New Horizons, Mysterious male neurons, and Remote-controlled T-cells

Hi everyone! I missed making a post on the last two Sundays, so today I’m bringing you a bunch of interesting discoveries that occurred over the last two weeks. Or rather, I am bringing you half of those stories, because there are simply too many to include in one post. I’ll be posting Part II in a day or two, so stay tuned for that.

Let’s begin!

Pluto Spills its secrets

The New Horizons spacecraft was launched from Cape Canaveral on January 19, 2006 with a mission to make a close flyby of objects in the Kuiper belt, the dark outer frontier of our solar system. By far, the most interesting target was Pluto, the erstwhile planet, of which we only had data from distant astronomical observations till now. New Horizons took about thirteen months to reach Jupiter and then used Jupiter’s gravity to get a boost in speed before making a beeline for Pluto. On July 14, 2015, it made its closest approach to Pluto, after having transmitted images and data relating to it for a period of almost six months. This month, the results from the flyby were published in the journal Science, exposing a wealth of new information.

For starters, Pluto seems to be unusually geologically active for a planet of its size and status. Its surface is dotted with craters alongside deep features like mountains that can only be formed as a result of tectonic activity and the presence of hard bedrock. The surface of Pluto is covered with nitrogen, carbon monoxide and methane ice, which do not fit the requirement for hard bedrock, and hence this suggests the presence of a harder substance below the surface layer – most likely water-ice. Also, certain parts of Pluto’s surface show really few craters, suggesting that these regions were formed relatively recently – strong evidence for continuing geological activity. Intriguingly, in certain places, the scientists even reported seeing ‘glacier-like’ features.

Another surprising discovery was the extent of Pluto’s atmosphere – with an almost 150 Km deep atmospheric ‘haze’ clearly visible above the surface. The surface pressure is low, about 10 microbar (for comparison, atmospheric pressure at the earth’s surface is approximately 1 bar, about 100,000 times that of Pluto). Methane and Nitrogen were among the gases detected. In addition to studying Pluto, New Horizons also took high resolution photos of Pluto’s biggest moon, Charon. Charon also shows evidence of tectonic activities, and has several large craters on its surface. New Horizon also sent back information about two more moons of Pluto – Hydra and Nyx – which are tiny, irregularly shaped satellites, whose highly reflective surfaces indicate that they are mostly covered with water-ice.
Till the New Horizons flyby, the highest resolution image we had of Pluto is the one shown on the top left, taken from the Hubble Space Telescope. Compare it to the latest images released by NASA (top right), if you want to know how much the recent flyby has added to our knowledge of this controversial member of our solar system.

Mysterious male neurons of C. elegans

Caenherrobditis elegans is a small soil-living roundworm (also called a nematode) found in temperate zones. In 1974, the famous South African geneticist Sydney Brenner, proposed the use of C. elegans as a model system for studying development in multicellular organisms.The worm is only about 1mm in length, can be grown in bulk, and has a nearly transparent body that makes it very easy to study. C. elegans has been used extensively for developmental studies, particularly in the nervous system. Every single cell in its body has been identified and precisely mapped, and in 1998, it became the first multicellular organism to have its complete genome sequenced. Till date, C. elegans is the first and only animal to have a full connectome (a map of how every neuron in the body connects to the others) generated.

It therefore came as a surprise when scientists working at University College, London, suddenly came across a pair of neurons sitting innocuously in a male worm’s head, right where they should not be. The researchers named these cells MCM neurons, standing for ‘mystery cells of the male’

A quick note about genders in the worm- C. elegans has two sexes – hermaphrodite and male. Hermaphrodites have male and female sex organs and can fertilize themselves. Alternatively, males can fertilize hermaphrodites. Male C. elegans worms have extra neurons and extra sensory and motor pathways that deal with mating behavior. However, sexual dimorphism (the difference between the sexes) does not stop at mating behavior. Males also show distinct learning behaviors different from the hermaphrodites which allows better pursuit of mates. One of these behaviors, called sexual conditioning, occurs when a male worm learns to forget that a certain situation can have bad outcomes (for e.g. starvation) if it has a sexual or mate-associated experience in that situation.

