Golden Medicine: Use of Plasmons for Cancer Therapy

Cancer is an immensely complex disease to treat. The number of mutations and combinations of mutations that can lead to its development make each “cure” more of a patch to a few specific cases. Couple that with the increasing rate of mutation within cancer cells, and it becomes difficult to even diagnose the issue. Plasmon therapy offers the potential for a broadly applicable treatment, and because it couples well with the bodies immune response, offers a therapy that could decrease the chance for metastatic tumor development.

Before we discuss this topic with greater specificity, a few terms should be defined. Plasmons, from the word plasma, are a material that has electrons that flow back and forth in a wave when light shines on them. Plasmas are just gaseous ions, like lightning or neon signs, and in the case of a plasmon, this plasma is confined to the surface of a nanoparticle. You can read more about plasmon theory here.

Nanoparticles abound in modern technologies and are defined by one dimension, the so called “critical dimension”, which is around two hundred nanometers. For reference, that’s roughly one hundred thousand times smaller than a human hair. This size can afford a variety of unique properties to a molecule: distinct colors, uncharacteristic electronic activities, and even the ability to move through a cellular membrane. All these attributes will come into play in how these molecules interact with cancer cells, so they’re important to keep in mind.  Plasmons are nanoparticles that are so small, that the plasma on the surface can be manipulated by light. This rapid movement of plasma gives rise to heat as it collides with surface particles just as your hands generate heat rubbing together. The type of light that does this can be visible or even radio waves, meaning that very low-energy and harmless beams can be used to generate this rapid heat.

The second bit of background knowledge necessary for this discussion is: how is cancer treated in the first place? Many current cancer therapies come from small molecules roughly the size of glucose. Whether they use metals or strictly carbon, small molecule cancer therapies usually rely on interrupting one or a few cellular pathways, like DNA replication or a checkpoint before mitosis (cell splitting). One of the first nanoparticles approved for cancer therapy have been gold nanorods, which are thousands of times larger than a small molecule and have used physical rather than chemical mechanisms for therapy. To clarify, instead of changing some pathway in a cell, these nanorods can selectively heat cancer cells until the cell dies. If you were to think about this in terms of pest control, nanoparticle therapy is like burning a nest of cockroaches. In that same case, using small molecules like cisplatin would be like spraying the cockroaches with the latest bugkiller.

Extending this analogy, it’s fairly obvious that setting a fire inside someone’s body is not a good medicinal practice, so it would be fair to question how plasmon therapy might be helpful. There are two strategies for plasmon cancer therapy: precision lasers and radio waves which can pass through a body. The earliest use of plasmon cancer therapy used a fiber optic that was inserted under the skin to a location near the tumor. Then, beams of light would hit only the tumor. This has the advantage of targeted dosing, but can still be considered fairly invasive. Others have begun using plasmons that generate that intense heat with radio waves so that no procedure is necessary: simply an injection or ingestion of nanoparticles and then stepping into a radio transmitter This can be impractical if the tumor is not in a confined space. Common gold plasmonic nanoparticles would go inside all cells so healthy cells would be damaged just as easily as cancerous ones. Recent work shows that the surface of the nanoparticle can be changed so that the majority of uptake occurs by cancer cells. Cancer cell metabolism makes the charge of cancer cell membranes different from the charge of normal cell membranes, so these nanoparticles can exploit that difference to target only cancer cells.

With this targeted dosing, plasmons show promise as a noninvasive form of therapy that do not harm the patient and would be applicable to most forms of cancer. Even though the safest and most effective nanoparticles will use gold, treatment costs are currently around  $1000, thereby promising a treatment that will not be prohibitively expensive for the future.

Peer edited by Kasey Skinner.

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The Science of Survivorship

As a cancer researcher, I often wonder about patients after their ordeal with cancer. How does the body change after facing a life-threatening illness? Do cells in our body hold the memory of disease in some way? Survivorship is a word that describes life after a traumatic event, a life in which many aspects of health, from the psychosocial to the physical, are changed. In this blog post, I hope to delve into the cellular level of survivorship and explore how surviving cancer and cancer therapy can alter our biology fundamentally.

All cells in our body contain DNA, which is an instruction manual for day-to-day duties that the cell must perform to sustain life. DNA is what we inherit from our ancestors, our parents, and what we pass on to our children. Therefore, the cells in our body are very careful about keeping DNA intact and unchanged through a biological process called “fidelity.” Interestingly, most cancer patients carry permanent changes to their DNA after treatment. One striking example is to think of patients that receive bone marrow transplants. These patients will always have two different types of DNA in their bodies: their own DNA and their donor’s! In other examples, the patient’s own DNA has minor or major alterations, changing the writing of the instruction manual, which in turn can affect how the manual is read and interpreted.  

If you were to take a look at many different cancer survivors, even long after they have stopped cancer therapy and have been cancer-free, DNA from various different parts of their body would show low levels of damage. What does damage mean? If you think about a china vase, and if you were to drop it so that it didn’t shatter, but merely cracked on the surface, that would be the closest metaphor for what’s happening here. If you consider the china vase to be the DNA, you can imagine that the DNA is damaged but not completely deteriorated. How does this damage occur? During the course of cancer therapy, patients are exposed to drugs or radiation that directly damage DNA. Most of the time, the cancer cells are the ones impacted; however, normal cells can also be affected. The major consequence of damage is accelerated aging in most survivors. Their tissues and cells look as though they are from an individual much older than they are.

