Led by Wolynes, the D.R. Bullard-Welch Foundation Professor of Science, professor of chemistry, biosciences and physics and astronomy and co-director of the Center for Theoretical Biological Physics (CTBP), the team focused on deciphering the complex energy landscapes of de-evolved, putative protein sequences corresponding to pseudogenes.

Pseudogenes are segments of DNA that once encoded proteins but have since lost their ability to do so due to sequence degradation — a phenomenon referred to as devolution. Here, devolution represents an unconstrained evolutionary process that occurs without the usual evolutionary pressures that regulate functional protein-coding sequences.

Despite their inactive state, pseudogenes offer a window into the evolutionary journey of proteins.

“Our paper explains that proteins can de-evolve,” Wolynes said. “A DNA sequence can, by mutations or other means, lose the signal that tells it to code for a protein. The DNA continues to mutate but does not have to lead to a sequence that can fold.”

The researchers studied junk DNA in a genome that has de-evolved. Their research revealed that a mutation accumulation in pseudogene sequences typically disrupts the native network of stabilizing interactions, making it challenging for these sequences, if they were to be translated, to fold into functional proteins.

However, the researchers observed instances where certain mutations unexpectedly stabilized the folding of pseudogenes at the cost of altering their previous biological functions.

They identified specific pseudogenes, such as cyclophilin A, profilin-1 and small ubiquitin-like modifier 2 protein, where stabilizing mutations occurred in regions crucial for binding to other molecules and other functions, suggesting a complex balance between protein stability and biological activity.

Moreover, the study highlights the dynamic nature of protein evolution as some previously pseudogenized genes may regain their protein-coding function over time despite undergoing multiple mutations.

Using sophisticated computational models, the researchers interpreted the interplay between physical folding landscapes and the evolutionary landscapes of pseudogenes. Their findings provide evidence that the funnellike character of folding landscapes comes from evolution.

“Proteins can de-evolve and have their ability to fold compromised over time due to mutations or other means,” Wolynes said. “Our study offers the first direct evidence that evolution is shaping the folding of proteins.”

Along with Wolynes, the research team includes lead author and applied physics graduate student Hana Jaafari ; CTBP postdoctoral associate Carlos Bueno ; University of Texas at Dallas graduate student Jonathan Martin; Faruck Morcos, associate professor in the Department of Biological Sciences at UT-Dallas; and CTBP biophysics researcher Nicholas P. Schafer.

The implications of this research extend beyond theoretical biology with potential applications in protein engineering, Jaafari said.

“It would be interesting to see if someone at a lab could confirm our results to see what happens to the pseudogenes that were more physically stable,” Jaafari said. “We have an idea based on our analysis, but it’d be compelling to get some experimental validation.”

In this study, participants were tasked with a simple letter recognition exercise. They performed the task once on their own and once supposedly aided by an AI system. Half of the participants were told the system was reliable and it would enhance their performance, and the other half was told that it was unreliable and would worsen their performance.

‘In fact, neither AI system ever existed. Participants were led to believe an AI system was assisting them, when in reality, what the sham-AI was doing was completely random,’ explains doctoral researcher Agnes Kloft.

The participants had to pair letters that popped up on screen at varying speeds. Surprisingly, both groups performed the exercise more efficiently — more quickly and attentively — when they believed an AI was involved.

‘What we discovered is that people have extremely high expectations of these systems, and we can’t make them AI doomers simply by telling them a program doesn’t work,’ says Assistant Professor Robin Welsch.

Following the initial experiments, the researchers conducted an online replication study that produced similar results. They also introduced a qualitative component, inviting participants to describe their expectations of performing with an AI. Most had a positive outlook toward AI and, surprisingly even skeptical people still had positive expectations about its performance.

The findings pose a problem for the methods generally used to evaluate emerging AI systems. ‘This is the big realization coming from our study — that it’s hard to evaluate programmes that promise to help you because of this placebo effect’, Welsch says.

