Complex Insight - Understanding our world

Patients do not access physicians at random but rather via naturally emerging
networks of patient flows between them. As retirements, mass quarantines and absence due to sickness during pandemics, or other shocks thin out these networks, the system might be pushed closer to a tipping point where...

Analysis: With experts concerned over rising UK case rates, where are we also with deaths, hospital admissions, long Covid and the economy?

Researchers at MIT have developed a synthetic gene circuit that triggers the body’s immune system to attack cancers when it detects signs of the disease.
The circuit, which will only activate a therapeutic response when it detects two specific cancer markers, is described in a paper published today in the journal Cell.
Immunotherapy is widely seen as having considerable potential in the fight against a range of cancers. The approach has been demonstrated successfully in several recent clinical trials, according to Timothy Lu, associate professor of biological engineering and of electrical engineering and computer science at MIT.
“There has been a lot of clinical data recently suggesting that if you can stimulate the immune system in the right way you can get it to recognize cancer,” says Lu, who is head of the Synthetic Biology Group in MIT’s Research Laboratory of Electronics. “Some of the best examples of this are what are called checkpoint inhibitors, where essentially cancers put up stop signs [that prevent] T-cells from killing them. There are antibodies that have been developed now that basically block those inhibitory signals and allow the immune system to act against the cancers.”
However, despite this success, the use of immunotherapy remains limited by the scarcity of tumor-specific antigens — substances that can trigger an immune system response to a particular type of cancer. The toxicity of some therapies, when delivered as a systemic treatment to the whole body, for example, is another obstacle.
What’s more, the treatments are not successful in all cases. Indeed, even in some of the most successful tests, only 30-40 percent of patients will respond to a given therapy, Lu says.
As a result, there is now a push to develop combination therapies, in which different but complementary treatments are used to boost the immune response. So, for example, if one type of immunotherapy is used to knock out an inhibitory signal produced by a cancer, and the tumor responds by upregulating a second signal, an additional therapy could then be used to target this one as well, Lu says.
“Our belief is that there is a need to develop much more specific, targeted immunotherapies that work locally at the tumor site, rather than trying to treat the entire body systemically,” he says. “Secondly, we want to produce multiple immunotherapies from a single package, and therefore be able to stimulate the immune system in multiple different ways.”
To do this, Lu and a team including MIT postdocs Lior Nissim and Ming-Ru Wu, have built a gene circuit encoded in DNA designed to distinguish cancer cells from noncancer cells.
The circuit, which can be customized to respond to different types of tumor, is based on the simple AND gates used in electronics. Such AND gates will only switch on a circuit when two inputs are present.
Cancer cells differ from normal cells in the profile of their gene expression. So the researchers developed synthetic promoters — DNA sequences designed to initiate gene expression but only in cancer cells.
The circuit is delivered to cells in the affected area of the body using a virus. The synthetic promotors are then designed to bind to certain proteins that are active in tumor cells, causing the promoters to turn on.
“Only when two of these cancer promoters are activated, does the circuit itself switch on,” Lu says.
This allows the circuit to target tumors more accurately than existing therapies, as it requires two cancer-specific signals to be present before it will respond.
Once activated, the circuit expresses proteins designed to direct the immune system to target the tumor cells, including surface T cell engagers, which direct T cells to kill the cells. The circuit also expresses a checkpoint inhibitor designed to lift the brakes on T cell activity.
When the researchers tested the circuit in vitro, they found that it was able to detect ovarian cancer cells from amongst other noncancerous ovarian cells and other cell types.
They then tested the circuit in mice implanted with ovarian cancer cells, and demonstrated that it could trigger T cells to seek out and kill the cancer cells without harming other cells around them.
Finally, the researchers showed that the circuit could be readily converted to target other cancer cells.
“We identified other promoters that were selective for breast cancer, and when these were encoded into the circuit, it would target breast cancer cells over other types of cell,” Lu says.
Ultimately, they hope they will also be able to use the system to target other diseases, such as rheumatoid arthritis, inflammatory bowel disease, and other autoimmune diseases.
This advance will open up a new front against cancer, says Martin Fussenegger, a professor of biotechnology and bioengineering at ETH Zurich in Switzerland, who was not involved in the research.
“First author Lior Nissim, who pioneered the very first genetic circuit targeting tumor cells, has now teamed up with Timothy Lu to design RNA-based immunomodulatory gene circuits that take cancer immunotherapy to a new level,” Fussenegger says. “The design of this highly complex tumor-killing gene circuit was made possible by meticulous optimization and integration of several components that target and program tumor cells to become a specific prey for the immune system — this is very smart technology.”
The researchers now plan to test the circuit more fully in a range of cancer models. They are also aiming to develop a delivery system for the circuit, which would be both flexible and simple to manufacture and use.

