Monthly Selection of Medical Essays: October Edition

A New Target for Metastatic Lung Cancer

Lung cancer is a type of cancer that is prone to metastasis. There are risk factors that can cause metastasis, but what they are for lung cancer is not yet known. In a new study published in the Science, researchers discovered a new polymorphism that could be one of the risk factors.

Thanks to the Human Genome Project, we can see single letter changes in our genetic code. These changes are called single nucleotide polymorphism (SNP). To find the genetic basis of a disease, scientists try to find common SNPs that they think are related to that disease in large groups of patients. This study applied the same method for metastasis in lung cancer.

There is a protein that inhibits metastasis already known for lung cancer: Breast cancer Metastasis Suppressor 1 (BRMS1). Liu et al. searched for SNPs on this protein and discovered a new one they found to increase the risk of metastasis: rs1052566. They showed that the mutation due to this SNP suppresses the function of the BRMS1 protein, furthermore, it causes activation of the c-fos proto-oncogene and promotes metastasis.

The researchers took their findings further and tried treating mice with tetracycline, a c-fos inhibitor used to treat arthritis. They found that this treatment prevented metastases.

With this study, Liu et al. showed a polymorphism that predisposes to metastasis in lung adenocarcinoma, determined the pathophysiology of this mutation at the cellular level, and showed that tetracycline was effective in reducing metastases. This treatment method, which can reduce the risk of metastasis in patients with SNP named rs1052566, may soon find a place in daily medical practice.

Organoids in a Rat Brain

Organoids are miniature forms of organs that originate from stem cells or a tissue, have the ability to self-renew and differentiate. These organs are produced in vitro and have been produced for many organs over the years. Thanks to organoids, we can observe how an organ develops from a single stem cell and how diseases occur during this developmental period.

I said that we can produce these tiny organs in vitro, that is, in a laboratory environment. In other words, these organoids do not have connections on humans, which are much more complex than a single organ. Therefore, they cannot become a developed organ, and their name remains organoid. Speaking of brain organoids, these organoids do not receive the external stimuli that are essential for their development. They are unable to develop new vessels and therefore cannot live for a long time.

In order to overcome such problems, a new study has been conducted. In this study, published in Nature, Revah et al. produced cortical organoids derived from human stem cells and transplanted them into the neonatal rat cortex.

Previous studies have shown that organoids transplanted into the rodent’s cortex are alive and able to form new connections, similar to a real brain. Because these studies were performed in adult rodent animals, the researchers speculated that this may have restricted the integration of organoids. Therefore, they used newborn rats. They observed that the organoids they transplanted to the somatosensory cortex received stimuli from rat whiskers and other sensory organs.

To demonstrate how their work could be used in developmental brain diseases, they developed a brain organoid from stem cells from three people with the genetic disorder Timothy Syndrome. When they transplanted the diseased organoids back into the rat cortex, they found that they didn’t work like other neurons and didn’t grow as much. In this way, they were able to show what is different in a brain with Timothy Syndrome from a healthy brain, with a rat brain.

Thanks to this discovery, we can better understand the developmental period of the brain. We can learn how the diseases seen in this period occur in the first place by creating new living organisms with the disease. Undoubtedly, drug discoveries will occur as well. These good developments also raise ethical problems. The level of consciousness of organoids is not yet known. It’s an enigma that it can evolve enough to give rise to human behavior. Also, considering the health of the rat, transplanted organoids can cause problems such as seizures or memory loss.

Our Genes May Have Mutated to Prevent the Plague, but It May Not Be a Good Thing

The disease caused by Yersinia pestis, which caused more than 50 million deaths in the 14th century, is called the “Black Death” today. Plague, one of the deadliest pandemics after smallpox and measles, still causes 600 cases a year.

This major biological event led to changes in our immune system, and as a result, deaths from plague were significantly prevented. A new study published in Nature has discovered that these mutations led to the largest natural selection in human history.

Researchers have characterized 206 ancient DNA extracts that lived before, during and after the Black Death. They found 245 variants that they thought were associated with the immune system trained for plague. They found that 4 of these 245 variants underwent selection at an unprecedented rate and intensity.