While powerful technologies like large language models undoubtedly streamline certain tasks, subtle differences between versions may be amplified or masked by the placebo effect — and this is effectively harnessed through marketing.

The results also pose a significant challenge for research on human-computer interaction, since expectations would influence the outcome unless placebo control studies were used.

‘These results suggest that many studies in the field may have been skewed in favour of AI systems,’ concludes Welsch.

The researchers will present the study at the CHI-conference on May 14.

Cat Royale is a unique collaboration between Computer Scientists from the University of Nottingham and artists at Blast Theory who worked together to create a multispecies world centred around a be-spoke enclosure in which three cats and a robot arm coexist for six hours a day during a twelve-day installation as part of an artist-led project. The installation was launched in 2023 at the World Science Festival in Brisbane, Australia and has been touring since, it has just won a Webby award for its creative experience.

The research paper, “Designing Multispecies Worlds for Robots, Cats, and Humans” has just been presented at the annual Computer-Human Conference (CHI’24) where it won best paper. It outlines how designing the technology and its interactions is not sufficient, but that it is equally important to consider the design of the `world’ in which the technology operates. The research also highlights the necessity of human involvement in areas such as breakdown recovery, animal welfare, and their role as audience.

Cat Royale centred around a robot arm offering activities to make the cats happier, these included dragging a ‘mouse’ toy along the floor, raising a feather ‘bird’ into the air, and even offering them treats to eat. The team then trained an AI to learn what games the cats liked best so that it could personalise their experiences.

“At first glance, the project is about designing a robot to enrich the lives of a family of cats by playing with them. ” commented Professor Steve Benford from the University of Nottingham who led the research, “Under the surface, however, it explores the question of what it takes to trust a robot to look after our loved ones and potentially ourselves.”

Working with Blast Theory to develop and then study Cat Royale, the research team gained important insights into the design of robots and its interactions with the cats. They had to design the robot to pick up toys, deploy them in ways that excited the cats, while it learned which games each cat liked. They also designed the entire world in which the cats and the robot lived, providing safe spaces for the cats to observe the robot and from which to sneak up on it, and decorating it so that the robot had the best chance of spotting the approaching cats.

The implication is designing robots involves interior design as well as engineering and AI. If you want to introduce robots into your home to look after your loved ones, then you will likely need to redesign your home.

Research workshops for Cat Royale were held at the Univeraity of Nottingham’s unique Cobotmaker Space where stakeholders were bought together to think about the design of the robot /welfare of cats. Eike Schneiders, Transitional Assistant Professor in the Mixed Reality Lab at the University of Nottingham worked on the design, he said: “As we learned through Cat Royale, creating a multispecies system — where cats, robots, and humans are all accounted for — takes more than just designing the robot. We had to ensure animal wellbeing at all times, while simultaneously ensuring that the interactive installation engaged the (human) audiences around the world. This involved consideration of many elements, including the design of the enclosure, the robot and its underlying systems, the various roles of the humans-in-the-loop, and, of course, the selection of the cats.”

Introns are perhaps one of our genome’s biggest mysteries. They are DNA sequences that interrupt the sensible protein-coding information in your genes, and need to be “spliced out.” The human genome has hundreds of thousands of introns, about 7 or 8 per gene, and each is removed by a specialized RNA protein complex called the “spliceosome” that cuts out all the introns and splices together the remaining coding sequences, called exons. How this system of broken genes and the spliceosome evolved in our genomes is not known.

Over his long career, Manny Ares, UC Santa Cruz distinguished professor of molecular, cellular, and developmental biology, has made it his mission to learn as much about RNA splicing as he can.

“I’m all about the spliceosome,” Ares said. “I just want to know everything the spliceosome does — even if I don’t know why it is doing it.”

In a new paper published in the journal Genes and Development, Ares reports on a surprising discovery about the spliceosome that could tell us more about the evolution of different species and the way cells have adapted to the strange problem of introns. The authors show that after the spliceosome is finished splicing the mRNA, it remains active and can engage in further reactions with the removed introns.

