Can we slow or even reverse aging? The good news is, slowing aging and gaining more than ten years is absolutely possible and doesn’t cost you anything except some discipline (yeah, I know, that’s the bad news here). However, to keep you reading, I’ll tell you a little later how that works. Whether it is possible to slow or even reverse aging is currently the topic of a lot of research.
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But let’s start at the beginning. If you want to treat something, you first need to define it clearly. The most obvious definition for aging is chronological. However, changing the actual flow of time falls more into the realm of physics and is probably not very practical. What we want to influence is the biological age. To measure this, we use a lot of different methods, called “clocks,” and they work with blood parameters, heart rate variability, epigenetics, simple photos of your face, or other data. Clocks are all somewhat linked to chronological age but can generally tell you how one (or several) aspects of your biological age compare to the average person your age. So they tell you if you’re younger or older than you actually are.

The specific unpleasant cellular effects of aging are summed up as the 9 Hallmarks of Aging that you see above. I won't go into detail, but they are all interconnected and lead to what we recognize as aging, like wrinkles, grey hair, loss of muscle mass, frailty, dementia, decreasing bone density, and all the other stuff that you're not keen on having.

Reading this list, you might already guess why treating aging might have other perks than just living longer. The biggest deal, not only for the individual but also for society, would be increasing the so-called healthspan. It can be argued that while in the last 100 years we have already more than doubled the average life span, the healthspan, the time lived in good health, hasn't grown accordingly. Our current medicine has become very good at treating most of the countless ailments that old age brings; however, many are more managed than cured. So wouldn't it be better (and cheaper, by the way) to treat the underlying cause of most illnesses instead of each of them at a time? The results of healthspan research could  revolutionize medicine and bring us from fixing what's broken to preventing the breaking.
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But how far along are we? Will we still get old like our grandparents? That depends. To cite one of the leading minds in this field of science, Professor David Sinclair: "It's easy to expand your lifespan. […] If you do the right things, which is: Don't overeat, eat less often during the day, do some exercise, don't smoke, don't drink! That alone gives you, compared to people who don't do that, 14 extra years. So living longer isn't hard, it just takes some discipline." Well, I told you, it's not too easy, but it's doable. However, there is obviously more to aging research than the typical advice on living more healthy.

Senolytics
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 First of all, there are drugs and supplements  that (at least in animal models) show a huge potential to give another few healthy years like Nicotinamide Mononucleotide (NMN), α-Ketoglutarate (AKG), Resveratrol, Metformin, and Rapamycin. I won’t go into detail on those now, but I’ll write some more articles about that on my blog soon.

Most of these, however, seem to work mainly as a prevention and not a cure. But there are other measures in the pipeline. An interesting idea is the so-called “Senolytics.” Instead of killing themselves as damaged cells normally do, some become senescent. Senescence occurs when cells sense an instability of their chromosomes after having divided a certain number of times or because of high stress (due to their Telomeres), so they permanently stop dividing. Senescent cells also secrete signals that lead to inflammation, changing the development of their surrounding cells and the extracellular matrix.

The more senescent cells in an organ, the less vital and functional the organ becomes. Senolytics like Dasatinib and Quercetin are substances that target and remove these senescent cells to rejuvenate the organ. There are ongoing clinical studies on human patients with these substances on several age-related diseases, and they show some promise, but there is still a lot of research to do.

Cellular Reprogramming

The idea that sounds probably most impossible but has the potential to slow the clock and actually reverse aging is cellular reprogramming. Each cell in our body has basically the same genetic information, the same construction plans packed into our DNA organized in chromosomes. But how does a cell in your brain know that it’s not in your foot and has to behave differently? And, even more important, how does a cell know that it’s not supposed to copy itself as often as possible or try to build a new complete clone of you? The answer is epigenetics (mostly). Epigenetics is quite a young field that has made huge progress in the last 15 years. Epigenetics determines which of the genes of a cell’s genome are switched on and switched off by modifying the DNA or proteins associated with the DNA. These bookmarks make a cell behave as it does. They are changed by environmental influences like sunshine, smoking, food, no food, or a thousand other things. Most of these factors and time itself lead to an overall decrease in these bookmarks, although certain areas of the genome also acquire more of them with time. So the idea is to reset these bookmarks to a “younger” state.​

