Using engineered mini-livers derived from donated human cells, MIT researchers have found that the time of day a drug is administered could significantly affect how much of it is available to the body and how much may be broken down into toxic by-products.

The researchers identified more than 300 liver genes that follow a circadian clock, including many involved in drug metabolism and others that are involved in inflammation. Because of these rhythmic variations in gene activity, enzymes that break down Tylenol, for example, are more abundant at certain times of day than others. 

The study also revealed that the liver is more susceptible to infections such as malaria at certain points in the circadian cycle, when fewer inflammatory proteins are being produced—possibly because its response to pathogens declines after meals, when it has typically been exposed to an influx of microorganisms that might trigger inflammation even if they are not harmful. 

“One of the earliest applications for this method could be fine-tuning drug regimens of already approved drugs to maximize their efficacy and minimize their toxicity,” says Professor Sangeeta Bhatia, SM ’93, PhD ’97, a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science (IMES), who is the senior author of the new study.

The MIT researchers are now working with collaborators to analyze a cancer drug they suspect may be affected by circadian cycles, and they hope to investigate whether this may be true of drugs used in pain management as well. They are also taking advantage of the cycles in inflammatory signals to study infections that are usually difficult to establish in engineered livers, including certain types of malaria.

Most people’s sweat contains a protein that can prevent Lyme disease, researchers at MIT and the University of Helsinki have discovered. They also found that about one-third of the population carries a less protective variant that makes the tick-borne infection more likely.

By running a genome-wide association study, the researchers identified three variants more common in people who’d had Lyme disease. One—in a gene for a secretoglobin, a type of protein that in this case is produced primarily in the sweat glands—was previously unknown. In vitro, it significantly inhibited growth of Lyme-causing bacteria, but a variant version required twice as much to do so. And when mice were injected with Lyme bacteria that had been exposed to the normal version of the sweat protein, they did not develop the disease. 

It’s unknown how the protein inhibits the bacteria, but the researchers hope it can be used in preventive skin creams or to treat the 10% or so of Lyme infections that don’t respond to antibiotics.

“We think there are real implications here for a preventative and possibly a therapeutic,” says Michal Caspi Tal of MIT’s Department of Biological Engineering, one of the senior authors of the new study. She also plans to study whether the 10 other secretoglobins in the human body could have antimicrobial qualities too.

Colonoscopies are a boon for preventing colon cancer, but patients may develop gastrointestinal bleeding or dangerous small tears in the intestine if doctors end up having to remove polyps in the process.

Now MIT researchers have developed a gel that can be sprayed through an endoscope onto the surgical sites, where it instantly forms a tough but flexible layer that protects the damaged area, reinforces the tissue, and allows it to heal. 

In an animal study, the researchers showed that the gel, called GastroShield, is simple to apply in the course of current endoscopic procedures and provides wound protection for three to seven days. 

In addition to its potential in colonoscopies, this gel could be useful for treating stomach ulcers and inflammatory conditions such as Crohn’s disease, or for delivering cancer drugs, says Natalie Artzi, a principal research scientist in MIT’s Institute for Medical Engineering and Science, who coauthored a paper on the work with colleagues including Professor Elazer Edelman ’78, SM ’79, PhD ’84, former MIT postdoc Pere Dosta, and former visiting student Gonzalo Muñoz Taboada. 

Members of the research team have started a company called BioDevek that plans to further develop the new material for use in humans. 

One of the immune system’s roles is to detect and kill cells that have acquired cancerous mutations. However, some early-stage cancer cells manage to survive. A new study on colon cancer from MIT and the Dana-Farber Cancer Institute has identified one reason why: they turn on a gene called SOX17, which renders them essentially invisible to immune surveillance.

The researchers focused on precancerous growths called polyps that often form as mutations accumulate in the intestinal stem cells, whose job is to continually regenerate the lining of the intestines. Using a technique they had developed for growing mini colon tumors in a lab dish and then implanting them in mice, they engineered tumors to express mutations that are often found in human colon cancers.

In the mice, the researchers observed a dramatic increase in the tumors’ expression of SOX17. This gene encodes a transcription factor that is normally active only during embryonic development, when it helps control development of the intestines and the formation of blood vessels.

The experiments revealed that when SOX17 is turned on in cancer cells, it helps them create an immunosuppressive environment. Among its effects, SOX17 prevents cells from synthesizing the receptor that normally detects interferon gamma, one of the immune system’s primary weapons against cancer cells. Without those receptors, cancerous and precancerous cells can simply ignore messages from the immune system, which would normally direct them to die off.

The absence of this signaling also lets cancer cells minimize their production of molecules called MHC proteins, which display cancerous antigens to the immune system, and prevents them from producing molecules called chemokines, which normally recruit T cells that would help destroy the cancerous cells.

When the researchers generated colon tumor organoids with SOX17 knocked out, and implanted those into mice, their immune system was able to attack them much more effectively. This suggests that blocking the gene or the pathway that it activates could offer a new way to treat early-stage cancers before they grow into larger tumors.

“Just by turning off SOX17 in fairly complex tumors, we were able to essentially obliterate the ability of these tumor cells to persist,” says MIT research scientist Norihiro Goto, the lead author of a paper on the work.

But transcription factors such as the one encoded by the SOX17 gene are considered difficult to target using drugs, in part because of their structure. The researchers now plan to identify other proteins that this transcription factor interacts with, in hopes that it might be easier to block some of those interactions. They also plan to investigate what triggers SOX17 to turn on in precancerous cells.

“Activation of the SOX17 program in the earliest innings of colorectal cancer formation is a critical step that shields precancerous cells from the immune system,” says Ömer Yilmaz, an MIT associate professor of biology, a member of the Koch Institute for Integrative Cancer Research, and one of the study’s senior authors. “If we can inhibit the SOX17 program, we might be better able to prevent colon cancer, particularly in patients that are prone to developing colon polyps.”