This discovery provides the strongest indication we have so far that spliceosomes could be able to reinsert an intron back into the genome in another location. This is an ability that spliceosomes were not previously believed to possess, but which is a common characteristic of “Group II introns,” distant cousins of the spliceosome that exist primarily in bacteria.

The spliceosome and Group II introns are believed to share a common ancestor that was responsible for spreading introns throughout the genome, but while Group II introns can splice themselves out of RNA and then directly back into DNA, the “spliceosomal introns” that are found in most higher-level organisms require the spliceosome for splicing and were not believed to be reinserted back into DNA. However, Ares’s lab’s finding indicates that the spliceosome might still be reinserting introns into the genome today. This is an intriguing possibility to consider because introns that are reintroduced into DNA add complexity to the genome, and understanding more about where these introns come from could help us to better understand how organisms continue to evolve.

Building on an interesting discovery

An organism’s genes are made of DNA, in which four bases, adenine (A), cytosine (C), guanine (G) and thymine (T) are ordered in sequences that code for biological instructions, like how to make specific proteins the body needs. Before these instructions can be read, the DNA gets copied into RNA by a process known as transcription, and then the introns in that RNA have to be removed before a ribosome can translate it into actual proteins.

The spliceosome removes introns using a two-step process that results in the intron RNA having one of its ends joined to its middle, forming a circle with a tail that looks like a cowboy’s “lariat,” or lasso. This appearance has led to them being named “lariat introns.” Recently, researchers at Brown University who were studying the locations of the joining sites in these lariats made an odd observation — some introns were actually circular instead of lariat shaped.

This observation immediately got Ares’s attention. Something seemed to be interacting with the lariat introns after they were removed from the RNA sequence to change their shape, and the spliceosome was his main suspect.

“I thought that was interesting because of this old, old idea about where introns came from,” Ares said. “There is a lot of evidence that the RNA parts of the spliceosome, the snRNAs, are closely related to Group II introns.”

Because the chemical mechanism for splicing is very similar between the spliceosomes and their distant cousins, the Group II introns, many researchers have theorized that when the process of self-splicing became too inefficient for Group II introns to reliably complete on their own, parts of these introns evolved to become the spliceosome. While Group II introns were able to insert themselves directly back into DNA, however, spliceosomal introns that required the help of spliceosomes were not thought to be inserted back into DNA.

“One of the questions that was sort of missing from this story in my mind was, is it possible that the modern spliceosome is still able to take a lariat intron and insert it somewhere in the genome?” Ares said. “Is it still capable of doing what the ancestor complex did?”

To begin to answer this question, Ares decided to investigate whether it was indeed the spliceosome that was making changes to the lariat introns to remove their tails. His lab slowed the splicing process in yeast cells, and discovered that after the spliceosome released the mRNA that it had finished splicing introns from, it hung onto intron lariats and reshaped them into true circles. The Ares lab was able to reanalyze published RNA sequencing data from human cells and found that human spliceosomes also had this ability.

“We are excited about this because while we don’t know what this circular RNA might do, the fact that the spliceosome is still active suggests it may be able to catalyze the insertion of the lariat intron back into the genome,” Ares said.

If the spliceosome is able to reinsert the intron into DNA, this would also add significant weight to the theory that spliceosomes and Group II introns shared a common ancestor long ago.

Testing a theory

Now that Ares and his lab have shown that the spliceosome has the catalytic ability to hypothetically place introns back into DNA like their ancestors did, the next step is for the researchers to create an artificial situation in which they “feed” a DNA strand to a spliceosome that is still attached to a lariat intron and see if they can actually get it to insert the intron somewhere, which would present “proof of concept” for this theory.

