The Blue Vanguard Vol.22

Editor's note

Jimin Seo

Hello readers!

It is my utmost pleasure to introduce the 22th edition of the Blue Vanguard, in which we cover various topics ranging from space medicine to emerging novel drugs to long-awaited campus festivals held, at last, in person. We always hope that the Blue Vanguard will be able to provide valuable knowledge and insight into the ever-morphing industry of pharmaceuticals and healthcare.

One of the more prevalent and obvious of such trends is the melding of technology with medicine and patient care. As we transition into the era of digital healthcare, this is Blue Vanguard’s attempt to explore the various technological applications - including but not limited to nanomedicine, smart devices, drug development platforms - as well as related issues, concerns, and implications through a series of thoroughlyresearched, meticulously-written articles.

Special thanks to professor Jong Hyeok Sung and the International Copper Association for their support - which we hope to reciprocate by aiding their cause to spread awareness on antimicrobial copper and shed light on its potential.

Two of the core responsibilities of a pharmacist, as outlined by the WHO, are being a communicator and a life-long learner. I have no doubt that our Blue Vanguardians have already proved themselves more than competent to excel in such aspects, given their desire to explore the latest pharmaceutical research and willingness to share their acquired knowledge with subscribers. It has been a delight working with everyone.

With that said, I hope you enjoy our 22nd issue. B

Plates to Wearable Nanomesh Antimicrobial Copper

Ancient

Jimin Seo jmdemi@hanmail.net

Antimicrobial Copper From

Even before humanity had a grasp of microbial knowledge, copper was an element that was used as early as ancient Egyptian times as plates and sterilizers for its antimicrobial properties. Recently its effectiveness in combating antimicrobial resistance - a big threat to modern medicine - have been highlighted and studied for various applications.

Antimicrobial resistance (AMR) arises when bacteria develop resistance to antibiotics via adaptation and evolution, rendering them useless when it comes to preventing infections. As this is applied from mild conditions to critical situations such as organ transplant proceudres and chemotherapy, AMR clearly has serious consequences. And it’s only getting harder and harder for the antibiotics pipeline to catch up with the speed at which resistant bacteria are emerging.

One prominent reservoir of bacteria are touch surfaces. Hospitals are particularly prone to sporadic cases and outbreaks of healthcare-associated infections (HAIs), which often originate from contaminated surfaces with bacterial pathogens and are assosciated with significant morbidity and mortality. The problem is that high touch surfaces don’t only facilitate transmission of bacteria from person to person - it also is the perfect environment for genetic material to be transferred between bacterial species in a process called horizontal gene transfer. This signifies that once one strain of bacteria develops resistance, it can be passed to many others to create new resistant strains. Of course, deep cleaning of environments like airports and hospitals can effectively reduce microbial populations, hence infection. But practically there’s a limit to how much cleaning can be done, which calls for the employment of an effective, durable antimicrobial material - copper.

Copper surfaces readily kill bacteria, yeast, and viruses, via a process coined “contact killing”. Its potential use in health care settings have given copper renewed attention. Copper’s killing of microorganisms is observed to take place at a rate of 7~8 logs per hour, and the microorganisms rarely recover after periods of prolonged incubation. The antimicrobial activity of copper and its alloys is well established, and copper is registered in the U.S. Environmental Protection Agency as the first solid antimicrobial material. Copper has been evaluated for use on touch surfaces such as door handles, bed rails, or bathroom fixtures to curb nosocomial infections.

The exact mechanism in which copper causes microbial death is controversial, its relative contribution in different proposed mechanisms unclear. One possible method is the physical interaction of copper nanoparticles (CuNP) with the cell, virus or plasma membrane, leaving the microbe susceptible to external damage from the copper ions and ultimately leading to its destruction. This mechanism is favored by smaller NPs (1~10nm), as they can easily attach to the membrane and infiltrate the cell. Another possible MOA is the generation of reactive oxygen species (ROS). Copper is reduced via a Fentonlike reaction, leading to both enzyme and non-enzyme mediated oxidative damage including lipid peroxidation, DNA damage, and protein oxidation. Lastly, it has also been suggested that the release of copper ions, Cu+ and Cu2+, can damage the cell membrane and induce an oxidative stress response involving endogenous ROS. The conclusion is that copper’s microbial killing is a combination of aforementioned mechanisms, the relative importance of each dependent on the microorganism.

Such properties of copper have been appliedespecially in hospital and healthcare settings - to reduce risks of HAIs, mostly in the form of microfilms. Pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus spp. (VRE), and Clostridium difficile, are able to colonize hospital surfaces and persist there for months in both spores and vegetative form. Routine deep cleaning can remove the majority of existing microorganisms, but are susceptible to recontamination. Thus, an alternative strategy of controlling HAI outbreaks - use of coppercoated surfaces and medical devices - have been suggested and successfully implemented.

After the outbreak of COVID-19, a novel transparent copper film has been developed, taking advantage of copper’s reported antiviral activity against norovirus, influenza virus, and SARS-CoV-2. Due to its additional transparency, this film can be applied more widelyincluding but not limited to face shields, partitions, control panel covers on various medical equipmentwithout imparing vision or disturbing their operation.

To promote more widespread implementation of antimicrobial copper, organizations such as the International Copper Alliance have donated various copper-coated utilities to schools and hospitals, hoping to raise awareness on the material while also helping out during the ongoing pandemic.

This particular nanomesh can stick to human skin and kill microbes almost instantly with minimum modification of intrinsic skin properties (temperature, humidity, interfacial morphology, etc.) while also preventing cross-infection. The thinness of the material along (3 microns) with its porous structure allows for conformal attachment to the fingertips regardless of any structural and mechanical variations of the appendages.

The most recent advancement in antimicrobial copper is the creation of wearable copper nanomesh, published in June of 2022 by a team of researchers from the University of Tokyo, the Korea Research Institute of Bioscience and Biotechnology, and the RIKEN Center for Emergent Matter Science.

The measured rate of microbial inactivation of copper nanomesh against E.coli and influenza virus A (H1N1) were 99.99% within 1 and 10 minutes respectively. The nanomesh structure actually contributed to the acceleration of bacterial inactivation compared to the previous copper film. Additionally, the nanomesh exhibited high biocompatibility with human skin cells and stable antimicrobial performance even after more than 6 hours of usage, including more than 1 hour of water immersion, proving for excellent utilization and application in various environments and situations. The researchers suggest the nanomesh is superior to copper films due to its high potency, given by the mesh’s bigger surface area.

Main applications of the copper nanomesh that the researchers foresee include surface cover for electronic devices such as smartphones and tablets, as the material has been shown not to affect their performance. Not to mention applying the mesh to surfaces that serve as bacteria and virus transfer sites - doorknobs and light switches to mention a couple. Perhaps the mesh can be molded into a coated glove so thin that the user is unaware of its presence, providing the best protection considering so many microbes are transferred via the hands themselves. Although at this stage this would require further optimization of size and density of the nanomesh, the potential of this antimicrobial platform to combat threatening infectious diseases, especially in the light of a global pandemic, is vast and expected to be advanced toward practical use in the near future. B

NATURAL STEROID : GLYCYRRHIZIC ACID

Seoyoung Kim katherina623@naver.com

What is Glycyrrhizic Acid?

Glycyrrhizin or 20-β-carboxy-11-oxo-30-norolean-12-en-3β-yl-2-O-β-d-glucopyranurosyl-α-d-glucopyranosiduronic acid is a triterpenoid glycoside (saponin) with glycyrrhetinic acid. The major constituents are glycyrrhetinic acid, flavonoids, hydroxyl coumarins, and b-sitosterol.

Use of Glycyrrhizic Acid

As a therapeutic agent, the glycyrrhizic acid as been used in a vast variety of formulations as it is reported to be anti-inflammatory, anti-ulcer, anti-allergic, antioxidant, anti-tumor, anti-diabetic and hepatoprotective. Also, it can stimulate endogenous production of interferons. Due to these properties, it has been used in the treatment of premenstrual syndrome, treatment of viral infections, anti-lipidemic and antihyperglycemic. It is also known to be used as a remedy for peptic ulcers, and other stomach diseases.

Mechanism of Action

Glycyrrhizic acid exists as alpha and beta forms. The alpha form is predominant in the liver and duodenum. Thus, it is thought that the alpha form is responsible for the anti-inflammatory liver effect of this drug. Its anti-inflammatory effect is generated via the suppression of TNF alpha and caspase 3. It also inhibits the translocation of NF-kB into the nuclei and conjugates free radicals. Some studies have shown a glycyrrhizicdriven inhibition of CD4+ T cell proliferation via JNK, ERK, and PI3K/AKT. Glycyrrhizic acid also has antiviral activity, which includes the inhibition of viral replication and immune regulation. The antiviral activity of glycyrrhizic acid has a broad spectrum that covers several different viral types such as vaccinia virus, herpes simplex virus, Newcastle disease virus, and vesicular stomatitis virus.

The effect of glycyrrhizic acid on metabolism is thought to be related with its inhibitory activity towards 11-beta-hydroxysteroid dehydrogenase type 1 which in turn decreases the activity of hexose-6-phosphate dehydrogenase. On the other hand, some studies have shown the potential of inducing lipoprotein lipase in non-hepatic tissues to improve dyslipidemic conditions. The glycyrrhizic acid also targets many other proteins in human. It is an antagonist of tumor necrosis factor and caspase-3, and a translocation inhibitor of nuclear factor NF-kappa-B.

