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Antiviral pills for COVID-19

Up to date, there are two oral antiviral pills with FDA emergency use authorization, Paxlovid from Pfizer, Molnupiravir from Merck. With these drugs, I believe that the COVID pandemic could end soon. What are those drugs? How does it work to treat COVID?

On December 22nd, 2021, the U.S. FDA issued an emergency use authorization (EUA) for Pfizer antiviral pills. Paxlovid could treat mild to moderate COVID-19 in adults and pediatric patients who are older than 12 years old and more than 40 kg. Additionally, Paxlovid could be prescribed and taken within 5 days of symptom onset. However, Paxlovid could not be utilized for the pre-exposure or post-exposure prevention of COVID-19 or any treatment for severe COVID-19. In the clinical trial, the result shows that Paxlovid could significantly reduce the proportion of people with COVID-19 induced hospitalized or died by 88%. Since we have known that Paxlovid could effectively treat COVID-19 within 5 days of symptom starting, we are interested in how Paxlovid works to treat COVID. One Paxlovid consists of 2 tablets of nirmatrelvir and 1 tablet of ritonavir and the patient should take these twice a day for 5 days. (30 tablets in total for one treatment). Nirmatrelvir in Paxlovid could inhibit a COVID protein to stop the virus from replicating, and ritonavir could enhance the stability of nirmatrelvir and help it to maintain at a high concentration in the body. Its potential side effects are impaired sense of taste, diarrhea, high blood pressure, and muscle aches. Furthermore, Paxlovid might have a significant drug interaction with certain drugs, and it would lead to HIV-1 drug resistance for those people who have uncontrolled or undiagnosed HIV-1 infection. Last, due to the potential damage in the liver and kidney, Paxlovid is not recommended for patients with severe kidney or severe liver impairment.

One day later(12/23/2021), the U.S. FDA issued an EUA for Merck’s Molnupiravir to treat mild to moderate COVID-19 in adults. Additionally, similar to Paxlovid, Molnupiravir should be prescribed and taken within 5 days of symptom onset. One important thing for Molnupiravir is that it can not be taken for patients who are younger than 18 years old because Molnupiravir might affect bone and cartilage growth. The mechanism to treat COVID-19 is that Molmupiravir could introduce errors into the COVID virus’ genetic code to prevent the virus from replicating. In the clinical trial, the result indicates that with Molnupiravir only 6.8% of patients were hospitalized or died compared to 9.7% of patients who received placebo. The treatment of Molnupiravir is to orally take 4 capsules (200 milligrams) twice a day for 5 days. (40 capsules in total) Its potential side effects are diarrhea, nausea, and dizziness. Moreover, from animal studies, Molnupiravir has been found to potentially cause fetal harm in pregnant women. Therefore, this drug is not recommended for use during pregnancy.

In conclusion, both Paxlovid and Molnupiravir could effectively prevent hospitalization or death, but these antiviral drugs could not be a substitute for vaccination or a booster shot. Please receive an FDA-approved COVID-19 vaccine and booster shot to maintain enough immune protection from COVID-19 including the omicron variant.

Reference:

  1. the U.S. Food and Drug Administration

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Things you need to know before entering the U.S. part I

If you are applying for graduate school, you might start to receive an interview notice or admission letter. Or if you are graduating from the Ph.D. program and plan to do your post-doctoral training in the U.S., Here are things you need to know before you board the flight.

The first thing we need to do is find a place to live, either an apartment or a house to rent. Fortunately, after the COVID pandemic, many landlords or leasing offices provide a virtual tour for the house or apartment. Although the virtual tour would be good enough to check the overview of the house, I would recommend having some local people check the place for you. It might be worth hiring a local student and asking the student to do a video chat while he/she is on tour. Some people would think this is a waste of money if there is a virtual tour service, but minor things might be easily neglected in the virtual tour. Or I would suggest that you stay at a hotel for 1-2 weeks before you have a tour and sign the contract. Do NOT pay any deposit without any house tour because it might be a fraud.