If the spliceosome is able to reinsert introns into the genome, it is likely to be a very infrequent event in humans, because the human spliceosomes are in incredibly high demand and therefore do not have much time to spend with removed introns. In other organisms where the spliceosome isn’t as busy, however, the reinsertion of introns may be more frequent. Ares is working closely with UCSC Biomolecular Engineering Professor Russ Corbett-Detig, who has recently led a systematic and exhaustive hunt for new introns in the available genomes of all intron-containing species that was published in the journal Proceedings of the National Academy of Sciences (PNAS) last year.

The paper in PNAS showed that intron “burst” events far back in evolutionary history likely introduced thousands of introns into a genome all at once. Ares and Corbett-Detig are now working to recreate a burst event artificially, which would give them insight into how genomes reacted when this happened.

Ares said that his cross-disciplinary partnership with Corbett-Detig has opened the doors for them to really dig into some of the biggest mysteries about introns that would probably be impossible for them to understand fully without their combined expertise.

“It is the best way to do things,” Ares said. “When you find someone who has the same kind of questions in mind but a different set of methods, perspectives, biases, and weird ideas, that gets more exciting. That makes you feel like you can break out and solve a problem like this, which is very complex.”

While melanoma may be found less frequently in people with darker complexions than fair ones, this potentially serious form of cancer can strike anyone. The study, which consisted of 492,597 patients with melanoma, suggests that added vigilance in early screening is particularly needed for Black men, whose cancers are often found at later stages, leading to worse outcomes compared to white patients.

“We compared non-Hispanic Black patients to white patients and saw striking differences in how patients presented with the disease,” says surgical oncologist Tina Hieken, M.D., senior author of the study and a researcher at Mayo Clinic Comprehensive Cancer Center. “We saw more extremity melanoma, and more later-stage disease.”

Extremity melanoma refers to skin cancer that can develop on the arms, legs, hands and feet. Various factors, including social risk factors and biological components, could be at play, but further research is needed to help determine why these differences exist.

Revealing differences in sex-based immune response

The research found that Black female patients with melanoma fared better than Black male patients.

Men tended to be older at diagnosis and more likely to have cancer that had spread to their lymph nodes compared to women. This translated to worse survival rates. The researchers learned that Black men with stage 3 melanoma have only a 42% chance of surviving for five years, compared to 71% for Black women.

Most research on melanoma hasn’t focused on how race and sex affect outcomes and hasn’t looked at the influence of race and ethnicity across all groups. Dr. Hieken says the study highlights the need to understand these differences better, noting that this is the first large study to confirm that sex-based differences in melanoma outcomes exist within the non-Hispanic Black population.

“When we talk about later-stage melanoma patients who are female versus male in that non-Hispanic Black patient cohort who ended up doing worse, some biological things may be going on here that are interesting,” says Dr. Hieken.

One theory centers on variations in immune response.

“Several immune signals suggest that women may respond better to some immunotherapies than males,” says Dr. Hieken.

Identifying the need

Researchers note that more studies focused on melanoma in a broader range of people, including more Black participants in clinical trials, is key to bridging this knowledge gap and potentially identifying more effective treatments.

“We want to broaden and deepen our reach to better understand the disease that affects all patients,” says Dr. Hieken.

She underscores the role played by the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery in this study.

“What we’ve done with the Kern Center, with this study and others, is to identify the need,” says Dr. Hieken. “We have a rich, integrated, multidisciplinary clinical research practice in melanoma, and we want to address clinical needs and knowledge gaps relevant to our practice.”

A wake-up call in the battle against melanoma

Dr. Hieken notes that this study is a wake-up call for everyone battling to diagnose and cure melanoma, regardless of the patient’s sex or skin tone.

She emphasizes that healthcare professionals should carefully examine areas like palms, soles and under fingernails, where melanoma might be more challenging to spot on darker skin.

“We can incorporate screening for skin lesions or lesions under the nails into the visit for patients as part of their regular checkups,” says Dr. Hieken. “What we want to do is elevate care for our patients.”

The Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery and Breast and Melanoma Surgical Oncology in the Department of Surgery supported this research.