In 2006 a set of four transcription factors (regulators for genes) were identified that can reset a differentiated cell into part of a certain tissue to a very similar state to that of the cells you find in an embryo. The cells treated with the transcription factors become stem cells and can be reprogrammed into almost any cell type within the body. These transcription factors are called Yamanaka Factors after one of the authors of this study from 2006. Using the Yamanaka Factors, there have been successful studies on animals. The aim is to reset the epigenetics of cells to young without dedifferentiating the cells, making the tissues they form fall apart. This technique is currently tested to restore vision in primates after successful tests on mice that have gone blind because of glaucoma. It is expected to be ready for human clinical trials next year. If this is successful, it would be a new hope for many blind people and be a proof of concept for rejuvenating a tissue by epigenetic reprogramming.

A possible future application of this could be to treat a patient's cells outside the body to become stem cells and then inject them to regenerate damaged tissue or to rejuvenate the patient as a whole.

Much is unclear about reversing aging. Many studies in the field show contradicting results, but what would have seemed impossible 20 years ago is rapidly evolving from promising basic research to clinical trials. Currently, you still need some discipline and changes to your lifestyle if you want to increase your lifespan and healthspan. However, the more life and health you win through your life choices, the closer scientists might be to real solutions to all the unpleasant effects of aging and maybe to aging itself.

We perceive light and color because of photoreceptor cells in our retina called rods and cones. Rods help us see low contrast images, motion, and during nighttime. Cones help us see high contrast sharp images and colors. Humans with normal color vision have three types of cones: s, m, and l cones. These cones help us see colors of different wavelengths, i.e., from lower wavelength color like blue to a higher wavelength color like red. Hence, a person with normal color vision is a trichromat, tri meaning three, chroma meaning colors. Trichromats can differentiate between about 1- 2 million colors. However, about 12% of women have a special 4th cone that enables them to see in more detail and can differentiate between 100 million colors. This condition is called tetrachromacy, tetra meaning four, chroma meaning colors. Women with tetrachromacy are called tetrachromats. 

Tetrachromacy is usually caused by a genetic mutation in the X-linked chromosome and is predominantly found in women. If you recollect middle school biology, you will remember that we have 23 pairs of chromosomes. One of the pairs among the 23 is called an allosome or a sex chromosome which determines the sex of an individual, i.e., XX (female) and XY(male). While a female mammal receives 1 X chromosome from each parent, a male mammal receives 1 X chromosome from his mother and 1 Y chromosome from his father. Color vision anomalies arise on the X-chromosome. Since women have 2 X chromosomes, they carry the genes (also known as carriers) for color vision anomalies from their fathers and pass them on to their sons. Carrier women do not have any color vision problems as they have another intact X chromosome inherited from their mothers. This is also why more men have some form of color vision anomaly, as they only have 1 X chromosome. For a female to be color blind, the gene must appear on both her X chromosomes.

Similarly, a female becomes tetrachromatic when she receives a normal X chromosome from her mother and an X chromosome with a color vision anomaly from her father. She develops a 4th set of cone cells in her retina, making her a tetrachromat. Since a male receives only the Y chromosome from their father, they usually cannot be tetrachromatic. 

Where else can we find tetrachromacy? 
While tetrachromacy is rare among humans and mammals, it can be seen commonly among certain species of plants, fish, insects, reptiles, and birds. This feature helps find food and mates. Since plants and insects mutually benefit from being symbiotic, they have evolved complex colors to attract each other. 

What extra colors do tetrachromats see? 
As mentioned, tetrachromats can differentiate between 100 million colors. Some sources claim that tetrachromats can see ten colors in a rainbow. As the 4th cone sits between the m and l cones, tetrachromats can differentiate between more colors in the red, yellow, and green parts of the spectrum. 

How can we test for tetrachromacy?
There is a lot of research ongoing to understand tetrachromacy and how to test it. Genetic testing is one of the best ways to profile your genes for this trait. The color matching test is also being used for confirming tetrachromacy in research labs. Researchers presented participants with a set of 2 mixtures of colors over a few sessions. Trichromats reported that they saw differences between the color mixtures. On the other hand, tetrachromats reported that the color mixture was the same in all the sessions. 

