Author Archives: bokang hou

Assemble Sugars with the Assistance of a “Secret Weapon”—Enzyme

Posted on March 23, 2020 | Leave a comment

People eat sugar every day, but do you know scientists can make whatever types of sugar they want? A group of researchers led by Dr Stephen Withers from the University of Columbia found an efficient method for creating new sugars. They selected a powerful type of biological catalyst called enzymes, which can assemble certain types of sugar molecules faster and cleaner than other chemical catalysts. This method has potential applications in drug development for diseases such as diabetes and obesity.

Sugars are referred to as a type of molecules that consist of units of hydrocarbons assembled in a long chain. The picture below shows various sugar molecules. Each hexagon represents a sugar unit, and different sugars have different numbers of units. Sugars with only one unit are called monosaccharides. Glucose and fructose are common monosaccharides. Our table sugar has one glucose combined with one fructose and is called disaccharide (of course!). Polysaccharides consist of starch, cellulose, and glycogen (sugar stored in your body). Sugars also exist on the cell surface and act as the receptor for many drug molecules. Therefore, knowing the properties of different sugars and how to synthesize them is an essential topic in modern biology and chemistry.

Figure 1. Sugar in daily life vs. Sugar in chemistry

Despite sugars are important to human, making the desired type of sugar molecules is a tricky problem. The reason is that many sugar units have a unique geometry. To maintain the biological functions of sugars, we also need to keep its original shape. Most of the synthetic chemical methods can assemble the sugar unit in the desired order, but cannot retain the geometry. To solve this problem, Withers and his group decided to use a “secret weapon” in biology—enzymes.

Enzymes are a special type of proteins widely existing in all organisms. They can accelerate the chemical reactions in our body and sustain normal metabolic processes. More importantly, enzymes are highly specific to particular sugar geometry. In other words, they only react with sugars that fit their structures and yield product that also has one specific structure. The type of enzymes accelerates sugar assembly is called glycosynthase, and the type accelerates disassembly is called glycoside hydrolase. Now, using enzymes seem to be promising, but where to find the enzymes we want?

To find the desired enzyme more quickly, scientists used a technique called metagenomics which allows them to sample the genes of millions of microorganisms without the need for individual culture. Instead of directly searching for enzymes that can link the sugar together, the first step is to find enzymes (glycoside hydrolase) which break sugar bond (Surprise!). Researchers used bacteria as factories to produce the enzymes and collect them together. Of course, we want enzyme glycosynthase that LINK sugar bonds. The next step is to reconstruct those enzymes such that they can assemble the sugar correctly. Researchers change the reaction centre of the glycoside hydrolase by muting some of the critical structures. By doing so, some of the glycoside hydrolases betrayed their original duties and started to assemble the sugar unit. Figure 2 shows the overall procedures for the experiment.

Abstract Image

Figure 2. Experimental procedure. Sugars are shown as chair-like hexagons. The aim is to link the sugars to various substrate molecules (shown in different colours).

Eventually, Withers and his group found eight types of enzymes that are specific to the assembly of different sugar molecules, which is almost impossible using traditional methods. As discussed before, sugars construct the receptors for drug and other signal molecules in our body. Understanding how to synthesize sugar will help scientists build new medicines targeted to specific body cells. Diseases such as diabetes and obesity that are related to sugars will also be better understood in the future.

Reference:

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.

https://pubs.acs.org/doi/abs/10.1021/acscatal.8b05179

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Posted in Biological Chemistry, Chemistry News, Organic Chemistry, Popular Science

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Surgery can activate cancer cells, but aspirin stops metastasis

Posted on March 15, 2020 | Leave a comment

When patients are diagnosed with breast cancer, the cancer cells have already metastasized to another part of the body. However, the number of cancer cells involved in this process is negligible, and current equipment cannot detect them. Cancer cells after metastasis remain inactive, which seems unlikely to threaten patients’ health. Nevertheless, those dormant cancer cells are time bombs. One way to set them off, surprisingly, is through cancer surgery.

Recent research led by Dr. Robert Weinberg of the Whitehead Institute found the mechanisms that may explain why surgeries activate the hidden cancer cells. They designed a set of comparison experiments based on mice that injected with breast cancer cells and observed how breast cancer developed in different conditions.

To simulate the postoperative recovery process, scientists implanted sterile sponges in the mice injected with breast cancer cells. This “unnatural” design may be controversial, but it maintains all animals experiencing the same experimental conditions.

“Weinberg gets some pushback because he works on artificial systems, but this is often the only way to expose fundamental principles of biology.” said biologist Sui Huang, professor of the Institute for Systems Biology, who was convinced by this experiment.[1]

Figure 1. (A) Schematic illustrating the experimental design. Mice had been previously wounded by sponge implantation at one or two distant sites. (B) Tumor diameter during the one-month experiment. (C) Tumor incidence as a function of time (n = 9 to 10 per group) for the experimental and control group. Data are plotted as means ± SEM. P values were calculated using the Mann-Whitney test (P < 0.05). Source: Translational Medicine Science

One month after the surgery, researchers tested the number of cancer cells that remained in mice’s bodies. Figure 1 summarizes the results: for those that accepted the surgery, 60% of mice developed tumors in other parts of the body. While in the comparison group, the value is only 15%. Based on the results from 270 mice, Weinberg concluded that surgery could accelerate the cancer cell metastasis and even facilitate tumor formation.