Prolonged levels of stress and damage to the DNA from cancer treatment can change the way a cell reads its DNA. Epigenetics is the study of how DNA is read and interpreted in the cell and epigenetic marks on the DNA help the cell figure out which parts of the DNA to read. In cancer patients, epigenetic marks are globally changed over the course of therapy and remarkably these changes remain long after exposure to chemotherapy is stopped. Patients with cancer have more epigenetic marks signifying “do not read” being added to the DNA. In normal individuals, an increase in these marks has been associated with routine aging., In cancer patients, irrespective of chronological age, these marks can be present post therapy, signifying profound molecular aging. What remains to be investigated is whether these marks and their subsequent accumulation in survivors is a direct result of toxicity of therapy or a by-product of DNA damage leading to changes in epigenetics

With roughly 15.5 million cancer survivors currently alive in the US alone, it becomes absolutely critical to understand the biology of survivorship. The science of survivorship helps us understand the biological burden of going through cancer therapy and, in turn, this valuable knowledge allows us to develop less burdensome therapies as a result. From a physical and now a molecular standpoint as well, survivorship is a monumental feat of resilience that comes with an unwanted side-effect: aging.

Peer edited by Denise St. Jean and Eliza Thulson.

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One Cancer Drug to Rule Them All?

As early as 1999, a scientific study in Denmark found that patients with Huntington’s disease (HD) are less likely to develop cancer when compared to their healthy relatives and the overall population. A decade later, another independent study looked into forty years of patients’ information from the Swedish Cancer Registry and identified a similarly low risk of cancer in patients with HD and related neurodegenerative diseases. Strikingly, this association was not limited to one specific type of cancer but applied to many different tumor types.

What is the connection between cancer and these neurodegenerative diseases, which cause a progressive loss in the structure of the nerve cells? Researchers at Northwestern University think the answer to this puzzle lies in HD-associated ribonucleic acids (RNA), molecules responsible for important biological functions like expression and regulation of genes.

An overabundance of repeated RNA sequences in HD can suppress genes crucial for the survival of nerve cells. A team of scientists led by senior author Dr. Marcus E. Peter at Northwestern recently discovered that these RNA sequences are also highly toxic to a broad variety of cancer cells, and thus have the potential to be a uniquely lethal weapon in the fight against cancer.

https://www.flickr.com/photos/mujitra/2559447601/in/photostream/

Triplet CAG repeats in Huntington’s Disease can be highly toxic to cancer

All major forms of life on the earth use the nucleic acids like DNA and RNA to perform critical biological functions. The nucleic acids are sequences of five basic building blocks called nucleobases, which are commonly represented by the Roman characters A, G, C, T, and U.  Sequences in nucleic acids can encode information and direct functions in a living system. In HD, a defective genetic alteration causes a “stutter” in a gene called huntingtin, resulting in a prolonged stretch of triplet repeats of C-A-G.

In the earlier phases of their study, Dr. Peter and his team tested a family of RNAs containing these CAG repeats in multiple human and mouse cancer cells. Within hours of treating the cells with the RNAs, the cancer cells stopped growing and eventually most of the cells died. Encouraged by these results, the researchers moved on to test the RNAs in a preclinical mouse model of ovarian cancer. They used small particles, known as nanoparticles, to enable better delivery of the RNAs to the tumor. The treatments were able to reduce the growth of the tumor and did not cause any prominent toxicity to the mouse.  Further, the cancer cells were not observed to be resistant to the therapy even after multiple treatments.

These “suicide” RNA molecules can be a breakthrough in cancer therapy. However, there’s a long journey ahead. The effect of the RNAs on normal cells is not quite clear yet. While a short-term therapy of a few weeks will probably not result in the neurological toxic effects of the repeated tri-unit RNAs, a transient therapy may not be adequate for long-term cancer remission. In fact, mice were observed to have a persistent tumor progression once the therapy was discontinued. Further, to achieve a robust tumor control, the mice had to be daily dosed with the RNAs for two to three weeks. The dosing can be a further delivery challenge in hard to penetrate solid tumors. Nevertheless, these issues can be addressed by rigorous optimization of the RNA formulations and using approaches like gene therapy to ensure long-term availability of the toxic RNAs in the tumor. Finally, it is rare to see a drug so effectively target so many different types of cancers, across species. Whether this is a “moonshot” against cancer, time will tell.

Peer edited by Paige Bommarito and Laetitia Meyrueix.

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Cell-based Therapies at UNC using Good Manufacturing Practices, with Dr. Paul Eldridge

T cell-based therapies, or “living drugs” as coined by Dr. Carl June, utilize the potent killing activity of T cells, an arm of the immune system, to target cancers. In the early stages of T cell-based therapy, T cells were isolated from tumors, expanded ex vivo, selected for specific anti-tumor clones, and infused back into the patient. Nowadays, T cell products are genetically modified to express receptors to more specifically target cancers with better persistence in patients. So how are these “living drugs” manufactured?