An online test called the Derval color test claims to detect tetrachromacy.

If you see 20 or fewer colors in the Derval spectrum, you have dichromacy with only two functional cones. If you see between 20-32 colors, you are a trichromat with three functional cones, and if you can see between 33-39 colors, you are a tetrachromat. However, research shows that this test is inaccurate. According to researchers at Newcastle University in the UK, computers cannot generate the spectrum of colors detectable by tetrachromats. Dr. Gabriele Jordon, a neurobiologist researching tetrachromacy, says that while 12% of women may be tetrachromatic with four functional cones, only 2-3 % of them are actually functional. In fact, in her 20-years of research, she has come across only one tetrachromat who passed the match test with flying colors (pun intended). Known as subject cDa29, her story was a news flash in the media. Concetta Antico, an artist and tetrachromat, also shared her experiences about how tetrachromacy influences her art. 

Research hopes to introduce new ways to test for tetrachromacy, especially by introducing new colors to observe if the fourth cone becomes functional in the other 10% of women. Maybe science can introduce a new set of colors beyond our imagination. ​

When we think of the term "mental health," what do we really mean? A broad definition would be the state of the psychological and emotional well-being of an individual. However, it has come to mean and involve so much more. Mental health also involves the conceptualization of self-reflection, self-awareness, and the development of a sense of self. This description of mental well-being may seem an abstract concept, but when we experience a decline in our mental health, it  often shows up in physical manifestations of stress/anxiety and bleeds into multiple parts of our lives. Graduate students are not excluded from this. In fact, the expectations and environment of academia make grad students more susceptible to mental health decline. And people are talking about it. 

A 2018 research article by Evans and colleagues highlighted how mental illness is an increasing concern within academia and that intervention-based policies can help curb the growing problem. Researchers found that "graduate students are more than six times as likely to experience depression and anxiety as compared to the general population." And of the 2,279 individuals who participated in the study (90% PhD candidates, 10% Master's students), 41% of graduate students scored as having moderate to severe anxiety, and 39% had moderate to severe depression. Even more alarming, the study found that the rate of anxiety and depression in transgender graduate students was significantly higher than their cis-gendered counterparts. Studies like this bring focus to the importance of mental health. Furthermore, mental health decline in response to the COVID-19 pandemic emphasizes the significance of understanding what mental well-being entails, supporting each other by telling our stories, and sharing our cognitive stress-processing strategies/resources. With that, here are some strategies on how graduate students can take steps to prioritize their mental well-being.

Be open to acknowledging the headspace you are in
Making a conscious effort to improve and maintain your mental health starts with an awareness of your mental health status. In my experience, it was my significant other and close friends who noted my mental health decline as I was no longer participating in social activities and began to speak negatively about myself. However, not everyone has a strong support system. As individuals, we need to be aware of our mental health regularly. Acknowledge how you feel and make a quick note about it on a daily/or weekly basis. Note apps, written journal entries, e-journal entries, and online spreadsheets are all tools to help you track your state of mind. The note can be as little or big of a description as you want but should include your overall feelings. Over time you can find patterns and identify what events/conditions activate specific emotions. Mental health management is a personal journey, and there is no right or wrong way to go about it when it comes to identifying your emotions and their validity.

Identify what conditions/environment may act as stressors on your mental health

If you know that a particular place or event will make you nervous or stressed, you need to prepare for that. In academia, you may not have the choice to avoid stress-linked locations or tasks. For example, if you identify a specific school building as an environmental trigger where exams are taken, avoiding that building may not be possible. But you can prepare for the emotions you might have by taking a note of feelings that arise when you are there and strategize how you can tamper down your nervousness. Take a look at the table below for some examples of stress and anxiety symptoms:

​Be prepared to set boundaries 

In the name of personal well-being, we have to become comfortable with setting up boundaries. For graduate students, a typical example that comes to mind is setting work/life boundaries about the time allocated to work and being comfortable saying no. Setting boundaries can trigger other stressors graduate students face, like imposter syndrome and a sense of self-worth tied to productivity. It is okay to prioritize your primary responsibilities and not take on extra work that may be asked of you. Also, setting boundaries between your professional and work-life helps ameliorate stressors associated with mental health decline.

