Category Archives: biomedical engineering

In my previous blogs in leadership development, I intrdocued “Become a successful leader (1): Everyday Leadership“, “Become a successful leader (2): Self-Awareness“, “Become a successful leader (3): Know who I am, and what personality I have.“, “Become a successful leader 4: Be an inspiring leader, The Golden Circle Theory“. Here, I would like to discuss another key component, “communication” in leadership development.

Communication is an art of understanding

Communication is an art where we need to keep creating understanding to deliver the right message between the talker and the listener. The communication process includes encoding our thought/ideas into words and behaviors and decoding this information into meaning. Misunderstanding occurs when the listener decodes the words and behaviors into a different meaning. To avoid the misunderstanding, we need to know 7C’s (correctcompleteclearconsistentcredibleconcerned/connectedculture) and 1 V (Volume). Moreover, what we do not say in the conversation and how we say it is very important to achieve effective communication.

Information transmission

Communication is a process of information transmission. Talker/Writer express ideas and thoughts in words or behavior, which encodes the message by one brain. The audiences decode the message to collect the information; however, each audience’s brain might translate it into different information. Also, in the human mind, emotions usually come faster than thoughts. Therefore, if you are in the mood, do not say anything or reply to any email because your emotion might highly affect your communication. In other words, we should always communicate with others in an adult-to-adult way.

Curse of knowledge

Cognitive bias usually occurs when an individual in a group unknowingly assumes that the others have the background to understand the message. For example, when we learn something new, such as cancer biology, we start to talk with professional words. Even if we are talking to other people without a biological background, we forget to explain the information or switch to simple terms to transfer the information. This is what we call the curse of knowledge. Therefore, we should always assume that we are not talking to experts if we do not know the audience.

Unconscious Communication

Sometimes there is a hidden message in our verbal or non-verbal expression. For example, intonation is a way to express the hidden meaning within a sentence. If someone said that “I didn’t say you broke my equipment,” we could try to stress a different word in the sentence to see if there is any difference.

  • I didn’t say you broke my equipment
  • I didn’t say you broke my equipment
  • I didn’t say you broke my equipment
  • I didn’t say you broke my equipment
  • I didn’t say you broke my equipment
  • I didn’t say you broke my equipment
  • I didn’t say you broke my equipment

Another example is body language. It is an interesting topic that sometimes we might unconsciously express our emotions through body language. If you found out that someone stands with folded arms when talking, you could assume this person disagrees with what you said.

Communication is based on trust

To have an effective communication, trust is an important factor to connect individuals in a group. There are 5 elements to build up trust: consistency, openess, loyalty, competence, and integrity.

  • Consistency: How often do you change your mind?
  • Openness: Do you share information about yourself or do you just expect others to do so?
  • Loyalty: Do you support people only when everything is great or also when they are struggling?
  • Competence: Do you know what you are talking about?
  • Integrity : Are your actions matching your words ? 

Communication Strategy for a good leader

A good communication strategy for a leader is to include both positive and negative aspects in your message and be specific and concise. An excellent example is that both U.S. President Abraham Lincoln and Massachusetts governor Edward Everett gave a speech after the Gettysburg battle in 1863 (Civil War). Everett’s speech was 2 hours long, and Lincoln’s was 2 minutes. However, everyone only remembers what Lincoln said in the address. Therefore, good communication should be short and specific.

If you are interested in Lincoln’s speech, it is the links for the speech and transcript.

Conclusion

Communication is very important not only for leadership but also for everyone in daily life. In the next blog, I will introduce how we communicate with people from different cultures and how we lead an effective meeting.

As a member of Professor Robert (Bob) Langer’s group, it is my pleasure to write a blog to introduce Bob and the journey to join the most creative group at MIT. If you want to know more about our research, please find my previous blog, “What engineers can do in the biomedical field?

The Journey to Langer Lab

I could vividly remember the first time I arrived in the U.S. in 2012, and the next day was the Cornell Biomedical Engineering annual retreat, where Bob was the keynote speaker. However, for an international student who had just entered the US, I did not know who he was and why so many people/faculties stood around him. After the retreat, I learned about him through a google search.