Here at UNC, a Good Manufacturing Practices (GMP) facility housed off of NC-54 generates all the T cell products used in phase I/phase II clinical trials by the Lineberger Comprehensive Cancer Center. These facilities are regulated by the US Food and Drug Administration under the authority of the Federal Food, Drug, and Cosmetic Act.

 

Image Provided by Dr. Paul Eldridge

Laboratory technicians working hard at UNC GMP.

I spoke with Paul Eldridge, PhD, Director of the UNC Lineberger Advanced Cellular Therapy Facility, to learn more about how GMP facilities work. Dr. Eldridge was recruited in 2014 by the Lineberger Comprehensive Cancer Center, which was interested in starting a cellular immunotherapy program and building a GMP facility. Dr. Eldridge’s personal interests are in chimeric antigen receptor T cells (CAR-Ts) and hematopoietic stem cells, with a focus in cancer immunotherapy.

 

An excerpt of our conversation is below, edited for clarity:

Lee Hong (LH): What products are manufactured at UNC’s GMP facility?

Paul Eldridge (PE): Here at UNC, we focus on advanced research products. The FDA divides cell products into minimal manipulation and more than minimal manipulation. Minimal manipulation essentially does not change the character of the cell, which means you can isolate, purify, or freeze the cells. More than minimal manipulation involves putting cells into tissue culture.

LH: Huh, why is that?

Image Provided by Dr. Paul Eldridge

Tissue culture facility at UNC GMP.

PE: Well, when you put cells into culture, they are dividing, experiencing a different stimulus in the culture medium, and may differentiate into other cell types. In other words, anything that could potentially change the innate nature of the cell is considered more than minimal manipulation. Certainly gene manipulation would be included here as well. How you intend to use the cell products, what the FDA calls “homologous use,” also matters. If the investigator is intending to use the cells in a manner that it is not normally functioning (i.e. non-homologous use), the FDA kicks those products up to a higher regulatory environment and calls them more than minimal manipulation.

LH: So at UNC, are most of the advanced research products you work on derived from peripheral blood?

PE: Yes, we mainly manufacture CAR-T cells from peripheral blood. We are also working with another investigator, Shawn Hingten, who is using skin fibroblasts. Outside of UNC, other investigators are using adipose-derived stem cells or mesenchymal stem cells common in regenerative medicine.

From: https://commons.wikimedia.org/wiki/File:CAR-Engineered_T-Cell_Adoptive_Transfer.jpg

Schematic of CAR-T cell synthesis using peripheral blood T cells

LH: How is UNC’s GMP facility set up?

PE: The facility is 5,000 square feet, with half of the space as clean room facilities. We have six separate processing rooms, five for patient samples and one with a different air system for virus protection. It’s a ISO-7 environment, meaning we use “bunny suits” and have to re-gown each time we enter or leave a room.

Patient rooms are positive air-pressured to the hallway in order to minimize anything coming back into the room. The air is 80% recirculated. In contrast, the virus room is negative pressure and the air is 100% single-pass filtered with no recirculation.

LH: Oh wow, there are a lot of details involved here.

PE: Yes, part of building a GMP facility is paying attention to construction details. We designed ours for an academic center, which is a different layout than that for pharmaceutical manufacturing.

LH: So how much of what you do in a GMP facility is automated versus manual?

PE: It really depends on where you are in product development. In our facility, we are focused on early phase I trials in which we have not nailed down a manufacturing process so we are pretty manual in most of our applications. Part of what we’re doing is learning how to manufacture the cells we need with minimal effort in a system that is as closed as possible.

As we move to phase II, then we start looking at scaling up due to the need for more cells. This is where bioreactors can be helpful and the steps become more automated. Cell therapy is where drug manufacturing was 75 years ago, in the sense that not much is automated. But nowadays, the technology is continually advancing. Miltenyi is offering a bioreactor called CliniMACS Prodigy that makes it sound as easy as pushing a button.

 Image Credit: Johnny Andrews/UNC-Chapel Hill

Katie McKay, Associate Director for Manufacturing, uses an inverted tissue culture microscope to count cells on a slide while working in the cell culture room at the UNC Lineberger Advanced Cellular Therapeutics Facility on June 16, 2017, in Chapel Hill.

LH: What sort of training and skill sets are needed for someone to work at a GMP facility?

PE: It breaks down into a couple of areas. One is whatever the process requires, in this case usually tissue culture (TC). We do a lot of TC as part of manufacturing cells. Another area is in regulated, quality control testing. We do a lot of characterization analysis on our cell products. We establish release specifications for every product we make so we have to do all the assays before patients can receive them. These assays aren’t necessarily done in the GMP facility, just wherever we can do it most easily.

The important thing is that all the assays need to be performed in a more GMP manner than you might encounter in a basic research lab. Documentation, Standard Operating Procedures (SOPs)…we do everything by SOPs. This is because we need to trace all of our materials, use everything within its expiration date, and keep up with instruments for calibration and maintenance. We also train people on site on whatever they’re doing, document the training, and ensure trainees maintain competency for quality control testing. In other words, we do all the tests you see in a typical research lab but in a more stringent, reproducible, and regulated manner.

