15 November 2015
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:
Nature News and Comment
Specific to my field:
Nature Reviews Clinical Oncology
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.
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 :)
*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
10 May 2015
I am pleased to announce that my company’s first peer-reviewed scientific publication is now available online and open access:
It’s been immensely rewarding (and quite fun!) to work with such an innovative team. The platform has allowed us an unparalleled view into the basic nature of circulating tumor cells, and we will be following this up with forthcoming publications.
As the title implies, it includes an analytical validation for detection of CTC surrogates (cancer cell line cells spiked into healthy donor blood) as well as an overview of the dimensions of molecular characterization enabled on our platform.
The liquid biopsy is not-so-slowly becoming a reality, and I could not be more thrilled. Optimal therapy guidance in oncology, especially for targeted therapies, frequently require a tissue biopsy. I yearn for the day that cutting and prodding patients prior to systemic therapy will be seen as blunt at best and draconian at worst. We can and will guide therapy without invasive biopsies, or even trips to a hospital.
Siddhartha Mukherjee has many eloquent lines to describe the nuances and struggles of oncology, of which this one particularly comes to mind:
Cancer’s life is a recapitulation of the body’s life, its existence a pathological mirror of our own.
To this, I would like to add that cancer is a recapitulation of basic tenants of population biology as well, namely the ability to evolve in response to selective pressures. What is truly needed is not a high-resolution snapshot of disease at one time point, but a movie of clonal evolution to expose shifting kinks in cancer’s armor. Solid tissue biopsies largely preclude repeat sampling, but single-cell protein and genomic analyses on circulating tumor cells might provide such a movie. Stay tuned!
29 March 2015
About a week ago I had the honor and privilege to attend Muirlands Middle School’s STEAM career day as an invited speaker. The last time I set foot on the Muirlands campus I was a student. As I walked by the front gate I had the distinct recollection of the sound of the principal’s voice telling me and my friends to get off our skateboards! (the kids thought that was pretty funny)
Muirlands has a big emphasis on STEAM (Science, Technology, Engineering, Arts and Math) and organized a career day lineup of about 35 speakers to attend and meet with students. The lineup of speakers was nothing short of impressive; they ranged from professors of medicine to large tech company CEO’s to accomplished artists and oceanographic explorers. It was both quite surreal and fun to be in the company of so many interesting people. After a short meet and greet with other speakers I was whisked away to the first of three classes by one of the student ambassadors.
For each class I had about 15 minutes to give a talk about my career and how I get there, followed by 10 minutes of what must be some of the most entertaining questions I’ve heard in a long time. I was asked questions like: “What would happen in the lab if someone mistook a tube of blood for fruit punch? Would you get cancer?” “Why do cancers come back and why can’t you give the same medicine again?” “What if the computers get so smart that you won’t have a job anymore?” (the last was in response to an overview on machine learning)
It never ceases to amaze me how amazingly curious and creative these young minds are. I am in awe at their collective potential and I am so thrilled to have been able to attend STEAM day at Muirlands.
Key messages from my talk:
1) There are a lot of different careers in science, it’s not just “scientists.”
2) Lots of different people practice the tools and methods of science.
3) Science and art have much in common; practicing science (as opposed to science taught from a book) is a very creative endeavor and shares a very similar tune to the artistic process.
4) Science and technology can make the world better. Going to work every day with that impetus is inspiring and fulfilling and I am very happy with my career trajectory.
I would like to give a huge thank-you to Lisa Bonebrake and all the volunteers for organizing such a wonderful event. The La Jolla Light had a great writeup on the event as well: http://www.lajollalight.com/news/2015/mar/18/steam-jobs-introduced-to-muirlands-students-2015/
Photo: I got a large envelope in the mail with a thank-you note from every student in the three classes I met. Aside from completely melting my heart, it never ceases to amaze me how much curiosity, optimism, and potential middle schoolers have.