Educational training of Bob

Bob is a pioneer in biomedical engineering, and he is the first engineer who worked in a hospital to do biomedical research. In his educational training, he received his bachelor’s degree in chemical engineering at Cornell University and a Ph.D. from the Massachusetts Institute of Technology (MIT). Unlike his classmates, Bob did not go into the petroleum industry after graduation from MIT. Still, he chose to do his postdoctoral training in Dr. Judah Folkman’s lab at Boston Children’s Hospital to develop anti-VEGF drugs for cancer treatment.

Bob Langer, Edison of Medicine

Bob is called Edison of Medicine; also, he is one of 12 Institute Professors at MIT, which is the highest honor that can be awarded to a faculty member.  Bob has written more than 1,500 articles, and he is the most cited engineer in history (h-index 299 with over 363,000 citations according to Google Scholar).  He also has over 1,400 issued and pending patents worldwide.  Additionally, his patents have been licensed or sublicensed to over 400  pharmaceutical, chemical, biotechnology, and medical device companies. More importantly, Bob is a co-founder of many companies, including Moderna, which developed great COVID-19 to help humans build immune protection from coronavirus during the pandemic. From 1999 to 2002, Bob served as Chairman of the FDA’s Science Board (its highest advisory board). Last, Bob received numerous awards, including both the United States National Medal of Science and the United States National Medal of Technology and Innovation (he is one of 3 living individuals to have received both these honors), the Charles Stark Draper Prize (often called the Engineering Nobel Prize), Queen Elizabeth Prize for Engineering, Albany Medical Center Prize, Breakthrough Prize in Life Sciences, Kyoto Prize, Wolf Prize for Chemistry, Millennium Technology Prize, Priestley Medal (highest award of the American Chemical Society), Gairdner Prize, Hoover Medal, Dreyfus Prize in Chemical Sciences, and the BBVA Frontiers of Knowledge Award in Biomedicine. He holds 36 honorary doctorates and has been elected to the National Academy of Medicine, the National Academy of Engineering, the National Academy of Sciences, and the National Academy of Inventors. That is why people called him the Edison of Medicine.

The Cornell alumni event in Boston where I first talk to Bob.

Cornell alumni event in Boston

In December 2017, I attended an alumni event in Boston where Bob was the host, and it was my first time to have an in-person interaction with Bob because it was a small event with 20-30 people. After the event, I connected with Bob. I received a lot of help from him, including the recommendation letter for my green card application, sharing his experience when I did not know what I decided to do after graduation, and advice for my career development. Now I am working in Langer/Anderson lab at MIT. It is a wonderful experience in this creative environment and being part of Langerites.

Langer Syndrome

It is a common genetic disorder (particularly in Langerites) caused by the overexpression of the genes for wanting to be like Bob. 😂 The symptoms are “carrying multiple mobile devices”, “tendency to respond to emails in <5 mins”, “High frequency of saying, “That’s gonna be big”,”Super”, “fantastic”,…”, “High craving for chocolate and diet coke”. I believe if you found someone has any symptoms above, he/she is highly possible one of the Langerites.

Bob’s advice

Bob always gives us simple, true, and powerful advice. Here, I would like to share with everyone: “Believe in yourself. If you love this work, pursue it. Be persistent. Don’t give up!”

Conclusion

This is my mentor, role model, Bob Langer, and my journey to Langer lab at MIT. I hope one day we could have seen/done further by standing on the shoulder of the giant, Professor Robert Langer.

On 4/25/2022, the U.S. Food and Drug Aministration (FDA) approved that the treatment of Veklury (remdesivir) is expanded to pediatric patients who are at least 28 days old, 3 kilograms are tested positive with mild-to-moderate COVID-19 and high risk to progress to severe condition.

Current drugs for COVID-19

In U.S., two types of anti-viral drug to effectively treat COVID-19 are Pfizer (Paxlovid) and Merck (Molnupiravir), However, they cannot be used in children due to its ability to block growth of cartilage and bone. Please find the detail in previous blog, Antiviral pills for COVID-19.