The majority of human emerging infectious diseases are zoonotic, with viruses that originate in wild mammals of particular concern (for example, HIV, Ebola and SARS). Understanding patterns of viral diversity in wildlife and determinants of successful cross-species transmission, or spillover, are therefore key goals for pandemic surveillance programs. However, few analytical tools exist to identify which host species are likely to harbour the next human virus, or which viruses can cross species boundaries. Here we conduct a comprehensive analysis of mammalian host–virus relationships and show that both the total number of viruses that infect a given species and the proportion likely to be zoonotic are predictable. After controlling for research effort, the proportion of zoonotic viruses per species is predicted by phylogenetic relatedness to humans, host taxonomy and human population within a species range—which may reflect human–wildlife contact. We demonstrate that bats harbour a significantly higher proportion of zoonotic viruses than all other mammalian orders. We also identify the taxa and geographic regions with the largest estimated number of ‘missing viruses’ and ‘missing zoonoses’ and therefore of highest value for future surveillance. We then show that phylogenetic host breadth and other viral traits are significant predictors of zoonotic potential, providing a novel framework to assess if a newly discovered mammalian virus could infect people.

One hundred and ten Zika virus genomes from ten countries and territories involved in the Zika virus epidemic reveal rapid expansion of the epidemic within Brazil and multiple introductions to other regions.

Zika virus evolution and spread in the Americas
Hayden C. Metsky, et al.

Nature 546, 411–415 (15 June 2017) doi:10.1038/nature22402

Zolgensma is a revolutionary gene therapy that can stop a deadly childhood condition called SMA in its tracks.It’s also one of the most expensive drugs in the world...

The pandemic has taught us that viruses are not easy to identify – and can spread like wildfire...

Results are in from the first phase 1 clinical trial for a Zika vaccine, and they are very promising. A new generation DNA-based Zika vaccine, developed by Wistar scientists in collaboration with Inovio Pharmaceuticals and GeneOne Life Science, was found to be safe and well tolerated by all study participants and was able to elicit an immune response against Zika, opening the door to further and larger trials to move this vaccine forward. 

The Indian vaccine, which protects against gastroenteritis caused by rotavirus, was tested in Niger.

We present a model of contagion that unifies and generalizes existing models of the spread of social influences and micro-organismal infections. Our model incorporates individual memory of exposure to a contagious entity (e.g., a rumor or disease), variable magnitudes of exposure (dose sizes), and heterogeneity in the susceptibility of individuals. Through analysis and simulation, we examine in detail the case where individuals may recover from an infection and then immediately become susceptible again (analogous to the so-called SIS model). We identify three basic classes of contagion models which we call \textit{epidemic threshold}, \textit{vanishing critical mass}, and \textit{critical mass} classes, where each class of models corresponds to different strategies for prevention or facilitation. We find that the conditions for a particular contagion model to belong to one of the these three classes depend only on memory length and the probabilities of being infected by one and two exposures respectively. These parameters are in principle measurable for real contagious influences or entities, thus yielding empirical implications for our model. We also study the case where individuals attain permanent immunity once recovered, finding that epidemics inevitably die out but may be surprisingly persistent when individuals possess memory.

A generalized model of social and biological contagion
Peter Sheridan Dodds, Duncan J. Watts