Meditations of an oncology geek

Can Ginseng Consumption Help Prevent Cancer?

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26 November 2017

Hi Everyone,

I know it’s been a while since I did a blog post in the spirit of my old “cancer for dummies” blog, but I thought it would be fun to tackle a question about cancer prevention using ginseng.

Ginseng is a family of herbs that grow mostly in colder climates, and feature prominently in eastern medicine, believed to aid the healing or amelioration of effects from a myriad of conditions including: cardiac function, sexual function, glucose metabolism, pulmonary disease, cerebrovascular disease, athletic performance, and warding off the development of cancer: https://www.ncbi.nlm.nih.gov/pubmed/21704950

Nutrition research is notoriously difficult, as touched upon in a fantastic post by FiveThirtyEight: http://fivethirtyeight.com/features/you-cant-trust-what-you-read-about-nutrition/

In short, for observational / questionnaire studies is very difficult for a study subject to keep track of intake with a high degree of precision, and the statistics surrounding nutritional studies must be handled with great care. With so many potential confounding factors, it’s often very difficult to isolate a particular variable with a high degree of certainty. Exploratory analyses can also be easily confounded by statistical multiple testing problems; the more time one tests for correlations, the higher the probability that a spurious correlation will come to the surface. From the FiveThirtyEight piece:

Nutritional questionnaire studies evaluating cancer incidence are also notoriously difficult because most of the study population will not get cancer in a particular time period; those following patients over time must follow patients for a *long* time: on the order of magnitude of decades.

Three studies in particular piqued my interest, by the authors Yun and Choi, a Koren-Chinese collaboration studying the effects of ginseng consumption in relation to cancer incidence that spanned over 15 years.

The first study was produced in 1995, using 1,987 case-controls (3,974 patients) comparing ginseng users to non-users. The authors found that ginseng users had a 50% lower risk of having developed cancer (Odds Ratio: 0.50, 95%CI: 0.44 – 0.58). The authors specifically sought to investigate cancer incidence, not a myriad of potential correlations that might cause spurious correlations, so there is less concern for multiple testing error: https://www.ncbi.nlm.nih.gov/pubmed/7655337

The second study, produced in 1998, utilized questionnaires to quiz 4632 people about their frequency of ginseng intake, kind go ginseng, etc. The authors reported that there was about a 60% lower risk of dying from cancer in the ginseng-using group compared to the non-using group on a whole: (RR: 0.40, 95%CI: 0.28 – 0.56) https://www.ncbi.nlm.nih.gov/pubmed/9698120

While these studies are fairly large, in questionnaire studies it’s very difficult to escape the correlation vs. causation problem: do people who consume more ginseng get less cancer because it prevents cancer, or are these people generally more proactive with their health in many areas of their lives? The observational study subjects are from a culture that respects and reveres ginseng as a panacea, and those more proactive about their general health might be more apt to consume more ginseng, while at the same time might also be more apt to exercise more, better manage chronic stress, or perform a multitude of small things that all might add up to a lower risk of cancer over time.

However, the authors did not stop there: in 2010 they produced results from a randomized, double-blind, placebo-controlled study evaluating the consumption of 1g of red ginseng extract powder per week for three years, or placebo, and followed the patients for 8 years. This type of study design is able to detangle the correlation vs. causation conundrum. The authors enrolled 643 chronic atrophic gastritis patients, presumably for a patient population with a higher risk of developing gastrointestinal tumors. Often, trials evaluating cancer prevention will enroll patients at higher risk of developing cancer because studies evaluating the incidence of cancer in unselected populations can take decades. This has the advantage of a shorter potential trial, but might potentially limit the breadth of application of results (i.e. can the results be applied to everyone, not just high risk people?). In the eight year period, 24 patients developed cancer. Unexpectedly, most were not of gastrointestinal origin. But, fewer patients in the ginseng vs. placebo group developed cancer: the observed odds ratio of the declared primary endpoint was 0.54 with 95% confidence intervals of 0.23 to 1.28, p = 0.13. This indicates that there is a 13% chance that the observed differences are due to random chance, and that there is 95% confidence that the true effect of 1g of red ginseng extract consumption per week for three years is between a 77% reduction in risk of developing cancer, to a 28% increase risk in developing cancer, with a mean of 48% reduction of risk. https://www.ncbi.nlm.nih.gov/pubmed/20521975

The prospective study followed patients for only 8 years, and additional follow-up would most definitely provide more power to see if the effect gets stronger with time (it should if it’s real). The study was published in 2010. It is not uncommon to publish a follow-up study from trials like this after more time has passed, and more potential cancer cases have been observed. Unfortunately, a search for this potential follow-up analysis came up short. It is my hope that the authors of the original study continued to follow patients over time and if so, will share these results.

My co-workers and colleagues often joke that I am a bit too much of a “data skeptic” and that perhaps my bar for evaluating research is a bit too high. I am often highly skeptical of nutritional studies (as you could probably tell from my above commentary) but I will say that the result of this literature dive has made me give a fresh look at ginseng. No medical intervention is without risk, but ginseng is generally well tolerated and few people experience side effects. https://www.ncbi.nlm.nih.gov/pubmed/21704950 I personally seldom take supplements, but even this data skeptic is considering purchasing red ginseng extract tablets!

If you have followed me this far I would like to thank you, dear reader!

Ryon

Written by Ryon

November 25th, 2017 at 7:51 pm

Posted in Science Blog

Two New Manuscripts: A Chaos Biomarker and Tracking Tumor Evolution with Liquid Biopsy

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3 October 2017

Dear Friends,

I have some good news to share. My team has had not one, but two scientific manuscripts recently accepted and published.

Part One:
Chaos *is* the Biomarker

This study was one a long time coming, that was originally selected as an oral abstract at ASCO GU early last year!

