Chemoattractants are chemicals towards which cells have a tendency to move. Just as receptors in our noses sense chemicals in the air, receptor molecules on the surface of a cell can pick up chemoattractants diffusing from a source. Cells move in the direction from which they pick up the strongest whiff of chemoattractant – enabling them to respond to chemical gradients. This strategy works well when the chemical source is nearby. However, just as our smelling abilities are limited by range, gradients are much harder to detect at long distances. In extreme cases, the gradient could be so weak that it is imperceptible. How, then, do cells decide where to orient themselves? 

An emerging hypothesis is that cells manage these situations by breaking down chemoattractants in their immediate vicinity, thus generating sharp concentration gradients (differences in the concentration of the chemoattractant across space) near the cell which can be used to determine direction. For example, cancerous epithelial cells break down and generate gradients of chemoattractants to migrate from their primary tumors to other locations.

To investigate this phenomenon, a study published in Science in August of last year challenged slime mold and cancer cells to solve complex microscale mazes. The scientists constructed microfluidic mazes consisting of thin channels in a silicone mold bonded to a glass petri dish, using techniques similar to those currently used to build organ-on-a-chip models. 

The researchers placed cells at the start of the maze and evaluated their ability to make it to a large chemoattractant reservoir on the other end. The cells solved the mazes by sensing, moving toward, and degrading chemoattractants along the way. These results demonstrate that these simple cellular functions could be sufficient to account for how eukaryotic cells traverse long distances in complex environments.

The maze setup reveals how such self-generated local gradients can be used to navigate complex environments. In the team's experiment, the concentration of chemoattractant was uniform throughout the maze at the start, so any direction-indicating gradient had to be generated by the cells themselves. To prevent interference between cells during the maze runs, the researchers mutated the cells so that they could no longer produce the chemoattractant themselves, but they could still respond to it and break it down.

First up in the maze was the slime mold Dictyostelium discoideum. For most of its life, this amoeba is a single-celled organism, but it has a remarkable social behavior: when starved, thousands of slime mold cells come together over long distances to form multicellular structures. This aggregation is guided by a chemoattractant known as cyclic AMP, which the cells produce and break down in periodic pulses. 

Before attempting the full maze, the slime mold cells first ran a race where one group of cells was exposed to regular cyclic AMP and the other had a version that was chemically modified to no longer be degradable. Cells migrated faster when they were able to degrade cyclic AMP than when they were not, confirming the idea that cells are better at moving towards chemicals that they are able to break down. Breaking down the attractant directs cells to move away from areas of high cell density, because the amoebae deplete cyclic AMP faster where there are more cells. This effect encourages the cells to disperse from the starting area and keep moving forward. 

Notably, unlike another maze-solving slime mold, Physarum polycephalum, which approaches the task by exploring every possible path before picking the best one, Dictyostelium discoideum cells were able to avoid going down incorrect paths using their self-generated chemoattractant gradients. The researchers obtained similar results using pancreatic cancer cells isolated from mice, which also generated gradients by breaking down chemoattractant, suggesting that the principles explored in the study are not specific to just one cell type. 

Finally, the researchers also supported their findings by tricking the cells with what they called a chemoattractant "mirage," and they were able to correctly predict with computational simulations what types of mazes would be easier or harder for the cells to solve. For example, they predicted that dead ends that branched or widened and thus acted as reservoirs for chemoattractant would lead more cells astray than short dead ends that did not hold much chemoattractant. As expected, the cells easily avoided going down short dead ends but were more often misdirected by complex branching dead ends. By switching up the designs of the miniature mazes on their microfluidic chips, the researchers took full advantage of the artificial chip microenvironments to experimentally test the predictions of their computational model.

In addition to helping us understand how cells navigate complex environments to find faraway attractant sources, this research may be useful to synthetic biology efforts such as regenerative medicine and multicellular system design. To regrow a whole organ or to generate a new biological system, cells of different types must sort themselves out and use chemical cues to find their proper positions, just as they do during embryonic development. Existing tools allow us to engineer cells to be attracted to chemicals to which they are not naturally responsive. For long-range communication, perhaps it will be equally important to teach these cells to break down their new chemoattractants. 

This question was answered in a recent study published in Science Advances. It identified a circadian clock in the non-photosynthetic bacterium Bacillus subtilis, which is often found in the human gut and in soil. The authors observed that biofilm-forming cultures of these bacteria could synchronize their gene expression activities to 24-hour light or temperature cycles. 

A biofilm is a collection of microorganisms that are held together by a sticky extracellular matrix. Different different parts of the biofilm can take on specialized roles; in this way, bacteria in a biofilm act like cells in a tissue, displaying behavior similar to multicellular development. It is plausible that adaptation to daily rhythms is tied to biofilm formation or maintenance, but the exact function of this newly-discovered clock remain unclear. Time and further research will tell whether circadian clocks also play roles in bacteria that aren’t inclined to live in biofilms. 

