Researchers at the Li Lab have developed oral insulin drops that when placed under the tongue are quickly and efficiently absorbed by the body, potentially replacing the need for insulin injections.

The drops contain a mixture of insulin and a unique cell-penetrating peptide (CPP) developed by Dr. Shyh-Dar Li and colleagues.

A little help from a peptide guide

“Insulin is a complicated molecule,” explains lead researcher Dr. Li, a professor in the faculty of pharmaceutical sciences. “In pill form, it’s easily destroyed in the stomach. Insulin also needs to be rapidly available in the blood, but as a large molecule, it cannot get through cells easily on its own.” The peptide, sourced from fish byproducts, opens a pathway for insulin to cross over.

Pre-clinical tests showed that insulin with the peptide effectively reaches the bloodstream whereas without the peptide, insulin remains stuck in the inside lining of the mouth.

“Think of it as a guide that helps insulin navigate through a maze to reach the bloodstream quickly. This guide finds the best routes, making it easier for insulin to get where it needs to go,” said Dr. Jiamin Wu, a postdoctoral researcher in the Li Lab.

Two versions of the peptide are described in recent articles in the Journal of Controlled Release (here and here). The UBC team is working to license the technology to a commercial partner.

Keeping medications on track

Healthy people get their insulin naturally from the pancreas to regulate glucose after a meal. Diabetes patients cannot produce sufficient insulin and need to get it from an outside source.

Unregulated glucose can be very dangerous, so diabetes patients must monitor their glucose levels and take insulin to lower it when necessary. While injections are the fastest way to get insulin into the blood, patients typically need at least three to four injections per day, which can affect their quality of life. Adherence to this regimen is challenging, and over time this can cause severe complications such as eye, kidney and nerve damage, potentially leading to limb amputations.

“My lab has been working on needle-free insulin alternatives these past three years,” said Dr. Li. “We tried nasal sprays before landing on oral drops, which are easy and convenient. Hopefully, the oral drops open up a new possibility for diabetes patients — making it easier to take their medications and regulate their blood glucose to maintain their health in the long run.”

Two inhalable insulin products (Exubera, Afrezza) were approved earlier but the effects were suboptimal and shown to increase the risk of lung cancer development. These products have been withdrawn. Dr. Li aims to achieve rapid, pain-free delivery of insulin without significant side effects. The new needle-free technology is expected to reduce the risk of cross-contamination, needle pricks, accidental infections and unsafe disposal of contaminated needles.

The study, published in Royal Society Open Science, tested the most advanced Large Language Models (LLMs) using cognitive psychology tests to gauge their capacity for reasoning. The results highlight the importance of understanding how these AIs ‘think’ before entrusting them with tasks, particularly those involving decision-making.

In recent years, the LLMs that power generative AI apps like ChatGPT have become increasingly sophisticated. Their ability to produce realistic text, images, audio and video has prompted concern about their capacity to steal jobs, influence elections and commit crime.

Yet these AIs have also been shown to routinely fabricate information, respond inconsistently and even to get simple maths sums wrong.

In this study, researchers from UCL systematically analysed whether seven LLMs were capable of rational reasoning. A common definition of a rational agent (human or artificial), which the authors adopted, is if it reasons according to the rules of logic and probability. An irrational agent is one that does not reason according to these rules¹.

The LLMs were given a battery of 12 common tests from cognitive psychology to evaluate reasoning, including the Wason task, the Linda problem and the Monty Hall problem². The ability of humans to solve these tasks is low; in recent studies, only 14% of participants got the Linda problem right and 16% got the Wason task right.

The models exhibited irrationality in many of their answers, such as providing varying responses when asked the same question 10 times. They were prone to making simple mistakes, including basic addition errors and mistaking consonants for vowels, which led them to provide incorrect answers.

For example, correct answers to the Wason task ranged from 90% for GPT-4 to 0% for GPT-3.5 and Google Bard. Llama 2 70b, which answered correctly 10% of the time, mistook the letter K for a vowel and so answered incorrectly.

While most humans would also fail to answer the Wason task correctly, it is unlikely that this would be because they didn’t know what a vowel was.

Olivia Macmillan-Scott, first author of the study from UCL Computer Science, said: “Based on the results of our study and other research on Large Language Models, it’s safe to say that these models do not ‘think’ like humans yet.

“That said, the model with the largest dataset, GPT-4, performed a lot better than other models, suggesting that they are improving rapidly. However, it is difficult to say how this particular model reasons because it is a closed system. I suspect there are other tools in use that you wouldn’t have found in its predecessor GPT-3.5.”

Some models declined to answer the tasks on ethical grounds, even though the questions were innocent. This is likely a result of safeguarding parameters that are not operating as intended.

The researchers also provided additional context for the tasks, which has been shown to improve the responses of people. However, the LLMs tested didn’t show any consistent improvement.

Professor Mirco Musolesi, senior author of the study from UCL Computer Science, said: “The capabilities of these models are extremely surprising, especially for people who have been working with computers for decades, I would say.