If you didn’t already know, I’m a huge fan of Siddhartha Mukherjee and his style of communication of various aspects of cancer’s biological underpinnings and history. In this Pulitzer prize-winning work (1), Mukherjee describes perhaps the most fearsome quality of what has been dubbed the “Emperor of All Maladies”

“This mirthless, relentless cycle of mutation, selection, and overgrowth generates cells that are more and more adapted to survival and growth. In some cases, the mutations speed up the acquisition of other mutations. This genetic instability, like a perfect madness, only provides more impetus to generate mutant clones. Cancer thus exploits the fundamental logic of evolution unlike any other illness. If we, as a species, are the ultimate product of Darwinian selection, then so, too, is this incredible disease that lurks inside us.”

This “perfect madness” described by Mukherjee exerts its effects to different degrees in different patients. It has become clear that in some patient cancers, every cell has about the same alterations that make them tick, and in some patients there is a great deal of heterogeneity in terms of what drives the disease from cell to cell (2, 3). This general movement in cancer research to acknowledge this phenomenon is happening in front of the backdrop of the “precision medicine” movement in oncology: the preferential use of very narrowly targeted therapeutics to specific alterations (4). The problem is, if one were to use a “precision” medicine with a patient with heterogeneous disease, one might eliminate a part of the disease while leaving the rest relatively intact. The patient would get all of the side effects but a portion of the benefit.

The current means to assess this phenomenon is by taking multiple biopsies in patients; cutting out multiple pieces of tissue and dissecting them to assess spatial heterogeneity of intra-patient disease. In metastatic prostate cancer, this would involve drilling into the bone in multiple locations, which is undesirable, impractical, immensely painful, and very expensive (5, 6).

We sought to determine if we could observe the echoes of this phenomenon through the circulating tumor cells in patient blood. We developed two metrics to quantify the phenotypic heterogeneity of rare cells: how different they looked from cell to cell (7).

We have been collaborating very closely with the fantastic folks at Memorial Sloan-Kettering Cancer Center, lead by Dr. Howard Scher. This collaboration allowed us to correlate patient outcome (i.e. how long they lived) on either precision therapies (abiraterone and enzalutamide), or chemotherapy (taxanes). Taxanes are microtubule stabilizers, affecting all quickly dividing cells, regardless of their drivers, including healthy cells that divide quickly. The hormonal therapies exert their influence through a very narrow molecular bottleneck (8, 9), which has less side effects and can work well, if the disease is not too heterogeneous and all of the cancer cells can be affected.

We developed two means to measure the phenotypic heterogeneity of circulating tumor cells (how similar or dissimilar cells looked to each other in a patient sample). We found that the more dissimilar they looked, the more generally aggressive the disease, and the more patients had better overall survival if given chemotherapy instead of hormonal therapy. The results suggest that the phenotypic heterogeneity of circulating tumor cells might be used to extend patient lives with more intelligent use of already existing drugs that are FDA-approved and reimbursed. A validation study is being planned. Open access article here: http://cancerres.aacrjournals.org/content/early/2017/08/16/0008-5472.CAN-17-1353

The clinical decision to give targeted therapy or chemotherapy is not unique to prostate cancer; while it remains to be tested, it is plausible that the described phenomenon and methods of measuring it could potentially be applied to lung cancer, pancreatic cancer, colorectal cancer, head and neck cancer, melanoma, and breast cancer.


Part Two: Emergent Resistance in Breast Cancer

The second study is our first study on breast cancer circulating tumor cells, and was accepted to PLoS One. Open access article here: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185231

We were able to confirm the presence of androgen (male hormone) receptors on circulating tumor cells in women with estrogen-driven disease. This admittedly might sound a little odd that there are male hormone receptors present on what is predominantly an estrogen-driven disease. However, emerging models of tumor evolution suggest that women with estrogen-driven disease, for which anti-estrogen drugs are administered, can use this mechanism as a bit of a short cut back to continued cell growth: the cancer changes over time by classic natural selection and Darwinian evolution.

We were able to observe this effect in breast cancer circulating tumor cells in actual patients (10). The next step would be to determine if women with this emerging mechanism of resistance to anti-estrogens might be put on anti-androgens to control their disease, or perhaps onto non-hormone targeting therapy.

The Big Picture

There is so much that is known about how cancer starts and grows, and much about how it acts once it spreads (metastasizes) within patients, but there is a relative lack of knowledge about the seeds in transit, the liquid phase of disease. It remains a fascination of mine to do research in this space, especially since the information we glean can be turned into very clinically-friendly diagnostic modalities for better cancer management.

Thanks for dropping by!
Ryon

References

1. Mukherjee S. The emperor of all maladies : a biography of cancer. New York: Scribner; 2010.
2. Hiley C, de Bruin EC, McGranahan N, Swanton C. Deciphering intratumor heterogeneity and temporal acquisition of driver events to refine precision medicine. Genome Biol. 2014;15(8):453.
3. Jamal-Hanjani M, Quezada SA, Larkin J, Swanton C. Translational implications of tumor heterogeneity. Clinical cancer research : an official journal of the American Association for Cancer Research. 2015;21(6):1258-66.
4. Shrager J, Tenenbaum JM. Rapid learning for precision oncology. Nature reviews Clinical oncology. 2014;11(2):109-18.
5. Joosse SA, Gorges TM, Pantel K. Biology, detection, and clinical implications of circulating tumor cells. EMBO molecular medicine. 2015;7(1):1-11.
6. Yap TA, Lorente D, Omlin A, Olmos D, de Bono JS. Circulating tumor cells: a multifunctional biomarker. Clinical cancer research : an official journal of the American Association for Cancer Research. 2014;20(10):2553-68.
7. Scher HI, Graf RP, Schreiber N, McLaughlin B, Jendrisak A, Wang Y, et al. Phenotypic Heterogeneity of Circulating Tumor Cells Informs Clinical Decisions between AR Signaling Inhibitors and Taxanes in Metastatic Prostate Cancer. Cancer research. 2017.
8. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. The New England journal of medicine. 2012;367(13):1187-97.
9. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. The New England journal of medicine. 2011;364(21):1995-2005.
10. Fujii T, Reuben JM, Huo L, Espinosa Fernandez JR, Gong Y, Krupa R, et al. Androgen receptor expression on circulating tumor cells in metastatic breast cancer. 2017;12(9):e0185231.