Second, everyone has a smartphone that requires wireless service. However, with smartphone technology, the only problem is that you do not have any wireless service, and you cannot do anything, go anywhere because modern people cannot live without a smartphone. There are three major wireless service companies in the U.S., T-Mobile, AT&T, and Verizon. I believe you could find the stores of these wireless service companies when you arrive at the international airport and get a prepaid sim card for your smartphone. Then you could still be a “smart” person to solve any problem with your phone.

Third, a driver’s license and a vehicle would be essential tools if you plan to live in the country because the bus schedule might not be as frequent as in the city. In the U.S., each state has its own motor vehicle laws and safe driving practices, for example, in New York State, when a school bus stops on street to load or discharge passengers, all the vehicles should stop for the school bus even you are on the opposite side of a divided highway. However, in New Jersey, if there is a divided highway and the vehicle is on the opposite side of the bus, the car does not need to stop but should drive less than 10 mph. So it is better for you to learn the local traffic law while you are new to the state. Additionally, the steps to get a driver’s license are to pass the written test for your Class D learner’s permit before you schedule the road test. About buying a car, I will prepare another blog to share my experience buying a car in the U.S. and share some tips to get a lower price.

In sum, I only listed the three most important things to those who are fresh off the boat. There are several minor things I could not discuss here due to the length of the blog, but feel free to leave a comment if you have any questions. Last, I would like to welcome you to the states and enjoy your lives here.

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Jason(Yen-Chun) Lu, All right reserved.

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COVID-19 and the variants

In December 31st 2019, first case of coronavirus disease 2019 (COVID-19) was reported to World Health Organization (WHO). On March 11th 2020, WHO declared COVID-19 a pandemic and US government declared COVID-19 a national emergency after 2 days. On December 31st, 2019, the first coronavirus disease 2019 (COVID-19) case was reported to the World Health Organization (WHO). On March 11th, 2020, WHO declared COVID-19 a pandemic, and the U.S. government declared COVID-19 a national emergency after 2 days. The COVID-19 is caused by a novel coronavirus, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), which emerged in December 2019 from Wuhan, China. COVID-19 might cause respiratory symptoms, such as fever, cough, shortness of breath, fatigue, body aches, and headaches. Some people might lose their taste or smell. Additionally, it might induce more severe diseases like SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome). Its transmission could be spread in three ways: First, an infected person could exhale tiny droplets and particles containing the virus. If another person is nearby within 6 feet, this healthy person might get the virus from these particles. Second, these small droplets and particles with the virus might land on the eyes, nose, or mouth through an infected person’s coughs or sneezes. Third, if your hand has a virus on it, and you use it to touch eyes, nose, or mouth, then you might get an infection. To protect ourselves and our family, wearing a medical-grade mask is an important step because the surgical mask constitutes an electrospinning fibers layer with static electricity to capture the virus. Moreover, keeping 6 feet distance from others might also lower the risk of getting an infection. The last way to protect ourselves from COVID-19 is vaccine administration. Up to date, there are three FDA-approved vaccines in the U.S., Moderna mRNA-based vaccine, Pfizer mRNA-based vaccine, and Johnson & Johnson adenovirus-based vaccine. These vaccines could effectively stimulate the immune response to allow our bodies to produce antibodies to fight coronavirus.