Another important skill is learning how to work in a clean environment. Everyone thinks they know how to use a biological safety cabinet (BSC), but there are good ways and bad ways, and there are ways you have to operate when you are trying to minimize the risk of cross contamination. So we do a lot of cleaning, and we have to document everything we do.

In general, I don’t necessarily need someone with PhD credentials but I do need someone who is smart, dedicated, and extremely detail-oriented. We are looking more for personality and attitude than specific qualifications.

Image Credit: Johnny Andrews/UNC-Chapel Hill

Katie McKay, Associate Director for Manufacturing, organizes supplies while working at the UNC Lineberger Advanced Cellular Therapeutics Facility on June 16, 2017, in Chapel Hill.

LH: How are careers and/or skills used at GMP facilities in academic centers different than in pharmaceutical companies?

PE: Well, in an academic center you see everything, and that’s the most enjoyable part of it. We will often break out into more research and development (R&D) work as opposed to hands-on, clean manufacturing work. People float back and forth between what they are comfortable doing. I have people with PhDs and high school degrees working in the facility.

From the industry side of things, a very different set of skills is needed. That’s because by the time you get to phase II/III clinical trials, the process is set and there is no situation where you’ll be making changes. Of course, you still need to have attention to detail and be thorough, but the important aspect is to follow the instructions and nothing else. However, when something doesn’t work, you’ll need enough wherewithal to understand whether it was a process accident or a random occurrence.

LH: Finally, where do you see cell therapy going in the next 25 years?

PE: It’ll become more rote, with more big pharma involved. The current model, as long as we are talking about autologous starting material (i.e. cells from the same patient), is not really scaled up so much as scaled out. There are still individual batches (or lots) made for individual patients. Where will we do this? It’s still not clear where it is economically advantageous to do so.

For example, Novartis has a centralized manufacturing facility [for Kymirah]. That works fine for now, but will Novartis keep up with material demands? It’s not just tissue culture media, they have to make lentiviral vector, and the suppliers right now can turn out product for only 25-30 patients at a time. No one has ever tried making 10,000 personalized products before. Moreover, the FDA requires lentiviral vectors to have a shelf life of couple years so vector suppliers are desperately trying to scale up. We are still in the early wild west stage but it is fascinating.

All pictures provided by Dr. Eldridge.

Peer edited by Justine Grabiec and Erin Langdon.

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One in a Million: The Importance of Cellular Heterogeneity and the Power of Single Cell Sequencing

One of the most overwhelming aspects of modern-day biomedical research is the overarching heterogeneity that consumes all realms of biology. Ranging from cell to cell to human to human, we have become increasingly aware of the important differences that drive divergent responses to therapeutics and biological stimuli.  The complexity of cancer is one such example.   

A landmark paper published by Gerlinger et al. in The New England Journal of Medicine demonstrated that analyzing multiple biopsies from a single patient’s tumor gives a much different picture of what the biology driving that tumor is, compared to examining a single biopsy alone. In addition, many studies characterizing the cellular heterogeneity of cancer have revealed that a tumor is much more than a mass of identical cells all growing out of control. Rather, a tumor is comprised of cancer cells at different stages of the cell cycle, engaged in different cell signaling pathways, as well as other cell types including immune cells and endothelial cells (the cells lining blood and lymphatic vessels).  

https://vimeo.com/157377539

Figure 1: A schematic showing the multiple biopsy sites in a single patient tumor. The study found that the number of private mutations (i.e., a mutation found only at a single biopsy site and not at any of the other sites) are immense, suggesting that looking at a single biopsy alone greatly undermines the mutational diversity of a given patient’s tumor.

New technologies are emerging to enable us to better dissect the heterogeneity of disease and biology.  One such technique is single cell sequencing. Sequencing is a technique with which we are able to get a readout of the entire genetic composition of a cell. In its most basic form, sequencing can be performed to get a readout of DNA or RNA, which are two types of molecules  involved in different levels of genetic regulation.  Sequencing has traditionally been performed on bulk samples comprised of hundreds to millions of cells in aggregate. While we have made remarkable advances in our understanding of biology using bulk sequencing, the emergence of single cell sequencing has now allowed us to begin to  probe the genetic profile of a single cell at varying levels of complexity. The technology often takes advantage of molecular indexing, which is a technique whereby individual mRNA or DNA molecules are labeled with a molecular tag that is associated with a single cell, and then the cells are all pooled together into one tube and sequenced. During the post-sequencing analysis, the molecular tags are re-associated with each single cell, and then the profiles of each of the single cells are compared to one another.

This novel technique has allowed us to begin investigating and understanding biology with a higher degree of resolution than we ever could have imagined before, and will undoubtedly lead to the discovery of many new exciting realms of biological regulation. For example, the biomedical company Becton and Dickson have performed a research study analyzing single cells from tumors of mouse models of cancer. They found that within each tumor sample, there were distinct populations of cells with unique gene expression profiles, and these profiles were associated with vastly different biological functions. Understanding how these different populations work together as a community to promote tumor growth may help us better understand how to develop new treatments for cancer.