Who can use Veklury (remdesivir)?

Before 4/25/2022, Veklury (remdesivir) could only use to treat adult patient and pediatric patients who are at least 12 years old and at least 40 kilograms with COVID-19. After 4/25/2022, the application of Veklury (remdesivir) is expanded to pediatric patients who are at least 28 days old and 3 kilograms to receive treatment because there is not vaccine for those children to prevent hospitalized and death from COVID-19 and also no effective drug to treat COVID-19 in these children.

Potential Side Effects

Possible side effects of using Veklury include increased levels of liver enzymes, which may be a sign of liver injury; and allergic reactions, which may include changes in blood pressure and heart rate, low blood oxygen level, fever, shortness of breath, wheezing, swelling (e.g., lips, around eyes, under the skin), rash, nausea, sweating or shivering.

Veklury (remdesivir) cannot replace vaccine

Although FDA approved the usage of Veklury (remdesivir) in children, this drug could not prevent any infection, hospitalization or death. Once FDA approve the COVID vaccine from Moderna or Pfizer/BNT in children, please bring your kids to receive the vaccine to protect your kids and family from COVID-19.

Conclusion

This is a great news for parents whose kids are less than 12 years old because there is no vaccine and drugs to protect younger kids from COVID-19. The most important thing for these parents is to maintain social distance, wash your hands, and be fully vaccinated until your kids could obtain protection from FDA approved vaccine.

Related Blogs

Rapid COVID test would be the key to end the pandemic?

Omicron, BA.2 subvariant, is it the last variant in the pandemic?

COVID-19 and the variants

Antiviral pills for COVID-19

How do we make 2 successful COVID mRNA vaccines?

Introduction

According to COVID data from World Health Organization (2022/02/28), total COVID cases have reached 400 million, and the COVID-induced death is close to 6 million people. On the bright sight, the COVID vaccines have been administered over 10 billion doses, and around 4 billion people are fully vaccinated now. Among the FDA-approved COVID vaccine, the primary modality is mRNA-based vaccines from Moderna or Pfizer/BNT. In February 2022, Moderna announced establishing subsidiaries in four Asian countries, including Taiwan, and planning to manufacture COVID vaccine and other mRNA-based drugs in Taiwan. What is the procedure to make an mRNA vaccine and mRNA-based drugs? Here I will explain how the lipid nanoparticles with mRNA are manufactured.

Figure 1, the mechanism of gene therpay: DNA transcripts into RNA which could translate into proteins in cells.

Mechanism of gene therapy

First, we need to know what mRNA is. In our cells, chromosomes composed of DNA and proteins in the nucleus control the gene expression by different DNA fragments. Additionally, the mechanism is that first, the DNA in the nucleus transcripts into messenger RNA (mRNA), and the mRNA would translate into protein to be expressed in the cells (Figure 1 ). Also, that’s why mRNA plays an essential role in molecular biology. To produce the mRNA, we would need a lot of DNA templates for in vitro transcription (IVT), and the easier way to collect a large number of DNA templates is to clone the desired DNA template into a plasmid and transforms it into E. coli, to use E. coli to grow and produce a lot of plasmids for IVT. After collecting the plasmids from E. coli, we would use enzymes to isolate the DNA template to make the RNA through IVT reactions. (Figure 2) The mRNA structure comprises the RNA coding region, untranslated region, capping, and poly-A tail. (Figure 3) Therefore, we need to add 5′ capping and 3′ poly-A tail to the IVT RNA before purification. The mRNA production is a simple reaction, but several essential elements affect the mRNA efficacy.