Interestingly, the name coronavirus is not named from Corona beers. It actually means crown structure because coronavirus has spike proteins on its capsid, and it looks like a crown. These spike proteins play an essential role not only in virus transmission but also in vaccine development. In the transmission process, the spike protein would bind to a typical protein receptor on the cell surface of human throat and lung cells, called ACE2 receptor (Figure 1), and fuse with human cells to transfect it. On the other hand, scientists have developed a COVID vaccine to produce antibodies to target the spike proteins. While the COVID virus has been widely spread, more and more variants appear with mutations in spike protein. For example, the Alpha variant of COVID-19 has ten mutations in the sequence of spike protein which could help the virus to bind to the human cell easier. Up to date, there are five significant variants that exit after pandemic: Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529). The Alpha variant was first found in the United Kingdom in September 2020. The Beta variant was discovered in South Africa in May 2020. The Gamma variant was documented in Brazil in November 2020. In 2021, Delta, the primary variant, was identified in India in October 2020. In 2022, the Delta variant was replaced by a higher infectious version, the Omicron variant, which occurred in multiple countries from November in 2021. At least 36 mutations were found in the omicron variant in the spike protein. These mutations might be the reason that omicron has become the most contagious variant in the world. Although the transmission rate of the omicron variant is higher than other variants, the toxicity/ damage to the lung is lower. In recent animal studies, scientists have discovered that the infection sites of the omicron variant would result mainly in the upper respiratory tract but less in lower respiratory and lung damages. This might imply that the pandemic would end soon because the trend of viral mutation would be a higher transmission rate but lower toxicity to humans.

Figure 1, The structure of coronavirus is constituted of single strand of RNA and envelop with spike protein which could bind to ACE2 receptor on human cells. Adapted from an image by Davian Ho for the Innovative Genomics Institute.

In sum, although the omicron variant might affect our daily lives, we could protect ourselves and our family by three methods described above, mask, 6 feet distance, and vaccine. If you have not received the COVID vaccine, please remember to get it, including a booster shot, to get full protection. With the oral pill from Pfizer (PAXLOVID) and Merck (molnupiravir), I believe the pandemic would end soon, and everyone could have a normal life again.

Reference:

  1. U.S. Centers for Disease Control and Prevention https://www.cdc.gov
  2. Megan Scudellari, Nature 595, 640-644 (2021)
  3. Leung, N.H.L. Transmissibility and transmission of respiratory viruses. Nat Rev Microbiol19, 528–545 (2021). https://doi.org/10.1038/s41579-021-00535-6

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The Road for Immigration to the US

As an immigrant and scientist, I would like to share my experience of applying for permanent resident in the United States. I received my Ph.D. degree from Cornell University in 2018, and I filed the documents for I140, Immigrant Petition for Alien Workers under EB-2: Employment-Based Immigration-Advanced Degree or Exceptional Ability with National Interest Waiver (NIW) at the beginning of February 2019. Additionally, I also submitted the I485, Application to Adjust Status, after receiving the receipt of I140 at the end of February 2019. Here is the timeline for my application.

In preparing the I140 documents, we have to fill the form I-140 with a solid petition to demonstrate the contribution that benefits the United States. In the petition, I have to include evidence of an advanced degree, a proposed endeavor with both substantial merit and national importance, and how I advance the proposed endeavor, such as my research in biomedical applications (cell therapy, biomanufacturing) recommendation letters. First, I have to show my diploma and transcript from Cornell University and the evidence of my current position at Boston Children’s Hospital/MIT to prove that I am a member of the professions holding an advanced degree. Second, I presented my previous research in the biomedical field and demonstrated how my research has both substantial merit and national importance. Second, there are two types of recommendation letters (RL), dependent RL and independent RL. Dependent RL is defined when a related faculty provide the RL in academia or a profession in the industry. Additionally, “related” is in a very broad range: Even you do not know all the faculties in the same institution or department, but any overlap in any institution or listed in the same publication with these faculties, they would be identified as dependent references by U.S. Citizenship and Immigration Services (USCIS) officer. To make sure you got strong references for your application, it is better to find three independent references who could support your petition and also evidence to show you are an expert in the field who could provide US national benefits.

