Voices from A*STAR

  • Jenner’s Legacy, Part 2: Challenges in Creating Ideal Vaccines for Modern Infectious Diseases

    ImmunologyVaccination

    Kaval Kaur

    Research Fellow

    Singapore Immunology Network

    The Singapore Immunology Network (SIgN) aims to advance human immunology research and participate in international efforts to combat major health problems. Researchers at SIgN investigate immunity during infections and inflammatory conditions, including cancer, using both mouse models and human tissues.

    Welcome to Part 2 of Jenner’s Legacy.  Following on from my discussion of Jenner’s pioneering work in smallpox vaccination, here I will explain why it’s so difficult use this approach to develop ideal vaccines for influenza and dengue.

    Inoculating against Influenza

    Influenza is a viral disease that we are all too familiar with.  Although we often think of the influenza virus as a single pathogen, the virus is in fact extremely varied.  There are two main types of influenza viruses that infect humans, influenza A and B, and these are further characterized into different subtypes and lineages.  Within each subtype, there are also numerous strains.  A wide variety of influenza strains exist because the influenza virus is continuously evolving through an ongoing process of mutations, which alters its surface proteins.  New influenza strains also emerge when two or more viruses present in a single host recombine their viral segments to generate a dramatically different strain, such as the most recent 2009 pandemic H1N1 strain.

    The ability of the influenza virus to constantly mutate and change allows it to fool the body’s natural immune response.  Our body’s immune system combats the influenza virus by producing antibodies that bind to the virus’s surface proteins.  If these surface proteins were constant from one strain of influenza to the next, Jenner’s methodology for vaccines would work brilliantly with the power of immunological memory, saving millions from the horrors of flu season every year.  Unfortunately, it is precisely the variable surface proteins to which majority of the antibodies of the immune system bind.

    However, that does not mean that antibodies produced from an influenza vaccination are entirely without use.  Antibodies produced in response to a particular strain of influenza are effective in protecting the body from future infections of that particular strain and similar strains.  In fact, this effect is the primary driving force behind the modern influenza vaccine that millions take each influenza season.  Every one to three years, the influenza vaccine is reformulated to contain the strains that are predicted to circulate in the upcoming influenza season.  When the vaccine strains match the circulating strains, there is good protection against influenza infections.  However, the predictions of which strains will circulate in a particular influenza season are not always accurate, and they cannot account for the unexpected emergence of recombined strains.  When mismatches between vaccine strains and those that infect in a given season occur, the vaccine does not provide the desired level of protection.  Hence, while the current influenza vaccine has tremendously reduced influenza infections and deaths, it is not yet an ideal vaccine that can provide complete coverage against all influenza strains.

    Mounting a defense against dengue

    Similarly, the dengue virus is another infectious agent characterized by many different virus types.  There are four distinct serotypes of dengue viruses (DENV1 to DENV4) that share 60–80 per cent similarity to each other.  To provide coverage against all 4 serotypes of the virus, the simplest strategy for a vaccine is to include all four serotypes in the vaccine formulation.  Indeed, Dengvaxia, the first dengue vaccine to be approved for human use in Mexico, Philippines and Brazil, employs this approach.  While Dengvaxia provides strong protection against severe dengue, it is far from a perfect vaccine.  Efficacy against each serotype is varied, with the lowest efficacy seen for DENV2, at only 42 per cent.  Furthermore, due to lower efficacy in the young and old, the vaccine is only approved for persons between the ages of 9 and 45, leaving vulnerable age groups without any protection.  Scientists are still trying to determine why such an approach to dengue is not entirely effective and why Dengvaxia fails to be the one-stop solution for dengue.

    Even though the diversity of the dengue virus poses some challenges for dengue vaccine development, it is really the nature of our natural immune responses against dengue that have scientists truly stumped. Upon first infection with any one of the four serotypes of dengue, our immune system gets activated and produces antibodies that bind not only to the infecting serotype but also the other three.  Referred to as cross-reactive antibodies, these kinds of antibodies against viruses are generally beneficial as they can provide a wide breadth of protection against future infections with different strains.  However, this is not the case with the dengue virus.  For reasons still unclear to scientists, cross-protection for the other serotypes is only short-term and life-long immunity is achieved only against the infecting serotype, but not the other three serotypes. Further, previous infection with dengue actually puts a person at risk of having more severe dengue upon secondary infections with different serotypes! This is a significant problem in regions where dengue is endemic and individuals are often infected more than once.  Scientists believe that although normally, antibodies with viruses bound are taken up by innate immune cells for the viruses to be destroyed within the cell, during a secondary dengue infection, cross-reactive antibodies weakly bound to dengue virus actually serve to facilitate viral entry into the immune cells, where the virus replicates and increases the level of infection.  Manipulating our immune responses to prevent such a phenomenon will be crucial in reducing the severity of secondary infections with and is currently a vibrant area of investigation.

    Moving beyond Jenner 

    While Jenner’s insights were brilliant and have revolutionized modern immunology, his straightforward approach to vaccination does not work for all infectious agents and we have many infectious diseases today that remain ‘unsolved’. Research on developing effective vaccines must now focus on rational vaccine design tailored to the complexities and nuances of a given infectious agent.  Vaccine formulations can no longer be restricted to contain solely dead or weakened whole viruses or bacteria.  Instead, scientists must make informed decisions by identifying the components of disease-causing agents that are most relevant for our immune system to recognize and develop long-lasting memory.  For instance, to get ahead of the ever-changing influenza virus, scientists are trying to reinvent the influenza vaccine by directing their research efforts on those vital viral proteins that do not mutate from strain to strain, but instead remain constant in all influenza types. In the case of dengue, while several other vaccine formulations are being tested in clinical trials, research efforts are focused on bridging our knowledge gaps on the interaction between our immune system and the dengue viruses.