Outlets for processing stress and anxiety

Many outlets can help ease anxiety, process your mental status in high-stress situations, or be utilized in real-time moments of high anxiety. Check out the table below for some methods:

Find a supportive community

When I was suffering a mental health decline, I heavily depended on my friends and family. But seeing and interacting with others within the academic community helped tremendously. Talking with others who knew the stress and anxiety associated with graduate school  gave me a sense of belonging. Online communities are abundant on social media platforms. There is a strong online support network of mental health advocates that want to help students with their mental health, and a few are listed at the end of this post. Also, if there are university faculty, staff, or previous mentors you feel comfortable confiding in about your mental health struggles, reach out! 

The T-word: Therapy

Therapy is a personal choice. If forced, it can backfire. For graduate students, two significant barriers to seeking therapy are finances and time. So, budgeting for therapy sessions and finding the time to do it can be overwhelming. Students should check if their programs offer therapy or if the school's insurance will reimburse them for therapy sessions. Online therapies are also a great resource, as many offer financial assistance and the convenience of multiple therapy approaches (phone calls, texting, and video chat). Furthermore, the convenience of online therapy allows students to realistically implement therapy in their daily lifestyle and have more emotionally comfortable options than the standard face-to-face methodology. For those on the fence about therapy, check out the podcast Science Vs by Gimlet media to hear more on whether therapy can be an option for you. They recently had a great segment on therapy and if it really helps people.

Last Remarks
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There are a lot of ways graduate students can take steps to prioritize and better their mental well-being. And, of course, this isn't going to happen all in one day. Our society for so long has stigmatized mental healthcare initiatives, and it intertwines with racial and socioeconomic barriers, making open conversations about mental health a societal taboo. But there is an ongoing active shift of change within the academic community and general population. I hope these tips serve our community well and help fellow graduate students on their path to maintaining their mental health! At the end of this post, readers can also find a list of resources for online and affordable therapy options, mental health group organizations, and online social media graduate student mental health support communities.

Resources for therapy:

• BetterHelp online therapy
• Talkspace online therapy
• Pyschologytoday.com Directory to search therapists available in any state

Resources for mental health crisis:

• National Suicide Prevention Lifeline: 1-800-273-TALK (8255), or text the Crisis Text Line (text HELLO to 741741)
• The Trevor Project: A support network for LGBTQ youth providing crisis intervention and suicide prevention, including a 24-hour text line (text “START” to 678678)
• Trans Lifeline: US (877) 565-8860 Canada (877) 330-6366
• United for global mental health International Help lines
• LGBT National Help center hotline: 888-843-4564
• SAMHSA's National Helpline US: 1-800-662-HELP (4357)

Resources for faith based mental health resources:

• National Alliance on Mental Illness Faith based mental health resource page

Mental health support communities in Academia on Twitter:
@cactusMHS
@academicvoices
@ZJAyres
@PhD students
@healthyscience1

Possibly the human body's most infamous protein, P53 is mutated in 50% of all cancers. That's right, TP53 (the gene that encodes P53 protein) is cancer's most mutated gene!
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P53 is a tumor suppressor, meaning it protects cells from becoming cancerous. In times of genotoxic and cellular stress, P53 activates cellular pathways that promote DNA repair, cell-cycle arrest, and cell death (killing off dangerous and damaged cells). If P53 is defective, the opposite occurs. Cells don't repair DNA appropriately, causing genetic mutations. Cells don't undergo cell death, allowing malfunctioning cells to survive and propagate. And cells don't stop dividing, enabling uncontrolled cellular growth that contributes to tumor formation.

In a nutshell, P53 is a good guy; he's the guardian of the genome. But if he becomes mutated, P53's hero status gets demoted. Mutant P53 presents quite the challenge for cancer biologists. Can P53's hero status be medicinally reinstated? Well — yes! We can reactivate P53 to guard the genome again. Two strategies to bolster P53's hero status have been quite successful in recent years and are setting the stage for a new class of chemotherapies:

1. Inhibiting MDM2, P53's sworn enemy

The P53 protein can be tagged with a small protein called ubiquitin, signaling P53 for degradation. P53 ubiquitination is a healthy, normal event in our cells to sustain P53 at an appropriate level (too much of a good thing can be a bad thing). However, if P53 is deficient, we don't need P53 to be ubiquitinated as frequently. So, scientists have developed inhibitors for MDM2, the protein responsible for P53 ubiquitination and destruction. By blocking MDM2, P53 is not ubiquitinated, and P53 levels in the cell rise, allowing deficient P53 the extra help to do its job.