In my application, I am not a lucky one because it took me two years and four months to get my green card. Also, during the COVID pandemic, I received my I140 approval notice twice (5/13/2020 and 11/23/2020). To understand the reason for 2nd approval letter, I have consulted with my immigrant attorney and requested help from a US senator in MA. However, none of them could provide an answer for this. Notably, while I am waiting for the case to be reviewed and approved by USCIS, I found several tools we could do to check the status of the applications. First, we could create an account on the USCIS website (https://www.uscis.gov) and the department of homeland security website (https://myaccount.uscis.gov) to track the case status. Sometimes the case status might only update on one of the websites. Moreover, there is another tool on the USCIS website, checking processing time. (https://egov.uscis.gov/processing-times/) In this tool, you have to choose what form you are looking for and what field office or service center you submit the application to. For example, in the I140 application, we need to choose I140 and Texas Service Center because my case was submitted to Texas Service Center. (see the picture below) Then we could find out the estimated processing time for different categories. If your case is outside of normal processing time, you could raise a service request on the USCIS website. If the case has been pending for over a year, I would suggest contacting the USCIS to talk with a senior officer to track the actual status and where the case is. If none of the officers from USCIS could provide any clue on your case, you could contact your local congressman/ woman or senator for help. The legislators could have access and the right to request information in your case, so don’t hesitate to get in touch with the local office of these federal legislators for assistance.

In my experience of the green card application, I understand that there is no rule to estimate when we will receive the notice from USCIS. If you are a lucky boy/girl, you might get your green card very quickly. Therefore, if there is anything I would suggest to do while your case is pending at USCIS, maybe “pray” is the only thing we could do. 🙂 Good luck to anyone waiting for the green application, and please feel free to leave a comment to let me know if you have any questions.

Friendly note: I am not an immigration attorney. This is my experience with my green card application. If you have any questions in the immigration process, please consult with an attorney. Also, if you like this blog, please remember to click the advertisement as your support. Thanks.

Jason(Yen-Chun) Lu, All right reserved.

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Introduction to Gene Therapy

Recently, gene therapy has become a hot topic in the biomedical research and pharmaceutical industry because the timeline of new drug approval for the US Food and Drug Administration (FDA) is shorter than traditional drug modalities, such as small molecular drugs. In addition, after the COVID pandemic, gene-based technology plays an important role in vaccine development with its advantage in completing the clinical trial for new drug applications (IND). Taking Moderna as an example, after Chinese authorities shared the genetic sequence of the COVID, the National Institute of Health (NIH) and Moderna finalized the sequence for its mRNA product for the COVID vaccine. Moreover, Moderna began the clinical trial in April 2020 and received the emergency use of its mRNA vaccine (mRNA-1273) for COVID-19 from the FDA in December. This is a great example to show how fast gene therapy could be approved and authorized by FDA.


Before discussing the types of gene therapy, I would like to briefly introduce nucleic acid, which is an essential sugar-based biomolecule in all cells and viruses. Nucleic acids are divided into two famous classes, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). These nucleic acids store pieces of information in the cells and also passage this information to our descendants. Moreover, the DNA is composed of 4 different units, Adenine (A), Thymine (T), Cytosine (C), and Guanine (G), and RNA is composed of Adenine (A), Uracil (U), Cytosine (C) and Guanine (G). DNA can transcript into RNA in the cells and then translate into protein to work for the cells. For example, the mechanism of the COVID vaccine from Johnson& Johnson or AstraZeneca is to deliver the DNA sequence of spike protein in coronavirus by adenovirus. When the DNA fragment is given in the cells, it will transcript into mRNA and translation into the spike protein. So the immune system could recognize the proteins and produce antibodies to protect the body if any coronavirus is found. In the mRNA vaccine, the mechanism is straightforward because the targeted mRNA could directly deliver to the cells and produce the proteins.