    My research is focused on furthering our understanding of the characteristics of human antibody responses during primary and secondary dengue infections.  There is still so much we don’t understand about human immune cell responses after a dengue infection.  As we learn more about how our immune system responds to the dengue virus and what is needed to acquire long-term protection, we can uncover strategies that can be leveraged during vaccine design.  And so, scientists like myself will continue to work at finding the answers to the problems posed by disease-causing agents like the influenza and dengue viruses. Hopefully, our answers will come sooner rather than later and we can rid the world of two more infectious diseases.  

    Dr. Kaval Kaur is a research fellow in Katja Fink’s laboratory at the Singapore Immunology Network. She was awarded the NSS-PhD scholarship to study immunology at the University of Chicago. She enjoys many different topics within immunology, but it is the interplay between viruses and the immune system that has always captivated her. Her research interests include the role of B cells and antibodies in the fight against the many viruses that invade us and investigating how we can manipulate the responses of the immune system for vaccine development. For her graduate studies, she focused on influenza and now, at SIgN, she has turned her attention to dengue.

  • Jenner’s Legacy, Part 1: How Smallpox Was Eradicated with Vaccination

    ImmunologyVaccination

    Kaval Kaur

    Research Fellow

    Singapore Immunology Network

    The Singapore Immunology Network (SIgN) aims to advance human immunology research and participate in international efforts to combat major health problems. Researchers at SIgN investigate immunity during infections and inflammatory conditions, including cancer, using both mouse models and human tissues.

    Over 200 years ago, smallpox was devastating humankind — 20 to 60 per cent of infections were fatal and those who survived were plagued with disfiguring scars and often went blind.  The deadly disease was feared by everyone except milkmaids, who intriguingly were immune.  An English physician and scientist, Edward Jenner, observed that milkmaids had blisters caused by cowpox, a disease similar to smallpox but much less dangerous, and hypothesized that having cowpox protected these milkmaids from smallpox.  In 1796, he went on to test this experimentally.  He took pus from the fresh cowpox blisters of a milkmaid and inoculated an 8-year-old boy — while it may be disconcerting from a modern viewpoint, inoculation was a standard medical practice at that time. Weeks later, Jenner inoculated the boy again, this time with pus from fresh smallpox blisters.  The boy did not contract smallpox and it was concluded that he was protected from the deadly disease.

    This simple, yet incredibly significant, piece of evidence went on to lay the foundations of vaccination and revolutionize modern immunology.  Scientists quickly realized that Jenner’s strategy of vaccination — inoculating a person with a less dangerous version of the disease-causing agent to provide future protection against the disease — was a powerful tool to tackle a host (no pun intended) of infectious diseases.  Over the years, the crowning glories of immunology have been the successes of vaccines as diseases such as smallpox, Rinderpest, and wild polio type 2 have been eradicated, while many others such as measles, mumps, rubella, tetanus and diphtheria have been significantly controlled and are on the road to elimination.

    While Jenner’s strategy of vaccination has been successfully validated time and time again over the past two centuries, it is only in recent years that scientists have determined how vaccination actually works.  When vaccines containing dead or weakened disease-causing agents — such as viruses or bacteria — are injected into the body, they prime the immune system to react, but do not actually trigger the disease.  Cells of the immune system recognize the vaccine components as foreign and launch an immune response, reacting as if it was a real attack.  Antibodies are produced, and activated immune cells go on to populate the long-term memory compartments of the immune system.  If the body encounters the same disease-causing agent in the future, pre-existing antibodies will neutralize it while memory cells will react rapidly to clear the invader before it can gain a foothold and cause disease.  The ability of vaccines to harness the power of immunological memory and provide future protection against disease gave the scientific community confidence that we had capacity to fight against all infectious diseases.

    Unfortunately, as scientists began applying Jenner’s methodology of smallpox vaccination to other infectious diseases, it became clear that his strategy was not a ‘one-size-fits-all’ approach.  Numerous diseases present challenges that make developing highly effective vaccines, with the dead or weakened versions of the disease-causing agent, very difficult.  Influenza and dengue, are excellent examples of such diseases — both are caused by complex viruses and the body’s natural immune response to them makes Jenner’s straightforward approach to vaccination fall short. 

    Stay tuned for Part 2 of Jenner’s Legacy, in which I will discuss the challenges in developing vaccines for Influenza and dengue.

    Dr. Kaval Kaur is a research fellow in Katja Fink’s laboratory at the Singapore Immunology Network. She was awarded the NSS-PhD scholarship to study immunology at the University of Chicago. She enjoys many different topics within immunology, but it is the interplay between viruses and the immune system that has always captivated her. Her research interests include the role of B cells and antibodies in the fight against the many viruses that invade us and investigating how we can manipulate the responses of the immune system for vaccine development. For her graduate studies, she focused on influenza and now, at SIgN, she has turned her attention to dengue.

  • Can an orange a day keep the doctor away?

    Vitamin CObesity

    Sandhya Sriram

    Programme Management Officer

    Singapore Bioimaging Consortium

    The Singapore Bioimaging Consortium (SBIC) aims to build a coordinated national programme for imaging research, bringing together substantial strengths in the physical sciences and engineering and those in the biomedical sciences. It seeks to identify and consolidate the various bioimaging capabilities across local research institutes, universities and hospitals, in order to speed the development of biomedical research discoveries.

