Author Archives: Kenny Lin

Sugars – The Key to Talking to Our Cells

Posted on April 9, 2020 | Leave a comment

We are one step closer to achieving communication with those 37.2 trillion tiny cells making up our bodies. Just last year, researchers at the University of British Columbia, led by Dr. Stephen Withers, found a way to modify the sugars essential to this communication by using chemicals found in bacteria. The same bacteria living in our gut!

WHAT EXACTLY ARE SUGARS?

No ambiguity here! Chemists work with sugars based off molecules in this sugar cube. Credits: The Verge

To be specific, the sugars Withers’ team studied were simple sugars; hexagonal-shaped molecules, often joined to other molecules known as “acceptors”. The problem chemists face is like the average love life. 

Similar to starting a relationship with someone, joining acceptors to sugars is also quite difficult. Luckily for sugars, Mother Nature has come up with some solutions: enzymes, which are helper molecules that speed up the pairing or unlinking of two molecules.

A SOLUTION UNDER OUR NOSES…

Instead of struggling to find ways of joining sugars and acceptors, Withers’ team thought: Why not hijack Mother Nature and use these enzymes? To make their idea a reality, they extracted sugar-specific enzymes from E. Coli, a type of bacteria that lives inside the human gut.

These bacteria manufactured 175 sugar-specific enzymes, and from these they chose eight enzymes that were compatible with the sugars and acceptors they were interested in.

It seemed like Withers’ team now had everything needed to join the desired acceptors to the sugars; however, there was still a problem. The sugar-specific enzymes they got from E. Coli did the exact opposite of what they wanted; instead of forming sugar-acceptor linkages, they specialized in breaking them.

Enzymes that break sugar-acceptor linkages are analogous to using a screwdriver to loosen a screw, while enzymes that form sugar-acceptor linkages are like tightening a screw.

A small modification changes the function of the enzyme. Credits: Blog post authors

To solve this problem, they reverse-engineered the enzymes specialized in breaking linkages into those that form linkages, by changing a small part of the enzymes’ structure, similar to changing the tips on a screwdriver. As a result, Withers’ team now had eight enzymes specialized in forming different sugar-acceptor linkages. 

MORE THAN JUST A BOND…

Now being able to freely and efficiently modify sugars, there is a big potential for researchers to join in on the conversations with our cells. Why is this important? Often, there is miscommunication within our cells which can lead to serious trouble. 

One example is cancer; which is partly caused by cancer cells using abnormal sugar molecules as a form of miscommunication, to avoid being cleared up by immune cells. One potential treatment is a sugar-based vaccine, which allows our immune cells to more efficiently target tumor cells.

The challenge of creating a sugar-based vaccine isn’t just relevant to cancer, but other diseases as well which also occur  as a result of miscommunication. With Withers’ research, designing these sugar-based drugs won’t be as difficult thanks to their novel way of bonding sugars to other molecules. This research brings us one step closer to talking to our cells, helping with the battle against diseases.

Story source

Armstrong, Z.; Liu, F.; Chen, H.-M.; Hallam, S. J.; Withers, S. G. Systematic Screening of Synthetic Gene-Encoded Enzymes for Synthesis of Modified Glycosides. ACS Catalysis 2019, 9 (4), 3219–3227.

– Kenny Lin, Pricia Ouyang, Tom Hou, Aron Engelhard (CO-10)

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Posted in Biological Chemistry, Chemistry News, Organic Chemistry, Uncategorized

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Sugars – The Key to Talking to our Cells

Posted on March 30, 2020 | Leave a comment

We are one step closer to achieving communication with those 37.2 trillion tiny cells making up our bodies. Our cells communicate using sugars, and different modifications to these sugars can change the way our cells communicate with each other. Just last year, researchers at the University of British Columbia, led by Dr. Stephen Withers, did exactly this! They designed a unique way to tinker with sugars’ chemical structures by using chemicals found in bacteria. The same bacteria living in our gut.

what exactly are sugars?