Written by Ryon

October 3rd, 2017 at 5:37 pm

Posted in Science Blog

Siddhartha, Time, and Lessons from Cancer Patients

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23 July 2017

Dear Reader,

I’m pleased to say that there are a lot of very exciting projects I’m involved in at the moment, with potential to push the boundaries of liquid biopsy and cancer treatment in general. Unfortunately, I won’t be able to discuss most of them until they are presented / published.

More broadly, I thought it would be a great time to re-visit central philosophies and motivations for pursuing science and medicine in the first place, in an (perhaps foolish) attempt to answer the hardest of questions: “Why?”

Science and medicine together is a physical manifestation of humanity’s will for a better tomorrow. We can objectively create tangible improvements that will make tomorrow better than today, and tomorrow’s tomorrow better than tomorrow. Science has cured many communicable diseases, made our lives much safer, and continues to make inroads for one of the most difficult of challenges: cancer.

But still, one may ask, why do these things make our lives better? If we can live longer, one might argue, we can experience more things, and live life with less pain and suffering. One might ask the question (as many have) if this is merely allowing ourselves the opportunity to live a fuller life, but in itself might not be something that allows our lives to be more fulfilling or happy?

Enter: Siddhartha by Herman Hesse. Originally published in 1922, it is a synthesis of many Indian spiritual traditions communicated through a fictional allegory of Siddhartha’s journey to enlightenment in the time of the Buddha. I was fortunate enough to have read Hesse’s short story (122 pages) back in high school, and at the time I was both deeply moved by the work, and vowed to read it again at some point. Now about 15 years later, I finally came through on that promise I made to myself.

The plot follows the protagonist Siddhartha through what many would consider an unconventional path to enlightenment, by both intent and result. He ostensibly eschews his Brahman status to spend many years as an Ascetic, living without possessions in the forest. Instead of devoting his whole life to this particular pursuit, he opted to move on to discover new things once he felt that he had reached the point of diminishing marginal returns in his spiritual development. His central Way to enlightenment was further solidified after a meeting with the Buddha himself, at the time the only man known to have actually reached nirvana, the ultimate goal of goals among Indian mystics. At the time, the Buddha was gaining many followers, and realized that the Buddha himself had not reached nirvana through any established teaching, that perhaps Siddhartha should not follow any teacher as well. Further, he felt that following any established Way or teacher would potentially be a trap, and that everyone’s path to enlightenment might thus be hidden in plain sight, wrought through a diversity of extraordinary, and more importantly, ordinary experiences.

I do not wish to synopsize the plot further, for others have done this far better than I could. Further, there are simply too many amazing lines from Hesse’s work to choose from, so instead I’d like to attempt to summarize his central thesis:

1) Knowledge can be communicated, but wisdom cannot
2) Wisdom must be learned individually; to become wise, one must become both life’s student, and one’s own teacher
3) In every instance in life is a piece of the wisdom we seek
4) Wisdom, from grand to sublime, is plentiful and everywhere, hidden in plain sight
5) Wisdom is made visible when hearts are vulnerable and minds are open

I adopted much of this central mantra as my own, and in the 15 years since it has been a powerful motivating force in my life and my career. Seen through the lens of Hesse’s thesis: to become enlightened, one must experience many things, take on many challenges, and recognize that the concepts of success and failure are but tempting distractions and states of mind; the real value is derived from the journey, not the destination.

It is part of this mantra that originally informed my decision to pursue my PhD and aim to change medicine for the better in a tangible way. I knew that these were both very, very high bars, that many people with more talent and resources have failed along the way, and that I would be making an immense sacrifice of some of the most productive years of my life. That said, I knew that the tribulations along the way would force me to grow in many ways, and allow me to experience diverse opportunities to catch drops of enlightenment along my journey. Good, bad, or ugly, I vowed to embrace each and every experience in life as an opportunity for learning.

I am very thankful to have walked down this path, and will continue to pursue my personal and professional life through this lens.

Even more broadly: I have come to realize that science is very hard (not a surprise I guess!) and creating new things (drugs, devices, treatment means) to extend patient lives is also incredibly difficult. These things come at the expense of many things, the most valuable of which is our time. Time itself is a bit of a peculiarity; it is both our most valuable resource, and it is ironically a resource that is very difficult to know with certainty how much any individual still has. From this, I have come to embrace the mantra that we must seize at least a little bit of every day for enjoyment and satisfaction, and we should invest our time with more care than we invest anything in life.

I find Hesse’s central thesis very enabling toward that end: allowing a “return” on the investment of our time, regardless of the activity, life situation, and challenges we face, both wrought upon us, and the ones we willingly accept.

Orthogonally is the realization that cancer patients are acutely aware of their mortality and their time, much more so than the general population. To grant an extra year of life to a metastatic cancer patient is to grant a year of life very well-fulfilled. In the evolving phases of my life, I strive to learn from cancer patients, to further seize every day, and keep my heart vulnerable and my mind open for the wisdom we seek.

If you have made it this far I would like to thank you, dear reader.

Yours,
Ryon

Written by Ryon

July 23rd, 2017 at 1:32 pm

Posted in Science Blog

New Publication and the Dream of Predicting Immunotherapy Response in Lung Cancer

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8 May 2017

Dear Friends,

I am pleased to announce that our recent publication “Cellular Expression of PD-L1 in Peripheral Blood of Lung Cancer Patients is Associated with Worse Survival” has been accepted for publication in Cancer Epidemiology Biomarkers & Prevention and is now available online, open access.

In this study, we recruited blood from patients about to receive biopsy to confirm lung cancer. We looked for rare cell populations in the blood, and found a subpopulation of cells with malignant morphometrics (i.e. nuclear morphology) that expressed PD-L1, but not blood-lineage CD45 or epithelial-lineage cytokeratins! These cells were very rare in patients without cancer, and for those with cancer, higher levels of them before treatment was associated with poor overall survival.