    © Jonathan Paciullo/Moment/Getty

    Everyone has heard about how an apple a day can keep the doctor away. Well, I have a different take on it — use an orange instead!

    Having worked with antioxidants and oxidative stress (harmful free radicals) for about a decade now, I am convinced that antioxidants are the way to go to prevent or relieve the symptoms of certain diseases — they also help to keep you energetic by detoxifying your body.

    Vitamin C, an antioxidant, is abundant in citrus fruits like oranges, lemons, and limes as well as papayas, guavas, pineapples, and my personal favorite, berries. Vitamin C supplementation has been shown to lower the risk of stroke, relieve common colds, protect against immune system deficiencies, prevent cardiovascular diseases, maintain healthy and wrinkle-free skin and improve eye health. My research, in particular, focuses on the effect of Vitamin C on obesity.

    Excess fat or ‘adipose tissue’ is what leads to obesity and adipose tissue like every other organ consists of stem cells. A stem cell is an undifferentiated cell which is capable of giving rise to more cells of the same type, or of certain different types of cells upon appropriate triggers. My work entails identifying inherent differences during obesity in adipose stem cells from different depots of fat — mainly, subcutaneous fat (‘good’ fat that helps you burn calories, located below the skin) and visceral fat (‘bad’ fat that stores calories, located around the abdominal organs).

    Obesity is a pandemic affecting majority of the world’s population. According to the World Health Organization (WHO), the world is getting fatter — approximately 850 million people were either overweight or obese in 1980, this skyrocketed to 2,100 million people in 2014!

    Obesity is defined by the Body Mass Index (BMI). According to the WHO; a score between 25 and 30 is considered overweight and anything above 30 is obese. Obesity is a metabolic syndrome that is related to arthritis, cancer, infertility, diabetes, heart diseases, stroke and back pain. The best way to avoid becoming obese and reduce your body weight is to follow the ABC rules — Adopt new healthy habits (bike to work, have a balanced diet, swim etc.), Balance your calorie intake and Control your weight gain. Overall, obesity is definitely a preventable disease.

    Being of Indian origin and having lived in Singapore for about 8 years now, I have always thought that the amount of rice consumed by Asians could be harmful. This feeling has been proven right by the latest report that, in Singapore, 4 in 10 adults are overweight and more than 400,000 are diabetic. These are alarming numbers for a nation that has a population of less than 6 million.

    That is why our lab specializes in identifying key characteristics of adipose stem cells that can contribute to obesity and ways to reduce fat accumulation. My research, in particular, is on the effect of Vitamin C on human subcutaneous and visceral adipose stem cells obtained from obese subjects and the mechanism by which it curbs the excess oxidative stress. For now, I can reveal only so much, but stay tuned for more exciting insights from my research in the near future.

    I can, however, tell you this — have an orange a day and keep the fat away!

    Sandhya is a scientist, entrepreneur, serendipitous journalist and a manager. She lives in Singapore currently and wears many hats – Programme Manager at SBIC, A*STAR; Founder & Director SciGlo; Co-founder & Author, Biotechin.Asia, Biotech Media Pte. Ltd.; and a mother of a very active and inquisitive toddler! Until October 2016, she was a Research Fellow at SBIC and also the Vice President & Publicity Chair of the A*STAR Postdoc Society (A*PECSS).

  • Chemotherapy and Infection: The Transformation from Dr Jekyll to Mr Hyde?

    Mutations

    Flora Teoh

    PhD Student

    Singapore Immunology Network

    The Singapore Immunology Network (SIgN) aims to advance human immunology research and participate in international efforts to combat major health problems. Researchers at SIgN investigate immunity during infections and inflammatory conditions, including cancer, using both mouse models and human tissues.

    Most people's ideas of bacteria and fungi tend to be negative, since we often think of them only as the cause of many human diseases. Yet we must not forget that the average human body is colonized by trillions of microbes belonging to these microbial groups. In fact, it has been estimated that the number of bacterial and fungal cells colonizing a human far exceeds that of the number of cells actually belonging to the human!

    In a healthy person, these microbes do not cause disease — many of them perform important functions, for example during the production of enzymes that break down food, the development of the immune system and even preventing disease from other microbes. This seemingly neutral relationship with the human host can take a nasty turn if the person's immune system stops working properly, which is often the case for cancer patients who are undergoing chemotherapy treatment. Cancer cells proliferate uncontrollably and rapidly, which is a double-edged sword, as uninhibited cell division enables their growth and invasion but makes them highly vulnerable to chemotherapy drugs that work by interfering with cell division and growth processes.

    However there are many healthy, non-cancerous cells such as those of the epithelial surfaces — which line our gastrointestinal and respiratory tract, among other things — and immune system which also need to undergo rapid cell division in order to maintain their function. As chemotherapy drugs do not distinguish between healthy and cancerous cells, these healthy cells become collateral damage in the war between cancer cells and chemotherapy drugs.

    Ironically, a patient could die from side effects resulting from the cancer treatment rather than from the cancer itself. This is because the immune system and epithelial surfaces are important defenses against microbial invasion and infection, and weakening them via chemotherapy treatment makes it more likely for cancer patients to develop infections, even from microbes that normally peaceably reside in the human body.

    Little is known about whether chemotherapy drugs have any effect on microbes themselves, and whether these effects contribute to the development of disease. Why should this be of interest? Because the targets of chemotherapy drugs present in humans, are often also present in microbes.

    As the processes governing cell division and growth are so crucial to life itself, variations within these processes are not well-tolerated or optimal for life, making them highly conserved in an evolutionary sense: simply put, there are very strong commonalities in these processes from the simplest microbe to the most complex mammal.