23 November 2014
A few weeks back I found out about the following:
1) My old high school is trying to raise funds for upgraded biotechnology labs
2) The La Jolla Community Foundation was to host a kickoff fundraiser for the event at LJHS
3) Craig Venter was going to speak at the fundraiser
Simply put, I was pretty excited to attend. Once there I had the pleasure of meeting current teachers, parents, and curious community members in the mixer before moving into the main auditorium to see a fantastic presentation by Timothy Scott of Pharmatek, and the somewhat surreal experience of seeing Craig Venter interviewed by basketball hall of famer Bill Walton.
Venter started off the night with the quip “the last time was at a high school and met the principal, it was not on the best of terms.” After a few laughs and anecdotes, he and Walton slowly moved to discuss a vision for the future of biotechnology and medicine, the cornerstone of which will be individuals who have hands-on experience with with the fundamentals of biotechnology. And here’s the kicker: that this education can happen in high school.
Equally important to hands-on technological experience is practicing science as problem solving as opposed to the current high school science educational model dominated by rote memorization.
While a few of the speakers portrayed a sentiment that we might produce the next Craig Venter through this project, a more subtle, and to me more practical vision emerged: the La Jolla High School Biological Science and Technology Center is also meant to teach marketable, vocational skills. A portrait emerged of what could be the “auto shop” style classes of the 21st century: Biotechnology.
At Epic Sciences I work in a highly dynamic, collaborative environment with those in business development, quality assurance, competitive intelligence, assay development, product development, and project coordination. Working at a small biotech company has especially driven the point home that there are many career paths and areas of expertise within biotech, but a common thread woven into all of them is the fundamental understanding of the biology and the technology. Most that work at my company have some hands-on experience in the lab. In fact, we value this so much that we have a hands-on training program in the lab at Epic that every new employee, from intern to VP, has to pass.
So, Could biotechnology be the auto shop of the 21st century?
Auto shop taught hands-on skills working with machinery, offering both the practical knowledge to work on one’s automobile, but also the type of primer for a career working in mechanistic industry. Auto shop was a course that offered vocational skills that might be especially valuable to one looking to go directly into the workforce from high school; the norm in generations past when ample jobs existed in that industry.
Large-scale mechanistic industry has been on the decline in the U.S. for more than a generation, outsourced overseas and replaced by other industries. The biotech industry, in contrast, is rapidly growing here in the U.S. and especially San Diego County. Biotechnology can be used to tackle many of the issues of our time, from medicine to energy to climate preservation. Craig Venter went so far as to argue that biotechnology is essential for our survival as a species.
Taking a step back, the possibility of having marketable, vocational skills taught at the high school level is especially attractive to my generation: the tandem increase in tuition rates and decrease in degree worth has made the college route more tenuous than generations past.
College route or not, I would argue that hands-on training in biotechnology and the practice of problem-solving science at the high school level is a very good investment of student time, and our public and private resources. The potential windfalls are great for both the individual and the whole.
Biotechnology Innovation as Positive Cultural Phenomena?
At this point in my blog post I realize that I might be in danger of rambling on about spurring jobs and development and helping produce a more scientifically literate generation. Perhaps we might even be able to start “dreaming of tomorrow” again as posited by Neil DeGrasse Tyson, who has eloquently spoken about the cultural value of optimism and progress that science and technology impart:
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.
The World’s Fair? – all of this was focused on enabling people to make tomorrow come. That was a – that was a cultural mindset the space program brought upon us. And we reaped the benefits of economic growth because you had people wanting to become scientists and engineers – who are the people who enable tomorrow to exist today.
And even if you’re not a scientist or technologist, you will value that activity. And that, in the 21st Century, are the foundation of tomorrow’s economies and without it, we might as well just slide back to the cave because that’s where we’re heading right now – broke.
(skip to 1:07 in the embedded video below for the above quote)
I encourage you, dear reader, to watch the first two minutes of this video and perhaps insert “biotechnology” in place of “space exploration”; many of the same messages hold true:
Perhaps the applications of biotechnology could be a source of optimism that we need as a culture? Could we start a trend here? I certainly hope so. The dreamer in me sees basic biotechnology labs in high schools everywhere, a generation from now a greatly expanded biotechnology industry producing wonderful medical advances and living much more harmoniously with our planet.