When orally administered, glycyrrhizic acid is almost completely hydrolyzed by intestinal bacteria for the formation of glycyrrhetinic acid, which is an active metabolite and can enter systemic circulation, and two molecules of glucuronic acid. This metabolite is transported and taken to the liver for its metabolization to form glucuronide and sulfate conjugates.

Adverse Effect

The most widely reported side effect of glycyrrhizin is the reduction of blood potassium levels. This can affect body fluid balance and the function of nerves. Chronic consumption of black licorice seems to increase blood pressure, cause irregular heart rhythm, and may have adverse interactions with prescription drugs. In extreme cases, death can occur as a result of excess consumption of glycyrrhizin acid.

Glycyrrhizic acid generates an inhibitor of 11-betahydroxysteroid dehydrogenase in the kidney which will increase the cortisol levels in the kidney. Moreover, the intravenous use of the ammoniated form was shown to produce convulsions and hemolysis. Preclinical overdose studies have shown that glycyrrhizic acid may produce excess mineralocorticoids in the body. However, glycyrrhizic acid has been proven not to have mutagenic, genotoxic, teratogenic, or carcinogenic effects. B

NANOMEDICINE

What is Nanomedicine?

Dah Eun Kim kcherry429@yonsei.ac.kr

The greek word “nanos” means a dwarf, so the term nanotechnology translates to “technology to do with small things”. In science, nano also means a billionth. Hence, nanotechnology is science, engineering and technology conducted at the nanoscale.

What if you could swallow a drug that could perform surgery on a DNA or cell-by-cell basis? What if you put a drug in a nano-scale spherical shape and take it easily, and the ingested drug is systematically delivered to the target site in the body? These drugs are nothing new. In 1994, a drug called Docso was approved, which is a lipids OMA formulation of a drug called doxorubicin. A lipids OMA formulation is a form of fat particle which can play a role in catching and delivering drugs. As a new version of this, nanomolecule were developed by researchers at MIT and collaborators in the field of therapy. When administered, nanomolecules can go around the body and circulate under the radar of the immune system, finding diseased tissues and getting into their cells. And once they are in, they release the drug component held inside. It is like a search-and-destroy system, which has the advantage of minimizing the side effects of drugs while targeting diseases aimed at elimination.

Targeting Mechanisms of Nanomedicine

Nanomedicine reaches the target site in two main ways. The first is passive targeting. A phenomenon in which specific target substances are not labeled selectively, but are labeled as differences in the biological and physical environment of the target tissue is usually referred to as “manual targeting”. In general, vascular tissues are formed somewhat loosely near cancer tissues that grow rapidly, and drug support may be greater than general blood vessels. At this time, nanomedicine, which circulates in the body and accumulates near cancer tissues, or penetrates through lymphatic vessels that are not properly connected due to fast growth rate, may not escape again and accumulate near cancer tissues. The phenomenon in which such a material of some size stays near cancer tissue for a long time is called the “Enhanced Permeability and Retention (EPR) effect”, and nanoparticles of less than 200 nanometers are known to be the most efficient. This accumulation effect is not only explained by size, but the degree of passive targeting can be controlled by factors such as the interaction between nanomedicine and tissues or molecules in vivo, half-life of blood circulation, extravation, permeation to lesion tissue, et cetera.

A method of introducing a ligand which binds specifically to the target membrane of a disease causing factor to the surface of nanomedicine is called “active targeting”. One of the advantages of nanomedicine over existing drugs is that it can maintain the properties of drugs while controlling surface chemistry. Breast cancer treatments Herceptin, folate, epidermal growth factor, transferrin, and galactose are used as target-oriented substances related to specific diseases. However, when nanomedicine is exposed to the in vivo environment, it can be non-specifically attached to the surface of the particle forming a ‘corona’. This is a phenomenon in which some of the proteins in plasma are nonspecificly adsorbed on the surface of nanomedicine, which induces the phagocytosis of nanomedicine into phagocytes. Best examples of these adsorbed proteins include opsonin and immunoglobulin. This action can significantly alter the final hydration size, colloidal stability, surface charge, intracellular granularity, circulation period in vivo, and toxicity of nanomedicine. Eventually, even if a marker is bio-bonded to nanomedicine for active labeling, its efficacy in vivo can be hindered by the corona effect. At the same time, it has also been reported that hypersensitivity reactions are rarely induced in some patients due to this corona effect. Therefore, nanomedicine’s targeting has been progressed starting with passive targeting in general and is inching its way towards active targeting.

Nanomedicine’s Research Direction and Challenges in the Future

In order to actually apply nanomedicine to clinical treatment and diagnostic medical use, it is essential to develop an efficient and reproducible method of synthesizing nanomedicine. Most synthesis methods for forming nanoparticles are problematic in that the polydispersity of nanomedicine (which refers to nonuniformity among nanoparticles, mostly size, shape, and surface properties) is very large. The synthesis technology of nanoparticles using various microfluidic substrates is in the spotlight as it is suitable for the synthesis of nanoparticles with narrow size distribution and high reproducibility.

In addition, it is essential to implement a mass production method for nanomedicine, which is about to be commercialized due to its proven efficacy in patients. Simple liposome or polymer-based nanomedicine is relatively less difficult to massproduce. However, nanomedicine that must be synthesized through bioconjugation of labeling factors or synthesize itself through multi-stage reactions is still difficult to mass-produce since the yield of each step is not very high. B

ANOREXIANT

Jiwon Son sonjw119@naver.com

Are you finding yourself becoming fatter and chubbier recently? If so, what would you do to lose weight and regain your past self? There are indeed people who would attempt to achieve healthy weight loss by implementing healthy eating patterns and exercising regularly. But some of them would go for medications. There are different types of weight-loss medication such as carbohydrate blockers, lipolysis inhibitors, awwwwnd metabolism boosters, but the most popular treatments are undoubtedly anorexiants. More and more people in Korea are looking for anorexiants, appetite suppressants, and prescriptions are increasing year by year. What is it exactly and how does it work? Is it safe? Let’s find out.

Hunger and Appetite

Why do we get hungry in the first place? Everything starts from the brain. The brain controls our movement, behavior, thoughts, and even hunger. Since the brain is hardwired to maintain energy homeostasis, it sends signals to our gastrointestinal tract to stimulate the appetite when our body gets low on energy. There are 2 ways for our complex body system to measure the amount of energy in our body.

The first way is by simply recognizing the existence of food in the digestive system. When our stomach is empty, so-called “hunger hormones” such as ghrelin are secreted in the stomach and stimulate food intake. When the stomach is full, GLP-1 and cholecystokinin, which are appetite-suppressing hormones, are released into the digestive system.

The second way is by identifying the amount of energy reserves in our body. Leptin, which acts on the appetiteregulating center of the brain and suppresses appetite, is secreted from the fat cells, and the amount of leptin secreted is proportional to that of the adipose tissue. To sum up, Ghrelin, GLP-l, cholecystokinin, and leptin are all hormones that act on the appetite control center in the hypothalamus that either stimulate or suppress hunger.

Types of Anorexiant

What are anorexiants, exactly? Anorexiants are drugs that suppress appetite by stimulating hypothalamic and limbic regions, which are known to control satiety. Taking anorexiants results in lower food consumption and ultimately weight loss.

Types of anorexiants can be classified into two groups. One is the psychotrpic anorexiant, and the other is the nonpsychotropic anorexiant. Typical examples of each drug group are listed below.

The term “psychotropic” is added to anorexiants like phentermine and phendimetrazine because they act on the central nervous system(CNS) and can do serious harm to our human body when misused or abused.

Psychotropic anorexiant exhibits pharmacological action by increasing the secretion of neurotransmitters such as epinephrine, norepinephrine, or dopamine in the appetite control center in the hypothalamus.

Phentermine, phendimetrazine, diethylpropion, and mazindol act on our brain by regulating the adrenaline receptors; each drug increases the activity of the β-adrenergic receptor, α-adrenergic receptor, and α 1-adrenergic receptor, in order. On the other hand, mazindol suppresses appetite by increasing the concentration of catecholamine neurotransmitters in the synapses by blocking catecholamine reabsorption.

Non-psychotropic anorexiant is considered a safer medication choice. The combination of bupropion and naltrexone inhibits dopamine and noradrenaline reabsorption and activates the appetite-suppressing center, pro-opiomelanocortin (POMC), in the hypothalamus. Naltrexone, an opioid antagonist, is usually added to block the self-suppression of POMC associated with opioid receptors, ultimately strengthening the appetite-suppressing effect of POMC.

Liraglutide is an anorexiant that was previously approved and used as a treatment for diabetes, which is more known by its product name Saxenda. It is the world’s first glucagon-like peptide-1(GLP-1) analog obesity treatment. Although its mechanism of action has not been identified yet, GLP-1 is assumed to act on the GLP-1 receptor in the hypothalamus decreasing gastrointestinal motility and increasing satiety. Since its launch in Korea in 2018, it has ranked first in the obesity treatment market for the past three years.

Safe Use Guideline for Psychotropic Anorexiants

The Ministry of Food and Drug Safety designates and manages psychotropic drugs that may develop dependence or resistance, and has drawn up a safe use guideline for psychotropic anorexigenic drugs. The following covers the key points of the guideline.