However, like all cutting-edge technologies, there are still limitations that need to be overcome. One concern is inefficient collection of sample, because the amount of genetic material in a single cell is much smaller than the amount of material from a large group of cells. An additional confounding variable is uncertainty of whether a low yield of genetic information from a single cell is the result of technical error, inefficiency of small sample collection, or simply the lack of expression of a gene in that particular cell. Discerning the difference between a true, biological negative result and simply a technical deficiency are often difficult to parse out.

Especially in fields such as cancer biology, we have increasingly begun to realize that heterogeneity has largely been an obstacle in our ability to develop effective therapies and to truly understand the mechanisms of regulation of biological processes. Advances in single cell sequencing research have allowed us to further realize that there is not one function or process driving disease progression, but rather a network of cells with distinct roles. Uncoupling the forces dictating the progression of this heterogeneity is what will help us to make the next great advances in therapeutic development in cancer and many other diseases.

Peer edited by Chiungwei Huang and Richard Hodge.

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Sunscreen: Not Just for Carolina Blue Days!

https://www.flickr.com/photos/nucleotidingsofjoy/2512356527/in/photolist-4Q1u4R-2r7tjD-fjNfNm-97ocMD-4UD8gp-mcGVW-cLPyV-iB9Ruz-ai4fiy-494D-5ziMZo-nSfLK-cWP15Y-7Nx6cP-7RAuS4-fas6zR-7Nx5SD-9xmJ9d-dTgYfS-a7AKaM-5xTftB-TU8W1J-vE76-or2Noa-ftFzsF-5erNjT-4UHkWY-dayVfJ-9rf4rk-848dMz-9xmJby-7RGw3E-WD4yKL-91vPHz-qbGLpD-cgHGE5-4he4sJ-cPJGRw-7RDMHE-7NB6C3-9oKjst-fBVt3Z-4rTmkH-bNQgA-qrnB-4Lbw8j-7HMF11-ozCzUE-CUNXqU-nSj1f5

Beach trips are a common activity during the summer months. Forgetting to apply sunscreen can ruin an otherwise perfect day at the beach.

Summertime is well underway, and you may find yourself lathering on sunscreen more often – or like me, you may forget you even have a bottle sitting in your bathroom cabinet. But, there are many reasons to keep that bottle within reach.

Sunscreen is particularly important for those with certain skin types. The Fitzpatrick scale is a numerical classification of skin types that have varying responses to sunlight. For example, type I skin is pale/fair that almost always burns and never tans, while type IV mostly tans and rarely burns. However, no matter your skin type, we are all susceptible to sunburns given enough sun exposure.

What causes sunburns in the first place? The same culprit that causes tanning– more specifically, solar ultraviolet rays that reach earth. UVA (320-400nm wavelengths) is more prevalent than UVB (290-320 nm) and can reach deeper layers of the skin, but both types can wreak havoc.  In skin cells (or keratinocytes), UV exposure induces DNA damage and increases oxidative stress. Tanning is a result of increased melanin production by skin cells (or melanogenesis), which absorbs UV rays.  The long-term effects of UV damage on our skin is also known as photoaging – irregular, spotty pigmentation, wrinkling, sagging, and dryness just to name a few. (check out this paper for more).

https://commons.wikimedia.org/wiki/File:UV_and_Vis_Sunscreen.jpg

Two photographs showing the effect of applying sunscreens in visible light (left) and in UVA (right). The sunscreen on the left side of the face absorbs the UV light, protecting the skin from damage, while the skin without sunscreen directly absorbs the UV light.

Sunscreen, like the name implies, blocks UV light from penetrating the deep layers of our skin through multiple active ingredients. Inorganic particulates such as zinc oxide and titanium dioxide are particularly effective at reflecting UVA and blue light. Other organic molecules absorb UV rays, such as aromatics. Newer brands of sunscreen include compounds such as avobenzone, Helioplex, and Meroxyl SX – all are not only safe, but also beneficial to blocking UV rays on the skin.

Something else to know about sunscreen – that SPF (Sun Protection Factor) written in huge numbers on your  bottle means something after all! Officially, it is a measure of the fraction of sunburn-producing UV rays that reach the skin. For example, SPF 15 means that 1/15th of burning radiation from the sun will reach the skin assuming the correct (i.e. thick) dose of sunscreen is applied. So, if you’re Fitzpatrick scale type I skin, it’s likely that you will get a sunburn from one application of SPF 15 sunscreen while your friend, who is type III or IV, does not burn with the same application.

Here are a few tips about picking and using the right sunscreen –

  1.       According to the American Academy of Dermatology, look for a sunscreen that has an SPF of 30 or higher that provides broad-spectrum coverage against both UVA and UVB light. The FDA recommends a broad-spectrum sunscreen with SPF 15 or higher.
  2.       Apply sunscreen anytime you go outside. UV light can still penetrate the atmosphere during cloudy days or in the winter!
  3.       Use the right dose. For an average adult, use at least 1 ounce (about what you can hold in your palm, or in a single shot glass) for all sun-exposed skin.
  4.       Re-apply every 2 hours to remain protected.
  5.       Check that expiration date. The active ingredients in sunscreen degrade slowly over time, and even though newer sunscreens have stabilizers be sure to replace your sunscreen if it’s expired.