The reason for the effect, as explained in the paper, has to do with the immune system. During the surgical wound recovery process, the inflammatory response restricts the immune system. Therefore, the “guard cells” cannot effectively monitor the cancer cells, resulting in metastasis and tumor formation.

Figure 2. Tumor diameter after the injection of cancer cells into previously unwounded (left) or wounded (right) mice treated with saline or meloxicam (n = 15 mice per group). Data are plotted as means ± SEM. P values were calculated the Mann-Whitney test P < 0.0005. Source: Translational Medicine Science

The good news is common pain killers, such as aspirin, can efficiently inhibit this process. Scientists found that many nonsteroidal anti-inflammatory drugs can effectively suppress tumor formation resulting from surgical wounds. Figure 2 shows that the wounded mice had a constant tumor size at around 2mm after given meloxicam, while the comparison developed tumors at average 5mm. Note the experiment only tested meloxicam; aspirin was also proved to be effective in the follow-up research.

Although the results are quite delightful, whether we can apply the same experiment to humans remains unclear. Weinberg pointed out that the aim of the investigation is not telling people not to trust lumpectomy or other tumor surgeries but develop a more effective treatment for postoperative recovery. He hoped that this research would promote further experiment on human and test whether drugs like aspirin has the same effect in the human body.

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The “AlphaGo” in Chemistry: Organic Retrosynthesis Using Artificial Intelligence

Posted on February 22, 2020 | 6 comments

Since the AlphaGo defeated the world Go champion in 2016, artificial intelligence (AI) has revolutionized many fields in our life. It has also become a new star in science and opened up new possibilities to solve the most complicated problems by computers.

Not long ago, a group of chemists and computer scientists built the “AlphaGo” in chemistry. Published in Nature, they designed an AI tool that can plan organic retrosynthesis faster than any similar programs. In a double-blind AB test, chemists on average considered the AI-generated routes to be equivalent to reported literature routes. This achievement may shorten the process for drug designs and accelerate pharmaceutical research in the future.

Retrosynthetic analysis is the canonical technique used to plan the synthesis of organic molecules. In the past, scientists have also tried to design retrosynthetic routes by computers. Although this method can improve the synthesis efficiency, the traditional algorisms are slow and have many errors.

However, the AI developed by Segler’s group speeds up this process significantly. Described by Segler, the synthesis of molecules is very similar to playing Go: Each molecule can be constructed by synthons which are the “playing pieces”. Computers then design routes for the synthons and combine them together.

Figure 1. Translation of the traditional chemists’ retrosynthetic route representation to the search tree representation. Source: Nature

In the research, the AI tool learned more than 12 million single-step chemical reactions by the deep neural network. This can help AI predict any chemical reactions in the synthetic sequence. AI can also apply the neutral network repeatedly to plan routes and construct synthons until ending up with accessible starting reagents.

So far, much research focuses on combing deep neural networks with Monte Carlo tree search (MCTS). Monte Carlo tree search is a method widely used in video games to evaluate the movement of an object. After the player moving one step in the game, the computer will simulate infinite possibilities that may occur and choose the best step. Similarly, computers can also use this network to find the optimal method in organic synthesis.

In a trial test, Waller’s group used this algorism to propose a six-step synthesis for a precursor used in Alzheimer’s treatment. It turns out the AI designed the same route as the literature in less than 5.4 seconds. 

Figure 2. Comparison between the MCTS and two traditional algorisms: Neural and Heuristic Best First Search (BFS). (A) Performance characteristics of the different search algorithms by finding synthesis routes. (B) Amount of time per molecule to find the optimal route. Adapted from: Nature

More surprisingly, the AI can perform as good as organic chemists in predicting synthetic routes for novel drugs. Segler and his team invited 45 world-leading organic chemists from Germany and China to examine two potential synthetic routes for nine molecules. One route was designed by AI and the other by humans. Results show that chemists cannot distinguish between the two methods. 

Figure 3. Double-blind AB testing of AI route (MCTS) against literature and traditional (BFS) routes. AI route is as preferable as literature routes and much better than traditional methods. (Original)

“What we have seen here is that this kind of artificial intelligence can capture this expert knowledge,” says Pablo Carbonell, a famous computational chemist at the University of Manchester. He describes the effort as “a landmark paper”. Maybe in the near future, AI will make a revolutionary change in chemical research and industry.

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Posted in Organic Chemistry, Popular Science

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Revised: Xenobots: World’s First Living ‘Flesh Robot’ was Created from Frog Cells

Posted on February 8, 2020 | Leave a comment

Scientists have created the world’s first living, self-healing robots using stem cells from frogs.