Key elements in IVT reaction

First, we need to add a T7 promoter in the DNA template because T7 RNA polymerase is required in the IVT. Second, the RNA coding region should be designed by codon-optimization to prevent the single-strand RNA from forming secondary structure to decrease the efficacy. Third, there is an untranslated region (UTR) on each side of the coding region. Although the UTR would not be translated into protein, these regions could affect the efficacy of mRNA in the cells. Additionally, a good UTR sequence could improve protein production in vitro and in vivo and alleviate the immune response triggered by the mRNA. In the biotech company, the UTR sequences are confidential because they could highly affect mRNA therapeutics’ efficacy. Last, the 5′ cap is also a crucial element in mRNA synthesis. In the COVID vaccine from Pfizer and Moderna, the capping system, CleanCapⓇ is from another mRNA biotech company, Trilink, to minimize the immune response in the body and increase the vaccine efficacy. Therefore, the whole production of mRNA is pretty complicated. I will prepare another blog to introduce the IVT reaction and the following procedure to produce mRNA.

Figure 2, scalable production of DNA template for in-vitro transcription (IVT) reactions.
Figure 3, The mRNA structure comprises the RNA coding region, untranslated region, capping, and poly-A tail.

Lipid nanoparticles production

Next, after purification of capped mRNA with polyA tail, we could mix the mRNA and lipid-like materials to manufacture the lipid nanoparticles (LNP). In the previous blog (introduction to gene therapy), I have introduced how cationic lipid-like materials form LNP under acidic conditions by electrostatic interaction. The critical factor in LNP production is mixing because well-mixing could allow the cationic materials and anionic nucleic acids to form a more compact structure and smaller nanoparticles. To make those mRNA-based LNP with less than 100 nanometers in diameter, we used a microfluidic device with a micromixer to better mix the organic phase (lipid-like materials) and aqueous phase (nucleic acids) by chaotic advection (Figure 4). The smaller size of LNP could prevent liver filtration after administration. Furthermore, another essential step is how we purify the LNP and remove the residuals during the process to minimize the side effects of the mRNA-based vaccine.

Figure 4, microfluidic device with micromixer is used to produce lipid nanoparticles with mRNA.

Conclusion

Although the whole process looks pretty simple, every step in manufacturing is critical to maintaining a safe and efficient vaccine. There is still a lot of work we could do in research to improve the mRNA therapeutics: How we design the coding sequences UTR sequences. How we develop a new capping system and nucleotides to alleviate immune response. Also, currently, all the FDA-approved mRNA-based vaccines are used non-degradable materials to deliver mRNA. Most scientists and biotech companies are working on new degradable materials in RNA therapeutics. Therefore, if you are interested in gene therapy, maybe you could consider contributing to the field of mRNA therapeutics.

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Rapid COVID test would be the key to end the pandemic?

The COVID pandemic might enter the late stage due to the low toxicity of new COVID variants, such as the Omicron variant. However, the omicron variant has high transmissibility than other variants. How could we stop the transmission and end the pandemic? Maybe a rapid COVID test could be the solution. Let’s understand why a quick COVID test would be essential.

There are two types of tests, diagnostic tests and antibody tests. Diagnostic tests are usually used to determine if we have an active COVID-19 infection. If tested for positive COVID, we need to take steps, potential treatment, and quarantine to isolate ourselves from others to prevent transmission. On the other hand, an antibody test is measured to determine the antibodies produced from the immune system in response to the COVID virus. It means that we could not use an antibody test to identify active COVID-19 infection. When should we get a COVID test? There are several conditions, you should do a COVID test, either molecular or antigen tests. 1. If you have any COVID symptoms, including fever or chills, cough, shortness of breath (difficulty breathing), fatigue, muscle or body aches, headache, loss of taste or smell, sore throat, congestion, or runny nose, nausea, or vomiting, diarrhea. Even you are fully vaccinated, you should have a COVID test. 2. If you have had close contact with someone who tested positive for COVID-19. The definition of close contact is to stay with a COVID-positive person within 6 feet for more than 15 minutes. 3. If you had any activities that might put you at high risk for COVID-19, such as traveling, attending a significant social event, crowded indoor gathering. Last, sometimes the workplace or school might establish a screening program to maintain a COVID-free environment. Depending on the program regulation, you might need to do the COVID test weekly.

Figure1, the real-time viral RNA replicates through reverse transcription-polymerase chain reaction (RT-PCR), and the cycle threshold (Ct) value is measured. When the Ct value is smaller, the higher the viral RNA is measured.