Seven MDM2 inhibitors are currently in clinical trials for various cancers, and a few have even progressed to phase III trials! 

Note: MDM2 isn't the only protein that regulates P53 levels in the cell. Other proteins for this pathway are also chemotherapeutic targets.

2. A direct approach: P53 activators 

Most P53 mutants are deficient in the DNA binding domain. If the DNA binding domain is unstable, the protein can't bind DNA and jumpstart the cellular pathways needed for cell death, DNA repair, and cell division arrest.

Scientists have designed small molecule activators that bind P53 and restore the structure of the DNA binding domain, allowing P53 to bind DNA and initiate gene expression. Two small-molecule activators are now in clinical trials and seem promising thus far. COTI-2 is undergoing stage II clinical trials for various cancers, while APR-246 has made it to stage three for blood cancers!

Forward

P53 activators aren't approved yet, nor is their approval for clinical use guaranteed. But the fact that P53 activators are in clinical trials, especially stage three, is a remarkable accomplishment by the scientific community! P53 is the holy grail of chemotherapeutic targets. With so many cancers harboring P53 mutations the therapeutic reach of these activators is substantial. There was a time when P53 was considered undruggable, an impossible chemotheraputic target. 

P53 activation is no longer a fantasy. Unlike Marvel movies and comic books, P53 reactivation is a reality. 

*Reposted from 09/11/20

If you follow any beauty influencers on social media, you may be familiar with hair vitamins, supplements designed to make your hair grow long and thick. Of course, these influencers already have long and luxurious hair; most are also sporting hair extensions or fillers. Yet, we are lead to believe their lush hair is the result of hair vitamins.

Insta influencers aren’t the most honest source for advice on beauty supplements — recall the skinny tea phase where celebrities advertised laxatives. But perhaps there is some truth to using hair vitamins. 

Hair vitamins come in a few brands, so let’s take a look at the ingredients of three common hair vitamins:

Ok, so we have real vitamins in these supplements. Great! But can they give me Kylie-grade hair?

Folate is essential for DNA and protein synthesis, and deficiency can cause hair and nail growth defects. Folate is naturally occurring in leafy veggies, fruits, meats, and grain. Folic acid is a form of folate that can be stored and supplemented in our food. Folic acid fortification of bread and other wheat products is mandated by many countries, including the US and Canada, to combat birth defects caused by folate deficiency. Therefore, if you eat a balanced diet, you likely acquire the necessary folic acid for healthy nail and hair growth and do not need further supplementation.

Zinc aids in protein synthesis, immune function, and cell division and can be found in meat, nuts, beans, fish, and whole grains. The relationship between zinc levels and hair loss is debated, with some studies showing a correlation between zinc levels and hair loss pathologies such as alopecia. Interestingly, zinc pyrithione shampoos seem to improve hair growth, but this is achieved topically due to reduction of oxidation on the scalp. However, there is no evidence to suggest zinc supplementation supports hair growth in individuals without zinc deficiency.

Seeing a pattern here?
Deficiency in several vitamins can cause hair loss, however, supplementation and overconsumption of these vitamins do not guarantee increased hair growth, especially in healthy individuals. Empirical evidence supporting the efficacy of hair vitamins is scarce. A well-balanced diet can easily substitute hair vitamins. So, save your money! This author declares hair vitamins to be pseudo-science.

Read our other Science Vs Pseudo posts:
Collagen
​Hyrauluonic acid

It's often believed that cancer results from a modern lifestyle, i.e., eating more processed foods, increasing exposure to various radiation sources, and the general fast pace of life. The truth is that the earliest report of cancer, or the disease that later became known as cancer, dates back to around 1600 BC in ancient Egypt. Yes, perhaps the modern lifestyle has increased cancer cases, but it has also provided us with the necessary technology to detect the disease earlier and treat it more effectively. It should also be noted that humans live significantly longer now than a century or two ago, so naturally, the incidence of cancer will increase.