PD-L1 is an important emerging biomarker with much promise to predict patient response to what was up until recently the black swan of oncology: immunotherapy. MIT Technology Review recently
produced a fantastic overview.

Immunotherapy, as the name suggests, removes checkpoints in the patient’s immune system to recognize their cancer as foreign. When this happens, tumors can almost literally melt away from patients. But, there is a catch: depending on the indication, only 10-20% of patients see benefit from these new drugs, and the rest continue to see their cancer progress, making it more difficult to treat. But, the patients for whom it works generally have very long, sustained responses, some have even been declared “cured,” a word seldom used to describe someone who previously had advanced, metastasized cancer. The biology surrounding the interactions of the immune system and tumors are bewilderingly complex, and there is unfortunately much basic biology that remains unknown, especially why some patients respond resoundingly well to immunotherapies and some do not. But, there is one biomarker that when present on tumor cells can sometimes predict these responses: a protein called PD-L1.

Current means to measure PD-L1 protein on lung tumor cells still requires a lung biopsy, where a large needle has to transverse healthy tissue and puncture the thoracic cavity, potentially causing complications like collapsed lung. There is a tremendous unmet medical need to predict immunotherapy response without biopsy. The patients in our study did not go on to immunotherapy agents, so it’s not possible to tell if these rare cells are predictive of response to immunotherapy agents. However, a follow-up study will be investigating the response to immunotherapy agents in relation to pre-therapy detection of these rare cells.

Thanks for reading!

Ryon

Written by Ryon

May 8th, 2017 at 7:47 am

Posted in Science Blog

16 Favorite Images of 2016

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31 December 2016

Hi Everyone,

I am going to take a slight diversion from my normal science / bio blog, and make a post about my 2016, as described through my camera’s viewfinder. As some reading this may know, back in college I was a staff photographer at the New University newspaper at UC Irvine, and especially in recent years I’ve been making concerted efforts to again explore describing life experiences through photographs. While the cliche about photographs being worth 1000 words may be true, I will add a few more for context to each of my 16 favorite of ’16.

17 January

I remember riding my bike this morning up the coast, and being completely blown away by how much the surf had picked up. The swell period was unusually long, and I suspected that Blacks Beach might be really shining with better tides later in the day. I had the most pleasant experience sitting for a couple hours atop the cliffs in the Scripps Reserve, watching groomed liquid avalanches methodically emerge from the depths of the deep underwater canyon, the rumbling echoing off of the cliffs as braver souls than I attempted to dance with the ocean on this day.

01 March

My mother tragically passed away 15 years prior to this day. I opted to re-visit the San Diego (Quail) Botanical Gardens that she really loved. I was not to be disappointed. While the enormity of the experience is a bit too much to describe here, I did a lot of just standing or sitting silently, which also had the effect of making small flighted animals more comfortable with my presence. I am including two photos from this day in my 16 of ’16. The first was a monarch butterfly that really liked an angularly appealing plant against a black backdrop. In many respects, this was a lucky shot. I shot this with my telephoto and did not have time to properly select the right aperture, but I was happy with the outcome!

The second one from 01 March was taken about half an hour later. This hummingbird was hovering just a few meters away from me and really seemed to like this group of flowers (it probably thought I was a tree or something). While slightly out of focus, I thought it was a fitting photograph for the day as well. The hummingbird hovered around me for what felt like five whole minutes, and I feel like we had a good time together.

06 May

A good friend of mine had recently gifted me a philodendron, which has been a great addition to my back patio. I took this photo amid what was a really heavy week of gray marine layer. I noticed that brief breaks in the gray would light up the underside of the leaves, so I grabbed my camera and waited. It’s one of those things that counterintuitively looks a lot better to a camera than to the eye, and I was really pleased with the result from a day dominated by gray sky palate.

07 June

My trip to Chicago this year was a bit of a turning point in my professional life. Days before we had published the results of a cross-sectional cohort study evaluating a biomarker that will be put to use to extend the lives of men with advanced prostate cancer. I was in Chicago with my research team at the American Society of Clinical Oncology (ASCO) annual meeting to present on this research and other exciting research. The last day I was in Chicago I was able to catch a late flight home, and did some exploring around Millennium Park. Coming from San Diego, what really struck me about Chicago is that there is no natural landscape by which the architecture defines itself, no mesas or canyons or inlets or mountains, and instead is a blank canvas for man-made form, function, and expression. This first photograph was taken when I get on a bridge of unknown (to me) destination. The angles seem to suggest it goes on into the horizon of buildings in the distance, and the pedestrians give a sense of destination as well. The bridge wound up leading me to the Art Institute of Chicago, a fitting destination! While not the most visually stunning photograph, it is nonetheless one that really captures a curious moment and experience of a formative trip.

This next one was from the same day, just a few hours later. I was walking back from the Art Institute of Chicago, through Millennium Park, and was surprised to find myself suddenly in about half an acre of lavender! I was not the only one there, as many bees were hopping from flower to flower. A particular aspect that draws me to this photo is the utter surprise I felt, not expecting to find myself in such a setting!

01 August

A couple months later I found myself on the east coast, racing my bike at the USA Cycling track nationals in Trexlertown, PA. While I have many fun action photos from the experience, I also feel that this photo from the flight home encapsulates a lot of the essence of the trip and experience: here the pilot is literally dodging thunderstorms. I feel that it is somewhat symbolic of the punctuated dynamic of track racing. It was a lot of work, and the racing had its fair share of drama, but at the end of the day we did find clear horizons and I am so glad my team and I went. This photo is from the plane window, deliberately shot at f/4.0 with focus at infinity, right up against the glass, to best avoid blemishes from the plane window.