Basically, they choose sex over food. Sounds familiar?

What happens if you get rid of the MCM neurons? No more sexual conditioning, and the males show a shocking lack of preference for terrible situations even when sex is promised.

The surprises with the MCM neurons did not stop there. Every neuron in C. elegans arises from epithelial or undifferentiated blast cells, similar to most invertebrate animals. However, upon studying closely the niche in which the MCM neurons were located, the authors found that the MCM neurons were formed from fully differentiated glial neurons, which lost their differentiation status to give rise to these new neurons. This is somewhat similar to neurogenesis in vertebrates where radial glia-like cells are believed to give rise to adult neurons, and is unlike any mechanism of neuron formation observed in invertebrates so far.

Remote control of cancer-fighting T-Cells

The idea of immunotherapy to fight cancer has been around for a while. In general terms, this means using the body’s own immune system to identify and eliminate tumor cells. In the early 1980s,  Professor Zelig Eshhar and his colleagues at the Weissman Institute of Science, came up with the idea of using engineered T-Cells (T cells are a type of white blood cells that release toxic molecules to combat infectious agents) to fight lymphomas.

The technique involves –

1. taking T-Cells out of the patient’s body
2. genetically engineering them to express novel receptor proteins, called chimeric antigen receptors (CARs) which recognize specific motifs on the cancer cell’s surface
3. amplifying these engineered T-cells in the laboratory, and
4. transfusing them back into the patient’s body

In Phase 1 clinical studies, this method has been shown to be effective in combating chemotherapy resistant forms of B-cell cancers. However, this therapy suffers from one major drawback – that of major, sometimes life-threatening side effects. The engineered CAR-T cells have a tendency of getting activated by non-specific signals and the resulting inflammation or cytokine waves can have severely toxic effects. As of now, there exist few ways of controlling the T-cell action once begun, and this makes treating the patients for this extremely difficult.

Chia-Yung Wu and colleagues at University of California, San Francisco, came up with a novel solution to this problem. They literally took apart the chimeric antigen receptor, and engineered it to require another small molecule, i.e. a drug, that needs to be injected into the patient’s body in order to activate the T-cells. This means that the extent, timing, and location of activation of the CAR-T cells can now be precisely controlled by simply injecting a drug in the right dosage, at the right time, and in the right location.

Wu and colleagues tested their therapy on mice, and obtained promising results. Hopefully this new therapy will make its way to clinical trials in the recent future.

Oxidative Stress and Tumor metastasis

Metastasis is the name of the process where cancer cells leave the site where they were born, and migrate through the body to set up new tumors in different locations. This is the part which makes cancer so difficult to treat surgically or locally, and is the crucial step at which many therapies have begun to be directed. Only a very small percentage of tumor cells become metastatic, as metastasis involves a drastic change in the cell’s basic nature, and needs heavy reorganization of structure and function. In a recent study, researchers tried to see what distinguished successfully metastasizing human melanoma cells from the cells that did not metastasize. They found that one key barrier to survival of metastasizing melanoma cells in circulation is the presence of oxidative stress. Oxidative stress is when oxygen molecules accept electrons and give rise to reactive intermediates (called reactive oxygen species, or ROS) which react with and damage cellular contents like proteins or lipids. The tumor cells which managed to successfully metastasize were shown to undergo metabolic changes in order to combat this oxidative stress, and these changes got reversed upon successful metastasis. Administration of antioxidants promoted tumor metastasis, while blocking the folate pathway reduced it. This appears to be a promising avenue for future therapeutic research.

Possibility of a new TB vaccine

Over a million people die annually from tuberculosis across the world, over 250000 of them in India. Almost one-third of all humans has been (or will be) infected with the tuberculosis bacteria during their lifetime, though only a few will develop symptoms of the disease. Tuberculosis is the second biggest killer of human beings among all infectious diseases caused by a single agent (behind HIV-AIDS), and often arises as a secondary infection in immunocompromised individuals. From infected individuals, it spreads quickly via the air when the patient coughs or sneezes.