<Safe Use Guideline>

1. CNS-stimulating anorexigenic drugs should be used for obesity treatment purposes.

2. The possibility of abuse and dependence should always be kept in mind when using and prescribing CNS-stimulating anorexigenic drugs.

3. “Phentermine, phendimetrazine, diethylpropion, and mazindol” must be prescribed for a short period, within four weeks of the permitted dose, and should be used within a maximum of three months.

4. CNS-stimulating anorexigenic drugs should not be used in combination with other CNS-stimulating anorexigenic drugs.

5. Children and adolescents should not be using CNS-stimulating anorexigenic drugs should.

Prescription Status of Anorexiants and Related Policies

Prescription of psychotropic anorexiants should be controlled with extra care because they can cause some serious issues when abused. To prevent drug abuse and dependence, the Ministry of Food and Drug Safety has implemented the ‘voluntary reporting system’ and the ‘pre-notification system’.

The pre-alarm system, first implemented in 2020, analyzes data reported as an integrated drug management system and informs doctors suspected of prescribing and administering drugs outside of safety standards. The voluntary reporting system is a system that requires doctors to report drugs in advance when they inevitably violate the safety standards.

Although the causal relationship has not been demonstrated, the total number of users has decreased slightly from 1.33 million to 1.27 million since the implementation of the pre-alarm system. Furthermore, while the number of patients prescribed over three months and the number of patients prescribed by two or more medical institutions have not shown noticeable change, the ratio of the number of patients prescribed and the number of patients by combination period decreased to one-tenth.

The number of abuse cases has indeed decreased thanks to the implementation of the systems above; however, appetite suppressants are still indiscriminately prescribed, and this remains a task to be solved in the future. B

METABOLIC ANTICANCER DRUG – Starving Cancer Cells

Nam Kyu Oh dhskarb1997@gmail.com

An Effort to Conquer Cancer

A variety of anticancer drugs have been developed so far to conquer cancer. Although chemotherapy (1st generation), targeted therapy (2nd generation), and immunotherapy (3rd generation) for cancers have been developed, it remains a human task to completely conquer cancer due to their adverse drug effects (chemotherapy), resistance (targeted therapy), and narrow coverage (immunotherapy). Recently, metabolic anticancer drugs, the 4th generation anticancer drugs, are expected to solve these problems. The Metabolic anticancer drug induces energy deficiency in cancer cells by blocking metabolic pathways that nourish them. In other words, it is a drug that starves cancer cells to death.

2 The Energy Metabolism

of Cancer Cells

Cancer cells multiply rapidly and require more oxygen and energy sources in the process. In order to overcome the environment that lacks oxygen and glucose, cancer cells have several metabolisms different from normal cells. In the presence of oxygen, normal cells produce ATP through oxidative phosphorylation carried out in mitochondria. In contrast, cancer cells use glycolysis producing lactic acid as their main energy metabolism rather than energy-efficient oxidative phosphorylation even in an environment where oxygen is present. This characteristic of the cancer cell metabolism is called the Warburg effect. Although the detailed mechanisms of the metabolic anticancer drugs currently being developed are all different, they generally target a specific process of this ‘aerobic glycolysis’ in mitochondria.

3 Various Mechanisms of Metabolic Anticancer Drugs

R&D for metabolic anticancer drugs is also actively underway by some bio companies in Korea. Among them, here are some mechanisms of metabolic anticancer drugs being developed by several well-known companies.

1) Starvanip (NYH817100)

Haim Bio, a domestic bio company, is developing a metabolic anticancer drug called Starvanip. Starvanip is a drug administered in combination with NYH817G (Aldehyde dehydrogenase inhibitor) and NYH100P (mitochondria complex 1 inhibitor). In some cancer cells, aldehyde dehydrogenase (ALDH) is overexpressed in mitochondria, which enables the new drug to inhibit the production of NADH produced by ALDH. Because NADH plays an important role in ATP production through the formation of hydrogen concentration gradient in the mitochondrial electron transport system, inhibition of ALDH specifically inhibits ATP production in cancer cells.

2) KAT-101 (3-Bromopyruvate)

NewG Lab Pharma, another domestic bio company, is developing a metabolic anticancer drug called KAT-101 (3-Bromopyruvate). Cancer cells produce ATP through anaerobic metabolism even in an environment where oxygen is present, so lactic acid accumulates in the cells. Since it causes changes in pH of the cells, the monocarboxylate transporters (MCTs), the lactic acid channels, are opened to release lactic acid out of the cells. KAT is an analog of lactic acid, allowing it to enter the cell through this channel. In cells, KAT binds to mutated HK2 (overexpressed in cancer cells), lactate dehydrogenase (LDH), and ATPase, inhibiting ATP production of cancer cells.

3) Glutamine metabolism in mitochondria

Cancer cells use glutamine as their main energy source. Glutamine works in mitochondria, but it had been unknown how glutamine is transported into the mitochondria of cancer cells. In 2020, a Yonsei University research team, led by professor Han Jeongmin, found a transporter that delivers glutamine to the mitochondria. This transporter is a gene variant produced by a gene SLC1A5, and it has been revealed that the gene expression is increased by a specific transcription factor (HIF-2 α) in a low-oxygen environment. Thanks to this study, the mitochondrial glutamine metabolism that appears specifically in cancer cells has been more clearly revealed. Furthermore, it is expected to be used as an important target of anticancer drug for glutamine-dependent cancer cells.

Future of Anticancer Drugs

These new anticancer drugs being developed by Korean bio companies are currently undergoing clinical trials. Starvanip (by Haim Bio) has successfully completed phase 1 clinical trials at Severance hospital and is preparing to apply for IND of phase 2 clinical trials. KAT-101 (by NewG Lab Pharma) has been approved for IND of phase 1 and 2a clinical trials by both MFDS and FDA, starting clinical trials in earnest. As R&D of metabolic anticancer drugs are actively underway, it can be expected that first-in-class anticancer drugs will be developed in Korea. However, it is too early to expect. The mechanism of metabolic anticancer drugs is very persuasive and attractive in theory, but the actual human metabolism is much more complex than the laboratory settings. So, it is difficult to be sure of the success of metabolic anticancer drugs until they are proven to be effective through the results of clinical trials. Nevertheless, we hope that these new attempts to help many patients suffering from cancer will allow us to take a step closer to the dream of Conquest of cancer by mankind. B

IMUUNOSUPPRESSANT FREE FUTURES FOR ORGAN TRANSPLANT PATIENTS

Daeun Choi daeundownchoi@naver.com

Although organ transplantation can be challenging, it is frequently the best or the only treatment for end stage organ failure. Organ transplant surgery in Korea began on March 25, 1696, in Seoul St. Mary’s hospital. At that time, Korea’s medical technology was very poor, since removing one’s organ and transplanting it to another patient was a historic challenge. In 1972, immunosuppressants were developed and produced in Switzerland. These immunosuppressants drastically reduced organ transplant rejections in patients. With immunosuppressants and the development of medical technology, the number of organ transplant casess in Korea tripled from 1,370 per year in 2001 to 4,116 in 2018. Amongst them, the number of liver transplants quadrupled from 364 in 2002 to 1,482 in 2017.

Survival rates after organ transplants have also improved significantly. In the case of liver transplants, the 5-year survival rate of liver cancer patients has increased from 30-40% in the early 1990s to 70-80% thesedays. The 10-year survival rate of kidney transplants has also risen from 25% in the 1970s to 92% since the 2010s.

However, after organ transplantation, patients must consume immunosuppressants for the rest of their lives. Our immune system plays an important role in defending our body from external foreign substances. After organ transplantation, the transplanted organ is recognized as an external foreign substance and our immune system rejects it by attacking it. Thus, patients take immunosuppressants to prevent organ rejections and to ensure that the transplanted organ functions well.

To optimize post-transplantation care, a combination of two or three different immunosuppressants that act on different mechanisms is being used simultaneously. This can block various immune processes that cannot be stopped by the usage of only one drug, reduce side effects, and increase effectiveness of the drug by reducing the dose of each drug. A combination of one of the calcineurin inhibitor drugs (cyclosporine, tacrolimus), mycophenolic acid, and steroids is widely used. However, the side effects of the immunosuppressants are quite severe. Side effects include vomiting, gastrointestinal disorders, and hair loss. Thus, countries around the world are eager to develop new organ transplant technologies that do not require immunosuppressants.

immuno-suppressant organpatientstransplant

In a new study, scientists created a long-term chimerism treatment protocol in kidney recipients. 8 patients had pre-surgical treatment with chemotherapy and radiation to knock down their own immune systems. A day after the transplant surgery, they received infusions of a complex cellular cocktail derived from the donor’s bone marrow. The mixture included not only blood-forming stem cells, but also the rare “graft-facilitating” cells. These cells, first isolated nearly 20 years ago, are thought to help foreign stem cells get established in recipient’s bone marrow. The researchers also removed donor immune cells that are likely to attack the transplant recipient’s own body. One month after the transplantation, all 8 patients had a variety of immune cells derived from the kidney donor in their bloodstream. Within a year, 5 of the 8 patients had achieved a long-lasting chimerism, with the donated immune cells eventually crowding out the recipient’s own immune cells. By then, these patients had stopped taking immunosuppressant drugs, and their transplanted organs continued to thrive. None of the patients showed signs of graft-versus-host disease.