Alas, a goal without a plan is fantasy. While these visions are admittedly grandiose, the common thread is transforming the basics of science education and biotechnology training at the high school level. The La Jolla Community Foundation is embarking on an ambitious fundraising campaign to do this at La Jolla High School. While LJHS is located in a posh neighborhood, roughly 40% of the student body is bussed in daily from other (less posh) regions of San Diego County. The geographic proximity of LJHS to the heart of the biotech industry lends potential internships and collaborations. After this bioscience center is established, the lessons from implementation can be translated to other high schools in the region, and beyond. I am following this with great interest.
29 September 2014
One week ago concluded the second annual Pedal the Cause. In lieu of a lengthy piece, I would like to present ideas / impressions that constitute small pictures of a larger portrait. And photos.
Let’s face it, riding 170 miles through mountainous territory is pretty hard regardless of the pace. There *will* be some pain and discomfort along the way. But, that’s sort of the point. Cancer patients go through tremendous pain and discomfort through the process of their disease and treatment, and a little bit of athletic-induced physical hardship is a great means to both empathize with cancer patients and to learn to appreciate our good health.
Image: at the finish line at UCSD on Day 2, 170 miles in our legs and smiles on our faces. I’m on the left.
Everyone at the Athletes’ Village in Temecula made the distance. Everyone had a story about their ride, about their life, and about cancer. Pedal the Cause brings together a truly impressive caliber of people that would be worth riding 170 miles and raising thousands of dollars to be able to spend an evening in the company of.
Image: The evening in Temecula brought together cancer survivors, patients, caretakers, and well wishers. And jokes by Bob Roll. Photo:A.Czapracki
Even if every research project funded by Pedal falls flat and fails to produce anything that will be of great value to cancer patients (a highly unlikely scenario), Pedal does one thing that is so essential: health promotion. There is one thing that we can never get back: time. None of us know with certainty how much time we have remaining in our lives. There are many things that are out of our control, but one thing that remains within our control is the QUALITY of that time, and aerobic exercise, specifically the promotion of a healthy-addictive habit like cycling, is a fantastic way to enhance the quality of anyone’s life, especially here in Southern California. (But keep that sunscreen close!) Cycling is a means for many people to make lasting, impactful habitual changes in their lives, and I am always so thrilled to hear of people who got back into, or started cycling just to partake in Pedal the Cause.
Quality and Speed of Research Funding
A lot of cancer charities give money to research, though some give only a fraction, and some give none at all, benefitting from the illusion of giving to research. Pedal the Cause gives all proceeds to cancer research in San Diego. It funds the type of collaborative, high-risk, high-reward research that is needed to make a dent in cancer. There is also the aspect of time: Federal funding usually requires years of preliminary research to even get within a country mile of any grant money, making it nearly impossible for innovative research to get funded. As the federal science budget continues to fall, this trend is expected to continue, undermining scientific innovation and discovery. Pedal the Cause completely sidesteps this process and directly funds very promising projects.
Pedal the Cause forces one to walk outside their comfort bubble and engage new people. I had the incredible fortune of being able to use Pedal the Cause fundraising as a bit of an icebreaker to get to know people at my new company, Epic Sciences. To make a long story short, I embarked on a fundraising campaign that involved getting many of my friends, old and new, to donate between $1 and $5 for every time I managed to go up and down Torrey Pines Grade in 5 hours. It was a LOT of fun and a great challenge. More here. I would like to give a huge thank you to my colleagues at Epic Sciences, who provided the lion’s share of donations for fundraising. There really is no shortage of generous, driven, empathetic, genuine people in the cancer / oncology community here in San Diego. It is my hope that Pedal the Cause will continue to grow, and attract more wonderful people to this burgeoning regional cultural event.
Image: The start line, day one. Cancer researchers and caretakers have green armband, cancer survivors have the bright orange helmets. Photo: A.Czapracki
14 July 2014
Dear Friends and Family,
I’d like to offer a life-update style post (I’ve been a bit off the radar, sorry!). In the span of the last 90 days the following events happened:
The short version is that, after a tumultuous last several months (years?) of my PhD, and the job interview process, I have found myself in a high-energy environment surrounded by diversely talented, innovative, genuinely cool, down to earth people all working together to change the face of oncology. I guess you could say I’m a little excited.