    Thus, a chemotherapy drug that affects a component in a human cell can also do so in a fungal cell. Moreover, the manner in which chemotherapy drugs act on cells also tend to produce mutations. What then, might these mutations do? Might the microbial population harbored by a cancer patient treated with chemotherapy drugs be more likely to mutate due to exposure to the drug? Might these mutations make them more likely to cause disease or be more resistant to antibiotic treatment: in short, to transform from Dr Jekyll to Mr Hyde? This is one of the main research questions I am studying in Candida albicans, a fungus which is a major resident of the human skin and gastrointestinal tract, yet is also a common cause of dangerous blood infections in cancer patients.

    A note before we end: this post is not meant to demonize chemotherapy drugs, or discourage people from seeking cancer treatment. That chemotherapy is a painful and arduous course to endure cannot be disputed, but we must also acknowledge that it was for many years, the only form of treatment physicians could offer to cancer patients, and before its advent, a cancer diagnosis was effectively a death sentence. Chemotherapy has prolonged the life expectancy of cancer patients, and together with modern medical interventions, can even produce cancer remission. We therefore should endeavor to avoid throwing the baby out with the bathwater. By learning more about how chemotherapy interacts with microbes and the consequences of such interactions, we may eventually be able to prevent such opportunistic infections in cancer patients, anticipate drug resistance and assist physicians in selection of therapy, ultimately improving the outcome of cancer treatments and the life expectancy of cancer patients.

    Flora Teoh received the A*STAR Graduate Scholarship in 2013 and began her PhD in the lab of Dr. Norman Pavelka, which focuses on studying the ecological and evolutionary forces that shape the interactions between Candida albicans, GI bacteria and the immune system. Her PhD project involves studying how chemotherapy influences the disease-causing ability of C. albicans by changing its behavior and genetic makeup. She applies a combination of molecular biology and immunological techniques, genetic manipulation and experimental evolution in her studies. Teoh’s research interests lie in evolutionary processes, genomics and yeast biology.

  • The impact of the media on scientific research

    Science communicationBiotechnology

    Sandhya Sriram

    Research Fellow

    Singapore Bioimaging Consortium

    The Singapore Bioimaging Consortium (SBIC) aims to build a coordinated national programme for imaging research, bringing together substantial strengths in the physical sciences and engineering and those in the biomedical sciences. It seeks to identify and consolidate the various bioimaging capabilities across local research institutes, universities and hospitals, in order to speed the development of biomedical research discoveries.

    © miakievy/DigitalVision Vectors/Getty

    “Did you know that cancer can be cured by eating XYZ (type of food) three times a day for just three months?” asked one of my aunts. I was taken aback and immediately told her that it was nonsense and asked her where she heard or read this so-called ‘information’. It turned out that one of her friends had posted it on her Facebook wall and she had assumed it was true without bothering to check the source of the information.

    Limited awareness and ignorance of biotechnology, biological sciences and its role in society has made it difficult for the general public, such as my aunt, to critically evaluate the veracity of clickbait-style health articles.

    The problem with science stories prepared by the mainstream media is that their focus is on increasing their viewership and subscribers, so they have an incentive to report anything and everything — spoon feeding the audience, with questionable fact-checking. This is exacerbated by the fact that many scientists don’t want to or don’t have the time to talk to journalists or corporate communications about their research and discoveries, or don’t bother to write or speak about it in layman’s terms.

    To bridge the gap in public perception and education of biotechnology and other related sciences scientists, doctors and researchers have a responsibility to engage in science communication, which means discussing their work in an intelligible and audience-friendly way. Science communication generally refers to the communication of science-related topics to non-experts and while it often involves practicing scientists participating in ‘outreach’ activities, it has also evolved into a professional field in its own right.

    My partners, Dr Laxmi Iyer and Prasanna Kumar Juvvuna, and I co-founded Biotechin.Asia, a news website for biotech and healthcare news to communicate fact-based scientific research written by scientists, doctors, medical professionals and researchers. Recently, in September 2016, I launched SciGlo, a one-stop solution for scientists which curates fact-based, reliable, science-related articles from all over the world. Both of these sites sought to provide a platform that represented science and scientists correctly and responsibly interpreted and communicated scientific findings to make it easier for laypeople to have access to credible science news.

    Some research institutes, universities and scientists themselves are revisiting scientific communication. Scientists seem to be more willing to speak to the media about their research. The impact of open access and social media on scientific research is catching on, and scientists are using social media to voice their opinions and let the public know if certain news items are bogus. Overall, scientists have a responsibility to work with the media to deliver the ‘right’ science to the public and make sure it reaches them in a timely fashion.

    Sandhya is a scientist, entrepreneur, serendipitous journalist and a manager. She lives in Singapore currently and wears many hats – Research Fellow at SBIC, A*STAR transitioning to a Programme and Grants Management role; Co-founder & Author, Biotechin.Asia, Biotech Media Pte. Ltd.; and a mother of a very active and inquisitive toddler! On top of all this, she just launched another startup and web platform to help scientists and students all over the world, called SciGlo. She is also the former Vice President & Publicity Chair of the A*STAR Postdoc Society (A*PECSS).

  • Cleaning up chemistry

    Green chemistry

    Russell Hewitt

    Scientist II

    Institute of Chemical and Engineering Sciences (ICES)

    ICES was established as an autonomous national research institute under A*STAR on October 1st 2002. ICES has established world leading laboratories, pilot facilities, and the necessary infrastructure to carry out a world class research programme in chemistry and chemical engineering sciences.

