Chemotherapy is a well-known treatment for cancer, using drugs to destroy cancer cells. However, doctors administrate these anticancer drugs with caution because they are also considered poisonous. After cancer treatments, excess drugs can stay in the human body, causing damage to healthy cells, resulting in unwanted toxic side effects. What if there was something that can absorb these drugs like a portable filter?
Various chemotherapy treatments on the growth of mesenchymal stem cells (MSC). MSC is found in bone marrow cells, that contribute to regenerating bone and muscle tissues. Source
Dr. Steven Hetts from the University of California Berkeley initially thought of an idea, to introduce a sponge-like polymer that can absorb excess chemotherapy drugs. Sponges have immensely grown in popularity in the pharmaceutical field, as the metabolites produced hold biologically active natural products. Approximately 5300 different natural products extracted from sponges have shown pharmaceutical properties, such as anticancer and antibacterial active properties.
Schematic diagram of the developed 3D printed porous absorber. Source
In early 2019, he shared this concept among researchers from other American universities, eventually publishing a paper that describes the development of a porous absorbent polymer. The researchers built the lattice structure using 3D printing that allows the blood to circulate through the bloodstream. In addition, they coated the polymer with a polystyrenesulfonate copolymer, essential for absorbing the chemotherapy drug, doxorubicin.
Doxorubicin: a chemotherapy medication used to treat cancer. Source: Wikimedia Commons
This innovative biomedical device showed great promise, as the polymer efficiently absorbed 64±6% of the drug. Even though this was tested on pigs with healthy livers, the understanding of this device allows researchers to focus on improvements. Lattice size, the type of coating, the thickness of the coating, and the number of absorbers are all possible approaches to a more effective drug sponge.
With this in mind, doctors can potentially administrate higher doses of drugs for more aggressive tumors. In addition, modifications to the drug sponge’s coating can absorb other types of powerful chemotherapy drugs. Although testings on humans are not yet approved by the FDA, the drug sponge is a huge step towards minimizing chemotherapy toxic side effects.
Alzheimer’s disease (AD) is a type of brain disease that causes problems with thinking, memory, and behavior and leads to dementia. AD is frustratingly common among seniors over the age of 65. Approximately there are 5.8 million people in the United States are suffering; by 2050, this number will probably increase to 14 million.
How Alzheimer’s Changes the Brain. Source: https://www.youtube.com/watch?v=0GXv3mHs9AU
Although there is no current cure, an early and accurate diagnosis can help patients to access proper treatments which can slow the worsening of symptoms and improve quality of life for those suffering from AD. However, no single and efficient test can provide a reliable diagnosis. After doctors conduct interviews with patients with possible signs of symptoms, several blood tests and brain imaging are needed to rule out the other brain illnesses and confirm the diagnosis. This process may take several months, and the accuracy is only up to 75 to 85%. Researchers have been working on better and more efficient diagnostic methods. One advanced tool is Positron emission tomography (PET) scans which can detect the hallmark of abnormal protein clusters in brains and afford reliable results. However, these tests can cost thousands of dollars, and most people do not have access and never get tested.
PET scan showing glucose metabolism associated with decreased cognitive function. Source: https://www.sciencedaily.com/releases/2009/07/090714085812.htm
For decades, researchers have been on the quest to develop a blood test for AD for blood testing is the most common and affordable medical diagnostics. The exciting news is that researchers have identified blood-based biomarkers of the disease that can provide fast and accurate measurements. A biomarker is a substance whose detection indicates a particular disease; in the case of AD, the particular substance is a protein called amyloids. One significant pathological signature of AD is the appearance of clumps of abnormal amyloid protein in brains. Those clumps are made of a mixture of peptides which form from the breakdown of the amyloid precursor protein (APP). In 2010, Bateman and his colleagues from Washington University School of Medicine found that the amount of a peptide known as amyloid-b 42 (Ab42) is significantly higher in the in a patient’s blood sample. However, several follow-up studies have suggested that the number of amyloid peptides, including Ab42, increases as people grow old, so the method of detecting Ab42 is proved unhelpful. In recent years, some research shows that the ratio of Ab42 to another peptide Ab40 indicates the significant difference in the diseased brain from a cognitively normal brain. Written in Nature last year, Yanagisawa and his team from the National Center for Geriatrics and Gerontology reported that using the ratio of these two peptides as the biomarker provides highly accurate results.
