We live in the 21st century: while we go about our everyday lives, twin robot geologists launched by NASA go over Mars’s surface, providing 360-degree, stereoscopic, humanlike views of the terrain. The internet has become the first global knowledge network connecting billions of people with an unlimited number of channels, and we are able to access most of them through small devices that we carry everywhere, namely smartphones. With all of the outstanding advances in science and technology, it seems surprising how many neurological diseases still remain unexplained.
What is ALS
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s Disease, was first described by Jean-Martin Charcot – considered the founder of neurology – in a series of studies conducted between 1865 and 1869. ALS is a neurological disease that consists of progressive degeneration of motor neurons in the brain and spinal cord. Upper motor neurons reside in the cerebral cortexand brain stem, and use axons (the wires of the nervous system) to transmit signals to the spinal cord, where the lower motor neurons reside. From the spinal cord, the axons of lower motor neurons send electric impulses to different muscles in the body, allowing some muscular groups to contract and release for movement. ALS affects both upper and lower motor neurons, causing damage and neural death. When these neurons die, they leave voluntary muscles paralyzed. We use these types of muscles not only to move, but also to speak, eat, and breathe – thus patients with ALS suffer a loss of mobility, loss of speech and eventually loss of breathing ability.
Even though there is pharmacological treatment to slow the diseaseís progression, there is still no known cure to this illness, almost 250 years since its first description. According to the ALS society of Canada, approximately 2,500 to 3,000 people in Canada are living with ALS; 1,000 will succumb to the disease and 1,000 will be newly diagnosed each year. It is a terminal disease with a lifespan after diagnosis of two to five years on average.
ALS awareness
ALS is commonly associated with Lou Gehrig – the deceased baseball player from whom the disease took its name – and the physicist, cosmologist, and science writer Stephen Hawking, who has shown an atypical course of his disease, surviving more than fifty years since the diagnosis. Last summer, millions of people started talking about ALS thanks to the “Ice Bucket Challenge,” which encouraged participants to film themselves while they had a bucket of ice water poured on their heads to raise awareness and funds for ALS research. The phenomenon quickly went viral on the internet, leading to more than 2.4 million tagged videos circulating Facebook, thrusting the disease into the foreground of public knowledge. In August, the ALS Association announced that their total donations since July 29 had exceeded $100 million. The ALS Association is just one of several ALS-related charities that have benefited from this awareness.
A breakthrough
In September 2015, a group of researchers from the U.S. National Institutes of Health (NIH) published an article in Science Translational Medicine titled “Human endogenous retrovirus-K contributes to motor neuron disease”, the findings indicate that a retrovirus could be implicated in the course of this mysterious disease.
In order to understand this, we must remember what viruses are: tiny infectious agents that are everywhere around us and inside us. They are considered “at the edge of life” because, despite having genes and evolving by natural selection, they cannot replicate on their own. They need the cell machinery of other species to replicate their genes and assemble their protective coats made of proteins, called capsids.
After infecting the cells of a bigger organism, viruses use cell organelles to build other viruses. Some types of viruses, such as retroviruses, will actually insert their genes in the host’s DNA in order to reproduce. Retroviruses are characterized by the presence of reverse transcriptase, an enzyme that allows them to insert copies of their genes into host chromosomes. Retroviruses are more prone to mutation than most viruses: one of the most common of these is the human immunodeficiency virus (HIV). HIV is the infectious cause of AIDS, which is treated with antiretroviral drugs that target reverse transcriptase enzymes. This is an example of an exogenous retrovirus, which means for infection to occur, transmision between humans must occur.
In contrast, endogenous retroviruses are remnants of ancient viruses that inserted their genes into human DNA long ago and persist through inheritance, generation to generation. This might sound surprising, but up to five per cent of the human genome consists of endogenous retrovirus genes. One of such viral gene sequences in our DNA is called human endogenous retrovirus-K (HERV-K), which is the virus that scientists from the NIH recently found to be related to ALS.
Retroviruses and ALS
Avindra Nath, the main investigator of the NIH group, started suspecting a link between a retrovirus and ALS after seeing a patient with AIDS and ALS whose neurological symptoms improved with antiretroviral drugs. This led Nath to look in the medical literature about ALS, where it was found that reverse transcriptase – the enzyme that characterizes retroviruses – had been found in the blood of ALS patients in various reports.
No exogenous retrovirus had been linked to ALS, so the researchers began looking into possible endogenous retroviral genes. When, in 2011, they finally found elevated levels of HERV-K in the brain tissue of 11 ALS deceased patients, they decided to test their hypothesis through more experiments. They found that the gene was present in cortical and spinal neurons of ALS patients, but not in healthy controls. They also inserted these genes into cultured human neurons, causing damage and death. Furthermore, they found a way for mice to express HERV-K. These mice developed classic symptoms of ALS: muscle atrophy, progressive paralysis, and death. The strength of this evidence finally convinced the scientific community of a link between these viral genes and the development of ALS, although the exact link remains unclear.
The future of ALS
What does all this mean in terms of treatment or detection of the illness? There are two steps after this discovery. The first one focuses on treatment: antiretroviral drugs similar to those used to treat HIV may be used in addition to the usual drug to slow the diseases progression. The second implication regards early diagnosis. If these sequences can be detected in patients’ DNA or blood, the retrovirus DNA could serve as a biomarker – a measurable indicator of the severity or presence of this disease – which could then lead to earlier intervention.
Although the “Ice Bucket Challenge” may have seemed silly, raising awareness for this disease and increasing funding for ALS research will surely continue to be fruitful in the future, guided by the light of this provocative discovery. However, we should never cast skepticism aside: Nath admits that the increase of HERV-K in ALS patients could be the result of something else that’s causing the disease. As Raymond Roos, a neurologist at the University of Chicago, has pointed out, “a link does not imply causality.” Finding these associations doesn’t mean that the genes cause the disease, but rather that they can be implicated in the development of the disease, accelerating ALS.