The main preventive control of tuberculosis that exists currently is the BCG vaccine, which almost all of us have taken as infants. The BCG vaccine consists of an inactive form of the bacteria which causes the bovine (cattle) form of the disease. This microorgansim has lost the ability to infect humans, but still can give rise to immune effects that can cause some protection against disease. Unfortunately, the effectiveness and duration of protection from the BCG vaccine has both been called into question. Several groups worldwide have been trying to find new and improved vaccination strategies to combat tuberculosis.

The causative organism of tuberculosis, Mycobacterium tuberculosis, is a tiny bacteria that infects the lung, and in a small percentage of infected humans, produces symptoms that are the hallmarks of TB, including chronic cough, chest pain, fever, weight loss and fatigue, sometimes leading to death. The bacteria are remarkably immune tolerant – resisting damage from the most persistent of macrophages and T-cells (some of the major defensive cells in the blood). One of the keys to this bacteria’s amazing toughness is the protein SigH, which confers protection against oxidative stress. Oxidative stress, as mentioned in the story above, is the damage to cellular contents produced by oxygen-derived reactive molecules, and is often used by immune cells to kill their prey. SigH counters this oxidative stress, and allows Mycobacterium tuberculosis to live on despite the odds.

The lab of Smriti Mehra at Lousianna State University, USA has been studying Mycobacterium tuberculosis since some time. They found that if SigH is deleted from Mycobacterium tuberculosis, and the resulting incapacitated virus is directly administrated into the lungs of macaque monkeys in an aerosol form, it effectively protects them from a fatal form of the disease. It is to be hoped that such alternate vaccination strategies are translated rapidly into clinical research, and implemented to counter the global load of tuberculosis.

A substance that sucks CO₂ from moist air

Carbon dioxide is a major greenhouse gas, and controlling its emission has been at the forefront of many environmental control programs. CO₂ is often a major byproduct in many industrial processes and is released as a flue gas, or an exhaust gas into the atmosphere. Many technologies have been developed to suck or remove CO₂ from the flue gases before it is released into the atmosphere, most of these relying on the absorption of CO₂ by microporous materials. Unfortunately, water tends to competitively inhibit the binding of CO₂ to these materials, significantly reducing the efficiency of the CO₂ removal process. As a result a step of dehydration needs to be added before the CO₂ adsorption step, which adds to the costs and operational difficulties of the process. One more issue is that flue gas tends to be at high temperatures, and adsorption of CO₂ is often sub-par at these temperatures.

A group of researchers in Korea have come up with a unique solution to the problem. They have produced a new material, a microporous coppersilicate that can efficiently adsorb CO₂ from moist air, without the efficiency being compromised by the presence of water. It achieves this by having separate binding pockets for CO₂ and water so that the binding is non-competitive for the two species. The coppersilicate is highly stable, and may have multiple industrial applications.

Early modern humans in Southern China

Homo sapiens, our very own branch of the human tree, arose in Africa about 200,000 years ago. For years, these early humans settled and spread through Africa, before venturing out into Asia about 60,000 years ago. They are believed to have colonized Australia and Europe about 40,000 years ago, and made the difficult overland trek to the Americas roughly 12,000 years ago.

This view has met its first solid challenge from recent discoveries in the Fuyan cave in Southern China. 47 fossilized human teeth were found in this location, that are almost unquestionably modern in nature, and have been dated to be a minimum of 80,000 years old. The upper limit on the age of these samples is 12,000 years, and this predates even the earliest known human samples in this region by 30,000 to 70,000 years. This shows that modern humans reached China much earlier than anyone had presumed, and their exclusion from other regions such as northern Europe where they did not appear until many thousands of years later remains a mystery to be solved.

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I will try discuss a couple of the papers mentioned today in more detail in the coming weeks, once we finish discussing the discoveries that led to the awarding of this year’s Nobel prizes. Also, for those of you who are looking for the original references, just click on the section headers. And don’t forget to watch out for Part 2 of this post, coming in a few days.

See you and have a great week!