In 2019, Professor Park Jae-beom and Professor Lee Kyo-won of Samsung Medical Center’s Organ Transplant Center also announced the results of kidney transplantation based on the previous chimerism protocol in 8 adult patients with chronic renal failure with mismatched main tissue complexes from December 2011 to December 2018. According to the research team, 5 out of 8 patients successfully stopped taking immunosuppressants, and 4 of them have been maintaining healthy transplanted kidneys without taking immunosuppressants for up to 55 months.

The results from these new protocols may have a major impact on the future of organ transplantation. With the refinement of this treatment, recipients may eventually stop taking harsh immune-suppressing medications, even after they had received mismatched organs. These preliminary findings may one day reduce the need for anti-rejection drugs and lead to more options for patients awaiting organ transplants. B

PARKINSON’S DISEASE MEDICATIONS

What is Parkinson’s Disease?

HyunJin Lee jennyhyunjinlee@gmail.com

What is Parkinson’s Disease?

Parkinson’s Disease(PD) is a long-term degenerative brain disorder that causes unintended or uncontrollable movements, such as stiffness, shaking, and difficulty with balance and coordination. It occurs when central nerve cells are damaged in the substantia nigra that secretes dopamine, and it worsens as you get older. Additionally, PD has a pathological characteristic that α-synuclein accumulates abnormally in the nervous system, resulting in excessive protein aggregates. Moreover, Alzheimer’s and Parkinson’s Disease can be thought of as the same disease since they both cause dementia, but each has different causes and symptoms. Alzheimer’s destroys nerve cells in the brain area, which are important for maintaining intellectual ability, while Parkinson’s Disease destroys the substantia nigra that are involved in the body’s sophisticated movement, reducing stride, or being speechless.

The main symptoms of Parkinson’s Disease are tremors at rest, bradykinesia/hypokinesia, rigidity, and postural instability. In addition, some symptoms are not related to motor function, such as urination disorders, constipation, and hypotension. There are also sensory abnormalities that cause pain in the waist, limbs, and neck muscles; and ‘mental dysfunction’ that slows down the speed of thinking and frequently accompanies depression and anxiety. Lastly, there are also symptoms related to the administration of therapeutic drugs including abnormal motility, motor fluctuation, cognitive and behavioral disorders, and standing hypotension.

Parkinson’s Disease Risk Factors and Causes

There are only a few factors that have the epidemiological evidence and the biological plausibility to be considered risky (pesticides, dairy products, β2-adrenoreceptor antagonists) or protective (smoking, caffeine intake, physical activity, gout, vitamin E intake, non-steroidal anti-inflammatory drugs and β2-adrenoreceptor antagonists) factors for PD. Possible modifiable risk factors of PD might depend on the uncertain biological and neuropathological reliability of clinical subtypes. However, advancing age, genetics, and environmental causes could be risk factors. It may be possible to target some of these factors for preventive interventions aimed at reducing the risk of developing and the rate of progression of PD.

There is no one definitive cause of PD, and is unknown yet, with both inherited and environmental factors believed to play a role. Also, there is no clear understanding of the reason why the nerve cell of substantia nigra degeneration occurs, and there is no way to treat the underlying cause. The term “idiopathic” is used when the cause of this apparent outbreak is unknown, and most PD corresponds to idiopathic PD.

Pathological sign in patients with PD is the agglutination of α-synuclein in Lewy bodies found in brain lesions. α-synuclein is an atypical protein, which aggregates to form lysosomes, and builds up mainly in black cells in the brain stem. The agglomeration of abnormal α-synuclein is associated with PD, and it is not yet clear what process the accumulation of agglomerates is in the progression of PD. However, many studies have shown that mutation and overexpression of α-synuclein are associated with PD, and α-synuclein aggregation across the brain is associated with various degenerative neurological diseases. α-synuclein must be removed from lysosomes when it becomes unnecessary, and mutations in α-synuclein proteins not only block the lysosomal proteolysis process but also prevent the breakdown of other proteins that need to be removed. As a result, neurons die, leading to neurodegenerative diseases. The association between PD and genetic variation lies in the SNCA gene expressing α-synuclein, and the SNCA gene overlap increases the amount of α-synuclein protein expressed in the body, resulting in PD. Additionally, a recent study has been published that α-synuclein secreted from the intestinal nervous system forms a cohesive nucleus and is transferred to the brain causing PD. These studies lead to the conclusion of removing α-synuclein or disabling agglomerate activity as ways to treat α-synuclein disorders, including PD.

What are Treatments for Parkinson’s Disease?

Types of PD treatments currently in place are largely medication and surgical treatment. Medication includes standard therapy with levodopa, a precursor of dopamine. This levodopa formulation has the disadvantage of disappearing the effect of relieving symptoms during long-term treatment, so dopamine antagonists have been attracting attention as an early treatment of PD since the 2000s. In addition, there are anti-choline drugs and NDMA antagonists that balance dopamine by lowering the concentration of acetylcholine, such as MaoB inhibitors that suppress dopamine concentrations to maintain dopamine concentrations and Comt inhibitors that increase levodopa’s action. Surgical treatments include local surgery, deep brain stimulation, and gene therapy. These treatments are currently focused on “symptom relief”, and there are no treatments that change the progress of the disease, or fundamental treatments yet. Therefore, research on the development of various treatments is being actively conducted to solve this problem, and it is essential to know some trends in the development of treatments for PD.

Trends and Future Development of Parkinson’s Disease

First, treatment for PD based on the α-synuclein mechanism is being developed. The function of α-synuclein is not yet clear, but it plays an important role in the intercellular signaling process. PD shows an increase in flexible α-synuclein and a symmetrical decrease in substantia nigra in normal aging. Also, genetic defects, chromosomal mutations, and pathological conditions cause pathological or disease conditions by increasing α-synuclein. Thus, a decrease in α-synuclein at the cellular level is the potential to lead to the development of a treatment for PD. In fact, the treatment of PD through the α-synuclein mechanism is being developed in 5 directions: 1) decreasing the overall number of α-synuclein, 2) inhibiting the variation or agglomeration of α-synuclein or controlling the formation of Lewy body, 3) eliminating intracellular α-synuclein, 4) eliminating extracellular α-synuclein, and 5) inhibiting intercellular metastasis. By 2020, there are 21 clinical trials of α-synuclein related to PD treatment. However, the most urgent matter is the development of a biomarker that can objectively measure the level of α-synuclein since no biomarker can objectively image or analyze α-synuclein in the before and after evaluation of the treatment. If these objective markers are developed, they could change the future of PD treatment development.

In addition to this, there is a clinical trend of ‘stem cell treatment’ for PD. Currently, there are a total of 12 clinical studies related to PD using stem cells, and as of March 25, 2022, most clinical studies are in phase 1 and 2, and phase 3 is being conducted in only one case. Most researchers use mesenchymal stem cells that are relatively free from safety issues, but there is no commercialized stem cell treatment for PD. If technological advances in improving in vitro/in vivo differentiation efficiency of dopamine-activated cells, checking cell function accurately, improving cell survival after transplantation, and ensuring the safety of transplanted cells, it is undeniable that stem cell-based technology is emerging as a new treatment for PD soon.

Furthermore, there is a recent study that shows that diabetes drugs currently in use can be reborn as a treatment for PD. Studies have shown that DPP-4 inhibitors not only prevent nerve cell loss in PD but also indirectly confirm that they have nerve protection effects. Although research is underway around the world on drugs that suppress the progression of PD, DPP-4 inhibitors are expected to play an important role in inhibiting the progression of PD.

Lastly, ‘nanobody’, which is the smallest unit of antibodies that has the binding ability and is very stable, is called the hope of treating PD. α-synuclein is mainly deposited in cells, so nanobodies that are smaller and easier to penetrate cells are more effective than relatively large antibodies. Moreover, the researchers removed the disulfide bonds of the nanobody and genetically modified them to facilitate penetration of brain cells, maintain stability within cells, and enable binding to α-synuclein. PFFNB2, which is a type of nanobody, has the advantage that it binds only to α-synuclein that causes PD symptoms. As a result, PFFNB2 bound to the α-synuclein complex in mouse brain tissue and inhibited complex formation. Therefore, the researchers believed that PFFNB2-based drugs will be potential treatments for α-synuclein-related diseases. As such, research is constantly being conducted to develop a fundamental treatment for PD. B

MONKEYPOX

Jungeun Kim zoekim2000@naver.com

Afew monkeypox virus (MPV) cases were reported in Europe earlier this year, and now it has been classified as an international public health emergency by the World Health Organization (WHO). Having experienced COVID-19 for the past two and a half years, we are naturally anxious about where the monkeypox outbreak will lead to.

What is Monkeypox?

Monkeypox, an enveloped double-strand DNA virus, is a viral zoonosis with symptoms similar to those of smallpox patients. It is a member of the Orthopoxvirus genus in the family Poxviridae, and was first discovered in 1958 when two outbreaks of a pox-like disease occurred in monkey colonies used for research. Regardless of its name, the source of the disease still remains unknown.

What are the Symptoms?

Major symptoms include fever, headaches, muscle aches, swollen lymph nodes, exhaustion, chills, and a painful rash. A rash may appear on the genitals, face, chest, hands, feet, or any other part of the body. These symptoms usually last from 2 to 4 weeks. The interval from infection to the onset of symptoms is usually from 6 to 13 days. The infection can be divided into 2 periods: the invasion period where symptoms appear, and the skin eruption period where rashes become severe. Severe cases can occur in children and people with underlying immune deficiencies. Complications of monkeypox include secondary infections, bronchopneumonia, sepsis, encephalitis, and infection of the cornea resulting in loss of vision. Monkeypox might not seem that horrible compared to smallpox, which at its worst killed roughly one out of every three affected people. However, without medical treatment or vaccination, one in ten people infected with monkeypox are at risk of fatal complications. In several observational studies, vaccination for smallpox was shown to be 85% effective in preventing monkeypox.