 

Peer edited by Christina Marvin.

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Don’t Fear Nutella Just Yet!

“Did you hear that such-and-such causes cancer?” Every time you turn around, there is a new report about a study supposedly linking a food or ingredient to some form of cancer. Your Facebook news feed is probably littered with posts about such studies. Or maybe your family and friends talk about it. It seems like there’s always something to be afraid of. The newest scare? The beloved and ever-so-delicious spread, Nutella.

Claims linking the famous chocolate-hazelnut spread to cancer should be taken with a grain of salt.

Claims linking the famous chocolate-hazelnut spread to cancer should be taken with a grain of salt.

Recently, a study from the European Food Safety Authority (EFSA) determined a chemical by-product produced in refined oil to be potentially cancer-causing. In the study, rodents exposed to it eventually developed tumors. The by-product is produced most highly in palm oil when it is cooked. Palm oil is a key ingredient in Nutella. Eventually, headlines claiming that Nutella causes cancer spread throughout the internet, causing sales to drop and leaving many to wonder whether they should adopt a Nutella-free lifestyle.

However, the claim that Nutella causes cancer is not really accurate. In truth, the EFSA study did not specifically look the effect of Nutella and it is not clear how much of the worrisome chemical is actually produced during the making of Nutella. The study did raise concerns about the safety of palm oil, but palm oil is found in many processed foods so there’s no real reason to specifically single out Nutella. Moreover, the study only looked at exposure and tumors in rats.  Although animals experiments are useful, more studies need to be done to determine the effect on actual humans.

So does Nutella cause cancer? The study cannot accurately claim that it does. While the headlines linking Nutella to cancer might be eye-catching, they are probably doing more to incite fear than convey any real information. If you’re deciding on the risks of eating Nutella, understand that a real link between Nutella and cancer has not been made. People should be aware of this flawed claim and keep an open eye and open mind…and maybe continue to have the joy of Nutella in your life. For many of us, that’s a risk worth taking.

Peer edited by Michelle Engle.

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Cells and Samples Have Race Too!

https://pixabay.com/en/photos/diversity/

Science should reflect the diversity of its subjects.

If I told you that a tumor DNA sequencing research study found 25% of lung cancer patients have a mutation in the gene KRAS, would that truly mean that if I were to gather together every person on this planet who has lung cancer, 25% of them would have a KRAS mutation? There are of course countless confounding factors to consider that would likely make it not so: age, race/ethnicity, and gender being a few. These traits are likely much more diverse in the global population than what they could ever be in a study population. And although we all consider it obvious that there are many such factors that we should consider when performing biomedical research – I wonder how much we actually bother considering them in practice. When we perform an experiment with a well-known cancer cell line that researchers have been using since the 1970s, for example, do we ever stop to think of who the cell line came from? What if we found that the majority of cell lines came from one specific ethnic group, age group, or gender? Would we still consider our findings as scientifically sound, or as relevant to general populations? Or if you read a paper and see that the authors are able to reproduce their findings in multiple cell lines or in a handful of patient samples in their final figure of data, are you satisfied that their results have clinical relevance? Or do you question how representative and relevant those samples are to the target patient population?

Take this example. The Cancer Genome Atlas (TCGA) is a huge, multi-million dollar sequencing effort involving 20 different collaborating institutions across the U.S. and Canada to obtain genomic, transcriptomic, and epigenetic information from multiple cancer types. In total, TCGA obtained data from almost 11,000 patients. This effort has resulted in a slew of high-profile, high-impact papers and has provided enormous data sets that countless groups are mining and using to inform their research. These data have allowed researchers to discover many new targets which are being investigated for developing into new cancer therapies. A vast cohort of researchers have invested a great deal of time and effort into following up on studies directed by findings from TCGA. But, who are the actual patients represented in these datasets, and from whom we are drawing all of these sweeping biological conclusions? According to a brief report published in JAMA Oncology, 77% of the patients enrolled in the study were white, 12% were black, and most other ethnic groups were represented less than 5%. Interestingly, this mirrors the composition of the U.S. population fairly well: according to the U.S. Census Bureau, as of 2015, 77% of the U.S. population is white, 13% is Black, and most other ethnic groups are at 5% or less (as of 2015). One dramatic difference to note, however, is that about 17% of the U.S. population identifies as Hispanic, but only 3% of the patients in TCGA dataset are Hispanic.

http://www.publicdomainpictures.net/view-image.php?image=84963&picture=globe-people

Cancer is a global disease, and requires study of all patient groups.