No ambiguity here! Chemists work with sugars based off molecules in this sugar cube. Credits: The Verge

To be specific, the type of sugars Wither’s team studied were simple sugars; hexagonal-shaped molecules, often joined to other molecules known as “acceptors”. The problem chemists face is like the average love life. Similar to starting a relationship with someone, joining acceptors to sugars is also quite difficult. Luckily for sugars, Mother Nature has come up with some solutions: enzymes, which are helper molecules that speed up the pairing or unlinking of two molecules. 

A SOLUTION UNDER OUR NOSES…

Instead of struggling to find ways of joining sugars and acceptors, Wither’s team thought: Why not hijack Mother Nature and use these enzymes? To make their idea a reality, they extracted sugar-specific enzymes from E. Coli, a type of bacteria that lives inside the human gut. These bacteria manufactured 175 sugar-specific enzymes, and from these they chose eight enzymes that were compatible with the sugars and acceptors they were interested in.

It seemed like Wither’s team now had everything needed to join the desired acceptors to the sugars; however, there was still a problem. The sugar-specific enzymes they got from E. Coli did the exact opposite of what they wanted; instead of forming sugar-acceptor linkages, they were specialized in breaking them. Enzymes that break sugar-acceptor linkages are analogous to using a screwdriver to loosen a screw, while enzymes that form sugar-acceptor linkages are like tightening a screw.

A small modification changes the function of the enzyme. Credits: Blog post authors

To solve this problem, they reverse-engineered the enzymes specialized in breaking linkages into those that form linkages, by changing a small part of the enzymes’ structure, similar to changing the tips on a screwdriver. As a result, Wither’s team now had eight enzymes specialized in forming different sugar-acceptor linkages. 

More than just a bond…

Now being able to freely and efficiently modify sugars, there is a big potential for researchers to join in on the conversations with our cells. Why is this important? Often, there is miscommunication within our cells which can lead to serious trouble. 

One example is cancer; which is partly caused by cancer cells using abnormal sugar molecules as a form of miscommunication, to avoid being cleared up by immune cells. One potential treatment is a sugar-based vaccine, which tells our immune cells to ignore this miscommunication and target tumor cells.

The challenge of designing a sugar-based vaccine isn’t just relevant to cancer, but other diseases as well which occur also as a result of miscommunication. With Wither’s research, designing these sugar-based drugs won’t be as difficult thanks to their novel way of bonding sugars to other molecules. This research brings us one step closer to talking to our cells, helping with the battle against diseases.

Story source

Armstrong, Z.; Liu, F.; Chen, H.-M.; Hallam, S. J.; Withers, S. G. Systematic Screening of Synthetic Gene-Encoded Enzymes for Synthesis of Modified Glycosides. ACS Catalysis 2019, 9 (4), 3219–3227.

– Kenny Lin, Pricia Ouyang, Tom Hou, Aron Engelhard (CO-10)

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Posted in Biological Chemistry, Chemistry News, Organic Chemistry, Uncategorized

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Sugar Chemistry: A Pathway to Antibiotics

Posted on March 18, 2020 | 1 comment

We’ve all heard it endlessly as kids. Don’t eat too much sugar, it’s bad for you. However, what if I told you that sugars aren’t all that bad and in fact, careful changes to its chemistry can lead to life-saving drugs, such as antibiotics! Just last year, researchers at the University of British Columbia, led by Stephen Withers, found a unique way to tinker with sugars’ chemical structures by using molecules in bacteria. The same bacteria found in our poop!

A view of E. Coli, the bacteria that was used by Wither’s and his team. Credits: The Philadelphia Inquirer

Sweet…but what are they?

Before we go further, let’s start with a simple question: What exactly are sugars? Sugars are molecules shaped like hexagons which are often joined to other molecules known as “acceptors”. In a way we are kind of like sugars; we find someone we like, confess how we feel, and they accept our love! Right? Wrong. As we all know the last part rarely happens and this is the same in sugars, as chemists have yet to find easy ways to join the sugar and acceptors. Luckily for sugars (and unluckily for us), Mother Nature has come up with some solutions, using helper molecules known as enzymes.