02 August

Just the next day I found myself in a place both familiar and somewhat unfamiliar. While I had raced all spring and summer at the San Diego Velodrome to get ready for track nationals, I had the fun experience of being on the other side of the railing and among the stands instead. I added a little bit of motion to this photo, using a slower shutter speed and a little bit of a speed pan. Again, not the most visually stunning photograph, but I feel that it captures the essence of a savored experience.

26 September

This day was the hottest I have ever seen at the coast in San Diego. The mercury reached 106F! It made for an especially pleasant walk on the beach later in the day. The surf and the way the sand had moved around lead for great conditions to finally capture a good reflection of the iconic Scripps Pier.

This one is my favorite of all year. Again, from 26 September. The most charismatic sandpiper was dancing with the ebb and flow of the light surf, and eventually turned to walk right toward me. It’s really the reflections that make this photo for me, alongside the sandpiper’s posture and swagger. I wish I would have shot it with a slightly wider depth of field, but sometimes it’s the slight blemishes that make a photograph seem real (or at least that’s what I tell myself!).

01 October

This one was from an impromptu trip up Nate Harrison Grade, a dirt road rising from 1000ft to about 6000ft of elevation on the western side of Palomar Mountain. About halfway up I realized that the encroaching marine layer from was starting to fill in some of the western valleys closer to the coast. It’s a shot that I’ve had in my head for many years, and was very gratifying to be able to capture.

16 October

I remember having to work most of this Sunday, and taking a break mid-day to just go sit by the Torrey Pines Glider Port. A light storm had just passed overnight, leaving a textured canvas against which gliders hovered. I remember sitting for about an hour, and suddenly one approached fairly close, and was able to capture it against the sun as well.

05 November 2016

My best friend from college visited me this weekend, resulting in a lot of surfing, taco eating, and also an impromptu trip out to the Anza Borrego Desert in search of ancient Kumeyaay pictographs. Along our hike we came across this view, looking south toward Mount Laguna in the distance, which a few months later would be capped in snow (see below photograph). A green desert oasis is even barely visible at the desert floor. The view was completely unexpected, and took my friend James by such surprise that he fumbled his phone, which wound up falling about 50 feet down the dry waterfall. Incredulously, he found a way to climb down to retrieve it, and both he and the phone wound up unscathed!

27 November

The geographic diversity of San Diego County never ceases to amaze me, and not even a month later the first snow fell on Mount Laguna (6000ft). In this case, the first snow caught many plants by surprise, including this oak tree. Amid a backdrop of snow, a leaf displays a fitting amount of chromatic heterogeneity for the rapidly changing alpine seasons.

29 December

I like this photo for both the scene, and the amount of work I had to put in to get there! This was 4 miles and 2000 vertical feet into my hike up El Cajon Mountain on a very clear day (two days post-rain). Visible on the right is Point Loma and downtown San Diego, with the Coronado Islands (Mexico) in the distance on the left. I am really a bit of a geographic geek at heart, and love the expanse and range of the corner of the world I call my home.

Thanks for reading. It was fun to share!

Ryon

Written by Ryon

December 31st, 2016 at 9:28 am

Posted in Science Blog

Chemistry in Context: AR-V7 in Metastatic Prostate Cancer

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23 December 2016

Hi Everyone,

I have some great news to share:

Recently, the work of my colleagues and collaborators was accepted and published in the prestigious journal European Urology. A retrospective analysis of the cohort presented in Scher et al. JAMA Oncology, this study investigated the scoring criteria of the AR-V7 biomarker in circulating tumor cells. We found that the AR-V7 is predictive of drug class-specific survival when the AR-V7 protein is localized to the nucleus of circulating tumor cells in metastatic prostate cancer patients: that patients who had these types of CTCs survived longer on taxane chemotherapy instead of androgen receptor signaling inhibitors like abiraterone, enzalutamide and apalutamide.

My individual contributions were lead biostatistician and drafting the manuscript. The open access article is available here: Nuclear-specific AR-V7 Protein Localization is Necessary to Guide Treatment Selection in Metastatic Castration-resistant Prostate Cancer

Ryon

Written by Ryon

December 24th, 2016 at 9:51 am

Posted in Science Blog

Nerd Nite, Liquid Biopsies, and the Future of Cancer Diagnostics

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14 December 2016

Hi Everyone,

Last week I had the privilege of being an invited speaker at Nerd Nite. From Wikipedia:

Nerd Nite is an event usually held at a bar or other public venue where 2-3 presenters share about a topic of personal interest or expertise in a fun-yet-intellectual format while the audience shares a drink. It was started in 2003 by then graduate student (now East Carolina University professor) Chris Balakrishan at the Midway Cafe in the Jamaica Plain neighborhood of Boston and spread to New York City in 2006, where Matt Wasowski was tasked with expanding Nerd Nite globally. Nerd Nite is held at more than 80 cities worldwide.

One of those cities is San Diego, where the venue started up a few months back, held just outside the Liberty Public Market, right next to Stone Brewery. The Wikipedia description is apt, as most of the audience has a beer in hand. While the outdoor venue and proximity to Lindberg Field lead to some noisy interruptions, it seems to be a custom to raise one’s drink and take a swig when the speaker is momentarily drowned out by jet noise.

All in all, there were about 40 people present of diverse intellectual curiosities and backgrounds, and when mixed with beer, lead to some really fun public discussions about the intersection of science and science fiction.

I gave a talk titled “The Future of Cancer Diagnostics: The Liquid Biopsy” where I outlined three main areas of cancer diagnostics (see photo) that can be revolutionized by emerging rare blood analyte technologies, especially those that can detect and characterize circulating tumor cells. In particular, I discussed our recent work on CTC-based AR-V7 protein as an emerging treatment selection biomarker in advanced prostate cancer. The next step will be clinical studies to investigate the clinical utility of monitoring resistance (i.e. once a patient gets a drug, not just before a patient gets a drug) using the same or similar types of tests.