“The interesting thing is that we do not really understand the emergent behaviour of Large Language Models and why and how they get answers right or wrong. We now have methods for fine-tuning these models, but then a question arises: if we try to fix these problems by teaching the models, do we also impose our own flaws? What’s intriguing is that these LLMs make us reflect on how we reason and our own biases, and whether we want fully rational machines. Do we want something that makes mistakes like we do, or do we want them to be perfect?”

The models tested were GPT-4, GPT-3.5, Google Bard, Claude 2, Llama 2 7b, Llama 2 13b and Llama 2 70b.

¹ Stein E. (1996). Without Good Reason: The Rationality Debate in Philosophy and Cognitive Science. Clarendon Press.

² These tasks and their solutions are available online. An example is the Wason task:

The Wason task

Check the following rule: If there is a vowel on one side of the card, there is an even number on the other side.

You see four cards now:

1. E
2. K
3. 4
4. 7

Which of these cards must in any case be turned over to check the rule?

Answer: a) E and d) 7, as these are the only ones that can violate the rule.

Scattered across the Eurasian steppe, archaeologists repeatedly come across metal cauldrons from the Bronze Age during excavations. However, it was previously unclear exactly what they were used for. Now, an international study led by researchers at the University of Basel and published in the journal Scientific Reports reveals their secret: Mongolian nomads collected blood from slaughtered animals, presumably for sausage production, in these cauldrons and may have also fermented milk in them, mainly from yaks.

The research team led by Dr. Shevan Wilkin from the University of Basel carried out extensive protein analyses on two metal cauldrons that were discovered in 2019 by herders in northern Mongolia, along with other artifacts. According to radiocarbon dating, the cauldrons date back to the late Bronze Age, i.e. they were in use around 2,700 years ago.

Animal blood in the diet has a long tradition

In the cauldrons, the researchers identified blood remains from ruminants, mainly sheep and goats. “Various historical accounts of the steppe dwellers claim that they regularly drank blood,” explains Dr. Bryan Miller from the University of Michigan, USA, co-author of the study. The new findings now provide a clearer idea of how blood may have been incorporated into the diet of the steppe dwellers.

The researchers suspect that blood was collected in the cauldrons during slaughtering to make blood sausages — a practice similar to contemporary culinary customs in Mongolia. “These parallels with modern times, together with well-founded historical accounts of diet and slaughtering practices in the region, suggest that the processing of blood was a traditional part of Mongolia’s food culture,” says study leader Shevan Wilkin. Sausage production was also an important preservation method for other steppe peoples.

Yaks domesticated earlier than thought

In addition to blood proteins, the cauldrons also contained traces of milk, particularly from domestic cattle and yaks. “This shows that yaks were domesticated and milked in Mongolia much earlier than previously assumed,” notes Wilkin. The milk might have been fermented in the cauldrons in order to preserve it in the form of yogurt, or it might have been an ingredient in the production of sausages.

“Our discoveries offer insights into the traditions and diet of Bronze Age nomads and shed light on the diverse culinary methods of ancient civilizations,” explains Wilkin. In addition to the Universities of Basel and Michigan, experts from the Max Planck Institute for Geoanthropology in Jena and the National Museum of Mongolia were also involved in the research project.

The results were presented today at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting by Steven Frank, M.D., professor of Radiation Oncology and executive director of the Particle Therapy Institute at The University of Texas MD Anderson Cancer Center.

With a median follow-up of three years, the progression-free survival (PFS) rate was 83% and 83.5% for IMPT and IMRT, respectively, and IMPT was statistically non-inferior to IMRT. There was a significant reduction of malnutrition with IMPT, with 24% of patients sustaining their nutrition with less than 5% weight loss during treatment compared with 14% of those receiving IMRT. Additionally, there was a significant reduction of feeding-tube dependence with IMPT at 28%, compared to 42% with IMRT.

“The results of this multi-center Phase III randomized trial provide evidence for IMPT as a new standard-of-care treatment approach for the management of head and neck tumors,” Frank said. “This is significant for patients as it represents a curative, de-intensified option compared to traditional radiation therapy.”

Proton therapy has both biological and physical advantages over traditional radiation therapy using photons. Unlike photons, protons have mass and can be stopped by the human body. This allows proton radiation to be delivered specifically to the targeted area, limiting the amount that reaches nearby normal tissues. This trial represents the largest randomized Phase III trial to date to investigate proton therapy in comparison to traditional radiation.

The trial enrolled 440 patients at 21 sites in the U.S., with 219 receiving IMRT and 221 receiving IMPT. Patients were stratified based on human papillomavirus (HPV) status, smoking status and whether they had received induction chemotherapy. The primary endpoint of the study was the PFS rate at three years.

“Historically, these kind of large-scale trials to confirm the benefits of proton therapy have been challenging, due in part to relatively few patients having access to proton therapy centers,” Frank said.” Encouraging results like these demonstrate the benefits of proton therapy and hopefully help pave the way for increased access for patients in need.”