One could maybe argue that the over-representation of certain ethnic groups in TCGA datasets is justified as it is a fair representation of the racial composition of the U.S. population, and thus we are focusing on understanding the majority of patients. But even, for example, the teeny 1% minority of the U.S. population classified as American Indian/Native Alaskan is still equivalent to about 3 million people – not at all a small number deserving to being ignored! Furthermore, cancer is not an American disease, it is a global one, and as arguably one of the most powerful, influential, and wealthiest nations in the world, it might be fair to hope that research in the U.S. is invested in finding cures for a larger cohort of human beings, and not just a subset that is the majority specifically in this country. The JAMA report further shows that for virtually all the cancer types they looked at in their report, there were only a sufficient number of TCGA samples for the White patient group, and not any other ethnic group, to detect a 10% mutational frequency rate. In short, TCGA datasets may have so poorly represented certain ethnic groups that we could be missing out entirely on important biology that drives their cancers. Thus, although TCGA is typically thought of as a huge dataset that is representative of a diverse population, the reality is that it may only be highlighting the biology of a specific subset of individuals.

https://pixabay.com/en/people-person-man-male-group-1099791/

Diversity within race needs to be considered in scientific studies.

Obviously, it is much easier to point fingers and complain than it is to actually do something to address the problem. And the issue, of course, is much more complex than even what I discuss here. White patients, Black patients, or Asian patients aren’t exactly homogeneous groups in and of themselves: the diversity within a socially-defined “race” is not something to be dismissed either. Regardless, this is certainly an important issue and one that we need to discuss more. TCGA proudly claims on their website that they obtained data from 33 cancer types, including 10 rare cancer types, but I hope in the future we can make similar claims about types of people.

Peer edited by Tamara Vital.

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UNCseq: The Journey from Cancer Biopsy to Cable TV

This past October, CBS 60 Minutes aired a feature on Artificial Intelligence. They were taking a peek into the world of Watson, a computer system developed by I.B.M that can answer questions framed in natural languages. The same 60 Minutes episode also featured Dr. Norman Sharpless, Director of the UNC Lineberger Comprehensive Cancer Center, who provided an overview of how Watson’s artificial intelligence is being used at UNC to make treatment decisions for cancer patients.

Watson became an instant celebrity in 2011 when it was successful in beating human champions of the quiz show ‘Jeopardy!’. Since then the ‘robo-geek’ has come a long way, and its ability to analyze and interpret information has taken a big leap, so much so that it can now read and keep track of thousands of academic papers, medical records and clinical trial results, and then translate that information to make potential treatment suggestions to clinicians.

In 2015, I.B.M. began collaborating with pioneering cancer institutes across the nation, including UNC Lineberger, to hasten the process of analyzing the patient’s cancer on a molecular level. By exploiting Watson’s data analysis and data visualization capabilities, I.B.M and UNC seek to tailor suitable treatment options. With the special segment on 60 Minutes, UNC got a fair share of spotlight in primetime national television. But, is crazy to use a computing device to make critical treatment decisions in a disease like cancer? 

https://upload.wikimedia.org/wikipedia/commons/0/00/Cancer_genome_sequencing_workflow.png

The progression of events from collection of patient tissue to recommendation of a treatment option

Every living organism, including humans, are composed of millions of cells, the basic fundamental units of life. Cells contain DNA, which encodes the necessary instructions required for a living organism to survive and grow. These instructions are found in segments called genes. During exposure to environmental factors like sunlight, smoking or  ageing, the DNA may become damaged. While the cells have their own tools to repair damaged DNA, sometimes the damage is too overwhelming and may escape the cell’s quality control mechanisms. The damaged DNA, also known as mutated DNA, may be passed onto subsequent generations of cells. The mutant DNA may now instruct the cells to grow uncontrollably, and as a result the cells can deviate from their normal functions. This is when a cell can turn cancerous. When a group of these cancerous cells clump together, they form a tumor. Historically, cancer treatment regimens have been directed toward where the tumor is located in the body, and while this has some positive therapeutic effects, it has not been very efficient.

Over the years, as genetic research progressed, scientists began to classify tumors on the basis of their genetic characteristics. They are now able to identify the genes and the corresponding mutations that drive tumor growth.  Drugs targeting these mutations have been designed, and some of them have demonstrated considerable improvement in patient survival. The question now is can cancer be effectively treated based on the broad pathology of the tumor in the body. An individualized approach based on the genetic makeup of the patient’s cancer is being considered as an alternative treatment.

If this sounds too abstract, let’s consider a clinical example. It is well established now that tumors in some breast cancer patients have high expression of estrogen receptors. This means that the cancer cells may receive signal from the hormone estrogen, which may facilitate tumor growth. A class of drugs called ‘aromatase inhibitors’ prevent the body from producing estrogen and may work well on this subset of patients. However, only about half of patients whose tumors tested positive for estrogen receptors responded to these class of drugs. With a genetic-based approach to cancer treatment, the genetic profile of the patients who respond to the therapy may be used to look for treatment patterns. Now, if these patterns are consistent with one another and they match the genetic map in a section of patients that respond positively to aromatase inhibitor therapy, then this may stand as an effective treatment strategy. Other estrogen receptor positive patients may be treated using a different strategy without wasting time on a therapy that may not work. This new era of treatment is referred to as the age of ‘precision medicine’.

At UNC, when a patient agrees to participate in the ongoing clinical trial UNCseq, a tissue sample is collected by biopsy or during surgery and is analyzed to determine the genetic makeup of the tumor.  A blood sample is also drawn to examine the genetic profile of the patient. The samples are then analyzed by rapid DNA sequencing methods. Then the building blocks of the cancerous and normal DNA are compared one block at a time to identify the mutations present in the tumor. Now, if a mutation affects a protein which helps a cell to survive and grow normally, it may be a cancer-driving mutation. However, there may be hundreds to tens of thousands of other ‘innocent’ mutations that do not affect  cancer growth. Rigorous analysis is required before key mutations can be determined.