The key advantages of liquid biopsy are accessibility, repeatability, and fewer side effects; no one will get a collapsed lung from observing circulating lung tumor cells, and there is no drill required to see circulating tumor cells from a bone metastasis in prostate cancer. Blood draws also do not require trips to hospitals, and can be repeated with much, much higher frequency than tissue biopsies, enabling the potential for sequential monitoring of cancer, which is a disease that evolves over time in cancer patients.

The challenges facing the use of circulating tumor cells lie in the sensitivity of detection, for which I discussed emerging technologies in tandem with established literature suggesting that there is biological feasibility for early detection of cancer using CTCs, and that the main hurdles right now are organizational (i.e. funding and time) required to run the clinical studies and clinical trials to expand clinical utility into the “early detection” area of cancer diagnostics. While treatment selection and recurrence monitoring are very important unmet needs in oncology, and are in late phases of clinical development, it is the early detection of cancer that could extend patient lives by decades, not just years.

It’s a tantalizing vision of the future of oncology, but it is important to underscore that oncology is not changed by technology alone, but by the application and testing (i.e. clinical trials) of technology: do the benefits outweigh the potential harms and costs? What patients benefit, and how much? Emerging technology and studies have clearly demonstrated that the scales can be tipped well into the patients’ favor, at least in the treatment selection area of advanced prostate cancer. It’s a great proof of concept, and this rigor of clinical studies will need to be applied to the recurrence monitoring and early detection areas of oncology diagnostics as well.

…and this is where I got of my soapbox and had a sip of my beer! I really enjoyed the vibe, and will be a regular at Nerd Nite, and it’s so incredibly important to have these types of public discourses about science and technology. Already looking forward to next month!

Written by Ryon

December 14th, 2016 at 9:29 am

Posted in Science Blog

The Epic Journey Continues: A First-In-Class Test Will Change Advanced Prostate Cancer Care

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6 July 2016

Hi Everyone,

I have some great news to share:

1) Recently, the work of my colleagues and collaborators was accepted and published in the prestigious journal JAMA Oncology. We developed a test to predict standard of care drug responses in advanced prostate cancer patients using only a blood draw. The clinical study suggests that use of our test could allow patients with the most aggressive subtype of prostate cancer could live about 4X as long. I was one of the authors on the study, drafting the manuscript and performing bio-statistical analyses. This represents the first “liquid biopsy” test to demonstrate clinical utility at a key medical decision point in cancer patient care.

Association of AR-V7 on Circulating Tumor Cells as a Treatment-Specific Biomarker With Outcomes and Survival in Castration-Resistant Prostate Cancer

2) Today I can publicly share: Genomic Health, arguably the most successful oncology diagnostics company in the world, has partnered with us to distribute and scale the test into clinics across the U.S. The announcement was covered by the Wall Street Journal.

Not too far into the future this test will be extending the lives of tens of thousands of men with very aggressive prostate cancer. Men who just want a fighting chance, and it’s an honor to give them that fighting chance. 10 years ago (summer of 2006) I made a conscious decision that I wanted to devote the most formative years of my life to using science to make tangible improvements in the lives of cancer patients. I’m living the dream. This is the first test of many. My team and I are just getting started.

Thank you all for your support.

Ryon

Written by Ryon

July 6th, 2016 at 10:47 pm

Posted in Science Blog

Re-directing Ingroup Psychology to Mass Human Identity through Scientific Futurism

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18 December 2015

Could a change in perspective, solidified by large works of science and engineering, creatively re-direct humanity toward a peaceful co-existence with our planet and ourselves, via creatively commandeering our evolutionarily-engrained psychological tendencies?

Today’s piece admittedly reflects a bit of the dreamer in me. I have taken a few ideas that have been floating around my head for a while and organized them into this essay that I would like to share, dear reader. I usually don’t try to condense this level of abstraction to words, but I figure there is no harm in trying. Today I ask the question: from a strictly non-utilitarian perspective (i.e. not making new things for the sake of making new things) could the large-scale cultural practice of science ignite the best angels of humanity’s nature?

I’d like to start off with the psychological concept of in-group vs. outgroup (wording from wikipedia):

In sociology and social psychology, an ingroup is a social group to which a person psychologically identifies as being a member. By contrast, an outgroup is a social group with which an individual does not identify. For example, people may find it psychologically meaningful to view themselves according to their race, culture, gender, age, or religion. It has been found that the psychological membership of social groups and categories is associated with a wide variety of phenomena.

It has been eloquently proposed elsewhere that this psychological phenomenon might be at the core of human cooperation. The evolution of the capacity for empathy has fostered cooperation in a way that few animals have, humans have cooperatively birthed civilization, becoming a dominant species on Earth. It was “us” against “nature” or “us” against megafauna or “us” against the rest of the world. Humans are very good at working as teams when the opposition is implicitly or explicitly defined. Unfortunately, this also expands into “us” against “other group of humans” as well, as recently expanded upon by Adam Piore in Nautilus Magazine:

This takes on real-world consequences when you consider the lasting legacy of competition and warfare between Serbs and Croats, for instance, or Sunni and Shia in the Middle East. Or Tutsi and Hutus in Rwanda. Solidarity with an ingroup and hatred of an outgroup, molded by history, culture, and perceptions rooted in subconscious forces, can explain the horrific actions of terrorists.

While terrorism is outside the scope of this essay, a topic of late that has firmly caught my attention is the perception and concept of a joint human identity. Short of contact with some extra-terrestrial competition to unite us against a common “other”, what sort of joint identity mantle could Earthlings assume to ignite the better angles of our in-group psychological tendencies for the betterment of all humans? If we were able to look beyond our cities, countries, and continents, collectively “zoom out” and adopt a more cosmic perspective, we might collectively be able to appreciate how small humanity, Earth, and out solar system neighborhood is compared to the scope of what is out there. We (humanity) might realize that there is a lot of “other” out there, and solidify a joint human identity by contrast.

While I propose that this perspective would be a very healthy mantle for humanity to adopt, most individual humans learn best not by pondering, but by doing. Is there some activity or challenge that we (humanity) can collectively take on as a vehicle to galvanize our psychological tendencies for cooperation?