Figure 1: The clearance rate of amyloid- 40 and 42 peptides of 12 Alzheimer’s disease participants (red triangles) and 12 control (blue circles). The average clearance rate of amyloid-40 and 42 peptides is slower for AD individuals compared with cognitively normal control groups, suggesting the potential usage of these two peptides as biomarkers. Source: https://www.nature.com/articles/nature25456.
Although blood tests are not approved for commercially used yet, most researchers in the field believe that an affordable and accurate blood test for everyone will be commercially available in five years, especially when more proteins, such as neurofilament light polypeptide, are also found to be good candidates for biomarkers.
References:
National Institute on Aging. What Is Alzheimer’s Disease? https://www.nia.nih.gov/health/what-alzheimers-disease (accessed on March 21, 2019)
Alzheimer’s Association. Facts and Figures. https://www.alz.org/alzheimers-dementia/facts-figures
RadiologyInfo.org. Positron Emission Tomography-Computed Tomography. https://www.radiologyinfo.org/en/info.cfm?pg=pet (accessed on March 21, 2019)
Strimubu, K.; Tavel, J. A., Curr. Opin. HIV AIDS.,2010,5, 463-466
O’Brien., R. J.; Wong, P. C., Annu. Rev. Neurosci.2011, 34, 185-204
Amyloid precursor protein, Wikipedia.org, https://en.wikipedia.org/wiki/Amyloid_precursor_protein (accessed on March 21, 2019)
Mawuenyega, K. G.; Sigurdson, W.; Ovod, V.; Munsell, L.; Kasten, T.; Morris, J. C.; Yarasheski, K. E.; Bateman, R. J., Science, 2010, 330, 1774
Arnaud, C. H., Study tests plasma biomarkers for Alzheimer’s. https://cen.acs.org/articles/96/i6/Study-tests-plasma-biomarkers-Alzheimers.html (accessed on March 21, 2019)
Last year, chemical engineer Frances H. Arnold from the California Institute of Technology earned the 2018 Nobel Prize in Chemistry for her pioneering and brilliant work with the directed evolution of enzymes. She became the second female to win the prize in Chemistry.
Figure 1: The flowchart for the directed evolution of enzymes. Source: Advanced Information. NoblePrize.org. https://www.nobelprize.org/prizes/chemistry/2018/advanced-information/
Enzymes are biological catalysts to promote biochemical reactions in living organisms, and different enzymes specialize in different reactions. When the environment changes, genes mutate, and hence enzymes evolve to help an organism develop desired traits and adapt to the new environment. Although natural enzymes are excellent at doing their job, there are limitations: they only make chemicals that organisms need and only function in water at room temperature. These restrictions narrow the application of enzymes in the chemical and pharmaceutical industries. To tackle these problems, Dr. Arnoldhas used the same strategy as nature does-introduce mutations to existing enzymes-and obtained evolved enzymes which can quickly adapt to unusual environments, i.e., organic solvents, and speed up desired reactions. In the early 1990s, she reported the first case using subtilisin E, a digesting enzyme, to make an enzyme with much higher activity. This well-designed enzyme is 256 times more efficient to function the same reactions than the original enzyme in a polar organic solvent. This work has been seen as the benchmark achievement for the field of directed evolution of enzymes.
Figure 2: Reaction rate of hydrolysis of sAAPF-pna by subtilisin E variants in the solution containing 40% (vol/vol) DMF. Data source: Chen, K.; Arnold, F. H., Proc. Natl. Acad. Sci. USA, 1993, 90, 5681-5622
Dr. Arnold and her colleagues have been devoting to developing a variety of enzymes to deal with different synthetic challenges. For example, written in Nature this year, they describe a new iron-based enzymatic system to activate inert C-H bonds, replacing noble-metal catalysts. As the directed evolution proceeds, the system has a higher total turnover number (TTN) which represents how much product can be made until the catalyst is no longer active. Higher TTN means that the system becomes increasingly active as the enzyme evolves. The evolved enzyme CHF exhibits excellent stereoselectivity which is significant in pharmacology as human bodies react differently to enantiomers.
Figure 3: The bar chart represents the mean total turnover number (TTN) values averaged over four reactions; the grey dots show each TTN; green diamonds demonstrate enantioselectivity data. Source: https://www.nature.com/articles/s41586-018-0808-5
Another recent pioneering work done by Arnold group is using a natural enzyme to form C-Si bond which is unknown in nature although Silicon is the most abundant element in Earth’s crust. Silicon has extensive applications in chemistry and material science, including pharmaceutical developments and productions of semiconductors, and preparations of silicon-containing molecules, especially organic compounds, usually require multi-step and unsustainable synthetic routes. This innovative and environmentally friendly method offers new avenues of producing organosilicon compounds and opens up more opportunities in pharmaceutical research. These findings also shine the lights on what silicon-based life might look like, which has long been a fantasy in science fictions!