Image: a circulating tumor cell (red) from a profile on Epic Sciences in Discover Blogs
To illustrate challenges in oncology, a quote came to mind from the Emperor of All Maladies:
Specificity refers to the ability of any medicine to discriminate between its intended target and its host. Killing a cancer cell in a test tube is not a particularly difficult task: the chemical world is packed with malevolent poisons that, even in infinitesimal quantities, can dispatch a cancer cell within minutes. The trouble lies in finding a selective poison—a drug that will kill cancer without annihilating the patient. Systemic therapy without specificity is an indiscriminate bomb. For an anticancer poison to become a useful drug, Meyer knew, it needed to be a fantastically nimble knife: sharp enough to kill cancer yet selective enough to spare the patient. – Siddhartha Mukherjee
There has been a wave of new anti-cancer therapies approved by the FDA in the last 5 years, many of which have been touted as ushering in the era of precision medicine. These therapies exploit small molecular discrepancies between cancer cells and healthy cells. The problem is, not all cancers have all the same vulnerabilities and the landscape is incredibly diverse, so much so that leading personalized oncology proponents like Dr. Razelle Kurzrock of UCSD refer to use the metaphor of an individual patient’s cancer molecular profile being as unique as snowflakes, and the correct combination of therapies for every patient might be equally unique.
These precision therapies need informed molecular roadmaps, so patients can receive therap(ies) most suited to them. Currently, this requires tissue samples for requisite molecular analyses. However, tissue biopsies are highly invasive to patients, and longitudinal sampling of how an individual patient’s cancer evolves resistance is nearly impossible with current technology.
The process by which the seeds of tumors establish into metastatic niches (i.e. what causes 90% of mortality from solid tumors) involves transit through the blood, which offers an opportunity for molecular characterization of these cells through a routine blood draw. For years I’ve been very interested in this process, so much so that I did a PhD in this area of research!
The last few years have seen an expanded interest in these circulating tumor cells (CTC’s), as new technologies have emerged to capture and analyze them. This is no easy task; it is literally akin to finding one in one *billion* cells in the blood. About a year ago I became aware of the CTC detecting technology of Epic Sciences. To make a long story short, I recently started working to apply circulating tumor cell (CTC) detection and characterization technology for use in guiding oncology clinical trials.
Image: The Scientist recently produced an overview of CTC detection technologies featuring Epic Sciences
As I alluded to before, tissue sampling of tumors in a cancer patient is highly invasive. No one likes being cut up or prodded, probably just slightly less so than having to get an MRI or PET scan. All of the aforementioned require a trip to a hospital, and a lot of the patient’s and health professionals’ valuable time. Advanced cancer patients might also be too sick for these means of examining their cancer, hindering decisions about what therapies to give (or not to give) or what other measures would be most ethical and humane for the patient and their family.
Blood draws, on the other hand, are minimally invasive, and can be performed even at a local clinic. Blood draws can also be performed frequently; it would be unthinkable to perform a tissue biopsy or a PET scan on a cancer patient twice a month!
While the mere presence of circulating tumor cells gives clues to the stage and progression of a patient’s cancer, the real value is in the molecular and genetic characterization of CTC’s. An immensely unmet need in oncology diagnostics and therapy is a means to confront the intratumor heterogeneity that exists within an individual patient’s disease. A patient’s tumor(s) can be very genetically diverse in both location and time and it’s powerful (and in my opinion pragmatic) to have clues about the cancer cells that can cause the most harm to the patient: the ones that make their way into the blood.
Molecular characterization of CTC’s is a fantastic companion to targeted anti-cancer therapies, and I am thrilled to work as part of a team developing the “Liquid Biopsy” for oncology. I have no reservations saying that I am genuinely excited to get out of bed every morning, and I consider myself a very fortunate man to be able to pursue my passions.
If you have read this far I thank you, dear reader. More (meditations) to come!
