Tag Archives: chemistry

Cancer Treatment Breakpoint: A Discovery of 225Ac – H4py4pa Complex

Posted on April 8, 2022 by billyang | Leave a comment

Like the Earth itself, the world of science never stops turning.

More specifically, the world of cancer research never stops turning; there are always improvements to be made. With this mindset, scientists Lily et al. from the Orvig group wrote and published a paper about the characteristics of a molecule called H4py4pa in early 2021. They studied the molecule at multiple locations, such as the UBC Chemistry Labs, TRIUMF and BC Cancer Research Centre, in hopes of improving the effectiveness of a specific type of cancer treatment called targeted alpha therapy. The paper supports the effectiveness of this new molecule by comparing characteristics, such as stability, with the original molecule used in targeted alpha therapy.

With all that said… What is targeted alpha therapy and how exactly does it work?

What in the Jargon?… A Carefully Defined Mechanism of H4py4pa

Before we get into the meat and potatoes, we need to define some of the terms here.

H4py4pa is a ligand, which is essentially a big molecule, that is able to bind to metal atoms. Ligands binding to metal atoms is a chemical phenomenon known as chelation. The metal atom in this case is Actinium-225 (225Ac). Essentially, chelation of H4py4pa to 225Ac can deliver four net alpha particles, which are a particulate form of concentrated radiation. Radiation is known to destroy cancer cells. In other words, radiation is tumoricidal. This process is known as targeted alpha therapy.

Molecular Structure of H4py4pa and visual summary of the study. Source: Bioconjugate Chemistry

Starting from 2:50, you get a visualization of how the mechanism works. Source: STORYHIVE

The Body is ASTOUNDINGLY Large

We, as humans, are fairly large organisms. So the question becomes: How does the 225Ac-H4py4pa find the tumour site? 225Ac is normally bound to a specific antibody, called Trastuzumab, which is attached to the HER2+ protein. The HER2+ gene most notably contributes to breast cancer. This means that 225Ac already has a natural affinity for certain tumour sites in the body. However, 225Ac is still capable of unintentionally interacting with other areas of the complex body. This is where H4py4pa comes in. H4py4pa is a very big molecule that hugs around the 225Ac and prevents it from binding to anything other than the intended antibody.

A good way to visualize this mechanism is through a 4-component arrow mechanism. The 225Ac is the arrowhead that will do the damage to its target (in this case the tumour) while the shaft and the feathers of the arrow are the directional components that direct the 225Ac arrowhead to the right area of the body.

The issue with solely injecting 225Ac into the body, however, is that it’ll go straight to the bone instead of the cancerous area. As you may have heard, opposites attract, so because 225Ac is positively charged, it’ll be attracted to the bone, which has a lot of negatively-charged phosphate groups.

This is where the H4py4pa comes into play.

The fourth component of the arrow is H4py4pa, which acts as the linker for the arrowhead and shaft, binding to the 225Ac and holding it in place as the directional components of the arrow move the 225Ac arrowhead straight towards its target.

We’ve prepared a video in order to visualize this:

So what are the Discoveries of this Study?

Through many trials and tests, it was found that H4py4pa was very effective in conducting targeted alpha therapy with 225Ac. It was the most stable ligand that was bound to 225Ac relative to previously used ligands. There was much more control inside the body and it was less likely to spontaneously react with molecules other than the intended antibody. Furthermore, 225Ac maintained its radioactivity in the body. With some ligands, 225Ac did not release its alpha particles due to incompatible binding. However, with H4py4pa, 225Ac still had high radioactivity in tumour areas and low radioactivity in non-tumour areas such as the bones and the liver. This reduces the risk of untargeted toxicity in the body.

How Does it Differ from Chemotherapy?