Published on  PNAS, a team of scientists from the University of Tufts and the University of Vermont created the first living robot named Xenobots without using any metals or plastics.

Those flesh robots constructed from frog cells can manipulate objects, move as directed and even interact with each other. The success of Xenobots promises advances in safe drug delivery, environmental remediation and understanding origins of life.

A New Star in Robotics

“They’re neither a traditional robot nor a known species of animal. It’s a new class of artifact: a living, programmable organism.”

explained by computer scientist Joshua Bongard, a collaborator of this project. Before Xenobots, genetic modifications on a single cell or 3D printing tissues have been attempted to construct living systems. Despite the success in simulating biological structures, those methods cannot predict any behaviors. So the question became how to construct a biological system that ‘knows’ what to behave.

A behavioral goal (e.g., maximize displacement), along with structural building blocks designed by computer. The blue and red regions indicate two types of cells. Source: PNAS

The Birth of Xenbots

Thanks to computer scientists, a method called ‘evolutionary algorism’ has been developed to achieve this goal.

During the robot design process, scientists first input some behavioral goals, for example, maximizing the moving area or leaving a hole in the center to carry drug molecules. The computer would then explore different building blocks with the assistance of evolutionary algorism. There are two types of frog cells for the building block, and by cleverly combining those cells, the robot may move as expected.

Xenobot under the microscope. The diameter is less than 1mm. Source: PNAS

Finally, from thousands of building block combinations, less than ten designs were selected for the experiment in vivo. The robots were manufactured under microscopy through a series of steps and tested in real conditions.

The result is surprising. Those robots can live for weeks in the water environment without additional energy. Once the energy dissipated, the cells die naturally and degrade as common organisms. Although they lack a nervous system, the robots can still change their motion regularly, and different individuals tend to exhibit various moving patterns.

YouTube Preview Image                                             Video from the University of Vermont

Will The Terminator Come True?

The incredible character of the living robot is the ability to self-repair in the face of damage. This feature is reflected in the Terminator, in which robots dominate the world.

Sam Kriegman, the first author of the study, admitted the moral issues brought by this project: the living robot variations may develop cognitive ability in the future. He also pointed out that, because this study is open to the public, society can discuss the topic and regulators should also formulate applicable policies. However, in the short term, this study is more likely to inspire future robotics and help us understand the innate creativity in life.

-Bokang Hou

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Posted in Biological Chemistry, Chemistry News, Popular Science

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Xenobots: World’s First Living ‘Flesh Robot’ was Created from Frog Cells

Posted on January 20, 2020 | Leave a comment

Scientists have created the world’s first living, self-healing robots using stem cells from frogs. Published on  PNAS, a team of scientists from the University of Tufts and the University of Vermont created the first living robot named Xenobots without using any metals or plastics.Those flesh robots constructed from frog cells can manipulate objects, move as directed and even interact with each other. The success of Xenobots promises advances in safe drug delivery, environmental remediation and understanding origins of life.

A New Star in Robotics

“They’re neither a traditional robot nor a known species of animal. It’s a new class of artefact: a living, programmable organism.”

explained by computer scientist Joshua Bongard, a collaborator of this project. Before Xenobots, genetic modifications on a single cell or 3D printing tissues have been attempted to construct living systems. Despite the success in simulating biological structures, those methods cannot predict any behaviors. So the question became how to construct a biological system that ‘knows’ what to behave.

A behavioral goal (e.g., maximize displacement), along with structural building blocks designed by computer. The blue and red regions indicate two types of cells. Source: PNAS

The Birth of Xenbots

Thanks to computer scientists, a method called ‘evolutionary algorism’ has been developed to achieve this goal. During the robot design process, scientists first input some behavioural goals, for example, maximizing the moving area or leaving a hole in the centre to carry drug molecules. The computer would then explore different building blocks with the assistance of evolutionary algorism. There are two types of frog cells for the building block, and by cleverly combining those cells, the robot may move as expected.

Xenobot under the microscope. The diameter is less than 1mm. Source: PNAS

Finally, from thousands of building block combinations, less than ten designs were selected for the experiment in vivo. The robots were manufactured under microscopy through a series of steps and tested in real conditions. The result is surprising. Those robots can live for weeks in the water environment without additional energy. Once the energy dissipated, the cells die naturally and degrade as common organisms. Although they lack a nervous system, the robots can still change their motion regularly, and different individuals tend to exhibit various moving patterns.

YouTube Preview Image                                             Video from the University of Vermont

Will The Terminator Come True?

The incredible character of the living robot is the ability to self-repair in the face of damage. This feature is reflected in the Terminator, in which robots dominate the world.Sam Kriegman, the first author of the study, admitted the moral issues brought by this project: the living robot variations may develop cognitive ability in the future. He also pointed out that, because this study is open to the public, society can discuss the topic and regulators should also formulate applicable policies. However, in the short term, this study is more likely to inspire future robotics and help us understand the innate creativity in life.

-Bokang Hou

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