    Chemical manufacturing is a huge industry that delivers much needed chemicals to a variety of industries. Almost all of the everyday things we buy or use have been made in part with man-made chemicals. Laws and regulations strictly control the use of chemicals to ensure that the chemicals we are exposed to are not harmful to consumers.

    Chemists want to make the chemicals cheaply, but the manufacturing process should still be safe. This is important, not just for worker safety, but also for the environment and for the public who could suffer due to accidents at chemical plants.

    News of chemical spills or explosions make for very scary reading. The latest most widely publicized one was the Tianjin explosions in 2015, which were started by chemicals that most chemists definitely wouldn’t want to work with, such as the explosive nitrocellulose. But this is not an isolated case — there have been many instances of huge explosions or severe accidents occurring at chemical plants or storage facilities. The Bhopal disaster, for example, which was caused by the release of a highly toxic chemical used to manufacture an insecticide, is regarded as the worst industrial accident of all time.

    Chemists can learn from these horrible stories, however, and try to clean up our operations. For example, we learned that by redesigning the synthesis process the toxic chemical that caused the Bhopal disaster could have been avoided. Thus by changing the reactions we set into motion, we can improve our processes, making safer chemicals in a safe way.

    So how do we do this? When chemists first design a synthetic process we often go for the ‘tried and true’ methods, which typically use more potent chemicals that are often explosive, very toxic and highly flammable — so we need to be really careful when carrying out the process! With a little work however, many of these chemicals can be replaced with milder choices. We try to make the whole process safer both for the people doing the work and for the environment — this is called green chemistry. If a chemical product is manufactured using green chemistry practices, a scenario such as the Bhopal disaster should not occur.

    The great thing is, greener is often cheaper! Removing harmful chemicals means you cut costs associated with safety precautions. By careful design, we also can reduce the amounts of chemicals we use, cutting cost even more! As a result, green chemistry is now a huge focus for chemical manufacturing.

    The biggest impact we can make to improve our processes in this manner is in solvent reduction. Chemists use solvents to dissolve our chemicals so we can make sure they mix and react together well, but we often use much more than we need. It is important to both reduce our consumption of these solvents and to remove the worse solvents in a process. Historically, diethyl ether, an explosive and extremely flammable solvent, was used for anesthesia — until doctors tired of explosions at the operating table and the resulting fatalities. Dichloromethane, a potent environmental polluter, is another solvent of concern, especially due to its high volatility. It is often used in paint thinners, but despite its relatively low toxicity, it has caused over 50 deaths since 1980 in the US alone. Because of these hazards, these solvents and others are either banned or are in the process of being phased out in drug manufacturing. In fact, the pharmaceutical industry is actually the front runner in this movement, with many voluntarily banning or reducing the use of harmful solvents.

    Chemists are now trying to make our processes green as early as possible both to improve throughput and hasten the development toward commercial production. Ultimately this delivers the chemicals we need, in quantities that we can use, with a holistic view on safety for workers, the public and the environment.

    Dr Russell Hewitt is an organic chemist whose work covers carbohydrates, green chemistry and scale-up. He obtained his PhD from Victoria University of Wellington, New Zealand in 2010.

  • White coats to Bowties, Part 2: Changing perspectives

    ImmunologyCancer

    Hweixian Penny

    Research Fellow

    Singapore Immunology Network

    The Singapore Immunology Network (SIgN) aims to advance human immunology research and participate in international efforts to combat major health problems. Researchers at SIgN investigate immunity during infections and inflammatory conditions, including cancer, using both mouse models and human tissues.

    Thank you for returning to White Coats to Bowties. In Part 1, I described the rise of cancer immunotherapy. Here, I will describe current therapeutic approaches in cancer immunotherapy and discuss the change in perspective needed in the design of new cancer treatments.

    The current therapeutic approaches of cancer immunotherapy can be broadly categorized into three main areas: non-specific, monoclonal antibodies (mAbs) and cell-based therapies.

    Non-specific immunotherapies include cytokines and other immune stimulators. They are often viewed as adjuvants that boost the immune response.

    mAbs bind to specific antigens on target cells and facilitate tumor destruction in different ways. They can carry drugs or toxins to tumor cells; tag a tumor cell for killing by immune cells; block or activate signaling pathways on target cells to alter growth and proliferation – this is the category checkpoint inhibitors fall under.

    Immune cells naturally utilize ‘checkpoint’ proteins to control and suppress the immune response after a pathogen is cleared, to ensure that the immune response does not persist unnecessarily. T cells have checkpoint proteins like CTLA4 and PD1 that act much like brakes on a vehicle. Engagement of these proteins suppress activation of the T cells. One of the Machiavellian ways that tumors circumvent an immune response against it is by upregulating CTLA4 and/or PD1, effectively staving off the killer attack from T cells. Checkpoint inhibitors get around this by releasing the brakes and unleashing the T cells to launch an unbridled attack against the tumor.

    Cell-based therapies consist of harvesting the patient’s own immune cells, stimulating and/or genetically engineering them to better recognize tumor cells ex vivo (outside the body) and re-infusing these immune cells back into the patient. These ex vivo modulations to the patients’ T cells equip them to dispatch the tumor more effectively upon re-infusion. Currently however, Adoptive T Cell Therapy (ACT) is a boutique therapy that awaits scalability.

    Despite all the good news, the field is not naïve. Decades of naysayers have taught us to reflect deeply on the full spectrum of clinical, regulatory and manufacturing challenges that this market faces.