5 May 2014
The realization of Precision Oncology involves developing many low-toxic therapeutics to specifically target genetic weak points in a patient’s cancer. The requisite technology for tumor genomic analysis will likely not be a limiting factor in a few years’ time, especially with the advent of sequencing platforms like HiSeq X Ten by Illumina. The remaining rate-limiting step is the clinical trial phase; clinical trials are immensely expensive to conduct, and measures that can reduce the costs (and time) of oncology clinical trials will allow new molecular scalpels to reach the clinic at a quicker pace.
The pivotal I-Spy1 trial (1) established a strong correlation between observed radiographic reduction of tumor size in the neoadjuvant (before surgery) setting, and long-term survival irrespective of surgery:
Primary objectives were to evaluate whether response to therapy—as measured by imaging (magnetic resonance imaging [MRI] volume) response and pathologic complete response (pCR)—would predict recurrence-free survival (RFS), overall and within biologic and imaging subsets.
I-Spy1 provided the ethical framework for use of radiographic imaging pCR as a surrogate for Survival, and opened the door for neoadjuvant testing of new targeted therapies. I-Spy1 paved the way for the transformative I-Spy2 clinical trial in progress (2). The result is a roughly six-month knowledge turn, instead of a knowledge turn on the order of magnitude of years.
However, radiographic / pathological monitoring of tumor burden is far from optimal. There is a level of subjectivity and noise that can flummox even the most skilled pathologist / radiologist. Also, mammograms, CT Scans, MRI’s are all highly invasive procedures, and very expensive ones at that. The use of these scanning techniques is a contributing factor to the immense cost of clinical trials in oncology.
The Liquid Biopsy has great potential for cancer diagnosis, risk assessment, and therapy. Its advantages are many: compared to more traditional forms of tumor monitoring like PET, MRI, x-ray and mammogram, a blood draw is much less invasive to the patient with much greater ease of re-biopsy and longitudinal monitoring, and potentially much less expensive. But, its technological hurdles are great. That said, they are not insurmountable, and it’s an area of technology that I can see greatly helping many facets of oncology.
Retrospective analyses indicate that numeration of circulating tumor cells (CTC’s) can be a strong prognostic factor, and might be able to predict tumor relapse and / or provide clinically actionable genetic and phenotypic information (3-5).
Perhaps CTC detection technology could be adapted for use in neoadjuvant monitoring of tumor burden? Would a clinical trial similar to I-Spy1, except using a CTC metric in lieu of radiographic tumor size reduction, enable the introduction of less invasive disease monitoring that might shorten clinical trial length and reduce cost? Could this enable a quicker turnaround for therapies to find their way into the clinic?
In the adjuvant (after surgery) setting, might a longitudinal increase in CTC burden indicate impending relapse? Such an increase in CTC number (or perhaps another metric?) could be detectable long before metastatic outgrowths become visible via PET, MRI, X-ray, etc. CTC’s could provide a quicker endpoint for clinical trials? For this to happen, a prospective clinical trial could be structured to establish longitudinal CTC-based metric (such as CTC number, gene expression, size, density, morphological shape, etc.) that strongly indicates impending relapse. Such information could then be used to reduce knowledge turn time for adjuvant clinical trial results, not to mention spare patients from additional chemotherapy for which their cancer is refectory, and begin alternative therapeutic regiments before establishment of radiographically visible tumors.
1. Esserman LJ, Berry DA, DeMichele A, Carey L, Davis SE, Buxton M, et al. Pathologic complete response predicts recurrence-free survival more effectively by cancer subset: results from the I-SPY 1 TRIAL–CALGB 150007/150012, ACRIN 6657. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012 Sep 10;30(26):3242-9. PubMed PMID: 22649152. Pubmed Central PMCID: PMC3434983. Epub 2012/06/01. eng.
2. DeMichele A, Berry DA, Zujewski J, Hunsberger S, Rubinstein L, Tomaszewski JE, et al. Developing safety criteria for introducing new agents into neoadjuvant trials. Clinical cancer research : an official journal of the American Association for Cancer Research. 2013 Jun 1;19(11):2817-23. PubMed PMID: 23470967. Epub 2013/03/09. eng.