Figure to illustrate how DNA convert into RNA and translate into proteins

Up to date, there are two types of gene therapy, virus-based, and non-virus-based delivery system. In a virus-based delivery system, adenovirus and adeno-associated virus (AAV) are the primary vehicles to deliver nucleic acids. In the COVID vaccines, two companies (AstraZeneca and Johnson&Johnson) used adenovirus to deliver the DNA sequence of spike protein on coronavirus. Also, there are two FDA-approved AAV-based therapies: First, Spark Therapeutics developed Luxturna for degenerative disease of the eye (retinal dystrophy). Second, Novartis uses Zolgensma to treat spinal muscular atrophy (type I). On the other hand, the non-viral system mainly focuses on synthetic materials, such as polymeric materials, ionizable lipids, peptides, and zwitterionic lipids and dendrimers. In the early research, scientists focused on cationic materials to form nanoparticles with nucleic acids; however, researchers have recently worked on pH-dependent ionizable materials with lower toxicity. In an acidic environment, the ionizable materials become cationic and form nanoparticles with anionic nucleic acids by electrostatic force. These ionizable materials could protect the therapeutic mRNA from degradation and selectively target the specific cells for delivery. Additionally, after the lipid nanoparticles enter the cells, the mRNA would be released in a neutral cytoplasm environment where the mRNA would start to translate into protein to treat disease or build up the protection from any virus or bacteria. Since the mRNA-based vaccine for COVID, the non-viral system for mRNA delivery has become a popular field in gene therapy development.

Illustrate how COVID (AstraZeneca) vaccine works in the body


In sum, with the fast developing timeline, gene therapy would be a major modality in pharmaceutical companies in the next decade and also benefit human health welfare, such as vaccine development in different viruses.

Reference:

  1. P. Kowalski et. al., “Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery.”, Molecular Therapy Vol. 27, No. 4, 2019
  2. S. Liu et. al., “Membrane-destabilizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR-Cas gene editing.”, Nature Materials Vol. 20, 2021

Jason(Yen-Chun) Lu, All right reserved.

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Introduction to promising treatment for type I diabetes

Cell therapy became a hot topic since chimeric antigen receptor (CAR) T-cell therapy was approved by U.S. Food and Drug Administration (FDA) for acute lymphoblastic leukemia and lymphomas. It is a milestone for cancer treatment, but cell therapy is also a promising solution for type 1 diabetes (T1D) patients. According to American Diabetes Association, nearly 1.6 million Americans had T1D in 2018. In each year, there are around 64,000 people diagnosed with T1D in the United States. Moreover, scientists and doctors predict that there will be 5 million T1D patients by 2050 in the United States. Additionally, according to American Diabetes Association, two different methods are used to identify diabetes, glaciated hemoglobin (A1c) test, and blood glucose test. The glaciated hemoglobin (A1c) test could indicate the average level of blood glucose in the past two to three months. The A1c level is divided into three intervals: A1c level below 5.7 is considered normal, between 5.7 and 6.4% is identified as pre-diabetes, and over 6.5% is diagnosed as diabetes. In blood glucose tests, there are three different methods to measure blood glucose: 1. Random blood glucose test: a blood sample is collected without fasting before the test, and the blood glucose less than 200-milligram per deciliter (mg/dL) is identified as normal. 2. Fasting blood glucose test: a blood sample is collected after overnight fasting. The blood glucose less than 100 mg/dL is normal, and between 100 and 125 mg/dL is considered pre-diabetes. When the blood glucose is higher than 126 mg/dL is diagnosed as diabetes. 3. Oral glucose tolerance test: After the fasting blood glucose test, a sugary solution would be provided for oral consumption. Several blood glucose tests would be measured for the next two hours. A blood glucose level less than 140 mg/dL is normal, and a level between 140 and 199 mg/dL is considered pre-diabetes. A level over 200 mg/dL is diagnosed as diabetes.

Four different tests are usually used to diagnose diabetes: Glycated hemoglobin (A1C) test, random blood glucose test, fasting blood glucose test, and oral glucose tolerance test.