How Does Monkeypox Spread?

Since monkeypox is a zoonotic virus, transmission occurs through an animal-to-human route and a human-to-human route. Human-to-human transmission can also occur from close contact with one’s respiratory secretions, their skin lesions, or recently contaminated objects. The first human case of monkeypox was in 1970. Before 2022, monkeypox had been reported in several central and western African countries. Before the recent outbreak, monkeypox cases were all linked to international travel to African countries. However, recent cases have shown people who had not been to those countries. There has been a fierce debate over the spread of monkeypox through sex. Because a lot of recent cases involved young men who self-identify themselves as having sex with men, experts are currently arguing over whether or not to classify monkeypox as a sexually transmitted infection.

Can We Treat It?

Monkeypox virus infection does not yet have an approved treatment. However, there are three antivirals used to treat smallpox and conditions related to monkeypox. These three antivirals are TPOXX(Tecovirimat), Tembexa(Brincidofovir), and Vistide(Cidofovir). Also, intravenous vaccination immune globulin is licensed for the treatment of complications from smallpox vaccination and monkeypox. TPOXX is an investigational drug, that has not yet been approved by the FDA to treat monkeypox. Research on these drugs is currently ongoing to verify their safety and effectiveness.

Will It be the New Pandemic?

On July 23rd, 2022, the WHO officially announced the outbreak of monkeypox to be a global health emergency of international concern. More than 16000 cases across 74 countries had been reported as of the announcement. The WHO is still coming to a consensus on whether the highest level of caution is required for monkeypox. Many experts have agreed that in comparison to COVID-19, monkeypox is not expected to cause drastic changes in daily life like a pandemic. The virus could remain endemic in a few countries since monkeypox is not a new virus and it spreads mainly through close contact. One big difference between monkeypox and COVID-19 is that monkeypox spreads much less effectively. Unlike COVID, monkeypox cannot aerosolize into the air and remain in the air for hours and days. Also, to be infected with monkeypox, a high dose is required. On the other hand, some experts claim that it may be the next pandemic, but different than COVID. Cases in several countries, especially the US, are rapidly increasing. Since monkeypox is currently affecting a specific risk group that involves intimate contact, it has a possibility of becoming a pandemic but rather a ‘nicer’ pandemic than COVID. B

SPACE MEDICINE

Seung Yeon Noh rsy9901@yonsei.ac.kr

Space medicine is a field of aerospace which studies new surroundings that humans will go through in space to maintain human performance in extreme conditions. It makes investigations on medical problems by minimizing human body change in weightlessness or by developing innovative medical technologies. In other words, the study on space medicine is conducted in two aspects. One is a study on medical problems that can occur in human body when exposed to space, and the other is a study on the application technology in medical devices and pharmaceuticals such as protein drugs and cell therapy drugs using space environment. The aerospace industry which we are very aware of is a branch that develops projectile technologies such as engines or satellites, but spacedeveloped countries are already paying attention to space medicine beyond these traditional space industries. To be honest, you might think this field of space medicine may sound irrelevant to most people except astronauts. However, experts believe that whatever studied in space medicine will be of great help to humanity on the ground.

Physical Changes in Space

Physical changes resulting from space exposure are mostly due to microgravity and space radiation, causing diseases in musculoskeletal system, vascular circulation system, brain nervous system, sensory nervous system, and endocrine system. When entering microgravity, blood and other fluids are no longer pulled down, which leads to the redistribution of fluid toward the head, causing the altered responses of baroreceptors, endocrine, and nervous systems. In terms of musculoskeletal system, microgravity induces the uncoupling of bone transformation between resorption and formation resulting in bone demineralization and muscle atrophy. Some studies suggested that the cause of bone loss may be due to the impairment of vitamin D production rather than the imbalance of hormones. Also, muscles lose both strength and mass as they are anti-gravity muscles, whose main function is to maintain our body upright in the gravitational environment.

Utilization of Space Medicine

Techshot along with NASA succeeded in building heart muscles using 3D printer on the International Space Station. Though technology for making tissues with 3D printers is being actively studied on the ground, cells are spread flat on earth due to strong gravity, making it difficult for the tissue to grow from top to bottom and from side to side. As the space station rotates around the Earth at a high speed, the tissue is well layered in a weightless state which makes three-dimensional culture through 3D printer possible. As such, cells can grow much faster in outer space, away from the constraints of gravity, revolutionizing medicine that replaces or regenerates human cells, tissues, and organs. Additionally, several multinational pharmaceutical companies have also embarked on space medicine research. Merck managed to manufacture the immuno-oncology ‘Keytruda’ on the International Space Station. Due to weightlessness, the lumps do not sink to the floor making the drug more homogeneous which increases the purity and medicinal effects of the drug.

Aside from these, many countries are now preparing to enter space station experiments. China is planning research using its own space station, Tiangong, and India and Russia are also preparing for the space station. Israel is developing a technology to use Cube satellites to conduct space medicine experiments in a weightless environment without having to go to the space station. This is a method of installing medical experiment equipment in a cube satellite and performing experiments by remote control after launching it.

Current State of Korea

Inha University's Aerospace Research Institute is the first private medical institution to establish a research foundation for space medicine in 2018. Research is largely conducted in three parts: the equilibrium system, the cardiovascular system, and the immune metabolism system. In the equilibrium part, they study alterations in the nervous system that recognizes the surrounding space, and in the cardiovascular part, they conduct research on the way to respond to cardiovascular changes that can be caused by space radiation and zero gravity. Lastly in the immune metabolism part, they study how immunological competence changes in high gravity in order to deal with a weightless environment.

As the support of the government is essential for the development of space medicine, in early 2022, the Ministry of Health and Welfare and the Korea Centers for Disease Control and Prevention proposed a project to build a space medicine research platform by investing 45.6 billion won over five years from 2023 to 2027. However, it is pointed out that there is no content related to space medicine in the Health and Medical Technology Promotion Act and Space Development Promotion Act, which could become a half-way race focusing only on the machinery sector. Therefore, national investment is needed in the mid-to-long-term roadmap to raise the level of domestic R&D and infrastructure for international joint research.

Prospects

Space medicine, a sort of special environmental medicine, can expand the scope of research to the space environment and yield new results. This field of medicine can prevent or treat diseases provoked by changes in the musculoskeletal system, vascular circulation system, brain nervous system, sensory nervous system, and endocrine system owing to the exposure to the space environment in manned space activities. In addition, through compound library screening, it is possible to bring about a group of drug candidates that can have therapeutic effects, which control the expression of genes related to exposure to noxious stimuli in the space environment. This makes it possible to evaluate the development potential of a new drug through in vivo preclinical verification of candidates, contributing to the research on drug application technology. B

LIQUID BIOPSY The Future of Cancer Treatment

Kyubin Kim kkb5252@naver.com

Humanity has suffered from cancer for a long time. Many patients with advanced-stage cancer often result in poor survival outcomes. To improve the prognosis of cancer, researchers have been taking great efforts to detect cancer sooner in a minimally invasive way and liquid biopsy has emerged as the key. In recent years, the analysis of cancers using specific biomarkerssuch as circulating DNA from cancer - has gained remarkable attention. These biomarkers derived from tumors have more potential to provide information for malignancy than a tissue biopsy, which is a traditional method to diagnose cancer that has the tissue taken from the body.

The term ‘liquid biopsies’ refers to specific biomarkers found in body fluids that provide information on the patient’s malignancy. The two main derivatives of liquid biopsy include circulating tumor DNA(ctDNA) and circulating tumor cells(CTCs). Extracellular exosomes and vesicles can also be used as biomarkers. As cells die within the body, DNA fragments are released into the blood. If a patient has cancer, the blood contains not only normal DNA but also DNA from tumor cells, which are ctDNA. ctDNA is known to be originated from apoptosis and necrosis of cancer cells. CTCs are cells detached from either the primary tumor or the sites of metastasis. These cells represent the existence of malignancy and are more easily obtainable than the original cancer tissue. Liquid biopsy is a test that uses ctDNA and CTCs in the field of cancer diagnosis and prognosis, which has great therapeutic potential.

What is a Liquid Biopsy? Technological Method for Liquid Biopsy

The current state of liquid biopsy technology is simple. Blood tests are done and analyzed. Specific proteins such as prostate-specific antigen(PSA) and carcinoembryonic antigen(CEA) from blood suggest malignancy. However, these tests have high falsepositive rates since it prioritizes sensitivity to detect the proteins, which leads researchers to come up with additional methods such as next-generation sequencing to overcome the shortcomings. Nextgeneration sequencing(NGS) is a technology used to determine DNA/RNA sequences and analyze any genetic variations that are associated with specific diseases.

Unlike the traditional Sanger sequencing methods which analyze a single DNA strand one at a time, NGS enabled the sequencing of thousands of genes in multiple samples at once. NGS enables the detection of ctDNA and CTCs – even in low abundance – with a high degree of both sensitivity and specificity. NGS covers a wide range of mutations and can easily identify tumor-derived alterations.