The diagnostic tests consist of molecular tests and antigen tests. The primary method is nucleic acid amplification tests (NAATs) in the molecular test. Its amplifying methods are divided into two groups, reverse transcription-polymerase chain reaction (RT-PCR), isothermal amplification including nicking endonuclease amplification reaction (NEAR), transcription-mediated amplification (TMA), loop-mediated isothermal amplification (LAMP), helicase-dependent amplification (HDA), clustered regularly interspaced short palindromic repeats (CRISPR), strand displacement amplification (SDA). Both amplifying methods measure the amount of viral RNA in the body, but the isothermal amplification method might shorten the time to get the Ct (cycle threshold) value. What is Ct value? In the RT-PCR, we used the fluorescent probe to measure the total amount of RNA in each cycle, and the number of cycles reaching the threshold is called the Ct value. In other words, when the Ct value is lower, there are more viral RNA to be detected. In current regulations, there is no standard for Ct value in NAATs. In general, the test result would be positive in COVID-19 viral RNA detection when the Ct value is between 35-40. This is why some people might receive a negative COVID test before the international flight but for a test positive after entering the U.S. On the other hands, the antigen test measures the protein from the virus to identify the infection. Usually, the antigen test is less sensitive to the COVID virus detection but has a shorter time to receive the result than NAATs. Here is the summary table to compare the NAATs and antigen tests:

Table1. Comparison between NAATs and antigen tests

The antigen test could provide a quick and cheap result to screen people who have a potential infection in a community, but it might need to repeat the test to confirm the result by NAAT. For example, in a community screening, we should use an antigen test as a rapid COVID test to quickly screen the people who might have contact with the COVID-19 virus. If a person does not have any symptoms of COVID-19, and the result of the antigen test shows positive, then this person needs to do additional NAAT to determine whether this person has COVID-19 or not. If a person has COVID symptoms, and the antigen test result shows negative, this person still needs a NAAT to confirm the infection. If the final result is positive in COVID-19, then quarantine would be required to stop the virus transmission. Also, if there is an outbreak in the community, serial testing should be done every 3-7 days until there are no new COVID-19 cases for 14 days.

Figure 2, the COVID-19 viral RNA accumulates in the infected body while the viral antigen also increases in the body for antigen test. The sensitivity of viral detection is higher by NAATs than antigen tests.

In sum, the COVID-19 pandemic might enter the late stage because the new variant shows a high transmission rate but less toxicity to humans, and what we need to do to prevent any recent outbreak from breaking down the medical system is frequent rapid COVID test to maintain a COVID-free environment. Then we could get back to our normal life soon.

Reference:

  1. the U.S. Centers for Disease Control and Prevenetion, www.cdc.gov
  2. Paul Drain, Rapid Diagnostic Testing for SARS-CoV-2. N Engl J Med 2022; 386:264-272 DOI: 10.1056/NEJMcp2117115

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

Omicron, BA.2 subvariant, is it the last variant in the pandemic?

Up to date, the COVID pandemic has not been ended due to the high contagious variant, omicron. The omicron variant has been found in four subvariants, BA.1, BA.1.1.529, BA.2, and BA.3 by World Health Organization (WHO). BA.1 is known as the original omicron variant, which was detected in most countries worldwide in early 2022; however, BA.1 is overtaken by BA.2 in Denmark, Nepal, Philippines, United Kingdom…etc. With the emergence of BA.2, BA.3 and Delta variants gradually disappear in most cases. Since researchers predicted that BA.2 will eventually become the dominant variant globally due to its higher transmission, what do we need to know about this subvariant?

Researchers have claimed that subvariant BA.2 is a stealth variant because, in BA.1 subvariant, it loses one of the three target genes we used in a standard PCR, but BA.2 does not. In other words, with a standard PCR test, if the expected result shows the absence of the particular gene, we could conclude that it is omicron, BA.1. But we could not find the same pattern in BA.2 and easily missed spotting this variant. That is why we call it a stealth variant. However, in my opinion, it is not invisible to us, and the only reason we cannot detect it is due to the wrong technique. Also, according to the evolution tree, BA.2 subvariant has been found on a different track than the original omicron subvariant, BA.1. Therefore, scientists have argued whether we need to set Omicron BA.2 as a new COVID variant.