A single patient’s genetic information may clog up gigabytes of storage space, and analyzing all of these data to search for patterns may require a fair amount of mathematical effort and computation time. All of this occurs in a situation where a patient awaits treatment, so every bit of time is precious. This is where a supercomputer like Watson comes in. Watson had been able to analyze the DNA profile of tumors very efficiently and proposed treatment regimens that matched the decision of the clinicians 99 out of 100 times. What is more interesting is that in about one third of the cases, it was able to identify new treatment strategies that the doctors had not previously considered. It is to be seen whether this approach helps improve overall standards of care in a large cohort of patients in the long haul.

Cancer therapy still has a long way to go. Just because we know about the aberrations in the cancer cell doesn’t mean we can develop a complete cure. Current chemotherapy drugs can effectively kill cancer cells, but they may pose significant toxicity to the patient as they also attack healthy cells. Targeted therapies against genetic mutations work very efficiently in a few cancers, but only for a short span of time. The cancer becomes resistant in days to months and returns aggressively. Immunotherapy approaches where the immune system is stimulated to fight cancer is the new hot-topic in clinical discussions. Unfortunately, only a small subset of patients respond to these therapies, and for unknown reasons. However, with precision medicine, we expect to provide the most appropriate care to each patient, resulting in considerable improvements to their survival and quality of life. We continue our fight against beating cancer, and as a Tar Heel, I am proud that UNC is leading the way.

Edited by Nicole Tackmann and Alison Earley.

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“You keep using that word. I do not think it means what you think it means.”

We all get that same question over and over again from everyone we meet — the old friend at the grocery store, an uncle at a family reunion, or even a stranger at the bus stop: “What do you do for a living?” If you’re a graduate student, you could be tempted to say something like, “I am a Ph. D student conducting research on the genetics of cancer. Specifically, I study the role of an RNA-binding protein in regulating tumor angiogenesis in both cells and mouse models, and I hope to eventually develop a therapy targeting this molecular pathway.” It’s likely, however, that an answer like this would mean something entirely different to the person who asked you the question than it does to you. Inigo Montoya would probably not be impressed. Why? Because if you look closely at the words in bold, you will realize that while most of them are not particularly complex or technical, they do have very specific meanings in a scientific context. As Ph. D students, it can be challenging for us to remember that many of the words we freely toss around every day in the lab mean something completely different to those that are not actively engaged in science.

https://commons.wikimedia.org/wiki/File:Lab_mouse_mg_3263.jpg and https://commons.wikimedia.org/wiki/File:Tyra_Banks_2011.jpg

A good-looking woman or a laboratory mouse injected with cancer cells – which model are you talking about?

Here are just a few of those words that have completely changed in their meaning for me during my time as a scientist. (Just a disclaimer, my Now definitions are far from comprehensive, but instead represent what first comes to my mind now as a Ph. D student in cancer biology).

Ph. D Student

What I used to think: An insanely intelligent human being who has the answers to all of life’s questions and is nothing short of a walking, talking encyclopedia.

Now: Someone who has absolutely no clue what’s going on at any given time of the day.

Research

What I used to think: Reading up on a topic on Wikipedia.

Now: Slaving away for hours at a bench, repeating experiments over and over again that never work, all while questioning the reason for my existence.

Genetics

What I used to think: The field that studies how you inherit traits from your parents.

Now: The field that studies the complex molecular underpinnings of diseases and biological processes at the DNA, RNA, and protein levels.

DNA/RNA

What I used to think: The stuff that determines what color your eyes are and whether or not you have attached earlobes.

Now: Enigmatic molecules we’ve been studying for almost 150 years and have only scratched the surface of in terms of our understanding. Among many things, they are molecules essential for controlling the amount and types of proteins found in a given cell.

Protein

What I used to think: That stuff in meat you should eat a lot of if you want to get buff.

Now: Complex molecules that are the core machinery for all biological processes and functions. When developing new treatments for diseases, these molecules are often what we try to target.  

Model

What I used to think: Tyra Banks.

Now: A mouse, fly, worm, frog, fish, or other critter whose genetics, tissues, or other aspect of their biology has been altered to try and mimic a human disease. We use these models to both better understand diseases and test potential treatments for them. Unfortunately, however, these models often fail to capture the full complexity of a given human disease, causing the conclusions we draw from working with them to have shortcomings. This is largely the reason why we have not yet completely cured diseases like cancer!

Therapy

What I used to think: Something you seek out if you are experiencing problems in your life.

Now:  A molecule, compound, or technique that targets a specific component of a disease to prevent or eradicate it.

Pathway

What I used to think: The yellow brick road.

Now: A series of molecules (i.e. proteins, DNA, or RNA molecules) that physically interact with or signal to one another to initiate a process or carry out a function.

So next time someone asks you about your research, instead of just trying to simplify your explanation, take the time to teach them the new meaning of a word or two!

Peer edited by JoEllen McBride.

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