Therapeutic Significance of Liquid Biopsy

A Liquid biopsy is a powerful tool when it comes to every aspect of immunotherapy. It is used not only for cancer screening and early diagnosis, but also used to make treatment decisions and monitor treatment responses. Furthermore, liquid biopsy technology can help to prevent relapse.

The 5-year relative survival for pancreatic cancer is 10%. This is due to late diagnosis since more than half of pancreatic cancer patients are diagnosed in the state of distant metastasis, after cancer spreads to other organs such as the liver or lungs. To change the outcome of the survival rate of such cancer, we need to diagnose earlier, when the tumor is regional or localized. The reason why early diagnosis is difficult is that the malignant tissue is inaccessible at the early stages. But by looking at ctDNA or CTCs, there is no need to access the original tissue; all we need is the DNA or cell derived from the tissue, which makes diagnosis much easier.

The Liquid biopsy also increases the accessibility of testing. Traditional methods such as solid tumor biopsy, which is a method of detecting tumors by invasively getting a sample of the tumor tissue can be difficult to carry out and may have severe side effects. Liquid biopsy is very much less invasive than solid tumor biopsy and it may reduce the burden on patients. Additionally, liquid biopsy is a very much effective tool when it comes to cancers with tumors that are difficult to access, such as tumors in the brain or lungs.

Liquid biopsy is used not only for diagnosing a tumor but also used to find the most suitable and effective treatment for an individual. A liquid biopsy can be used to easily determine whether the tumor responds to a particular therapy, and it may also help to monitor response and relapse. The decrease of ctDNAs to undetectable levels indicates that the current treatment is successful and increased biomarkers in the bloodstream imply crucial things regarding therapy such as the tumor has developed mutations.

Conclusion

There are still remaining challenges, including finding methods to detect mutations that are in low frequency and diagnosing cancer at an early stage when there are extremely low levels of ctDNAs or CTCs. Detecting single mutations in early-stage patients is tremendously demanding. Lack of standardization is another problem, allowing only a few preclinical and clinical trials so far. Nevertheless, it is clear that liquid biopsy technologies have great clinical potential. It may be the key to early diagnosis and individualized patient treatment, which are crucial to reducing the morbidity rate of cancer. More research, investment, and trials will be needed, and hopefully we may soon find liquid biopsy used worldwide, becoming the key to cancer treatment. B

NEXT GENERATION nEW DRUG dEVELOPMENT PLATFORM

JinYoo Park truthfree@yonsei.ac.kr

How is life structured, and how does it works? Organisms are made up of cells, which are the basic structural and functional units. Among them, humans are made up of 30 to 40 trillion cells. Cells work through the interaction of numerous molecules. Protein, one of the substances that play a crucial role in cells, is estimated to be 500,000 to 3 million per cell. When several proteins aggregate and interact, properties that do not appear when only one protein is present appear. This characteristic is called emergence. Emergence in living things produces surprising results. One of the results is the vast signaling system inside the cell. If we look at emergence from a reductionist point of view, the result of emergence is ultimately revealed by the elements constituting the system and the interaction between the components. In other words, if we know the features that make up a cell and can calculate the interactions, we can predict the behavior of the cell. This possibility is a very interesting topic for the pharmaceutical world. This is because if the appropriate elements and interaction logic are discovered for a cell, what will happen when a drug is put into the cell can be predicted. The question of whether this is feasible has been resolved by the rapid growth of computer science.

Cell Simulation Status

It seems that the era of realizing cells in the virtual space of a computer and simulating the reaction when administering drugs is not far away. Scientists at the University of Illinois at Urbana-Champaign have created a 3D simulation in virtual computer space based on physicochemical interactions. The research results on this were published in Cell in January 2022. To create the simulation, the researchers wanted to implement mycoplasma, the world’s simplest cell. Mycoplasma lives with fewer than 500 genes. Compared to humans with more than 20,000 genes, it is a very simple organism. Zaida Luthey-Schulten, the paper’s corresponding author and codirector of the university’s Center for the Physics of Living Cells, said she got enough data from the simulations. She also emphasized that the reason the simulation reflected reality well was not that the motion itself was programmed but because the logic with which the molecules interact was well matched to reality. The paper’s first author, Zane Thornburg, said that many calculations were made possible through parallel calculations, suggesting the possibility of making the calculations faster.

What impact will the development of cell simulations have? Cell simulations will give scientists new insights and ideas to explore uncharted territory for living things. And the data obtained by verifying this will repeat the virtuous cycle that becomes the basis for developing the simulation again. In addition, technological advances will increase observation technology, advances in hardware will enable faster computational speed, and advances in software will enable more efficient computation. This suggests that more sophisticated simulations will be developed. These developments are still taking place today. In February 2022, Professor Jaeseung Jeong of KAIST published a paper titled “Development of high-accuracy robotic arm control brain-machine interface based on artificial intelligence and genetic algorithms.”

<3D simulation in virtual computer space>

The key is to move the arm only by imagination by analyzing the signals from the cerebral cortex that are generated when the arm is about to move. What gained new insights through artificial intelligence was the inverse analysis of artificial intelligence’s computational model to specify the areas of the cerebral cortex involved in imagining directions. Although it is an application on a larger scale than cell simulation, this case shows new possibilities for artificial intelligence. In this way, the cell simulation will be more sophisticated. And it is thought that we will move on to the simulation of human cells. Unlike prokaryotic cells, human cells have organelles, and the way genes work is very different. However, if the basic logic is well structured, moving to this stage may not be such a big obstacle.

If human cell simulation becomes possible, it is possible to predict what effect it will have on cells by administering drugs designed in the previous step in the virtual world. It has already been calculated based on the interaction between substances in the movement of cell components. That is, it is not difficult to run a simulation when a single substance is added. Through this, it will be possible to confirm whether the drug actually binds to the expected site within the cell or whether there is an unexpectedly bound site.

As human cell simulations are developed, new drug development research will accelerate, and the nextgeneration drug development platform will appear. The next-generation drug development platform refers to a system that can obtain virtual results by searching for a target for a drug to act through simulation and actually administering the medication.

Next-Generation Drug Development Platform and Pharmacist

Where will the pharmacists be when the next-generation drug development platform emerges? You can jump into platform development with computational thinking skills. In this case, it is possible to find ways to explore new drug possibilities in the platform development process. In the process of processing a large amount data, the data necessary for drug development is collected and developed so that users can use it easily. Another method is to extract the essential data from a lot of data after the platform is developed to derive the possibility of a new drug. In order to select and use data necessary for new drug development among more than 500,000 protein data, it is required to have a fundamental understanding of drugs. Therefore, the pharmacist is essential to this role. Of course, pharmacists will need to be prepared to handle large amounts of data.

As long as minimal cell simulation has already been developed, it is expected that future development will proceed faster than expected. Alpha Fold, an artificial intelligence for protein structure prediction, predicted 360,000 protein structures a year ago but has now predicted 100 million structures. If enough logic is prepared like this, the development of artificial intelligence will happen in an instant. At the same time, if more detailed data for the development of artificial intelligence models are added as the development of life science technology and engineering observation technology are added, it will not be too far for a simulation of a human cell to be created.

This simulation is not simply limited to the field of research. Even a pharmacist at a large hospital will use a patient’s gene-based cell simulation to determine drug suitability. From this point of view, cell simulation will be in a critical position when considering personalized medicine for the next generation of medical professionals. In addition, if you are in the field of research or new drug development, it is expected that the pharmacist will be in a position where you need to touch and deal with cell simulation more closely than this. In the role of pharmacists that will gradually expand, we think that we need to recognize the existence of cell simulation and prepare to adapt and utilize the massive data obtained from simulation one step at a time. B

<Development of high-accuracy robotic arm control brain-machine>

SMART WATCH

: Wearing Healthcare on Your Wrist

YouYoung Cho youyoung0129@naver.com

Today, watches are no longer used only for checking time. The new emerging main functions are digital health care and sports functions. For instance, the Apple Watch Series 2 has a built-in GPS, which allows the wearer to measure exercise records, and has a heart rate sensor and a waterproof function that can be used up in water to 50m deep. Also, Apple has collaborated with Nike to launch an Apple Watch for people who work out. Although there is a difference in depth and variety of functions compared to sports-specific smartwatches such as GARMIN, it creates a pleasant exercise environment without having to wear a heavy mobile device on the armband. As such, after smartwatches demonstrated their ability to improve quality of life, companies began to produce smartwatches as a main celling item. The global smartwatch market size was USD 18.62 billion in 2020. The market is projected to grow from USD 22.02 billion in 2021 to USD 58.21 billion by 2028, with a CAGR(compound annual growth rate) of 14.9. The global market exhibited a stellar growth of 21.23% in 2020 as compared to the average year-on-year growth during 2017-2019. The growing consumers’ inclination towards technological devices owing to incredible attributes to help simplify their life has a significant contribution towards spiking the product usage. Nowadays, key brands, including Apple, Samsung, Amazfit, and Immo, are offering innovative wristwatches.

The devices come with multiple positive aspects, including navigation, fitness tracking, notification checking, and others, which thus help users with various needs ranging from athletes, tech enthusiasts to regular users. But among them, the most unique function of smartwatches is the digital healthcare technology.

What is Digital Health Care?