    Not surprisingly, checkpoint inhibitors work so well in killing tumor cells that they inadvertently attack normal tissue as well and can have serious, though treatable, side effects.

    For cancer immunotherapy, several modifications to trial design will help to fine-tune the review criteria. First, the one-dimensional Response Evaluation Criteria In Solid Tumors (RECIST)-defined criteria used for response rates in traditional chemotherapies is not sufficient. In the context of immunotherapy, immune cells often flood the tumor site, resulting in what appears to be an increase in tumor size initially, thus it may take several months before the tumor visibly regresses. Second, the immune response against the tumor often elicits fevers due to its natural ‘pyrogenic’ — or fever inducing — effect. These fevers should not be classified as a negative side effect, as they would in traditional drug development studies. Thirdly, there is a need to define patient responder populations by enforcing a biomarker-driven patient sub-selection strategy. Fourthly, a careful choice of primary endpoints is pivotal. Regulators often desire overall survival but in the context of cancer immunotherapy, it may be prudent for the FDA to emphasize clinical outcomes such as progression-free survival or surrogate endpoints that demonstrate a very strong correlation with extended survival and are true indicators of real medical benefit.

    Manufacturing is yet another glaring hurdle in terms of scalability of cell-based therapies. Specialized cell production facilities which can engineer and distribute large quantities of cells that comply with Good Manufacturing Practices (GMP) standards will only exist if companies are convinced of their long-term profitability.

    Recently, investigators everywhere have rushed to try all sorts of combinatorial therapies in a haphazard fashion, hoping to hit the jackpot. However, we should take a rationally designed approach to find targeted therapies based on well-understood immune or tumor escape mechanisms. This way, we do not devalue our patients’ lives and the decades of hard science that we have fought so hard to be validated for.

    After decades of focusing on cancer genetics, it is now clear that a shift in perspective is required. No longer can the genetic view of cancer dominate how we design new treatments. The ideal treatment regimen would be one that delivers a one-two punch in which the tumor is crippled intrinsically and the immune system marshals an attack extrinsically, retaining immunologic memory in the event of recurrence.

    As tumor immunologists of this era, we went from being vilified to vindicated, chaffed to championed, discredited to distinguished. Yet we bear in mind the many challenges we face as we bask in the prevailing exaltation. We remember all the nameless scientists, who never donned suits or bowties for prize ceremonies — just their plain white coats. They, together as a community made the momentous discoveries upon which we built the armory for our current siege against the disease.

    In my work here in Singapore, collaborations with clinicians like Toh Han Chong from the Singapore General Hospital and Angela Pang from the National University Hospital, local superheroes who run several concurrent clinical cancer trials, continue to inspire and encourage me with their persistent efforts.

    Recently, I sat in a 500-strong audience at a cancer inflammation conference. At the podium was Jim Allison, delivering his closing address. I saw with my own eyes the survival data that had dazzled scientists and oncologists alike and could not help but be blown away myself. I thought of a friend whose mother succumbed to metastatic melanoma years ago, and I struggled to fight back hot tears thinking how she might still be here today if she had received immunotherapy. But then I thought of my son’s grandmother, with her scarlet hair and pale skin under cloudless Kansas skies, and knew that if her melanoma ever came back to haunt her, we would be ready.

    Hweixian Leong Penny is a research fellow in Wong Siew Cheng's laboratory at the Singapore Immunology Network. She was awarded the NSS-PhD scholarship to study at Brown University for her Bachelor's and then at Stanford University for her graduate degree, where she majored in immunology at both schools. Her primary interest has always been cancer, but she concluded midway through freshman year in college that the best way to battle tumors was by manipulating the body's natural self-defense mechanism — the immune system. By studying immunometabolism in both mouse tumor models and patient samples, she has been on a rescue mission ever since.

  • White coats to Bowties, Part 1: The silent coup d'état of Cancer Immunotherapy

    ImmunologyCancer

    Hweixian Penny

    Research Fellow

    Singapore Immunology Network

    The Singapore Immunology Network (SIgN) aims to advance human immunology research and participate in international efforts to combat major health problems. Researchers at SIgN investigate immunity during infections and inflammatory conditions, including cancer, using both mouse models and human tissues.

    In his Pulitzer prize-winning book, Mukherjee bestowed on cancer the title “The Emperor of all Maladies”. In 2010 when the book was published, there was little room for disagreement. Today however, with the rise of cancer immunotherapy, a treatment regimen that harnesses our immune system to launch an attack on the tumor, Mukherjee would find pause to reconsider.

    The concept that our immune cells can respond to an aberrant growth of self-cells is not new. In the late nineteenth century, Coley, a young surgeon from New York, deliberately infected his cancer patients with bacteria, curing nearly a quarter of them, a statistic astounding even by today’s standards. However, scientists then did not fully understand the mechanisms that underlie infection or tumor regression, and Coley’s work was dismissed and faded into oblivion.

    In 1957, Burnet and Thomas put forth the Cancer Immunosurveillance theory, in which they propose that immune cells are able to survey, recognize and eliminate nascently-growing tumor cells in the body. Subsequent decades of research buttressed this hypothesis. It is now understood that the immune response to tumors is as follows. Antigen-presenting cells (APCs) roam and survey the body for ‘foreign’ cells such as tumor cells. The APCs capture and process the tumor material and present it to immature T cells in lymph nodes. This presentation process activates the T cells to proliferate, spew out cytokines and mature.

    The maturation process has several downstream effects. Some T cells become effector T cells, which call on another type of immune cell, the B cell, to produce anti-tumor antibodies. Other T cells become killer T cells that traffic back to the tumor and eradicate tumor cells. A subset of T cells retain memory of the tumor antigen so that the body can rapidly respond to a second encounter.