Perhaps you’ve heard of chemotherapy before? It’s a fairly common and well-known treatment for cancer. While it is effective, there are drawbacks to chemotherapy as well; to quote Dr. Orvig:

“…the thing about cancer chemotherapy is just using conventional chemicals is that you basically poison the patient. And because the cancer is a little more susceptible, you’re poisoning the cancer a little bit more.”

Dr. Chris Orvig, March 2022

Essentially, chemotherapy reduces cancer by targeting fast-growing cells in the body. Unfortunately, this includes the entire body, so while the fast-growing cancer cells are affected by chemotherapy, fast-growing healthy cells can be affected too.

On the other hand, targeted alpha therapy is able to directly target the tumorous areas of the body by binding to the antibody of the tumourous cell. This means that the 225Ac is able to directly destroy the cancerous cells without doing as much damage to the surrounding healthy cells.

Who were the people behind this all?

Well, the initial propagator of the idea behind H4py4pa was Dr. Lily Li who, at the time of the study, was a Ph.D. student with Dr. Orvig. After hearing about that idea, Dr. Chris Orvig, a UBC Chemistry Professor and an associate member of the faculty of Pharmaceutical Sciences, initiated the study. He also gathered the funding and the people for the study and helped conduct it as well.

For a bit more detail behind the history of this study and Dr.Orvig, we have a podcast prepared:

Now, that was all about the past, but what does this mean for our future?

Why is this so important?

Significance of H4py4pa and Targeted Alpha Therapy

H4py4pa and targeted alpha therapy could lead to many advancements in cancer treatment research.

As mentioned before, targeted alpha therapy is able to directly target tumours with less damage to the patient’s healthy cells; this could potentially reduce the fatigue most chemotherapy patients experience throughout their entire body. However, it does has limitations.

Before H4py4pa, the molecule used for target alpha therapy tended to bind to Actinium slower than preferred in its surrounding temperatures, which can lead it to be less effective.

This is why H4py4pa is so important.

Not only is it able to bind quicker to Actinium, but it’s also more stable than the previous molecules, all while remaining just as effective against cancer

In the future, this means that different companies can use Actinium and H4py4pa against different types of cancers. In reference to the arrow metaphor, they could adjust the directional components of the arrow (the shaft and the feathers) and direct the Actinium to different areas of the body.

“… I think it’s quite possible that we will see in the future Actinium used in different chemical constructs to treat a number of different cancers. And the hope would be that you give a patient one or two or three shots of this over a two or three-month period, and that we could drive many different cancers into remission. “

Dr. Chris Orvig, March 2022

[Group 5: Bill Yang, Evelyn Zhong & Christine Sun]

Enzymatic Browning in Granny Smith Apples

Posted on April 5, 2022 by chenyang luo | Leave a comment

Introduction

Browning is the darkening of the flesh that occurs shortly after fruits such as apples and pears are cut, exposing the flesh to air. Although browning is not toxic to humans since the pigment is composed of melanin, browning makes the fruit unsightly and unappetizing to eat . The main cause of browning is polyphenol oxidase (PPO), an enzyme that catalyzes the first two steps of converting the amino acid tyrosine into melanin in the presence of oxygen. Physical and mechanical stresses from slicing fruit physically damage the cellular structure of the flesh, which catalyzes PPO activity as it becomes exposed to oxygen .

Why Do Apples Turn Brown After You Cut Them? | Let's Talk Science from lets Talk science

what is an effective tool to delay apple browning?

Past studies have investigated the effects of different consumable solutions on browning, and citric acid, found naturally in fruit juices, was identified to be a moderate to a high inhibitor of browning . Citric acid is able to slow the onset of browning by lowering the pH of PPO’s environment so that the pH is outside the optimal pH range of 6-7 required for PPO to oxidize the flesh . Although other agents such as chelators and antioxidants can also inhibit PPO through reduction and inhibition, citric acid is more commonly found in foods, especially fruit juices that, when applied to apples, are more likely to preserve the apples’ taste

