell. This approach is called the lytic cycle.
The second way that viruses reproduce is to use the host cell’s own materials. A viral enzyme called reverse transcriptase makes a segment of DNA from its RNA using host materials. The DNA segment gets incorporated into the host cell’s DNA. There, the viral DNA lies dormant and gets reproduced with the host cell. When some environmental cue happens, the viral DNA takes over, makes viral RNA and proteins, and uses the host cell machinery to assemble new viruses. The new viruses bud off. This approach is called the lysogenic cycle; these viruses are called retroviruses and include herpes viruses and HIV.
Once free from the host cell the new viruses can attack other cells and produce thousands more virus particles, spreading quickly throughout the body. The immune system responds quickly by producing proteins to interfere with viral replication, pyrogenic chemicals to raise body temperature, and the induction of cell death (apoptosis). In some cases simply continuing the natural immune response is enough to eventually halt viral infection. But the virus kills many host cells in the meantime, leading to symptoms ranging from the characteristic runny nose and sore throat of a cold (rhinovirus) to the muscle aches and coughing associated with the flu (influenza virus).
Any virus can be deadly, especially to hosts with a weakened immune system, such as the elderly, small children, and persons with AIDS (though death is actually often due to a secondary bacterial infection). And any viral infection will cause pain and suffering, making treatment a very worthwhile goal. So far, the most successful approach to stopping viral infections has been prevention through the ubiquitous use of vaccines. The vaccine— either a weakened form of a particular virus or a mimic of one—stimulates the immune system to produce antibodies specific to that virus, thereby preventing infection when the virus is encountered in the environment. In another approach, antiviral medications are administered post-infection and work by targeting some of the specific ways that viruses reproduce.
However, viruses are very difficult to defeat. They vary enormously in genetic composition and physical conformation, making it difficult to develop a treatment that works for more than one specific virus. The immense number of viral types in nature makes even their classification a monumental job as there is more enormous structural diversity among viruses. Viruses have been evolving much longer than any cells have even existed and they have evolved methods to avoid detection and to overcome attempts to block replication. So, while we have made some progress in individual battles, those pesky viruses have definitely been winning the war.
Which is why the announcement of a broad spectrum antiviral therapeutic agent is such huge news. In their paper, Rider et al. describe a drug that is able to identify cells infected by any type of virus and which is then able to specifically kill only the infected cells to terminate the infection. The drug, named DRACO (which stands for Double-stranded RNA (dsRNA) Activated Caspase Oligomerizer), was tested against 15 viruses including rhinoviruses, H1N1 influenza, polio virus, and several types of hemorrhagic fever. And it was effective against every virus it was pitted against.
Dr. Rider looked closely at living cells’ own defense mechanisms in order to design DRACO. First, he observed that all known viruses make long strings of doublestranded RNA (dsRNA) during replication inside of a host cell, and that dsRNA is not found in human or other cells. As part of the natural immune response, human cells have proteins that latch onto dsRNA and start a biochemical cascade that prevents viral replication. But many viruses have evolved to overcome this response quite easily. So Rider combined dsRNA detection with a more potent weapon: apoptosis, or cell suicide.
Basically, the DRACO consists of two ends. One end identifies dsRNA and the other end induces cells to undergo apoptosis. When the DRACO binds to dsRNA it signals the other end of the DRACO to initiate cell suicide, thus killing the infected cell and terminating the infection. Beautifully, the DRACO also carries a protein that allows it to cross cell membranes and enter any human or animal cell. But if no dsRNA is present, it simply does nothing, leaving the cell unharmed.
An interesting question is whether any viruses are actually beneficial and whether wiping all viruses out of an organismal system may have negative consequences (as happens when antibiotic treatment eradicates both invading pathogenic bacteria and non-pathogenic flora, often leading to symptoms such as digestive upset). After his recent presentation at the 6th Strategies for Engineered Negligible Senescence (SENS) conference in September 2013, Dr. Rider fielded this question and stated quite adamantly that there are no known beneficial, symbiotic, or non-harmful viruses. This point is further emphasized in a recently published interview in which he is asked whether DRACO-triggered cell death could lead to a lesion in a tissue or organ. Rider responds that “Virtually all viruses will kill the host cell on the way out. Of the hand-full that don’t, your own immune system will try to kill those infected cells. So we’re not really killing any more cells with our approach than we already have been. It’s just that we’re killing them at an early enough stage before they infect and ultimately kill more cells. So, if anything, this limits the amount of cell death.”
So far, DRACO has been tested in cellular culture and in mouse models against a variety of very different virus types. Rider hopes to license DRACO to a pharmaceutical company so that it can be assessed in larger animal trials and, ultimately, human trials. Unfortunately, it may take a decade or more to complete this process and make the drug available for human therapeutic purposes, and that’s only if there is enough interest to do so. Amazingly, the DRACO project was started over 11 years ago and has barely survived during that period due to lack of interest and funding. Even now, after the DRACOs have been successfully engineered, produced, and tested, no one has yet reached out to Rider about taking them beyond the basic research stage. Let us hope that those of us who do find this work unbelievably exciting can make enough noise that Rider’s work continues to the benefit of all mankind.
Originally published as an article (in the Cooler Minds Prevail series) in Cryonics magazine, November, 2013