Curious as to what type of sugars chemists work with? There’s no ambiguity here, chemists use the same molecules found in sugar cubes. Yes! The ones you put in your coffee. Credits: The Verge

a solution under our noses…

Instead of struggling to find ways of joining sugars and acceptors, Wither’s team thought: Why not just use these enzymes? In other words, hijack Mother Nature. To make their idea a reality, they extracted sugar-specific enzymes from E. Coli, a bacterium that lives inside the human digestive tract. Their efforts gave them 175 sugar-specific enzymes, and from this they chose 8 enzymes that were most specific to the type of sugars and acceptors they were interested in.

“With the 8 enzymes in hand, Withers and his team could now easily make these sugar-acceptor linkages” is what I would like to report; however, things are never so simple. It turns out that the sugar-specific enzymes they got from E. Coli did the exact opposite of what they wanted. Instead of forming sugar-acceptor linkages, they were specialized in breaking them.

Unsurprisingly the savvy researchers expected this and already had a reliable strategy to reverse-engineer these enzymes from linkage breakers to linkage makers. You may be wondering how they re-purposed something to work completely opposite of what it was intended for. To reconcile this, think of this example: hammers. If you’re feeling angry one day you would likely use the hammer to smash things. However, if you’re feeling innovative one day, the hammer would help you build things by hammering in nails. These enzymes are similar; an enzyme that breaks sugar bonds differs very little from one that builds sugar bonds.

more than just a bond…

Sugars go way beyond than just satisfying your sugar fix. They are molecules essential to the maintenance and regulation of not only your body, but in most living things! Because they are found everywhere, including infectious bacteria, sugar-based molecules serve as effective antibiotics, however making these drugs are difficult. Why? Well as mentioned before, chemists have trouble making these sugar-acceptor bonds; however, the research done by Wither’s team show that this will not remain the case. On a lighter note, they also created a sugar-based molecule that had nothing to do with health; detergent. This just further shows that these bonds are far-reaching and relevant in many contexts.

Story source

Armstrong, Z.; Liu, F.; Chen, H.-M.; Hallam, S. J.; Withers, S. G. Systematic Screening of Synthetic Gene-Encoded Enzymes for Synthesis of Modified Glycosides. ACS Catalysis 2019, 9 (4), 3219–3227.

-Kenny Lin

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Posted in Biological Chemistry, Chemistry News, Organic Chemistry

Gold: Precious in a Different Way

Posted on March 17, 2020 | 2 comments

Let’s face it, to most people gold is just an over-glorified rock with no real value; however, that’s not the case at all! Just this month, researchers from University College London have created a novel light-activated coating that kills infectious bacteria. The key ingredient? Gold.

upgrading with gold…

The invention of a bacteria-killing coating sounds ingenious; however, Hwang’s team was actually not the first to come up with this idea. Previous studies have already shown that coatings incorporating the chemical crystal violet can adequately kill bacteria. The problem was that the coating had to be light-activated by UV rays, which harm the skin by promoting skin cancer.

This was exactly the problem Hwang’s team looked to solve; to make a coating that did not require harmful wavelengths of light. They overcame this challenge by incorporating small clusters of gold into a polymer containing crystal violet. The result? Now this new coating could effectively eliminate bacteria upon activation with low intensity white light – the level of light found in offices.

Concentration of bacteria (CFU/mL) across three conditions after 6 hours exposure to low-intensity white light. Star indicates bacterial concentration is undetected. Sample size = 6 per treatment, error bars are standard deviation. Adapted from Hwang et al.’s data

The figure above perfectly illustrates their result. Statistical analyses show that bacterial concentration does not significantly differ between the violet crystal and control (no coating) condition. This indicates that low-intensity white light cannot activate the bacterial-killing function in the violet crystal coating. What’s interesting is that addition of gold with the violet crystal, reduces the bacterial concentration significantly to near zero values, indicating successful activation.

More than a novelty…

The results of Hwang’s study are truly impactful. It is well known that hospitals are a hotbed for infectious bacteria. In fact, 27% of surfaces in hospital rooms are contaminated with bacteria even after regular and thorough cleaning. As such, applying the coating on these surfaces will definitely reduce the chances of contracting a hospital-related disease. Who would have thought? Not only is gold more than just a hunk of rock, it can also save lives.