ReaLemon 100% Lemon Juice, 15 Fl Oz Bottle, 1 Count - Walmart.com from Walmart

Despite citric acid being an effective tool for delaying browning, the concentration at which its effects last for an extended period of time is unknown. Therefore, lemon juice was chosen since it is known to be composed of approximately 6% citric acid . Lemon juice also contains other acids, like ascorbic acid and malic acid, but their concentrations are negligible since citric acid comprises about 95% of the acid content of lemon juice . Granny smith apples were used as they are a common fruit consumed in households and are known to brown quickly after being sliced. It was hypothesized that lemon juice will delay the onset of browning due to the citric acid making the juice’s pH too acidic for polyphenol oxidase to initiate the conversion of tyrosine into melanin. If lemon juice delays browning, then the surface area of browning that appears on apple slices over a set period of time would decrease as the concentration of lemon juice the apple is exposed to increases.

Conclusion

This result shows that increasing lemon juice concentration results in the decrease of browning due to the low pH of the juice compared to the pH that browns apple flesh. These results provide insight for future studies to find more effective anti-browning agents and to further investigate environmental temperatures to avoid to delay browning.

—–Chenyang Luo

Reference

Son, S. M., Moon, K. D., & Lee, C. Y. (2001). Inhibitory effects of various antibrowning agents on apple slices. Food Chemistry, 73(1), 23-30

Tinello, F., & Lante, A. (2018). Recent advances in controlling polyphenol oxidase activity of fruit and vegetable products. Innovative Food Science & Emerging Technologies, 50, 73–83. https://doi.org/10.1016/j.ifset.2018.10.008

Tortoe, C., Orchard, J., & Beezer, A. (2007). Prevention of enzymatic browning of apple cylinders using different solutions. International Journal of Food Science & Technology, 42(12), 1475-1481.

Yapo, B. M. (2009). Lemon juice improves the extractability and quality characteristics of pectin from yellow passion fruit by-product as compared with commercial citric acid extractant. Bioresource Technology, 100(12), 3147–3151. https://doi.org/10.1016/j.biortech.2009.01.039

How to Synthesize 40,000 Biochemical Weapons in Six Hours!

Posted on March 21, 2022 by billyang | 1 comment

In the media, we constantly hear about Artificial Intelligence (AI) advancing for the benefit of society. It is assumed that this advancement will aid us in fields such as healthcare and drug development by simplifying complex human tasks. However, what if it did not? What if this AI was abused to potentially harm society?

Collaborations Pharmaceuticals, Inc. had designed a molecule generator called MegaSyn, which discovers new potential drugs that can target and prevent human diseases through machine learning model predictions. This functions as the AI of the story. Essentially, the model depicts all of the predicted target drugs that are synthesizable, while deleting all of the molecules that are considered toxic to humans. The company proposed the idea that they could synthesize toxic molecules by simply inverting this program. Due to the universal abundance of possibilities, they used VX, which is one of the most toxic biochemical nerve agents developed, as a model to focus the results. In less than six hours, the program produced a model that generated 40,000 molecules that were within the same calibre of toxicity as VX.

A few grains of VX (6-10 mg) are enough to kill a person. Source: Periodic Videos

The Potential Misuse of AI Programs

Although the company did not synthesize any of the molecules in their model, this experiment raises serious concerns over the consequences of AI misuse. There are hundreds of commercial companies with technologies that are able to replicate MegaSyn. Furthermore, another AI program that can make this risk more severe is retrosynthesis software, which can computationally break down a molecule into the steps from which it is synthesizable. Although this model was based on VX-like compounds, it would be simple to look for other toxic molecules through minimal adjustments to the program. The abuse of AI should be alarming because all you need is the ability to code in order to greatly lower the technical skills required to synthesize potentially dangerous biochemical weapons.