Figure 4: The active environment of the enzymatic system for C-Si bond formation Source: http://science.sciencemag.org/content/354/6315/1048
Figure 5: Artist rendering of Si-based life form Source: https://media3.s-nbcnews.com/j/newscms/2017_16/1969741/organosilicon-based-life_c18e68cad6b3bf817a28e03558a7bfba.fit-2000w.jpg
As a winner of the Nobel Prize, Dr. Arnold will encourage more people, especially women, to do science, and inspire more research in biocatalysis. As she pointed out in her essay, using well-functionalized enzymes rather than transition metals as catalysts allows for the development of sustainable chemical and pharmaceutical industries, and hence producing many of chemicals with biocatalysts will be the trend in the near future.
Dr. Arnold’s Nobel Lecture: Innovation by Evolution. Source: YouTube
References
Directed evolution, Wikipedia.org, https://en.wikipedia.org/wiki/Directed_evolution (accessed on Feb. 28, 19)
Many small molecules are crucial to life—not only are they used for life-saving drugs, but they also regulate important biological processes within our bodies. In order to understand these small molecules better, scientists have developed various methods to probe what atoms they are made up of, and how these atoms are connected.
Yet one of the newest and most promising of these methods is not so new at all—in fact, it has been a mainstream tool in the field of structural biology for years.
Think about one chemical used in daily life. I guess most non-chemists would say water. Water is the basic necessity of all living organisms on Earth. It has a very simple structure: two hydrogen atoms stick with one oxygen atom, but it took the Universe 1.6 billion years to make the first water molecule and 13.6 billion years to make water on Earth!
Have you ever wondered why water is so vital to life? One of the answers is proteins. Proteins are the MVP in the body; they do almost everything in cells and make sure tissues to grow and organs to function. Proteins can fold into complex 3D structures, and their biological reactivity depends on how they fold. Although the mechanism remains unclear, studies indicate that interaction between protein and surrounding water controls protein folding. For example, using a theoretical protein-solvent model and a statistical physics approach, Oliver Collet from Nancy University in France suggests that the hydrogen bonding formed between water and proteins promotes fast protein folding as it is relatively easy to break and reform hydrogen bonds at a high temperature.
Protein before and after folding. Image taken from Wikimedia Commons. https://upload.wikimedia.org/wikipedia/commons/a/a9/Protein_folding.png
In the Catcher in the Rye, the protagonist, Holden Caulfield, wonders what happens to the ducks and fish in Central Park when the large pond freezes. I don’t know about ducks, but I can tell Holden that fish stay at the bottom of the pond and survive over the winter because of the unique thermal properties of water. Hydrogen bonding pushes molecules further apart when water is frozen, so ice is less dense and floats. Oddly, at 4℃, liquid water expands on heating or cooling and has the highest density. This means that water at the bottom is the warmest and maintains a temperature around 4, allowing fish and other aquatic life to survive. In some extreme low-temperature environment, fish use supercooling to avoid freezing. Supercooling is when water is cooled below -40℃ without freezing, and you can even try at home.
How to make supercooled water at home. Video taken from YouTube
Although water is largely used as a solvent in most reactions, it has been found that water can act as an electron donor for certain biocatalytic reactions, enabling more efficient and greener synthetical routes. Avelino Corma, Frank Hollmann and co-workers report water as the electron donor for biocatalytic redox reactions using enzymes, like oxidoreductases. Despite the requirement of additional energy, activation of water as an electron donor is a common natural process: photosynthesis where visible light provides energy to promote water oxidation, generating oxygen along with electrons and protons. Inspired by nature’s method, the researchers come up with a strategy to accelerate water oxidation using photocatalysts, in this case, metal-doped TiO2.
As water is so common in our daily life, it is often underappreciated. It facilitates not only biological activities but chemical reactions and ensures all creatures to survive even under the harshest conditions on Earth
Reference:
Francl, M., Nature Chemistry, 2016, 8, 897-898
Collet, O., J. Chem. Phys, 2011, 132, 085107
Chaplin, M., Water structure and Science, http://www1.lsbu.ac.uk/water/water_anomalies.html#j (accessed Jan. 20, 19)