-Kenny Lin

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Posted in Biological Chemistry, Inorganic Chemistry

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Stress and Grey Hair: An Answer to a Biological Mystery

Posted on February 29, 2020 | 2 comments

Everyone has heard that too much stress will cause grey hair. This is easily seen in former president of the United States, Barack Obama, whose hair could not escape the stress of the Oval Office! But what exactly links grey hair and stress? This year, researchers at Harvard University found that the nervous system eliminates pigment-regenerating stem cells responsible for coloring our hair!

Barack Obama’s hair color at the start of his presidency versus seven years after. Credits: DailyMail.com

the root of the problem

When you are stressed, your body responds in three distinct ways: the activation of your immune system, the activation of your sympathetic nervous system (SNS), and the release of cortisol, an energy-stimulating hormone. All these responses put your body into a “fight or flight” mode; increasing heart rate and blood pressure. The challenge for Zhang’s team was to sort through these three responses and determine which caused grey hair.

Zhang’s team tackled this problem by performing a series of experiments on black-furred mice. They first tested if immune system activation was the cause by seeing if the fur greyed under stress, even when the immune system was deactivated. They indeed found that stressed immune-deficient mice still greyed, indicating that stress causes greying, independent of an immune response.

They also ran similar experiments using mice mutated to not respond to cortisol or noradrenaline, a molecule involved in SNS activation. The idea being that if  a response was involved, stress should not cause the fur to grey if it was removed. In mice lacking response to cortisol, the fur still greyed; however, in mice lacking the response to noradrenaline, their fur remained black! This indicated that the SNS was the main driver in hair greying.

Figure 1. The results of the experiments described above are shown. Note that mice unable to respond to SNS activation do not grey under stress. “Control” refers to unmutated mice. Also note that a different type of control (non-stressed vs stressed) was ran in the immune-deficient case. (Sample size = 6 for each condition, standard error bars). Credits: Adapted from Zhang et al.’s data.

Zooming in further…

With the culprit in hand, Zhang’s team didn’t just stop there! Through further experimentation, they illustrated that the SNS over-stimulates MeSC, the stem cells involved with hair pigmentation. During hair growth, these MeSC cells transform into pigment-producing cells and color the hair. Under stress, the SNS causes these MeSC cells to transform at an abnormally high rate, quickly depleting these cells and leading to grey hair.

The reason behind this link?

In truth, the reason why this MeSC and SNS interaction exists is unclear. Zhang’s team suggests an evolutionary perspective. Since octopuses, a distant relative to mice and humans, can modify pigmentation of their skin using the SNS, they hypothesize that this interaction was simply conserved. Whatever the reasons may be, this just further shows that the mystery has yet to be completely solved!

-Kenny Lin

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Posted in Biological Chemistry, Popular Science

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Revised: Embarassed of Asian Glow? Don’t Worry, The Future is Promising

Posted on February 15, 2020 | Leave a comment

Ever find yourself beet red after one small drink? You’re not alone! Over one-third of East Asians and eight percent of the world population experience this awkward phenomenon; however, a solution is in the works. Just last month, researchers from Weill Cornell Medical College have solved this problem by experimenting with targeted gene therapy on mice.

What does asian glow look like? A before and after comparison. (Credits: Wikimedia Commons)

The Dangers of Asian Glow

Apart from causing embarrassment, asian glow comes with more serious consequences than just flushing red. The red glow is caused by a deficiency in the ALDH2 enzyme, a key component in detoxifying alcohol. When you drink alcohol, your body converts the alcohol into acetaldehyde. Normally, acetaldehyde is further converted to a safer compound by ALDH2; however in individuals with asian glow, ALDH2 does not function, causing acetaldehyde to build up. Since acetaldehyde is a cancer-causing agent, its accumulation drastically increases the risk of developing esophageal cancer by six to ten folds.