A powerful genome editing technology, CRISPR allows researchers to alter DNA sequences, and has become a versatile tool of modern molecular biology and medicine. But long before humans developed this technology, CRISPR systems naturally evolved in bacteria as antiviral immune responses. It seems fitting, therefore, that some of the most promising applications for CRISPR are developing antiviral therapies.

Recently, American researchers successfully used CRISPR to eliminate HIV in mice. HIV is a retrovirus — a type of virus that inserts copies of its own genetic code into the genomes of the cells that it infects. An existing HIV treatment, LASER ART (which stands for long-acting slow effective release antiretroviral therapy), is very effective at stopping the production and insertion of new copies of the virus, but it can't remove genetic code that has already been created. In other words, modern therapies can stop the HIV infection from spreading, but can’t eliminate it entirely. That's why HIV is considered a chronic disease that requires lifelong treatment.

A permanent cure for HIV (and other retroviral diseases) would require removing or inactivating the viral DNA that is mixed with the host’s own genome. Conveniently, cutting through unwanted DNA sequences is CRISPR’s specialty.

In bacteria infected by viruses in natural conditions, special enzymes recognize the intrusion of foreign DNA. They use that DNA as a template to produce guide RNAs, which Cas9, a DNA-cutting enzyme, can use to find its intended targets. The next time a bacterium encounters this foreign DNA, Cas9 can recognize and destroy it. This protects the bacterium from repeated infection by the same viruses.

With CRISPR, scientists can use artificially-created guide RNAs to direct Cas9 to the targets they're interested in. In this particular HIV study, after suppressing the HIV infection with LASER ART, the researchers treated the mice with edited guide RNAs that excised the viral DNA from the genome — actually "curing" the mice of the chronic disease.

Although this approach is incredibly promising, an important caveat is that the editing worked in less than half the mice. The excision of the viral DNA was incomplete in the rest. It is plausible that the excision efficiency could be improved by increasing the duration of CRISPR-Cas9 treatment. But a worrying possibility is that the HIV virus will quickly develop mutations that help it avoid detection by the synthetic guide RNA. This exact scenario was encountered in a recent attempt to use a similar CRISPR technique to protect the food crop cassava from gemini viruses (note: the lead author of this cassava study, Devang Mehta, is a Massive contributor). Native bacterial CRISPR systems would naturally develop new guide RNAs to combat the new viral strains. But for use in mice, cassava, or humans, scientists might find themselves forced to constantly re-engineer synthetic guides, or to use multiple guides for simultaneous targeting of different parts of the viral genes.

We've seen similar arms races with other types of medical treatments derived from natural sources. The first modern antibiotic, penicillin, was isolated from a mold. Many clinically-useful antibacterial agents have since been isolated from microbes — but the problem of antibacterial resistance is growing. When conventional antibiotics fail, doctors have recently started turning to viruses that can be used to specifically target bacteria to fight off infection, a strategy known as phage therapy. 

This demonstration of CRISPR as an antiviral therapy may be among the first of many — but it is part of a longstanding trend of borrowing tools from simple organisms for our own battles.

Chimeras, creatures containing parts from multiple animals, are not a new concept in biology. Chimeras can even arise naturally: on occasion, two fertilized eggs occupying the same womb can fuse and eventually develop into a single organism. However, the creation of hybrid chimeras with cells from two different species tends to give us pause, especially when the hybrid is part human. Such experiments blur the boundaries between human and animal that we use to justify animal experimentation in the first place, raising difficult ethical and philosophical questions.  

Earlier this year, Japan lifted its ban on bringing human-animal hybrid embryos to term (scientists had previously been required to abort such embryos after 14 days), and Japanese scientists are taking advantage of the new legality of hybrid experiments to attempt to grow human organs. The strategy is to deprive the host animal embryo of its ability to form a specific organ of its own, instead providing it with human cells, with the hope that the host animal will then use the human cells to build the organ it lacks. 

Time will tell whether this approach will be successful, but there's so much to consider here ethically. For instance, it is possible that the human cells get integrated into other organs inside of the host animal. We need to somehow reconcile our cultural concepts of humanity with our views on other animals before biotechnology forces us to take positions on fraught ethical issues.    

A recent study published in Science analyzed satellite photographs of the Earth and determined that our planet could theoretically support just under a billion new hectares of forest cover without impinging on existing urban and agricultural land, potentially enough to allow us to meet climate goals. However, this estimate assumes current environmental conditions, and the actual potential forest cover could be much lower due to climate change itself. 

While a global reforestation effort would likely require international collaboration, over half of the estimated potential forest is in one of six countries: Russia, the United States, Canada, Australia, Brazil, or China. Tree planting is considered the cheapest and simplest solution to climate change, but it will certainly have to be mixed with emission reduction and other carbon capture strategies to represent a clear path forward.