Cancer treatment comprises of three different areas, surgery, radiation, and chemotherapy. However, when you think of a cancer patient, it is the jarring side effects of chemotherapy that come to mind. While there are many resources on the internet to describe the different side effects of chemotherapy and how to deal with them as patients or caregivers, they rarely discuss the mechanisms through which the drugs work.

Becoming Cancer

Cancer arises from a change in the DNA of a single cell that causes it to multiply and grow unchecked. The causes are varied, such as exposure to too much radiation (which is why radiology technicians walk out of the room when taking an X-ray), exposure to chemical carcinogens such as tobacco smoke or asbestos, viruses such as HPV, or copy errors during DNA replication. These events give rise to the same problem: a cell that replicates faster consumes more resources and does not die when it should. And here lies the crux of the problem: cancer cells are not that much different from healthy cells, so anything that kills the cancer cells will likely kill the healthy cells as well. The trick lies in killing the cancer cells faster than the healthy cells. 

How to get away with killing cancer

Since cancer cells grow and replicate faster than healthy cells, most anticancer drugs aim to inhibit the replication process. This can be achieved through targeting DNA or proteins related to cell replication, obstructing the metabolism of the cells, or impeding cell division. Some commonly used drugs like oxaliplatin and carboplatin are involved in all three processes and are referred to as cytotoxic compounds.
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And now for the kicker: cancer is treated with a combination of the different types of drugs with varying therapeutic mechanisms for specific cancers in different patients. Therefore, each cancer patient receives a cocktail of various medications that have been optimized to treat their particular cancer. 

Modifying DNA
The compound classes that target DNA include alkylating agents, anticancer antibiotics, and some transition metal complexes. These compounds bind directly to the DNA, climbing in between the DNA base pairs or associating with the DNA so that the DNA cannot be replicated. The inability to replicate DNA causes the cancer cell to senesce (stop multiplying) or die.

Interfering with metabolism
Drugs targeting metabolism include antifolates and antimetabolites, which replace compounds in the cell's metabolic cycle. I.e., folic acid is crucial in cell growth and replication, so antifolates take the place of folic acid but do not perform the necessary functions, so the cancer cells are essentially starved. 

Blocking cell division
Antimitotic compounds target cell division, and the most used compounds are plant alkaloids such as vincristine and vinblastine. These compounds prevent the formation of microtubules that guide the separation of cells during mitosis. So, if the cells cannot separate, they cannot replicate.

Right on target: creating cancer-cell specific therapies

While the above mentioned compounds are very effective in treating cancer, they do not discriminate between healthy cells and cancer cells, which gives rise to the nasty side effects we have come to associate with cancer treatment. A more recent class of compounds called "targeted therapies" provide more selective interaction with cellular components specific to the cancer cells.

Targeted therapies include:

• Drugs linked to a biomolecule that has an affinity for cancer cells
• Cutting off hormones from hormone-dependent cancers
• Recently developed cancer vaccines
• Designing protein inhibitors that only kill cells harboring a cancer-causing mutation
• immunotherapy 

At the intersection of cytotoxic agents and targeted treatments lies hormone therapies and kinase inhibitors. While they are more selective towards the cancer cells, treatments may still negatively impact the patient.

Hormone therapy can treat hormone-dependent cancers, such as certain types of breast, ovarian and uterine cancers dependent on estrogen and certain types of prostate and testicular cancers dependent on testosterone. By cutting off access to the necessary hormones, the cancer cells are starved of an essential building block. Removing the hormone from the rest of the body also has extensive side effects relating to fertility, secondary sex characteristics, and sexual performance. Still, the side effects are generally less detrimental than other cytotoxic agents.

Kinase inhibitors target kinetic enzymes that contribute to cell growth. Some cancers express more of a particular kinase than healthy cells, while other cancers express a mutated kinase that is specific to the cancer cells. The mutated KRAS has been a holy grail in medicinal chemistry since it is found in numerous high fatality cancers. The development of an inhibitor has long eluded scientists; however, the FDA recently approved a KRAS inhibitor, Lumakras.

And finally, the current buzzword: immunotherapy. Immunotherapy involves using antibodies that bind proteins specific a cancer cell, thereby recruiting the immune system to clear the cancer. Immunotherapy is the most specific chemotherapy available, but since it is so specific, the number of cancers that can be treated are still limited. Personalized treatments come into play here, where a sample of a patient's cancerous tissue is used to develop an antibody for that patient, like designing a key for a specific lock. 