Conversion of alcohol to acetate is stopped in people with asian glow. This leads to toxic buildup of acetaldehyde. (Credits: Me – created with Notability)

A Glowing Solution…

Matsumura’s team reasoned if a lack of ALDH2 enzyme was the problem, maybe they could simply add it back in.

“We hypothesized that a one-time administration of a […] virus […] expressing the human ALDH2 coding sequence […] would correct the deficiency”

They tested their idea on three strains of mice: mice with functional ALDH2, mice lacking ALDH2, and mice with a non-functional version of ALDH2. The latter two simulated the asian flush syndrome seen in humans. After introducing all the mice with the ALDH2 gene and feeding them alcohol, the researchers carefully monitored acetaldehyde levels in the blood.

Their hard-work paid off! In the two strains deficient for ALDH2 function, acetaldehyde levels and abnormal behavior associated with alcohol consumption were back to near-normal levels. Furthermore, they found that one dose was enough to confer persistent and long-term protection.

From Mice to Humans: A Complicated Decision

Matsumura’s team emphasize that a long-lasting treatment for ALDH2 deficiency currently does not exist. Although making the jump from mice to humans will be challenging, they assure that virus-mediated gene therapy shows the most promise in becoming an effective therapy. The million-dollar question is whether the risks of the glow outweigh the benefits of reduced alcohol consumption seen in affected individuals. To this Matsumura’s team say:

“the overall burden […] on human health, particularly […] cancer, supports […] gene therapy.”

What do you think?

-Kenny Lin

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Embarassed of Asian Glow? Don’t Worry, The Future is Promising

Posted on January 26, 2020 | Leave a comment

Ever find yourself beet red after having a small drink? You’re not alone. Over one-third of East Asians and eight percent of the world population experience this awkward phenomenon; however, a solution is in the works. Just last month, researchers from Weill Cornell Medical College have solved this problem in mice, using targeted gene therapy.

What does asian glow look like? A before and after comparison. (Credits: Wikimedia Commons)

The Dangers of Asian Glow

Despite the variety of memes and jokes poking lighthearted fun at this phenomenon, asian glow comes with much dire consequences than just flushing red. The red glow is related to a deficiency in the ALDH2 enzyme, a key component in detoxifying alcohol. When you drink alcohol, the body converts this substance into acetaldehyde. Normally, acetaldehyde is then converted to the safer acetate via ALDH2; however in individuals with asian glow, this enzyme does not function normally and acetaldehyde builds up to toxic quantities. Since acetaldehyde is a cancer-causing agent, its accumulation drastically increases the risk of developing esophageal cancer by six to ten folds.

Conversion of alcohol to acetate is stopped in people with asian glow. This leads to toxic buildup of acetaldehyde. (Created with Notability)

A Glowing Solution…

Matsumura’s team reasoned if a lack of ALDH2 enzyme was the problem, maybe they could simply add it back in.

“We hypothesized that a one-time administration of a […] virus […] expressing the human ALDH2 coding sequence […] would correct the deficiency”

They tested their idea on three strains of mice: mice expressing functional ALDH2, mice lacking any ALDH2, and mice expressing a non-functional version of ALDH2. The latter two simulated the asian flush syndrome seen in humans. After introducing the mice with the ALDH2 gene and feeding them alcohol, the researchers monitored acetaldehyde levels in the blood.

Their hard-work paid off! In the two strains initially deficient for ALDH2 function, acetaldehyde levels and abnormal behavior associated with alcohol consumption lowered to near-normal levels. Furthermore, they found that one dose was enough to confer persistent and long-term protection.

From Mice to Humans: A Complicated Decision

Matsumura’s team emphasize that apart from nutritional supplements, ALDH2 deficiency has no current therapies. Although making the jump from mice to humans will be challenging, they assure the concept of virus-mediated gene therapy presents as an effective therapy. The million-dollar question is whether the risks of the glow outweigh the benefits of reduced alcohol consumption seen in affected individuals. To this Matsumura’s team maintains:

“the overall burden […] on human health, particularly […] cancer, supports […] gene therapy.”

What do you think?

 

-Kenny Lin

 

 

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