On a smaller scale, I wrote briefly about the possibility of biotechnology as the auto shop of the 21st century, where I referenced a talk by Neil Degrasse Tyson:

Meanwhile, however, that entire era galvanized the nation. Forget the war driver, it galvanized us all to dream about tomorrow. To think about the homes of tomorrow. The cities of tomorrow. The food of tomorrow. Everything was future world – future land.

Throughout his talk, Dr. Tyson paints a portrait of a united humanity working toward a common goal. In this instance, it was the NASA Space Program of the 1960s. The scientific and engineering advances are an undeniable tangible benefit. However, Tyson argues that while significant, the greatest value is the cultural practice of progress, of building a better world for tomorrow. It is a tantalizing dream to galvanize our nation, if not humanity, under a common banner of progress: scientific, humanitarian, philosophical. I find this to be a curiously optimistic mindset, with a rough framework for action.

A question I am left to ponder is how the well-studied ingroup vs. outgroup psychological phenomena could be craftily re-directed for the betterment of humanity as a whole? Could we somehow ignite humanity under not a common flag, but a common goal? A mission to Mars? The building of a space elevator? The vision of harmonious co-existence of Earth and humans? If we (humanity) do need an “other” to define ourselves by contrast, could it be the cosmos as our wilderness? To get to that contrast, could we adjust our perspective? And to reinforce that contrast and perspective, could we use large works of science and engineering to do it?

Expanding every human’s ingroup to encompass all humans would be very powerful. Imagine if we did not identify as “Californians” or “Americans” or “Jews” or “Christians”, but instead as “Humans” or “Earthlings.” We would expand our spheres of empathy, be not merely tolerant, but accepting of our differences, in part because the differences seem trite by contrast. We might even strive to harmonious co-existence with our planet, and our collective human family, galvanized by the cultural practice of large-scale science and engineering to reach common goals that concurrently re-directs our psychological tendencies toward mass human identity.

…and with that, I’ll get off my soapbox and go crunch some organic granola. If you have made it this far, dear reader, I would like to thank you for dropping by!

Ryon

p.s. recommended further reading by Neil Degrasse Tyson: http://www.haydenplanetarium.org/tyson/read/2012/03/07/past-present-and-future-of-nasa-us-senate-testimony

Written by Ryon

December 17th, 2015 at 10:41 pm

Posted in Science Blog

From PhD to Biotech: Key Lessons and Insights

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15 November 2015

Dear Reader,

This post has been a long time in the making. I apologize in advance for the length and degree of philosophical waxing, but I nonetheless feel compelled to share. I have chosen five key areas and insights that were of great value to me, and continue to hold water:

1) The clinic is queen
2) Twitter is a wonderful gateway to understand biotech and pharmaceutical trends
3) LinkedIn is the de facto e-business card
4) Writing and communication skills are immensely valuable and should be practiced
5) Networking matters (an understatement)

Intro (i.e. philosophical waxing)

Academic research and the biotech industry intersect not merely where medicine is practiced, but how medicine changes and progresses. Without medicine, science loses much application. Without science, medicine loses its eyesight. Modern medicine is based on what we can repeatedly observe and test, and the results have unequivocally transformed the physical well-being of humanity. The manner in which scientific knowledge turns into action requires physical vectors: drugs, tools, devices. Venerable academic traditions and contemporary scientific and technological evolution mix into a kaleidoscopic dance of research, development, and business that is biotechnology. It is this broad swath of industry from which the vectors emerge that literally change medicine. It is immensely exciting, and many young scientists seek to make the transition from academic science to the burgeoning biotechnology industry.

Freshly minted PhDs can often struggle to make the transition from the yin of academic research to the yang of biotechnology. The reasons for this phenomenon are many, and have been described eloquently elsewhere.* I defended my PhD 18 months ago, and have since made that jump, and I would like to share some of the lessons I’ve learned along the way, in hopes that this might be of use to my scientific siblings. I realize that my experience/advice is far from all-encompassing, and that it is highly biased by my personal experiences, and I do not in any way expect my experiences to completely mirror those of anyone else. However, there is a good possibility that at least some of my experiences will rhyme with those of others in similar situations. To this tune, I am sharing some of the lessons I have observed and insights gained along the way.

1) The clinic is queen

In my view, all PhD Candidates should spend some time in the clinic. If one wants to improve patient lives, one has to change clinical practice. If one wants to change clinical practice, one really needs to understand clinical practice. The nuances of the clinical cannot be learned didactically.

I was very fortunate in this regard, as my PhD program was open to me taking part in the HHMI-sponsored program Med-Into-Grad. For three months I spent a large portion of my time away from the bench and in the clinic, learning the basics of pathology, attending tumor boards, shadowing oncologists, and getting to know residents and fellows.

Coming away from this experience, I am still amazed at how much effort is wasted in basic research, and even highly invested biotech companies, on ideas and projects that seem laughably implausible to impact patient care for reasons that become painfully obvious in the clinic.

2) Twitter is a wonderful gateway to understand biotech and pharmaceutical trends

Twitter is a fantastic platform to follow trends in research, regulation, clinical trials, and investment in biotech and pharma. It’s also a platform to create a professional, personal online footprint. A fantastic recent post on Quora by a top engineering recruiter for the likes of Facebook, Google, and Expedia listed a few things that can be done to make a candidate stand out, among them:

Include URLs for online footprints — Nuff said. And within your comfortability of course. I get it. We’ve overshared our way to a more private society, but if you’re looking to stand out, write some stuff on the Internet. Contribute to open source repositories. Demonstrate some level of domain expertise/interest outside of your 9-5.

It is best to use twitter to follow key people and organizations in the field while it is wise to post to twitter sparingly. When posting, anything other than a re-tweet should be well thought out and provide some element of originality in idea or perspective. I include my twitter handle (@RyonGraf) on my resume.