    With the surge of cancer immunotherapy these concepts are now widely-accepted — printed over and over again in the highest-quality journals in the world and shouted from the mountaintops. The sad truth is that it was not always this way.

    In my first cancer biology class in college, my Russian professor introduced us to the six hallmarks of cancer, as detailed in the seminal treatise by Hanahan and Weinberg in 2000. I had recently decided on an immunology major, and was alarmed that there was no sign of immunology anywhere in the Hanahan and Weinberg paper.

    In graduate school, my professors asked the cancer biology class to raise their hands if they believed that there was an immune response to cancer. I raised my hand without hesitation, only to whip my head around the classroom to see that the only other hands raised were my fellow immunologists.

    I was beyond flabbergasted. The year was 2006. I held my ground even though I believed staying in the tumor immunology field could mean flying in the face of ridicule, and facing an uphill battle the rest of my career. Thankfully, my misgivings proved unfounded. In a span of a few short years after the turn of the decade, events in the burgeoning cancer immunotherapy pipeline brought about a renaissance.

    In 2011, Hanahan and Weinberg published a revision of their initial discourse on the Hallmarks of Cancer. The manuscript now included Immune Evasion. In late 2010, the US Food and Drug Administration (FDA) approved the first therapeutic cancer vaccine for prostate cancer. Within a few years after, three checkpoint inhibitors received approval for advanced melanoma. The data turned heads and silenced critics. Science magazine unabashedly pronounced cancer immunotherapy as “Breakthrough of the Year” in 2013. Tumor immunologists all around the world held hands and celebrated.

    Stay tuned for White Coats to Bowties, Part 2 where I will describe current therapeutic approaches in cancer immunotherapy and discuss the change in perspective needed in the design of new cancer treatments.

    Hweixian Leong Penny is a research fellow in Wong Siew Cheng's laboratory at the Singapore Immunology Network. She was awarded the NSS-PhD scholarship to study at Brown University for her Bachelor's and then at Stanford University for her graduate degree, where she majored in immunology at both schools. Her primary interest has always been cancer, but she concluded midway through freshman year in college that the best way to battle tumors was by manipulating the body's natural self-defense mechanism — the immune system. By studying immunometabolism in both mouse tumor models and patient samples, she has been on a rescue mission ever since.

  • Surface Structuring — From 2D to 3D

    Biomedical engineering

    Qunya Ong

    Scientist

    Institute of Materials Research and Engineering (IMRE)

    A*STAR's Institute of Materials Research and Engineering (IMRE) is a research institute with a unique combination of R&D capabilities, commercial partnerships and strategic alliances. Comprehensive materials-related solutions for global and local partners are developed here at IMRE.

    A nanoinjection molded lens with anti-reflective structures. It emits a beautiful, deep blue hue when tilted at a particular angle as its surface structures strongly reflect the blue wavelengths.

    A nanoinjection molded lens with anti-reflective structures. It emits a beautiful, deep blue hue when tilted at a particular angle as its surface structures strongly reflect the blue wavelengths.

    © 2016 A*STAR Nanoimprint Foundry

    Biomedical engineers are used to applying engineering principles to solve problems in biology and medicine. As a biomedical engineer by training, I find it interesting that the converse is also true — the world of biology can be a source of inspiration for engineering designs. In the last few decades, micro/nano-scale structures, discovered on the surfaces of plants and animals, have been found to confer multiple and inherent surface functionalities. Examples range from the lotus leaf to the moth’s eye. The lotus leaf is resistant to both water and dirt due to the randomly distributed micron-sized bumps, covered by branch-like nanostructures, on its surface. The surface topography of the moth’s compound eye, consisting of arrays of microsized lenses called ommatidia that are further patterned with dome-shaped nanostructures, give rise to anti-reflective and anti-fogging properties.

    Our team at the A*STAR Nanoimprint Foundry has fabricated numerous bioinspired micro- and nano-scale topographical features on thin films via nanoimprint technologies. Surface properties that have been achieved include anti-reflection, anti-fogging, water pinning, superhydrophobicity, superhydrophilicity, and biofilm-reducing.

    Engineering functionalities through surface structuring is a highly attractive approach as it does not require the use of chemicals and offers a durable and environmentally friendly solution. Besides nanoimprinting on thin films, we have recently come up with an elegant solution to incorporate micro/nano structures on the surfaces of free-form three-dimensional (3D) everyday products via nanoinjection molding. Our nanoinjection molding technique integrates inserts with micro/nano-scale features into existing injection molding processes, enabling easy adoption at minimal additional cost. Using this novel technology, we have successfully produced lenses that possess anti-fog, anti-UV and anti-reflective properties. It has been gratifying for me to witness firsthand the translation of research work that has been incubated right here in A*STAR into real life products. Moving forward, our team is very excited about utilizing nanoinjection molding to translate various surface functionalities previously developed on thin films onto everyday 3D objects — something never thought possible!

    Our work at the A*STAR Nanoimprint Foundry goes beyond the four walls of the laboratory. In my short 7 month stint here, I have interacted with several companies and co-organized a nanomanufacturing roundtable (industry outreach) event to engage local small and medium enterprises (SMEs) and multinational corporations (MNCs) with our technologies. Working with industry at the forefront of advancing manufacturing capabilities in Singapore instills a strong sense of purpose in my colleagues and I. I am very blessed to be given the opportunity to pursue my scientific interests and to play a role in helping our local enterprises stay globally competitive. Given my stimulating and rewarding experience so far, I expect nothing short of a fulfilling career with A*STAR.