In particular, they showed that these 4 variants are more protective from the plague than those who do not have the variant, cause fewer deaths, and thus cause the inheritance of these variants for generations.

Natural Selection vs. Gene Drift

Natural selection is a process that develops as a result of the occurrence of some genes in populations more than the genes they are superior to over time and the inheritance of these superior genes to new generations. So it takes a long time. For example, peacocks choose their mates based on their tail lengths. Long and shiny tails attract more attention and these mates get ahead of the others in perpetuating their lineage. That’s why male peacocks with short, non-glossy tails are very rare today.

Gene drift is the variation of the gene variant in a population due to random chance. In other words, it can develop suddenly, unlike natural selection. For example, consider a garden of yellow and blue flowers. If a fire in this garden affects the part of the yellow flowers and only the blue flowers remain, we will see blue dominance in the newly blooming flowers. Gene drift has occurred in the flowers in this garden.

If we compare it to a fire in the garden, the 14th century plague may have caused a gene drift mechanism in Europe, leading to the dominance of the genes protecting from the plague.

The Exchange: Plague or Other Autoimmune Diseases

Cystic fibrosis (CF) is a genetic disease that develops as a result of the mutation of a protein that enables the glands, tissues and cells that produce secretions such as mucus and sweat in our body to function. Carriage of the gene that causes cystic fibrosis is more common in the Caucasian population. One hypothesis developed as to why this is the case is that the protein mutation seen in CF patients confers a protective feature for tuberculosis disease, therefore it was selected evolutionarily.

Sickle cell anemia is a disease that affects the shape of oxygen-carrying red blood cells. The red blood cells that move away from the disc shape become sickle, cannot pass to small vessels and cannot provide oxygen distribution. This disease is caused by a mutation in the hemoglobin protein found in red blood cells. The onset of sickle cell anemia correlates with malaria disease. For malaria, which causes disease through the bloodstream, intact red blood cells are required. In places where malaria is common, such as Africa, South America, and South Asia, populations have found a way to protect themselves from this disease by developing sickle cell anemia. In other words, they exchanged malaria with sickle cell anemia.

In this article, the researchers also showed that these genes, which were naturally selected for protection from plague, overlap with alleles that currently cause autoimmune diseases such as Crohn’s Disease, Rheumatoid Arthritis, and SLE.

We do not yet know whether other infectious diseases we experienced in the past caused current diseases, but we were able to see this in the case of plague. Cystic fibrosis to ward off tuberculosis, sickle cell anemia to ward off malaria, and other autoimmune diseases to ward off plague. It’s up to you whether it’s a fair trade-off.

Researchers Designed a New Fast-Acting Antidepressant

Medications prescribed for many mental disorders, such as major depression, are often associated with serotonin. For example, Prozac, which is frequently used for this purpose, uses the active substance called fluoxetine and shows its effects by preventing the reuptake of serotonin. This group of drugs is called SRIs for short.

SRIs require at least 2 weeks to take effect. While no effects on depression are observed within 2 weeks after taking the drug, on the contrary, side effects of the drug occur first.

That’s why fast-acting antidepressants are gaining importance. In a new study published in the journal Science, Sun et al. have identified a new fast-acting antidepressant mechanism by disrupting the relationship between the serotonin transporter (SERT) and neuronal nitric oxide synthase (nNOS).

nNOS controls SERT localization at the cell surface. Depending on this localization, the concentration of serotonin in the cell varies. The researchers thought that by disrupting this interaction between SERT and nNOS, they could increase the circulating serotonin concentration.

To test this, in their study on mice, they applied chronic unpredictable mild stress and saw that the SERT-nNOS complex was elevated. They produced a peptide that would disrupt this relationship between SERT and nNOS, and when they injected it, they found that the serotonin signal increased and a fast-acting antidepressant effect developed. Moreover, they found that the side effects of other antidepressants did not develop as a result of this injection.

Sun et al. say that this compound could be a new, fast-acting antidepressant with a low side-effect profile that could be used for diseases such as major depression.