Influential scientific papers get shared frequently and ricocheted around the twittersphere. Many times I have come across said articles within my areas of discipline before pubmed! it is also a wonderful exercise to see what influential people within the field find interesting, and why. When researching or investigating something entirely new (biomarker, drug, etc) I typically do both pubmed and twitter searches as my first steps. While pubmed will have peer-reviewed research and published commentaries, twitter offers a much wider net to how people *receive* or *interpret* available research, especially in realms peripheral to the research realm. Additionally, it offers near real-time trends and developments at major scientific conferences.

The Beaker has a list of great Twitter accounts to follow

Some of my personal favorites include:

General science:
Matthew Herper
Virginia Hughes
Carl Zimmer
Nature News and Comment
NEJM

Specific to my field:
Nature Reviews Clinical Oncology
ASCO
OncLive

Others:
The Economist
The Atlantic
Nautilus Magazine

3) LinkedIn is the de facto e-business card

Rule #1 about LinkedIn: Have a nice photo (this applies to Twitter too). I know this sounds trite and shallow, but I have found this to be extremely valuable. LinkedIn is not a dating website, but many of the same rules about first e-impressions apply. A photo is worth more than 1000 words, and is a first impression for many. People DO judge others by their photo. A poor photo is even worse than no photo.

Descriptions of previous work, awards, projects, publications, should be as succinct as possible. Potential employers and co-workers will be the main viewers of a profile, and they are not looking for an essay. Like a resume, it is best to leave the viewer curious for more. It is best to spend LinkedIn development time at making things succinct and getting a decent profile photo.

4) Writing and communication skills are immensely valuable and should be practiced

I went off the deep end in this regard, creating my science blog in February 2011. Writing about scientific topics both within and peripheral to my realm of expertise gave me an opportunity to turn esoteric into succinct, to make science relatable to a wide audience. Writing for my science blog also forced me to become more aware of societal, historical, and ethical contexts for current science topics. I found that this exercise helped me become much more fluent in conversations at social gatherings, and fed back into networking.

Crafting the occasional science tweet on Twitter forced me to practice extremely succinct communication, which is a very important skill in the biotech realm. I also enjoy writing haikus. There, I said it. I don’t write them about science, mind you, and I don’t post them online, but writing haikus is a similar exercise in describing a sensation, scene, or act in 17 syllables.

Higher level (responsibilities and compensation) positions require a greater breadth of knowledge scientific and peripheral. Following trends (*cough* *Twitter* *cough*) and engaging in conversations on these topics lay the foundation for upward advancement.

5) Networking matters

Networking is an overtly extroverted activity. Many scientists are not extroverted. There are two primary, practical benefits to networking as I see it:

a) Expanding the group of people one knows in similar or peripheral fields
b) Improving social skills

Compared to the academic realm, projects in the biotech realm are generally larger in scope and work, and require more diverse skill sets that are best accomplished by many people at once. In other words, it is much more collaborative, and with that comes a necessity for social skills and a level of extroversion. Time spent among diverse people in diverse situations will help build the social skills not merely to help get a job, but to do a job well.

In biotech, who one knows rivals or even exceeds the importance of what one knows. From my experience, the vast majority of people at my company either found out about the job opening through someone they knew, and / or it was also the recommendation of people they knew that helped land them the job once applying. Social currency goes a long way, and it’s very hard to vet someone in an interview process. It’s much more comprehensive to additionally survey the people for whom have built up social currency with a candidate through a history of in-real-life interactions.

I want to drive the point home that networking is far more than looking for a job. At a not-so-infrequent cadence, people I peripherally know (with whom I have had very little interaction and had not built rapport) enter the job market suddenly take up an interest in building rapport with me for recommendations. Depending on the situations, I find this anything from unappealing to utterly disingenuous and fake, and sometimes leads to worse impressions than not interacting at all. I would be a lot more comfortable recommending someone for a position if I had known and worked with for years and developed a history of rapport, someone whom I had observed and could vouch for in many situations. After all, I want good people at my company, and when we open position it’s not out of charity; we need that position filled and the job conducted. To that end, I want to not only help good people I know find a good fit, but I also want my company to succeed, and I want my work environment and company culture to thrive as well. Building that social currency is very difficult to do when one *needs* a job. One can’t grow a garden when hungry, and growing a garden takes many small, constant, efforts. The same rules apply to networking; it is something to be practiced all the time. (with that, I just got up to water my indoor plants)

Networking is not going to networking events, especially not “postdoc” or “grad student” networking events filled with academics. It’s best to go to events pertaining to the interests one has outside of lab. Some of the best networking I have done was at charity events, art gallery happy hours, and while cycling. In truth, any social activity shared by intelligent, successful people is where you want to be.

As I alluded to above, this requires a level of extroversion that many young scientists are not used to, and although I am very much an introvert at heart, I came to learn to be somewhat of an extroverted introvert, and learned to actually enjoy being in social situations surrounded by people I do not know. I learned to become curious about others’ stories and careers, and how they got to their current walk in life. This also allowed me to spend time with people who were in successful careers elsewhere (IT, finance, defense) and become aware of the norms of professionals in fields outside of academia.

In closing

If you’ve made it this far, read reader, it is my hope that this blog post might provide some bit of illumination. As I mentioned before, I am a far cry from a seasoned veteran of the biotech realm. That said, I will risk going out on a limb to share some of my insights thus far in hopes that they will be of use to my scientific siblings. It’s been an absolutely wild 18 months since defending my PhD. The pace is unrelenting, the innovation is inspiring, and I jump out of bed every day excited to go to work. It is my hope that you will find the same :)

Yours,
Ryon

*I offer a few commentaries on the current career prospects for young PhDs in academic science:
Boston Globe: Glut of postdoc researchers stirs quiet crisis in science
Science Commentary: The Postdoc: A Special Kind of Hell
Times of Higher Education: Too many postdocs, not enough research jobs

**also, a useful article for introverts learning extroversion:
Forbes: 5 Qualities of Charismatic People

Written by Ryon

November 14th, 2015 at 8:33 pm

Posted in Science Blog