T1D is an autoimmune disease; the patients’ immune system cannot recognize their own cells/tissue and attack them. In the human body, the pancreas plays an important role in maintaining the blood glucose level by two hormones, insulin, and glucagon. After each meal, blood glucose increases, and insulin is secreted to lower blood glucose. On the other hand, when a person feels hungry and the blood glucose is lower than the normal level, the alpha cells in the pancreas will secret glucagon to increase blood glucose level. However, in T1D, the pancreas is no longer functional to respond to dynamic blood glucose. In T1D patient’s daily life, insulin injection is required after every meal to prevent high glucose levels, which might cause cardiovascular disease. Up to date, researchers have been developed two potential treatments for type I diabetes, cell therapy, and artificial pancreas.

Islet cells in pancreas are comprised of different cell types: alpha cells, beta cells and delta cells. Additionally, alpha cells could respond to hypoglycemia (low blood sugar) by glucagon secretion, and beta cells could secrete insulin while hyperglycemia occurs. However, the alpha and beta cells are detroyed by T1D patient’s immune system and the body would lose the ability to maintain blood glucose level.

In cell therapy, it is a simple idea that we could transplant the pancreatic cells to replace the destroyed cells; however, the transplanted cells would be attacked by the patient’s own immune system again. To solve this, many researchers have been worked on cell encapsulation to protect the cells from immune cells attack. In 2015, Prof. Minglin Ma and his group at Cornell University developed a novel design to incorporate nano-fiber and hydrogel together to protect the pancreatic cells by hydrogel and enhance the mechanical property by stiff nano-fiber. In 2018, a retrievable and scalable cell encapsulation device was designed for the potential treatment of type I diabetes. The common design of these potential therapeutics is that the hydrogel material could not only protect the cells from antibody attack but also allow the mass transfer, such as nutrients, oxygen, insulin, to respond to blood glucose. Therefore, the transplanted cells could respond to the blood glucose immediately. On the other hand, the artificial pancreas is another option to treat type I diabetes with precise control release of insulin and glucagon to maintain blood glucose. Two methods we could use to manipulate the release, chemically and electronically management. In chemically management, a smart hydrogel is designed and synthesized to respond to the blood glucose in material property change to release glucagon in low plasma glucose and insulin in high plasma glucose. For instance, in 2020, Prof. Zhen Gu and his team at UCLA developed a dual responsive micro-needle system to manage blood glucose levels. Although the chemically responsive design is an intelligent approach to deliver the therapeutic peptides, the delivery of peptides relies on mass diffusion, which might not be effective immediately. In the electronically management, electronical device could measure the blood glucose in real time and inject the insulin or glucagon directly. However, the embedded needle of the electronical device need to be replaced every 2-3 days. In sum, cell therapy and artificial pancreas could be promising solutions to treat or “cure” type I diabetes in the future.

Hydrogel could protect the encapsulated cells from immune system and the porous structure allows mass diffusion of nutrients and waste.

Reference:

  1. Centers for Disease Control and Prevention (CDC), Nataional Diabetes Statistics Report, 2020
  2. American Diabetes Association, Statistics About Diabetes
  3. D. An et al. Developing robust, hydrogel-based, nanofiber-enabled encapsulation devices (NEEDs) for cell therapies, Biomaterials 2015
  4. D. An et al. Designing a retrievable and scalable cell encapsulation device for potential treatment of type 1 diabetes, Proceedings of the National Academy of Sciences 2018
  5. Z. Wang et al. Dual self-regulated delivery of insulin and glucagon by a hybrid patch, Proceedings of the National Academy of Sciences 2020

Jason(Yen-Chun) Lu, All right reserved.