Quantitative Structure-Activity Relationship is an example of a similar program that is used for Drug Discovery. You can substitute VX as the molecule to apply to this study. Source: Data Professor

Rapid Synthesis Using Combinatorial Chemistry

Complimenting the advancements on the technological side, there have also been significant advancements on the chemical side in the last century. The development of combinatorial chemistry allows for the synthesis of mass numbers (perhaps millions) of similar compounds within a single process. Essentially, there is a large array of structurally diverse compounds, also known as the chemical library, which interacts with biological targets of interest to simultaneously synthesize thousands of peptides. With the AI-generated model acting as the chemical library with its toxic-focused molecule (such as VX), the process of combinatorial chemistry becomes much more easily accessible.

Combining different structures together using biological target interactions to synthesize multiple compounds. Source: Wikimedia Commons

So, Is This Technology Beneficial Or Not?

The molecule-generating AI program is concerning due to its applications in biochemical warfare. If the program is misused, it can easily be employed in war and cause the loss of thousands of lives, not to mention the environmental impacts of such chemicals. However, this program could just as easily be used for the benefit of mankind. The key is transparency. Collaborations Pharmaceuticals decided to be transparent with their findings and inform the public about the power of their program. Therefore, there is peace of mind that they will use this program for the benefit of drug discovery.

~ Bill Yang

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Posted in Biological Sciences, Issues in Science, Public Engagement, Science Communication, Science in the News

Tagged Artificial Intelligence, Biochemical Weapons, Biotechnology, Chemical Synthesis, chemistry, Drug Development, Nerve Agents, Pharmaceuticals

Does reflection data from MARSIS reflect presence of water on mars?

Posted on January 31, 2022 by jonathan hao | Leave a comment

One of the questions many people have wondered about at some point or another is the existence of extraterrestrial life. Some answers to what these extraterrestrials life forms would be like are in the form of novels such as The War of Worlds by H.G Wells, in which extraterrestrial life from Mars, Martians, invade Earth. While The War of Worlds is a fictional work, perhaps Martians are not fictional at all? In a recent article on the Earth and Planetary Science Letters journal, a rather shocking question was asked, has the MARSIS radar detected proof of water on mars? For context, the Mars Advanced Radar for Subsurface and Ionosphere Sounding, or MARSIS for short, is an advanced radar attached to a satellite currently orbiting Mars. Recent radar data has shown that odd reflections mimicking the reflections you would find from a scanning of brine water on earth has been found on Mars. Brine water simply means that the water contains salt, so does this mean that water has been found on mars?

On a news outlet PHYSORG, one of the authors, Stillman, says a ice brine mixture or a brine sediment mixture in the Martian ice cap can mimic the reflection found by MARSIS.

Credit: NASA/JPL-Caltech/USGS/SwRI

SwRI scientist helps confirm liquid water beneath Martian south polar cap

Description: The image above shows a proposed rendition of the potential water in the South Pole of Mars.

The science behind the claims.

In the recent article titled “Assessing the role of clay and salts on the origin of MARSIS basal bright reflections” , it is stated that the bright basal (bottom layer) reflections detected by the MARSIS radar at the south pole of Mars are similar to scans of earth’s subglacial waters. As the temperature at these locations on Mars are colder than 200K , or negative 73 degrees Celsius, any water found at this temperature is surely frozen, thus any water is in liquid form as a salt solution, or in other words, salt water. Hydrous minerals (minerals containing water) and salts have been found in rocks on Mars ranging back decades, from meteorites and orbital/lander observations. Thus the fact these minerals/salts are known to fragment and otherwise be destroyed allowing them to be spread around as dust means that they will be present in the water ice at the polar caps, such as the southern pole that we discussed earlier.

Description: A picture of frozen salt water on earth in the form of ice on the baltic sea, a similar version is proposed to be hiding underneath the South Pole on Mars by Stillman.