On the other hand, in a report from Denmark, Omicron BA.2 has been found to have a higher transmission rate than BA.1 subvariant because of these different mutations. Additionally, BA.2 subvariant has been the dominant subvariant of COVID-19 in Denmark since January 2022. In the study, scientists collected the data to follow the spreading of Omicron variants within Danish households from December 2021 to January 2022. The result shows that the secondary transfection rates from infected people are 29% and 39% with Omicron BA.1 and BA.2, respectively. This means that BA.2 subvariant could be spread out more quickly than BA.1 subvariant and other COVID variants. In the study, BA.2 subvariant would have a higher possibility for breakthrough infection in fully vaccinated individuals and those with booster vaccination. Also, scientists found that the transmissibility of BA.2 from unvaccinated primary cases is increased when compared to BA.1. Fortunately, researchers did not observe the same pattern in vaccinated individuals. That is, although the BA.2 subvariant could infect fully vaccinated people with and without booster shots, these vaccinated people are less likely to spread the new COVID Omicron BA.2 subvariant. It seems that COVID vaccine could potentially stop the spread of Omicron BA.2 subvariant.

The cumulative COIVD-19 cases by date. The figure was adapted from Johns Hopkins University on 2/9/2022

In the original Omicron variant, BA.1, animal studies and clinical data have shown that BA.1 subvariant is less toxic to humans because it mainly accumulates in the upper respiratory tract and less in the lower respiratory and lung. It means more minor damage to the lung and a lower severity/death rate. And now we are curious that what about subvariant BA.2? Although we do not know the toxicity of BA.2 yet, in the current data, which claimed that Omicron subvariant BA.2 is likely to have the same severity rate as subvariant BA.1. Moreover, at the end of January 2022, Denmark decided to lift all the domestic COVID-19 related restrictions, including wearing masks, despite the increase in COIVD cases. This might indicate that although the omicron variant is more contagious, this virus no longer qualifies as a critical threat to the country with a high vaccination rate. More than 80% of the population has been fully vaccinated in Denmark, and over 60% have received the booster shot. This is excellent news to us to know that the end of the pandemic might be close. However, even though the Omicron variant has a lower severity rate, its high transmissibility might cause the crush of the medical system. For example, the new COVID cases by omicron variant since December 2021 has reached ~20% of the cumulative cases in the United States. This is an alarming number to me. Within 2 months, more than 20 million cases were reported in the United States, and these cases might break down the medical system. In sum, to end the pandemic, please wear a surgical mask (N95 or KN95 are even better.) and get COVID vaccine. With these, I believe that we could have our regular lives soon.

Reference:

  1. Johns Hopkins University, Coronavirus resource center
  2. Meredith Wadman, Scienceinsider 2022 doi: 10.1126/science.ada0810
  3. UK Health Security Agency
  4. Frederik L. et al, “Transmission of SARS-CoV-2 Omicron VOC subvariants BA.1 and BA.2: Evidence from Danish Households”, medRxiv, doi: https://doi.org/10.1101/2022.01.28.22270044 

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Rejuvenation, next generation therapeutic could transform our lives in 10 years?

Aging is one of the reasons that scientists work hard to do biomedical research, however, rejuvenation is an unreachable dream. Especially in fiction movies, rejuvenation is always a key element. Is it possible to let people keep young-looking forever? How does it work? If so, how does it change the current biomedical industry or even the cosmetic industry?