    Dr Ong Qunya is a scientist at the Nanoimprint Foundry at the Institute of Materials Research and Engineering. She was awarded the A*STAR National Science Scholarship to pursue her PhD in Medical Engineering and Medical Physics at the Massachusetts Institute of Technology. Her current research is focused on developing nanomanufacturing technologies for biomedical applications.

  • Go Big and Go Deep: Mining Data at Scale

    Data miningNeural networks

    Pravin Kakar

    Scientist

    Institute for Infocomm Research (I²R)

    The Institute for Infocomm Research (I²R) is a member of the Agency for Science, Technology and Research (A*STAR) family and is Singapore’s largest ICT research institute. Established in 2002, our vision is to power a vibrant and strong infocomm ecosystem in Singapore. We seek to foster world-class infocomm and media research and develop a deep talent pool of infocomm professionals to power a vibrant knowledge-based Singapore.

    The phrase ‘big data’ is thrown about a lot these days. You may have heard it in reference to disease outbreaks, insurance assessment, as well as banking and e-commerce. Big data mining refers to leveraging huge volumes of data from various sources and unearthing patterns that can explain or predict phenomena. Indeed, the phones we carry in our pockets, the credit cards we use, the EZ-Link cards that we tap on public transport and the Fitbits we wear are a treasure trove that can help to understand who we are. Now multiply the amount of data you generate by the number of people with similar data sources, and you can visualize the scale of data that is available for analysis.

    My research here in the Institute for Infocomm Research’s Data Analytics Department focuses on ‘deep learning’ algorithms to utilize this big data in a rather elegant way. Deep learning refers to using ‘deep’ neural network algorithms that consist of several layers of artificial neurons that are supposed to mimic the way a human brain functions. While still a far cry from the actual complexity of the human brain, the fundamental idea that stacking layers of fairly simple computations can allow for solving really complex computations holds. The field of neural networks itself has had a long and checkered history from great optimism in the ‘50s and ‘60s to the Artificial Intelligence (AI) winter of the ‘70s, from the ground-breaking discovery and application of techniques like backpropagation to neural networks in the ‘80s, to the steady increase in data and computation power through the ‘90s and into the 21st century.

    I became interested in working with neural networks during my undergraduate studies, when I designed a system that could take my hand-drawn electronic circuit diagrams and, using neural networks and some image processing techniques, convert them to a format that I could simulate on a computer. I was introduced to deep learning techniques when I read about their breakthrough performance in image recognition tasks back in 2012. The proposed neural network, AlexNet, was able to reduce a classification error metric by over 40 per cent, at a scale of over a million training images, spread across a thousand classes. Since then, the entire field of visual computing dived into deep learning, experimenting with outrageously bigger and more complex networks and coming close to human-level performance in image recognition, a task that even half a decade ago would have seemed impossible.

    A neural network basically takes some data as an input, passes it through multiple internal layers of mathematical transformations and produces an output corresponding to some objective. This also means that it can be trained to perform a complex task by providing it with several examples of inputs and desired outputs, and letting it figure out how best to optimize its internal transformations. One major problem with neural networks is that to perform significantly complex tasks they, unsurprisingly, need to have several stacked simple transformations. However, with several layers, they need new computational tricks to be successfully trained, greater computational power, and last but not least, more data. The latter factor is a bit subtle, but it stems from the fact that neural networks tend to be a bit too eager to reproduce the data they are presented with during the training process. This ‘overfitting’ can be detrimental to the generalization of new data. As an analogy, consider the case of a child learning multiplication tables. While he may be able to learn many such tables by rote, unless he understands what multiplication actually is, he will not be able to multiply any two arbitrary numbers.

    One of the easiest solutions is to simply use more data to make it difficult for the network to perfectly reproduce the training data, forcing it to learn the relationship between the input and output, rather than the data itself. In our analogy above, this would be equivalent to presenting the child with, say, a thousand multiplication tables, thus making it more efficient for him to simply learn how to multiply any two numbers. Until quite recently, we did not have many sources of large amounts of data for real-world problems. With the advent of the internet to crawl for data and the ability to cheaply label the data via crowd-sourcing, it has become possible to have truly massive datasets, which has gone a long way towards solving the overfitting problem for deep neural networks.

    My research involves using the lessons learned from visual and speech recognition in deep learning, and seeing how they can be adapted to other sources of data such as sensor data and regular text. The Data Analytics team has had some masterstrokes of creativity in applying these lessons, including creating image-like structures from non-image data and using neural networks intended for images on them. I work on creating and modifying other neural network architectures for such data analysis. Additionally, I also examine scalability issues involved with deep learning, such as studying how incorrect training data impacts performance, and what can be done to mitigate it. Finally, I look into dynamic neural network architectures that are increasingly showing promise in areas like sequence labelling and creating captions for images.

    Deep learning is still a very nascent field, and there are lots of competing ideas and frameworks to experiment with. We have not even come close to the limits of the technology and we already have incredible results from industry giants like Google, Facebook, and Microsoft. It is an exciting time to be riding this wave of big data, and I am looking forward to seeing how far this takes us!  

    Dr. Pravin Kakar is a research scientist in the Data Analytics Department at the Institute for Infocomm Research (I2R). He obtained his PhD from the School of Computer Engineering at Nanyang Technological University, Singapore where he researched techniques for passive image forensics. Prior to joining I2R, he was the lead algorithm developer at Graymatics Singapore, a computer vision start-up. His research interests lie in machine learning, data analytics and computer vision.