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Tips for preparation of graduate school application in US

I have mentored two Taiwanese undergraduate students in U.S. graduate school applications through Project Tyra mentoring program. I believe that many students might have the same questions when they are preparing for the documents, so I would like to have an article about the tips for applying to U.S. graduate schools, especially in the STEM field (Science, Technology, Engineering, and Mathematics). In graduate school applications, the most important documents are a statement of purpose (SOP) and curriculum vitae (CV). Here are some tips for SOP preparation and CV.


In the application materials for graduate school in the U.S., SOP is the most important document because it would allow the graduate committee to know more about you. For example, academic experience, research interest, academic performance, and motivation. In the educational background, you could write the concentrations in college and any award or scholarship you have received. Also, if you are top 5 % or better in class, you could mention this in the SOP. In the research experience and interest, you could list any related experience in academic research and your research interest in any potential lab you would like to join. Another critical element in the SOP is motivation which the committee wants to see from the applicant. The motivation includes the passion for science, the interest in academic research, and the future goal after the training from graduate school. Notably, in the U.S., the faculty has a significant influence in accepting graduate students because the faculty needs to pay tuition and living expenses/insurance for the graduate students. So, if you are interested in any faulty’s research, you could also mention the faculty in your SOP. Then you might have a chance to talk to the faculty. In the structure of SOP, I think it is similar to a cover letter for a job application. The first paragraph should be an abstract of the SOP because the committee member might decide if he/she wants to read the rest of the SOP by the first paragraph. In the following sections, we could have experiences in research, outreach education, and the motivation to pursue a graduate degree in applied school. Moreover, the most important part is the passion for science and motivation. Most of the faculties want to see the passion in applicants. Suppose there is a great story to describe the passion for science and research. In that case, this SOP will be a great document to persuade the committee/faculty to take you as a graduate student. On the other hand, a CV is also a very important document to highlight the applicant’s background, education experience, and research experience. In addition, the recruiting committee might use a CV as an initial screening to select the top candidate for potential interviews. In general, the length of the document is 1.5-2 pages for SOP and 1 page for CV. If you have many publications that list in the CV, you could extend it to 2 pages.


In sum, application documents, SOP and CV, should be simple and easy to read. More importantly, remember to highlight the critical information and list this information on top of the CV and the first paragraph to make sure the committee member read these.

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Jason(Yen-Chun) Lu, All right reserved.

What engineers can do in biomedical field?

An engineer is trained to solve problems through science and math. We can see engineers everywhere in our lives, such as civil engineers, chemical engineers, electrical engineers, and software engineers, to improve our daily lives. What can engineers do in the biomedical field? A pioneer, professor Robert Langer, an internationally well-known biomedical engineer and inventor, is a perfect example illustrating how engineers can contribute to biomedical science. Dr. Langer holds the title of David H. Koch Institute Professor at the Massachusetts Institute of Technology (MIT) as well as that of Senior Lecturer on Surgery at Harvard University’s Medical School. It is worth to mention that being an Institute Professor at MIT is the highest honor that can be awarded to a faculty member. Besides, Dr. Langer has more than 1,500 published papers and over 1,400 issued patents and pending patents worldwide. In his research, he focuses on solving biomedical problems from an engineering aspect, such as developing materials for drug delivery, cell engineering, and tissue engineering. Here we have some examples to demonstrate how engineers contribute to the field.

First, Dr. Langer and his colleagues with Bill & Melinda Gates Foundation created pulsatile-release PLGA microspheres for single-injection vaccination1 for developing world. Poly (lactic-co-glycolic acid) (PLGA) is an FDA-approved degradable material for clinical application, and core-shell decoupled microspheres are fabricated by a new microfabrication method (StampEd Assembly of polymer Layers (SEAL))2. Despite the immense increase in vaccine coverage worldwide over decades, vaccine-preventable infectious diseases still claim the lives of approximately 1.5 million children every year because of inadequate distribution and administration of vaccines in the developing countries. Currently, around 19.4 million infants do not receive fully immunized against diphtheria, tetanus, and pertussis. Moreover, 6.6 million of them with one dose of the vaccine remain at risk for these diseases due to lack of full series of doses. With the pulsatile-release PLGA microspheres and SEAL technology, the problem of inadequate distribution and administration of vaccine could be solved, and millions of people in the developing world would benefit.