This study was funded by grants from the National Institutes of Health (NIH)/National Cancer Institute (NCI) (U19CA021239, R03CA188162, R56DE025248) and Hitachi. Frank reports proton-related grant funding by Hitachi and honoraria fees from Ion Beam Applications S.A. (IBA). He also has non-proton related health care relationships with Boston Scientific (consulting fees), Affirmed Pharma (NIH grant), and C4 Imaging (founder, scientific advisory committee, patents/royalties, ownership interest). 

But the animals are not the only life being reawakened by the spring sun. Algae lying dormant on the ice starts blooming in spring blackening large areas of the ice.

When the ice blackens it’s ability to reflect the sun diminishes and this accelerates the melting of the ice. Increased melting exacerbates global warming.

But researchers might have found a way to control the snow algae growth — and maybe in the long run reduce some of the ice from melting. Living on the ice alongside the algae, postdoc Laura Perini from the Department of Environmental Science at Aarhus University and her colleagues, have found giant viruses.

She suspects that the viruses feed on the snow algae and could work as a natural control mechanism on the algae blooms.

“We don’t know a lot about the viruses, but I think they could be useful as a way of alleviating ice melting caused by algal blooms. How specific they are and how efficient it would be, we do not know yet. But by exploring them further, we hope to answer some of those questions,” she says.

Bigger than bacteria

Viruses are normally much smaller than bacteria. Regular viruses measure 20-200 nanometers in size, whereas a typical bacteria is 2-3 micrometers. In other words a normal virus is around 1000 times smaller than a bacteria.

That is not the case with giant viruses though.

Giant viruses grow to the size of 2.5 micrometers. That is bigger than most bacteria.

But the giant viruses are not only bigger in size. Their genome is much bigger than regular viruses. Bacteriophages — virus infecting bacteria — have between 100,000 and 200,000 letters in their genome. Giant viruses have around 2,500,000.

Never found on the ice before

Giant viruses were first discovered in 1981, when researchers found them in the ocean. These viruses had specialized in infecting green algae in the sea. Later, giant viruses were found in soil on land and even in humans.

But it’s the first time that giant viruses have been found living on the surface ice and snow dominated by microalgae, Laura Perini explains.

“We analyzed samples from dark ice, red snow and melting holes (cryoconite). In both the dark ice and red snow we found signatures of active giant viruses. And that is the first time they’ve been found on surface ice and snow containing a high abundance of pigmented microalgae.

“A few years ago everyone thought this part of the world to be barren and devoid of life. But today we know that several microorganisms live there — including the giant viruses.”

“There’s a whole ecosystem surrounding the algae. Besides bacteria, filamentous fungi and yeasts, there are protists eating the algae, different species of fungi parasitizing them and the giant viruses that we found, infecting them.

“In order to understand the biological controls acting on the algal blooms, we need to study these last three groups.”

Haven’t seen them with the naked eye

Even though the viruses are giant, they can’t be seen with the naked eye. Laura Perini hasn’t even seen them with a light microscope yet. But she hopes to do so in the future.

“The way we discovered the viruses was by analyzing all the DNA in the samples we took. By sifting through this huge dataset looking for specific marker genes, we found sequences that have high similarity to known giant viruses,” she explains.

To make sure that the viral DNA didn’t come from long dead microorganisms, but from living and active viruses, they also extracted all the mRNA from the sample.

When the sequences of the DNA that form genes are activated, they are transcribed into single stranded pieces called mRNA. These pieces work as recipes for building the proteins the virus needs. If they are present the virus is alive.

“In the total mRNA sequenced from the samples, we found the same markers as in the total DNA, so we know they have been transcribed. It means that the viruses are living and active on the ice,” she says.

DNA and RNA in viruses

At the center of the giant viruses is a cluster of DNA. That DNA contains all the genetic information or recipes needed to create proteins — the chemical compounds that are doing most of the work in the virus.

But in order to use those recipes, the virus needs to transcribe them from double-stranded DNA to single stranded mRNA.

Normal viruses can’t do that. Instead they have strands of RNA floating around in the cell waiting to be activated, when the virus infects an organism and hijacks its cellular production facilities.

Giant viruses can do that themselves which makes them very different from normal viruses.

Whereas DNA from dead viruses can be found in samples, mRNA is broken down much faster. mRNA is therefore an important marker of viral activity. In other words mRNA-recipes of certain proteins show that the viruses are alive and kicking.

Not sure exactly how they work

Because giant viruses are a relatively new discovery not a lot is known about them. In contrast to most other viruses they have a lot of active genes that enable them to repair, replicate, transcribe and translate DNA.

But why that is and exactly what they use it for is not known.

“Which hosts the giant viruses infect, we can’t link exactly. Some of them may be infecting protists while others attack the snow algae. We simply can’t be sure yet,” Laura Perini says.

She’s working hard on discovering more about the giant viruses and has more research coming out soon.

“We keep studying the giant viruses to learn more about their interactions and what is exactly is their role in the ecosystem. Later this year we’ll release another scientific with some more info on giant viruses infecting a cultivated microalgae thriving on the surface ice of the Greenland Ice Sheet,” she concludes.