3. Wallwiener M, Hartkopf AD, Baccelli I, Riethdorf S, Schott S, Pantel K, et al. The prognostic impact of circulating tumor cells in subtypes of metastatic breast cancer. Breast cancer research and treatment. 2013 Jan;137(2):503-10. PubMed PMID: 23271327. Epub 2012/12/29. eng.
4. Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 2013 Feb 1;339(6119):580-4. PubMed PMID: 23372014. Epub 2013/02/02. eng.
5. Friedlander TW, Premasekharan G, Paris PL. Looking back, to the future of circulating tumor cells. Pharmacol Ther. 2014 Jun;142(3):271-80. PubMed PMID: 24362084. Epub 2013/12/24. Eng.
Edit 5/16/2014: Embarrassing spelling errors
28 April 2014
The primary focus of the last five years of my life has been the pursuit of a PhD, culminating with my PhD dissertation and defense. A week ago I defended my PhD and was awarded a Doctor of Philosophy in Biomedical Sciences, more colloquially known as a “PhD” or “doctor of science.” I’ve decided to coalesce some thoughts and impressions into something resembling a narrative on the process.
Images: On April Fools’ Day, three weeks before my PhD defense, I sent my good friend Eric Murphy an email: “Hey Eric, I’ve attended a few PhD defenses, but I’m still at a loss whether this would be proper attire?” and included a link to the image below. His response was short: “I’m doing it.” Being April Fools’ Day, the mischievous ambiguity of his response made me unsure whether he was actually planning something. Following the vein of mischievous ambiguity, I opted to not ask him to clarify, and he showed up to my PhD defense with, yes, a D Fence. Friends and family in attendance signed the D Fence after the talk.
The dissertation is a written document describing any and all of my even remotely meaningful work from my PhD. It included some published work, and some work that has not yet been published. I wish I could go into detail about the work I’ve spent several years of my life performing, but some of it needs to go through peer review before I can open it up to the world. C’est la vie.
To complete a PhD, one must host a defense, or public lecture followed by questions by curious specialist and non-specialist minds alike. The public lecture is the first formal occasion for a new doctor to open up their research, ideas and insights to society, to be pondered and questioned by anyone.
More practically, a PhD defense is the final meeting between the PhD candidate and their thesis committee. The main difference from previous meetings is that the public is invited to attend and interrogate the logic, reasoning, research, and knowledge of the PhD Candidate. The public lecture must make something highly esoteric understandable to curious non-specialist minds. But, the talk must remain technical enough to satisfy the Thesis Committee as well. It’s also a rare chance for a PhD Candidate to display their work to friends and family, and making a presentation that can meet all of these demographics is no easy task.
I have many friends and family in the area, many of whom I’ve had to somewhat neglect in my long hours (years?) pursuing new knowledge through research. It’s entirely possible for a PhD candidate to have very few people attend their defense, but where’s the fun in that? I had given many scientific talks to scientists, but rarely to the audience I was expecting. I saw it as a tremendous opportunity to practice my presentation skills, and perhaps have some fun in the process. I’m not referring to a hedonistic, lost-in-the-moment type of enjoyment, but the rare, fleeting satisfaction of doing something well, wrought by blood, sweat and tears.
After all, my original reasons for pursuing medical research were because I wanted to learn to wield the tools of science to have a shot at making a small contribution to medicine. Medicine is a physical manifestation of humanity’s will to live longer and more free of physical ailments and pain. The last century has seen a significant maturation of the relationship between medicine and science, the process by which we reproducibly uncover and define the way the world works. In tandem we can do incredible things like cure infections, eradicate communicable diseases, and make a dent in perhaps the most difficult of diseases to treat: cancer.
Image: Dated to 2600 BCE, the Edwin Smith Papyrus is an ancient Egyptian combination of surgical trauma manual with recommended therapies for fractures, dislocations, lacerations, infections, etc. Among the nearly 50 cases are two describing cancer, for which there was no recommended therapy. The ancient Egyptians clearly recognized cancer as a very difficult disease to treat, perhaps also recognizing the futility of trying to treat it with their medical tools at the time; that intervention was worse than leaving patients to slowly perish. Image courtesy U.S. National Institutes of Health
Along this theme, I dedicated the first chapter of my dissertation to the history of cancer metastatic theory from ancient times until the 20th Century: from fossilized clues about cancer metastasis to the 4700 year old written case studies on cancer patients, to Hippocrates, Galen, Paget, Halstead, and Fisher. At some point in the future I hope to be able to reproduce (with permission) this chapter of my dissertation here on my blog.
