It’s always exciting when major scientific discoveries change the way we view and understand human biology and complex diseases. Recently, two studies published in high impact journals created an internet and social media buzz because of their game-changing discoveries in the fields of cancer and neuroninflammation. Their findings not only further our comprehension of the mechanisms behind these diseases, but also open doors to entirely new areas of research that have the potential to develop more effective therapeutics and possibly even cures.

A novel mechanism for how cancer cells combat replicative senescence.

A cell is programmed to divide a certain number of times as it ages, and eventually it enters a state of senescence where it no longer proliferates. Cancer is an age-associated disease and it occurs when cells overcome these built-in biological roadblocks and begin to proliferate uncontrollably. Well-known causes of cancer include genetic gain of function mutations in proto-oncogenes (MYC, RAS, ERK) and loss of function mutations in tumor suppressor genes (TP53, RB1).

Telomeres are the caps at the ends of chromosomes that protect the loss of DNA. (Source wikimedia)

Telomeres are the caps at the ends of chromosomes that protect the loss of DNA. (Wikimedia)

Another mechanism that seems to be necessary for many cancers is excessive telomerase activity. Whether telomerase activity is sufficient to initiate cancer is still debated (see here, here, and here). Telomerase is the enzyme that adds specific repeat sequences of DNA nucleotides (TTAGG) onto the ends of chromosomes to form protective caps that prevent loss of important genetic information. Every time a cell divides, DNA replication enzymes duplicate chromosomal DNA. Because DNA replication machinery originally evolved to replicate circular DNA (like circular chromosomes found in yeast and bacteria), the very ends of linear DNA in mammalian chromosomes are not fully replicated. Consequently, chromosomes shorten with each cell division. Telomeres act as a buffer of “junk” DNA that protects our chromosomes from DNA loss. They also serve as a safety mechanism to tell the cell when to stop dividing; when the telomeres are too short, cells tend to enter a state of senescence. In the case of cancer, unwanted telomerase activity can lengthen telomeres in senescent cells and allow them to proliferate indefinitely, which is one hallmark of cancer.

Telomerase activity is dependent on its catalytic subunit hTERT (telomerase reverse transcriptase), which is the key component required for adding TTAGG subunits to the ends of telomeres. In normal somatic (adult) cells, TERT is dormant, but in approximately 90% of aggressive cancers, TERT is overexpressed. This is typically due to genetic mutations in non-coding (sections of DNA that aren’t translated into genes) regions of DNA such as the TERT promoter (a region of DNA that when activated initiates transcription of the gene it regulates).

Image of a glioblastoma, a type of cancer found in the brain. (Wikimedia)

Image of a glioblastoma, a type of cancer found in the brain. (Wikimedia)

A study by Bell et al. published last month in Science, discovered that a specific transcription factor GABP, binds and activates the mutant TERT promoter in a majority of cancer tumors. The authors first screened a panel of transcription factors known to bind the mutant TERT promoter using siRNA knockdown in human glioblastoma cancer cell lines. They discovered that the transcription factor GABP was specifically responsible for aberrant TERT activity. When they knocked down expression of GABP, only mutant TERT activity was abolished and not wild type (normal) TERT, indicating that GABP selectively binds the mutant TERT promoter sequence.

The authors then confirmed this phenomenon using in vivo ChIP-seq (chromatin immunoprecipitation sequencing) data from a wider variety of human tumors and in vitro GABP ChIP in multiple cancer cell lines with or without TERT promoter mutations. In both experiments, they found that GABP was only associated with the mutant TERT promoter and not the wild type.

To summarize, this study identified a novel mechanism that explains how the expression of TERT in increased in aggressive forms of human cancer. Mutations in the TERT promoter result in binding of the GABP transcription factor and facilitate TERT activation. This ultimately results in telomerase activity and cancer cell proliferation. The larger implication of this study is that future cancer therapeutics could be designed to block GABP-mediated TERT activation in mutant TERT promoter expressing cancers.

New link connecting the immune system and the brain.

If you look at the lymphatic system in a human anatomy textbook, you will notice that the brain is the only organ that isn’t connected to this important structure. The lymphatic system is a network of lymph nodes and vessels that transport a clear fluid called lymph. Lymph contains white blood cells and extracellular proteins and is derived from interstitial fluid (the liquid found between cells) that accumulates in tissue. The lymphatic system acts as a drainage system for interstitial fluid and mediates the reuptake of lymph into the circulatory system. It also removes foreign contaminants such as bacteria, dead cells, and cancer cells, and plays an important role in the immune system.

For decades, scientists have thought that the central nervous system (CNS) lacked a lymphatic system. This notion along with knowledge of the blood-brain barrier was in part responsible for the theory of “immune privilege” within the brain, a situation where factors that normally would elicit a peripheral inflammatory immune response are tolerated. This idea was disproved with the discovery of immune surveillance cells in the spaces between the meninges membranes that cover and protect the brain and spinal cord (the central nervous system or CNS). Immune cells that either reside in the brain (microglia) or originate from the blood circulation (macrophages, dendritic cells, T lymphocytes) protect the CNS from foreign agents that could cause infection and disease and help maintain brain homeostasis and function.

On the left is a diagram of the lymphatic system that you will find in anatomy textbooks. This recent discovery proved that the CNS has its own lymphatic system that connects to the peripheral system. (Source)

On the left is a now outdated diagram of the lymphatic system that you’ll find in your anatomy textbook. Scientists have now proved that the CNS has its own lymphatic system that connects to the peripheral lymphatic system. (Credit: University of Virginia School of Medicine)

How immune cells enter and leave the CNS is less well known. A recent study published last week in Nature found a missing clue that may address this question. Louveau et al. discovered the presence of meningeal lymphatic vessels in the CNS of mice. Using a novel tissue mounting technique, they were able to isolate intact meninges and visualize their cellular components using fluorescence microscopy. They observed that T lymphocytes, macrophages, and other immune cells were confined to the meningeal compartments very close to a structure called the dural sinuses. Interestingly, the immune cells were organized in a pattern characteristic of being inside vessels. With further probing, they discovered that these immune cells were actually located within lymphatic vessels.

A close look at the meninges of the mouse brain reveals lymphatic vessels (red) located around the blood vasculature (green).

A close look at the meninges of the mouse brain reveals lymphatic vessels (red) located around blood vessels (green). (Credit: University of Virginia School of Medicine)

Next, the authors conducted experiments to prove the functionality of meningeal lymphatic vessels. First they injected a fluorescent tracer dye into the ventricles of mice brains and observed that cerebrospinal fluid, or CSF, (the fluid surrounding the brain and spinal cord) drained into meningeal lymphatic vessels. Second, they discovered that these lymphatic vessels in the CNS were directly connected to the cervical lymph nodes (located in the neck), and served as the main drainage system of CSF into the peripheral lymphatic system.

By identifying the presence of a meningeal lymphatic system, Louveau et al. discovered a direct connection between the immune system and the brain. Their work reveals a new pathway by which CSF can drain into the peripheral lymphatic system and a potential new pathway for immune cells to enter and exit the CNS. The implications of this study are numerous and worthy of a separate blog. But to give you a taste of what’s to come, scientists will need to reevaluate the mechanisms behind age-related neurodegenerative disorders associated with immune system dysfunction including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Alzheimer’s disease and determine whether changes in function or degeneration of the meningeal lymphatic system are to blame.