The first thing I would like to introduce is “Yamanaka factors,” which brought Kyoto University researcher Shinya Yamanaka to win the Nobel prize in 2012. What are Yamanaka factors? Four transcription factors (Oct3/4, Sox2, c-Myc, and Klf4) are the Yamanaka factors, and they could be applied to reprogram somatic cells into pluripotent stem cells. In other words, with Yamanaka factors, we could generate unlimited stem cells from people or any patients who need organ transplantation. We could think of the stem cells as age zero because every fetal is grown from embryonic stem cells, and the Yamanaka factors could induce the cells from a mature state to the original condition. This fact allows scientists to think about rejuvenation; what if we only partially reprogram the cells? Is it possible to make the cells younger? In 2020, Dr. Sinclair and his group used the adenovirus-associated virus (AAV) to deliver three Yamanaka factors to restore vision in mice, and this work has been published in Nature. Also, Dr. Vittorio Sebastiano and his group demonstrated how Yamanaka factors with two additional factors (LIN28 and NANOG) reverse the epigenetic methylation of cytosine-guanine dinucleotides (CpG) on DNA to make the human cells younger with restored regeneration. Here, I would like to explain what epigenetic methylation is and what epigenetic clock is? First, CpG islands are the region on DNA that could be added a methyl group (CH3 group), and the DNA methylation could regulate gene expressions. In this hypothesis, stem cells would have less methylation of CpG on DNA. Second, with epigenetic methylation, a new definition of age is epigenetic clock/age, calculated and measured by the change in DNA methylation and the biomarkers of age. It is different from the chronological age counting by time, but epigenetic age is measured by the methylation of DNA. An exciting discovery is that the rate of epigenetic aging is slower in supercentenarian and their descendants. This might explain why those people could live longer than others. On the other hand, previous studies give us hope that if we could use the Yamanaka factors to partially reverse epigenetic methylation frequently, we might make dreams come true that we all become centenarians and have young-looking forever.

With the potential as therapeutics, several companies have been found to develop anti-aging as rejuvenation therapy. For example, Calico Life Sciences/Alphabet, which was founded by Bill Maris and Arthur Levinson in 2013, focuses on basic research in partial reprogramming mechanisms. Life Biosciences which was found by David Sinclair and Tristan Edwards in 2017, focuses on using AAV to deliver reprogramming factor genes. Turn Biotechnologies which was found by Vittorio Sebastiano, Marco Quarta, and Jay Sarkar in 2019, focuses on mRNA-based delivery of reprogramming factors. Last, a newly launched biotechnology company, Altos Labs, which is invested by the founder and former CEO of Amazon, Jeff Bezo, focuses on transforming medicine through cellular rejuvenation programming. The company has three Altos Institutes of Science based in the San Francisco Bay Area, San Diego, and in the UK (Cambridge). In the increase in aging research and newly launched biotech companies, maybe rejuvenation is a potential therapeutic to extend average human life; however, the current research only accomplished the epigenetic reprogramming in a rodent model and human cells in vitro. I believe it will not be an easy task to reverse the epigenetic methylation in non-human primates and also in humans. The four Yamanaka factors are not enough to completely reprogram the cells in the body. Therefore, there will be a lot of things we could do in the aging research, especially after the COVID-19 pandemic, mRNA therapeutic becomes a very popular tool to deliver genes in the human body, for instance, the COVID vaccine.

In sum, rejuvenation was a myth story to us, but with accelerated development in biotechnology, anti-aging would be accomplished and improve human health in the next decade.

Reference:

  1. Michael Eisenstein, nature biotechnology 2022 https://doi.org/10.1038/d41587-022-00002-4
  2. Sarkar, T.J., Quarta, M., Mukherjee, S. et al. Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells. Nat Commun 11, 1545 (2020). https://doi.org/10.1038/s41467-020-15174-3
  3. Lu, Y., Brommer, B., Tian, X. et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature 588, 124–129 (2020). https://doi.org/10.1038/s41586-020-2975-4
  4. Chiavellini P, Canatelli-Mallat M, Lehmann M, Gallardo MD, Herenu CB, Cordeiro JL, Clement J, Goya RG. Aging and rejuvenation – a modular epigenome model. Aging (Albany NY). 2021; 13:4734-4746. https://doi.org/10.18632/aging.202712
  5. Altos Labs company website

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

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 a 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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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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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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