Licence: CanStockPhoto

The heartbreaking conclusion

Through analysis of the dielectric properties, or the ability to have electrons move through the material (thus affecting scans by how reflective they are), Stillman and his colleagues have demonstrated that these well known water containing minerals and clays are not the reason for the reflection found at the southern pole. The revelation of the material responsible for the reflection however is not the sensational discovery everyone had wished it to be. It has been concluded that water is not the identity of the mysterious reflections as at these temperatures (-73 Celsius) where water is completely and totally frozen, reflection from water is actually not that high, instead, the conclusion is that a magnesium and chlorine brine or calcium chlorine brine (In the form of perchlorate) is the true inhabitant of the southern poles of mars. So sadly, there still is no science backing the existence of water on Mars.

License: Wikipedia Commons

Description: Magnesium Perchlorate, one of two brines proposed as the true resident underneath the South Pole in Mars.

-Jonathan Hao

The tiny but mighty solution to antibiotic resistance

Posted on January 29, 2022 by Parham Asli | 2 comments

So picture this… It’s the year 1928 and penicillin has just been discovered. Penicillin revolutionized modern medicine and with other antibiotics to come, it would go on to treat the untreatable and save millions of lives. Now, let’s flash forward to a more grim version of the future. It’s the year 2022. Antibiotics were supposed to be our precious resource but every time we misused them or overused them, we gave bacteria a chance to evolve and become resistant, and at the same time our scientists were unable to bring new antibiotics to the market. The World Health Organization (WHO) is calling antibiotic resistance “one of the biggest threats to global health today” so in recent years scientists have been looking for new multi-dimensional strategies to combat this issue. One of those is the use of light-activated quantum dots.

Over-prescription and patient non-compliance exacerbate the issue of antibiotic resistance. Getty Images/Joe Raedle

What are quantum dots?

Quantum dots are tiny particles made of semiconducting material, meaning they partly conduct electrical current. They are only a few nanometres in size and can be engineered in terms of shape, size, and material. The way these quantum dots kill bacteria is not all that complicated. Basically, when our bodies are infected with bacteria, they naturally produce what scientists call Reactive Oxygen Species (ROS) in our immune cells to kill bacteria, and what light-activated quantum dots do is that they essentially mimic this natural killing process of the body by producing ROS of their own.

How is the killing initiated?

Now you may be thinking, how do we ensure that the cells that are not infected with bacteria, don’t end up getting killed? Well, the answer is quite simple. In application, quantum dots are specifically injected at the site of bacterial infection in the human body, so as to not affect other tissues, and when they receive an input of light of sufficient energy in a process called photoactivation, their electrons (particles with a negative charge of electricity) jump from a region of space with lower energy called the valence band to a region of space with higher energy called the conduction band. The energy difference between these two is referred to as the “bandgap” and when the electrons relax back to their ground level (i.e. the valence band), a photon of light is released that provides the energy needed for producing the killer Reactive Oxygen Species.

An input of light causes electrons of the quantum dots to move around, energy is released, and the killer ROS come to life! Adapted from Redox-Active Therapeutics

What are the consequences?

The killer ROS will break down bacterial biofilms (self-contained bacterial communities), damage the bacterial cell wall and cell membrane and inactivate enzymes needed for bacterial survival. And because the ROS are killing these microbes through all these different non-specific ways, the microbes can no longer develop resistance!

Quantum Dots and their many ways of killing bacteria! Adapted from McCollum et
al. and Imlay

One for the future?

It is abundantly clear that quantum dot technology shows great promise in combating the widespread issue of antibiotic resistance. Although the clinical use of the technology is a long way off, the strategy is an intriguing new approach at a time when the rate of drug development is much slower than the rate of antibiotic development and the pharmaceutical industry is lagging behind.

Student research on the applications of quantum dots at The University of Colorado. Materials Research Society

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Posted in Biological Sciences, Issues in Science, Science Communication, Science in the News

Tagged antibiotics, bacteria, chemistry, multi-drug resistance, nanoparticles, nanotechnology, quantum dots, Quantum Mechanics