The broad scope of digital health includes categories such as mobile health and telemedicine. Health information technology, wearable devices and personalized medicine are also included. Digital health technologies implement computing platforms, connectivity, software, and sensors. They include technologies intended for use as a medical product, in a medical product, as companion diagnostics, or as an adjunct to other medical products (devices, drugs, and biologics). Digital health tools have the vast potential in improving our ability to accurately diagnose and treat disease. Also, they are useful in enhancing the delivery of health care. Most smartwatches have built-in HR measurement functions. Then let’s find out what this most basic HR tells us, the principle of measurement, and the accuracy. Next, we will look at what happens to other health indicators. Furthermore, we will look into the future of digital healthcare.

What Does Your HR Tell You?

A man from the UK whose heart stopped 138 times in 48 hours was saved by his Apple watch David Last, age 54, received the watch as a birthday gift from his wife Sarah. The watch immediately showed that his resting heart rate was as low as 30bpm. The resting heart rates for an adult male are usually between 60-100bpm. David initially thought the watch was faulty and didn’t take much notice of the readings - despite Sarah urging him to get checked out. Eventually he went to see his doctor who referred him to a cardiologist at Norfolk and Norwich University Hospital, where he was booked in for an MRI scan. When the results of the scan came out, doctors told him that he was at risk of sudden cardiac death. He said that the hospital sounded “really panicky” on the phone. Once he got there, they had a bed ready immediately. In fact, his heart had stopped 138 times in 10 second intervals over a 48-hour period. Heart block is a condition where the heart beats slower or with an abnormal rhythm. There are three variations of how severe a heart block is - with the least severe categorized as a 1stdegree heart block, which may not cause symptoms, while 3rd-degree heart block can be a medical emergency.

Another exemplary case is of a 27-year-old woman who quickly discovered her hyperthyroidism through her heart rate. Heather Hendershoy, a Kansas resident, was a 26-year-old woman who was confident in her health. This wass because she worked out steadily at a young age and had no history of ailment. One night, while resting on the sofa, she was warned by her Apple Watch that her heart rate was over 120 times per minute. Thinking strangely of the reading, she visited the hospital the next morning and was diagnosed with hyperthyroidism after several tests, so she was able to receive quick treatment Heart rate anomalies can show the onset of diseases as such. Although the watch cannot diagnose just by reading heart rate abnormalities, it can urge you to visit the hospital where a medical expert can give you one. The abnormalities of the body that HR can inform are mostly abnormalities in the heart and blood vessels, and hyperthyroidism.

How Smart Watch Measures Your Heart Rate : Photoplethysmography

The optical heart sensor in Apple Watch uses what is known as photoplethysmography. Most smartwatches measure HR in the same way. This technology, while difficult to pronounce, is based on a very simple fact: blood is red because it reflects red light and absorbs green light. Apple Watch uses green LED lights paired with light-sensitive photodiodes to detect the amount of blood flowing through your wrist at any given moment. When your heart beats, the blood flow in your wrist — and the green light absorption — is greater. Between beats, it’s less. By flashing its LED lights hundreds of times per second, Apple Watch can calculate the number of times the heart beats each minute — your heart rate. The optical heart sensor supports a range of 30–210 beats per minute. In addition, the optical heart sensor is designed to compensate for low signal levels by increasing both LED brightness and sampling rate.

The optical heart sensor can also use infrared light. This mode is what Apple Watch uses when it measures your heart rate in the background, and also for heart rate notifications. Apple Watch uses green LED lights to measure your heart rate during workouts and Breathe sessions, and to calculate Heart Rate Variability (HRV). B

BIOINFORMATICS

Jihui Jeong jihuijeong21@yonsei.ac.kr

Throughout history, scientists have strived to understand the miracle of life. They have studied every living thing, exploring deeper and deeper. Biologists and clinicians have always struggled to collect various data and clues to find the correct answers to fundamental questions. New technology eventually enabled them to capture more biological data at unprecedented speed, thanks to the efforts of an international project called ‘the Human Genome Project (HGP)’. Indeed, so much data has become available that it can no longer be processed by the human mind alone. This is where bioinformatics comes into action.

What is Bioinformatics?

Bioinformatics is a hybrid science that links biological data to techniques for information storage, distribution, and analysis to support multiple areas of scientific research. Data-intensive, large-scale biological problems can be resolved by using a computational approach. According to the National Human Genome Research Institute, bioinformatics, as related to genetics and genomics, is a scientific subdiscipline that involves using computer technology to collect, store, analyze and disseminate biological data and information, such as DNA and amino acid sequences or annotations about those sequences. Simply put, it is the application of computer technology to the understanding and effective utilization of biological data. Thanks to bioinformatics, we can uncover the biological information hidden inside mass sequences.

The Data of Bioinformatics

Data banks are used to store and organize data. The journal Nucleic Acids Research regularly publishes special issues on biological databases and has a list of such databases. A few popular databases are GenBank from NCBI (National Center for Biotechnology Information), EMBL from EBI (European Bioinformatics Institute European Bioinformatics Institute), SwissProt from the Swiss Institute of Bioinformatics, and PIR from the Protein Information Resource. GenBank (Genetic Sequence Databank) is one of the fastest-growing repositories of known genetic sequences which provides nucleotide sequences. The EMBL nucleotide sequence database is a comprehensive database of DNA and RNA sequences collected from scientific literature and patent applications. Lastly, SwissProt and PIR is a protein sequence database of minimized redundancy and enhanced integration with other databases.

Applications of Bioinformatics

Not only is bioinformatics vital for basic biology research, but it also has a major impact on biotechnology. Applications of bioinformatics have been found in many fields, particularly in the field of medicine. Bioinformatics can be used to identify correlations between gene sequences and diseases, discover protein structure and their functions from amino acid sequences, design novel drugs, and provide better-targeted therapy through efficient personalized medicine. Currently, it is applied in genomics, proteomics, metabolomics, transcriptomics, and molecular phylogenomics. Let’s take a closer look at proteomics, the study of the overall composition of intracellular protein, protein structure, and protein interaction. For example, the function of a protein can often be estimated based on the similarity of its amino acid sequence with those of proteins whose functions are already known. Along with the Needleman-Wunsch algorithm, the first algorithm to be proposed to measure sequence homology, another computer algorithm variation known as BLAST (basic local alignment search tool) is used to rapidly search through a database of known protein sequences to find those with significant similarity to the sequence of a query protein. Also, experimental data can be expanded based on predictions. The spontaneous folding of proteins can be predicted from an amino acid sequence by biennial CASP (Critical Assessment of Structure Prediction) programs. Furthermore, bioinformatics can be used to predict docking systems which is a key step in drug development. The bioinformatic analysis includes similarity searching, clustering, QSAR modeling, virtual screening, etc. Such analyses will play an increasingly important role in almost all aspects of drug discovery and development. Computer programs can simulate and predict optimal spatial relationships by calculating weak interactions, such as the burial of hydrophobic surfaces, hydrogen bonds, and van der Waals forces. For example, an inhibitor of anoctamin1 (ANO 1), a calcium-activated chloride channel, was discovered using three-dimensional quantitative structure-activity relationship (3D-QSAR) pharmacophore modeling. It was used to identify the essential chemical features required in the inhibition of ANO1. In the future, clinical medicine will become more personalized with the development of pharmacogenomics. Doctors will be able to analyze a patient’s genetic profile and prescribe the best treatment accordingly.

Conclusion

Bioinformatics has become an essential interdisciplinary field that incorporates computer science and biology to process large sets of biological data. To simply talk about the future of bioinformatics, in the short term, bioinformatic analyses will prompt a big step forward in the development of targeted therapy by identifying more disease genes and designing new drug targets. In the long term, integrative bioinformatic analysis of genomic, pathological, and clinical data in clinical trials will reveal potential adverse drug effects in individuals through simple tests. Ultimately, pharmacogenomics will likely bring a new age of personalized medicine - that is, individualized therapy and targeted medicine free from side effects, taking each patient’s unique genetic profile into account. B

Digital Biomarkers, Promising Tools in Healthcare and Drug Development

DIgital biomarkers 012345

Jungyoon Ryu jungyoon_r@yonsei.ac.kr

Traditional Biomarkers and Digital Biomarkers

Digital Biomarkers, Promising Tools in Healthcare and Drug Development

The advent of digital means to access reports on individuals’ health status or measurements of bodily functions revolutionized the way people approach healthcare. Especially prevalent in the context of our daily lives nowadays are wearable Internet-of-Things (IoT) devices such as smart watches and fitness bands with multiple health and wellness features: heart rate monitors, physical activity trackers, sleep monitors, etc. Such digital tools are bestowing a wider range of freedom upon the public to track quantifiable data regarding their own physical fitness. For one thing, it has become a common practice at the gym for people to evaluate their workout routine based on the heart rate data collected via their wearable devices of choice. However, the digitization of data acquisition in health-related fields opens up possibilities for much more than just personal healthcare guides. Together with the advance in data analysis and communications technology, the availability of such digital health data, otherwise termed ‘digital biomarkers’, lays the foundation for telemedicine, personalized and preventive healthcare, and time-saving transformations in drug development procedures.

Traditional biomarkers, or biological markers, are indexes that can be used to objectively confirm the presence and track the progress of a disease or assess reactions to a particular regimen. Biomarkers thus must be accurate and reliable while being characteristic to a certain condition so that they act as a specific indicator of it. Hence, its usefulness encompasses various fields including biomedical research, diagnostics, therapeutics, and prognostics. Traditional biomarkers can be classified into four types based on their characteristics: molecular (e.g. blood glucose level), radiographic (e.g. bone mineral density), histologic (e.g. grading and staging of cancers), and physiologic (e.g. blood pressure, heart rate) biomarkers. Such traditional biomarkers can usually be obtained usually by way of invasive and expensive methods that requires the aid of a skilled practitioner and the visitation of the subject to a clinical facility.