Personalized treatments are still highly specialized and expensive pursuits, yet they might become the future of cancer treatment. Immunotherapy also includes the development of cancer vaccines, such as mRNA vaccines targeting KRAS.

For further reading on the topic, I highly recommend the Pulitzer Prize-winning book by Prof. Siddhartha Mukherjee, The Emperor of all Maladies. The book is accessible to scientists and non-scientists alike and does not assume any knowledge in the field of cancer biology. It tells the tale of how theories around cancer evolved and how the current treatments were discovered and refined, all interspersed with gripping tales of the author's own experiences as a practicing oncologist. 

Similarly, the National Cancer Institute's website also provides a lot of practical information if you or a loved one is currently busy with cancer treatment and need some guidance.

Hyaluronic acid sells. It’s in serums, moisturizers, and masks. So, does it help our skin? Or is it just a fancy science term used to drum up business?

Hyaluronic acid (HA for short) is a naturally occurring molecule in the extracellular matrix of our cells. HA is a polysaccharide, a chain of sugars. Small and medium length HA promote blood vessel formation and inhibit cell death, while large HA is immunosuppressive. HA is found in connective tissues, joints, the eye, and the umbilical cord. However, in the cosmetic world, HA is best known for its ability to bind water molecules within the skin, allowing for increased moisture. But that’s not all; HA is an overachiever and also aids in collagen remodeling and fights free radicals.  

Clinical trials of topical HA

In theory, hyaluronic acid should be moisturizing and have anti-aging effects. If HA binds and retains water in our skin, it should have a plumping effect that reduces wrinkles.

Fortunately, there is empirical evidence to suggest HA helps with anti-aging. In one study, females aged 30-60 who used a 0.1% HA cream for 60 days experienced increased moisture and elasticity. Decreased wrinkles were only observed in participants who used low molecular weight HA (30, 150 kDa). Another study agrees, stating that topical HA treatment increased elasticity and moisture, and decreased roughness after twice-daily use over 2, 4, and 8 weeks. HA treatment was also most effective with lower molecular weights, citing increased skin penetration.

Other uses

Fillers

In addition to topical application, HA can be injected to plump up skin and lips. As mentioned previously, HA is non-toxic and is, therefore, a favored filler method. Although, uncommon complications can happen, including infection, vascular injury, allergic reactions, and displacement of filler. 

Medicine

HA is an abundant biomolecule that affects more than just our skin. Research suggests HA is also beneficial for wound healing, bone regeneration, and possibly cancer treatment. 

Science or Pseudo:

Thus far, in our science or pseudo series, I'm delighted to say that we are 2 for 2. Both collagen and hyaluronic acid are science-approved cosmetic agents!

Plenty of medicines are protein inhibitors, meaning the drug binds to a protein to block its function. One example of a common inhibitor medication is angiotensin-converting enzyme (ACE) inhibitors used for high blood pressure. ACE is an enzyme in the blood that creates angiotensin II, a molecule responsible for constricting blood vessels. ACE inhibition limits this constriction, alleviating high blood pressure. A second example of an inhibitor medicine is selective serotonin reuptake inhibitors. These drugs bind to serotonin transporters, allowing serotonin (the happy neurotransmitter) to stay in neuronal synapses longer and are therefore used to treat depression. 

Old School - Attacking the active site

Both ACE inhibitors and serotonin reuptake inhibitors bind to proteins at their active sites: the central place of function in a protein. ACE inhibitors bind to the catalytic site – the portion of the protein that creates angiotensin II, while serotonin reuptake inhibitors bind and block the channel that serotonin passes through. 
It's intuitive that to inhibit an enzyme, a researcher designs a small molecule that binds and directly impedes a protein's active site. This strategy for inhibitor design is favored for a few reasons:

1. Active sites tend to be small, concave, and hydrophilic (likes water), an ideal size and chemistry for a small-molecule inhibitor to bind.
2. Testing active site inhibition is easy to do in a lab. Plenty of enzyme assays are optimized to validate inhibition.
3. Most inhibitors with clinical approval bind active sites, proof that this method of action works.

