Proteins are built by mixing and matching amino acids, but researchers want to create new functions by adding noncanonical amino acids (ncAAs). However, this process often requires complex whole genome editing. This inspired Ahmed Badran, a chemical and synthetic biologist at the Scripps Research Institute, to develop an easier method for adding ncAAs to proteins.

“The assignment of the genetic code has some inherent malleability, which one can change to assign existing codons to new amino acids,” said Badran. His team leveraged this by using a plug-and-play strategy with quadruplet—not the usual triplet—codon translation to insert ncAAs at specific sites without altering the whole genome. 

The findings, published in Nature Biotechnology, demonstrated that using sets of four RNA nucleotides could produce more than 100 new cyclic peptides.¹ This approach capitalizes on the programmability of proteins to reengineer existing proteins or create entirely new ones.

Badran’s team investigated how codon location and usage affect quadruplet decoding with a modified superfolder green fluorescent protein (sfGFP), replacing a tyrosine codon at position 151 with a quadruplet codon. Screening for sfGFP expression suggested that codons at the downstream plus one position influenced quadruplet decoding and ncAA incorporation efficiency, serving as a location guide for plugging in engineered tRNAs.

During tRNA development, the researchers identified 12 highly active tRNA synthetase/tRNA pairs in Escherichia coli that can add canonical and noncanonical amino acids. Then, Badran’s team used iterative rounds of genetic mutations and screening to enhance the quadruplet-decoding tRNA’s ncAA incorporation ability. They tested five optimized pairs in E.coli, playing with individual or combined pairs, and produced more than 100 new cyclic peptides, each containing up to three ncAAs.

“[The study] is definitely novel,” said Ya-Ming Hou, a biochemist from Thomas Jefferson University, who was not involved in the study, noting the method’s potential to improve protein stability for industrial or medical purposes. “Ultimately, we want to make proteins and enzymes that are diversified with a broad array of noncanonical amino acids,” said Badran. 

Beata Mierzwa, a postdoctoral researcher at the University of California, San Diego combines science and art through her brand, Beata Science Art. As an IF/THEN ambassador for the American Association for the Advancement of Science, she inspires girls and other underrepresented groups to explore careers in STEM. When the program announced an opportunity for STEM outreach projects, Mierzwa drew on her love of video games to create an interactive experience that showcases the incredible world of cells through art, called Microscopya.

How did you create Microscopya?

I wanted to bring what we see under the microscope to life in a more engaging way than what is represented in textbooks. To achieve that, I learned how to draw on a tablet and do animation. My partner helped me with the science communication and quality assurance aspects. I also worked with a developer for the coding, and we collaborated with artists from my favorite band for the soundtrack. We did several iterations of testing with different age groups to balance the learning and fun in the game. This was probably the hardest project I’ve ever worked on, but it’s also probably one of my favorites because it’s been so unique.

What happens in Microscopya?

Players go on a journey as a customizable character inside of a cell where they learn about cellular energy and transportation through puzzles and by collecting trophies that provide more information on the topics. Right now, there is just one chapter, but I’m currently working on creating a second that will be longer and cover more topics. I took the feedback that I got from educators to integrate more educational content throughout the game and make it easier to incorporate into lessons. 

What has been the response to Microscopya?

My cocreators and I released the game two years ago and presented it at the San Diego Comic-Con, and the response was amazing. My target audience was middle school students, but I learned that adult learners also enjoyed the game and got interested in what happens in cells. Besides being educational, it’s also a great outreach tool to encourage STEM minorities to consider pursuing science. 

This interview has been edited for length and clarity.

For decades, placebo effects have plagued clinical trials, with as many as one third of patients responding to supposedly inactive treatments for conditions like depression and pain.^1,2 Instead of discarding these responses, some researchers were intrigued: What neurobiological mechanisms could explain how a “fake” treatment produced real effects?

As early as the 1980s, researchers identified a key role for endogenous opioids in placebo analgesia: Administering the opioid blocker naloxone also blocked the pain-relieving effects of a placebo.³ Tor Wager, a neuroscientist at Dartmouth College, wanted to identify how endogenous opioid activity was altered in key brain regions during placebo pain relief. Using a radiolabeled μ-opioid receptor agonist, researchers assessed the availability of these receptors; greater endogenous opioid activity would mean less receptor binding by the labeled tracer. When participants were experiencing placebo-induced pain relief, the brain scans revealed altered endogenous opioid activity in several regions including those involved in pain modulation and emotion processing and regulation.⁴

But how do these brain regions work together to create a conscious experience? Researchers believe that pain is influenced by both bottom-up processes, like the signals coming in through peripheral nerves, and top-down processes, like attention. Placebos might intervene at either end. “They can block what's coming up from the spinal cord, which is the textbook definition,” said Wager. “And they can change how the brain constructs the experience of pain.” Recent research from Wager’s lab suggests that the latter may be more prevalent, indicating that nociceptive systems in the brain responded similarly to a painful stimulus regardless of whether the person reported feeling less pain due to a placebo treatment.⁵ Instead, said Wager, “[the placebo] works by changing the central value and motivational systems, so it's changing the suffering and changing the evaluation of pain.”