Digital biomarkers, on the other hand, are relatively recent and innovative tools that make up for the limitations of traditional biomarkers. Digital biomarkers share all the requirements that traditional biomarkers satisfy but differ in that they are collected based on digital technology. Since data is assembled digitally through rather simple maneuvers, they can be tracked regardless of the subject’s location. The methods for obtaining information are usually non-invasive and low-cost, which makes it even more patient-friendly.

There are various measures that can be adopted for the collection of digital biomarkers, including wearable devices, mobile apps, other devices and platforms, or PCbased software. Wearable devices include fitness bands or smart watches that collect data based on consistent physical contact on the wrist or chest. Apple, Samsung, Garmin, and Fitbit have respective series of smartwatches and fitness bands that allow monitoring of physical activities and an array of physiological biomarkers.

AliveCor’s Kardiamobile is a portable device for taking an ECG regardless of time and location, compatible with a mobile app that reads the results using an AI-based algorithm. Mobile apps are often used as a channel for managing and analyzing measurements made by sensors on separate devices or also used as a system for keeping track of and reporting simple measurements of fitness. Most digital therapeutics nowadays are converting cognitive behavioral therapy to online methods per mobile apps as such. Even more recently, there are attempts to integrate the use of implantable or ingestible biosensors with apps on smartphones, thereby offering digital biomarkers to carry data collected from beneath the surface of the skin or inside the internal organs. Since data can be acquired via various routes, a data integration system is necessary for organizing and controlling all the different types of information.

Drug & healthcare

Applications of Digital Biomarkers in Medical Care

Digital biomarkers are gaining attention in related fields owing to their potential applications and anticipated improvements in medicine. Physiological and behavioral cues of diseases can be detected from digital biomarkers collected in the course of one’s daily life. Such physiological and behavioral markers can add on to the pool of information practitioners can use to assess patients’ health over a distance, laying grounds for more precise diagnostic experiences in telemedicine. Moreover, digital biomarkers can be used to promote personalized or preventive medicine since more intimate information of the patient can be accessed. Closer patient monitoring and real-life data acquisition takes us a step closer to precision medicine, which tends to the more personalized needs of a patient in a very specific state of a disease. Data collected daily can be analyzed by AI or machine learning to be matched to symptoms linked to an impending disease. Hence, preventive measures can be taken so that the disease does not take on a serious path.

Currently, there are attempts to apply digital biomarkers in diagnostics, therapeutics, prognostics, and preventive care of mental illnesses or neurological disorders such as depression and Alzheimer’s disease.

An Israeli startup ‘Beyond Verbal’ offers a program that analyzes vocal intonations to monitor depression. Also, motor skills, eye movements, sleep patterns can be digitally measured by sensors so that the resulting data can be processed to discern whether they are indicative of Alzheimer’s disease.

Digital Biomarkers in Drug Development

The COVID-19 pandemic has brought about changes in drug development procedures in that they generated novel barriers in conducting clinical trials. Due to restraints in social activities, clinical trials were forced to experience early termination or postponement. Considering the colossal budget put into clinical trials, it stands to sense that pharmaceutical companies turned to methods that enable procedures to be carried out remotely. The use of digital biomarkers makes remote patient monitoring and decentralized clinical trials a feasible choice since researchers can obtain clinical data of patients from a distance through digital methods, thereby abating the need for in-person contact. This significantly accelerates phases 2 and 3 of clinical trials. But not only is the application of digital biomarkers in clinical studies time-efficient but is qualitatively advantageous since it makes available longitudinal, real-world data which provides more comprehensive insights into the outcomes of therapeutic interventions.

The application of digital biomarkers is useful over the entire process of drug development even other than clinical trials. Digitally acquired data can be processed by AI-based data integration systems which elicit useful information that can be used as guides for patient recruitment or drug discovery.

Despite the enticing aspects of employing digital biomarkers in healthcare and drug development, there is yet a lot of progress to be made for complete application of the technology. Utilizing digital biomarkers entails challenges concerning privacy, adherence problems, a shortage of infrastructure, and difficulties in validation. The technical aspect of the solution necessitates the involvement of more complex analyses and bigger data storage. Once these obstacles are overcome and reliability as well as feasibility are confirmed, digital biomarkers will become powerful tools to enhance quality of life in terms of health in the digital era. B

AKARAKA & Daedongjae Back to our School Life in Three Years

Ha Neul Roh skyroh0416@yonsei.ac.kr

Due to the COVID-19 pandemic, students have not been able to enjoy the usual things that they have been enjoying for granted. This was the same for all universities. For the past three years, since most university festivals have not been held. Many students had a sense of loss because university festivals can be said to be a crucial source of the vitality of college life. There were even some students who came to Yonsei University dreaming to participate in the festival ‘AKARAKA’. As the social distancing eased early this year, universities have gradually begun to return to normal. Likewise, Yonsei University was able to reopen the festival after three years. From September 21st to 23rd, 2022, the General Student Council Emergency Exigency Committee hosted the 137th school anniversary Muak Daedongjae. Yonsei University’s cheering squad held the festival ‘AKARAKA’. As it is the first festival in three years, many students have been looking forward to it, and the Daedongjae Planning Group also prepared a lot to revive the expectation and to successfully host the festival.

The festival began on September 21st, at the International Campus in Songdo. The Yonsei International Campus Student Representative Council(YIC) held various sports competitions such as the ‘YIC Olympics’, which includes group jump rope, jegichagi, and the three-legged race. In addition, the Daedongjae Planning Group held a stamp event to increase student participation. Also, there were various food trucks and meal zones, where students could eat freely. In front of the Underwood Memorial Library many club performances were held. ‘One Beer’, a band club of the College of Pharmacy, performed as well. “The weather was so nice, and I was very happy to once again feel the lively energy of the International Campus after a long time! All the One Beer members worked hard to prepare for the Daedongjae, and we had a lot of fun as well! Many students from our major came to see the performance, and it was so fun to perform on an open stage outdoor!” said Jiwon Yang, a 4th grade Pharmacy and the president of One Beer. ‘Blue Knights’, the color guard of Yonsei University, came to cheer along with students in the International Campus after all club performances were done. The Songdo Muak Daedongjae was a festival that revitalized the international campus where about 20,000 freshmen along with the students of the College of Pharmacy live in.

Muak Daedongjae at Sinchon Campus was held for two days from September 22nd to 23rd. There were various department and club unit booths along Baekyang-ro. Students from the College of Dentistry opened a free oral examination booth. It was a meaningful opportunity for people to volunteer their talents related to what they are majoring in. The food booth which many people anticipated the most was open in the baseball stadium. A total of 53 organizations held booths at the baseball stadium during the two days. Many students could enjoy food from various food trucks. At the Grand Stadium, many performing clubs performed dances, songs, and band performances. Since it was the first face-to-face Daedongjae Festival in a long time, the Daedongjae Planning Group also held a special event. In front of the alumni plaza, the large Bellygom bear was set as a photo zone. The KBS entertainment show “Hong-Kim dongjeon” visited Yonsei University as well. “It was very nice to have a festival at school after a long time, and the campus felt livelier!

I bought dinner with my friends at the baseball stadium food truck, looked around the booths, and made a lot of memories. It felt like I was enjoying my campus life!” said Jungyun Ryu, a 3rd grade Pharmacy student. As such, students were able to enjoy the festival and have a meaningful time, making good memories with their friends.

‘AKARAKA’ has become one of the largest university events since it first started in 1986. It is meaningful as it was the university’s first cheering event hosted by Yonsei University’s cheering squad. It is a festival that is held at the outdoor amphitheater called the Nocheon Theater. ‘AKARAKA’ was not held in 2020 and 2021, and it was the first face-to-face event since COVID19. On September 24th, the Yonsei University amphitheater was filled with blue waves, and students were thrilled to cheer along with the cheering squad. The first part of the festival started with club performances and cheering, followed by guest performances, and finished with cheering with the cheering squad. Yonsei University’s central clubs ‘Jazz Feel’, ‘HARIE’, and ‘Sonagi’ performed. After that there was a cheering session led by the cheering squad where the students could learn the school fight songs. The second part of the festival was guest performances which is what most of the students look forward to. Many famous artists visited to celebrate the festival with the students. NewJeans, 10cm, LE SSERAFIM, WINNER, and Zico performed, which shows off the prestige of Yonsei University’s festival. Finally, the last part of the festival started with fireworks. All the students enjoyed cheering along with the cheering squad. B

Journalist

Editor in chief Jimin Seo VICE Editor in chief Jungeun Kim COPY MANAGER Ji Won Son

Daeun Choi

Dah Eun Kim Namkyu Oh Ha Neul Roh

Seo Yeong Kim You Young Cho Seung Yeon Noh Kyubin Kim

Jinyoo Park Jungyoon Ryu Hyunjin Lee Jihui Jeong Designer

Design MANAGER

Ji Won Kim

Ji In Shin

Seo Kyung Kim Tae Ho Kim

Ji Won Yang

Hwan Lee Yeong Seo Park Jinyoo Park