Fig. 1, Using different molecular weight of PLGA to control degradation time to release the therapeutics to evoke immune response. (modified from McHugh, K. J. et al. Science, 2017).

Second, Dr. Langer and his colleagues discovered three chemical materials which can suppress foreign body response to minimize fibrosis in rodents and at least 6 months in non-human primates3. These materials were conjugated to alginate hydrogel, and these hydrogel microspheres were transplanted in mice and monkeys. In addition, these anti-fibrotic materials could be applied in cell therapy, such as beta cell replacement treatment for type I diabetes. In type I diabetes, patients’ pancreatic islet cells are destroyed by their own immune system. To date, the most common treatment is a daily insulin injection to control blood glucose. However, insulin injection cannot cure type I diabetes or prevent the many devastating diseases associated with diabetes, such as blindness, hypertension, and kidney disease. Islet cell transplantation could provide an alternative treatment for type I diabetes to avoid daily injection and restore normoglycemia. However, foreign body response is a major challenge for cell therapy. The cellular and collagenous deposition would isolate the transplanted device from the host, which could induce tissue distortion, cut off the nourishment of encapsulated cells, and finally lead to device failure. With these new anti-fibrotic materials, the transplanted device with insulin-producing beta cells could maintain its function in the long term to cure type I diabetes.

Fig. 2, Three chemical materials can suppress foreign body response to minimize fibrosis in rodents and non-human primates. Encapsulated by these materials, the therapeutic cells can be protected from host immune system and also suppress its immune system to reduce foreign body response.

Third, Dr. Langer’s group developed a combinatorial library of ionizable lipid-like materials to identify mRNA delivery vehicles that facilitate mRNA delivery in vivo and provide potent and specific immune activation4. The cationic lipid-like materials could encapsulate therapeutic mRNA in lipid nanoparticles by electrostatic interaction. To date, mRNA therapeutics is a promising strategy for disease treatment and vaccination. In contrast to DNA therapeutics, mRNA delivery results in transient expression of encoded proteins, and so avoids complications associated with insertional mutagenesis. Currently, mRNA therapeutics, including disease treatment and vaccination, are in the process of clinical trials. For instance, TranslateBio has conducted phase ½ clinical trials in delivering mRNA encoding fully functional cystic fibrosis transmembrane conductance regulator (CFTR) protein to treat cystic fibrosis by nebulization. For COVID-19, Moderna (co-founded by Dr. Langer) and Pfizer all utilize lipid nanoparticles to deliver mRNA encoding for a prefusion stabilized form of spike protein. Moderna also has two mRNA cancer vaccines in phase 1 and phase 2 to target solid tumors and melanoma. These clinical trials with mRNA delivery are incorporated to cationic lipid-like materials to enhance mRNA stability and lead to an increase in intracellular protein expression.

Fig. 3, Illustration for the formulation of lipid nanoparticles in mRNA delivery

In sum, biomedical engineering is a combination of multiple disciplines, such as engineering, biology, medical science, and chemistry. To date, biomedical engineers have contributed to the biomedical field in different aspects, such as new materials, fabrication methods, and medical devices to improve current medical treatments and solve emerged medical problems, for instance, COVID-19.

Reference:

1.        Guarecuco, R. et al. Immunogenicity of pulsatile-release PLGA microspheres for single-injection vaccination. Vaccine 36, 3161–3168 (2018).

2.        McHugh, K. J. et al. Fabrication of fillable microparticles and other complex 3D microstructures. Science (80-. ). 357, 1138 LP – 1142 (2017).

3.        Vegas, A. J. et al. Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates. Nat. Biotechnol. 34, 345 (2016).

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