However, inhibiting active sites has its setbacks. Active sites of one protein might mimic that of another. Consider that humans have about 2000 protein kinases (signaling proteins that phosphorylate other proteins). Therefore, designing a specific inhibitor that solely binds one kinase active site is challenging. In fact, many active site inhibitors fail during preclinical studies and clinical trials due to cross-reacting with other proteins. Another drawback to active site inhibition is that not all proteins have enzymatic activity and do not have active sites. Some proteins participate in structural support, cell organization, protein complex formation, and protein recruitment.

But never fear; scientists are innovative. To increase the number of possible pharmaceutical targets, researchers are designing inhibitors to target a new class of pharmaceutical targets, protein-protein interactions. 

New School - Protein-protein interaction inhibitors

Active sites aren't the only essential interface of a protein. Protein interaction interfaces are also necessary for several reasons. 
From a protein's point of view, cells are large and confusing places. So, proteins bind to one another to ensure they are in the proper place at the right time to do their jobs. Additionally, proteins are often made of multiple subunits and function similar to a machine. The subunits of these molecular machineries are held together by protein-protein interactions. Therefore, inhibiting a protein-protein interaction can block a protein's function by displacing its localization in the cell or breaking apart a protein complex. 

For some time, protein-protein interactions were deemed "undruggable" because, unlike active sites, protein-protein interfaces are large, flat, and hydrophobic. Overall, most protein-protein interfaces have a suboptimal shape and chemistry for small-molecule inhibitors to bind. However, in the last decade, research has shown that although protein-protein inhibitors' design might be taxing, it's certainly possible. 

Dealing with the large interfaces
Although protein-protein interfaces are large (averaging 28 amino acids), researchers have found that a small portion of amino acids, termed "hot spots," are responsible for most of the energy required for protein binding. Therefore, the entire protein-protein interface is not the target for site; rather, the hot spot amino acids are. 

Struggling with flat target sites
At first glance, most protein-protein interfaces seem flat, but that isn't necessarily the case. Hot spot residues often reside in "pockets" of a protein surface comparable to the size of an active site. And even if it seems hot spots reside on a flat surface, proteins are dynamic, and interfaces may have pockets that appear upon binding to its partner protein. 

Combatting the hydrophobicity issue
When it comes to hydrophobic and hydrophilic properties, "like likes like." Hydrophilic molecules bind hydrophilic molecules, while hydrophobic molecules bind hydrophobic molecules. So, a hydrophobic interface will bind hydrophobic inhibitors. 

Hydrophobic inhibitors perform poorly in the human body since we are made of mostly water. Therefore, scientists can optimize hydrophobic inhibitors by adding hydrophilic chemical groups to the inhibitor and removing unnecessary hydrophobic groups. And although the core of the protein-protein interaction is often hydrophobic, charged residues often support the interface, which an inhibitor can also target. 

Where we stand now

Tirofiban, an integrin disrupter, has earned FDA approval to treat stroke patients. Its mechanism of action is to break apart integrins in the blood and prevent blockages in the brain's blood vessels. Additionally, MDM2-P53 disruptors are undergoing clinical testing for cancer. These inhibitors selectively kill cancer cells by breaking apart the MDM2-P53 interaction. MDM2 inhibits P53, a protein that signals cell death during stress. Stabilizing P53 activity allows P53 to amplify the cell death signal in cancer cells. 

Since the strategy for targeting protein-protein interactions is new, few approved drugs target protein-protein interactions. However, the mere fact that some protein-protein inhibitors are undergoing clinical testing is astronomical, considering this class of drugs was once declared impossible. The success of tirofiban and MDM2-P53 inhibitors garners optimism that more protein-protein inhibitors will develop into novel medicine. 

Will protein-protein inhibitors replace active site inhibition? Likely not. However, this new class of inhibitors will significantly increase the number of protein targets and hopefully improve our chance of creating new life-saving and life-improving drugs. 

Authors note:
This post is a science communication piece derived from my recent review article: "Targeting Protein-Protein Interactions in the DNA Damage Response Pathways for Cancer Chemotherapy" published in RSC Chemical Biology. The information shared here encompasses the first half of the paper. A second post about targeting the DNA Damage Response for cancer chemotherapies is soon to follow.