I opened my defense talk with a short historical context on cancer, stressing that ancient societies clearly recognized cancer as a very difficult disease to treat. Hippocrates is credited with coining the term “cancer” because he likely recognized the ability of it to crawl throughout a cancer patient, or the physical appearance of autopsied tumors reminded him of a crab. He is also credited with the term “Metastasis” which translates loosely to “dislodgment” or “to be set free.”
For visceral effect, I also included a PET scan of an advanced stage cancer patient (to the right, courtesy uchicago.radiology.edu) with metastatic tumors throughout the body. I then asked my audience to imagine being a surgeon tasked with removing the tumors with a scalpel, stressing the difficulty in treating advanced disease, and how imperative it is for us to understand the process by which this happens so we may target it in means more precise than, well, a surgeon’s scalpel.
I really wish I could go into details about my talk from this point out, but as I mentioned before some of the data has not yet been published, and even more is not yet available via open access (i.e. the publications are owned by entities that charge a fee to the public to view). A discussion on the merits and pitfalls of the antiquated publication model and its (mal?)adaption to 21st century medical research is warranted, but perhaps not here right now.
The abbreviated version of the rest of my talk: Cells have mechanisms that allow for recognition of their physical surroundings and biological zip codes in the body. The means by which they interpret these signals and decide to commit cell suicide or to migrate and grow are integral to the behavior of cancer cells, and at the center of this is my favorite protein: Caspase-8. Through rigorous experimentation employing recombinant protein biochemistry, cell culture models and experiments in vivo, I demonstrated how this protein can play a dual role in cancer malignancy. My research model suggests that this behavior might be toggled by combining two yet-to-be-tested-together classes of drugs that are currently in the clinic and in late phases of clinical development.
Image: A slide from my talk, introducing the concept of metastasis as a multi-step process with hurdles for a cancer cell at every step using very crude illustrations.
Cancer is actually a group of many heterogeneous diseases with overlapping etiology and behavior. My research alone is a far cry from a “cure.” Medical research is the combined efforts of thousands (millions?) of scientists past and present, and my work builds heavily upon work performed by those that came before me. It’s a tremendous honor and privilege to take part in this tradition. By communicating my results and ideas, I am closing a small piece of that loop and contributing (a very small part) to this process.
On a personal side, perhaps the most important and practical thing I have learned in the process is that, after five years of blood sweat and tears (and a healthy helping of head banging) I want some more. I have tested the depths of my motivations and I have found that I am indeed very deeply passionate about using science to improve the physical well-being of cancer patients. There are many times where I could have thrown in the towel, but at every hurdle and hill in my way I found motivation to continue. I remain easily excited by new prospects and developments in science as they pertain to oncology, and when I grab my morning coffee I often get distracted by reading scientific papers and oncology clinical trials results.
In terms of my career, I am allowing myself to be guided by the onus of finding the most impactful, efficient way to improve cancer diagnosis, risk assessment, and therapy. I am currently exploring several options in academia and the biotech industry toward these ends.
If you’ve made it this far I thank you, dear reader.
4 March 2014
The emerging view of cancer is an increasingly diverse set of rare diseases with overlapping etiology and molecular drivers (1). The evolving definition of personalized oncology centers on the development and vetting of many specific, targeted, low-toxicity molecular scalpels that can be used individually or in combinations to tailor a patient’s cancer treatment. The bottleneck of drug development is the testing phase, and there are numerous barriers to novel chemotherapeutic introduction to the clinic.
The I-SPY2 trial has received a lot of press lately, and rightfully so: it’s a bayesian study designed to adaptively match patient genotypes of appropriate therapies in a rotating 5-arm clinical trial that can quickly take on a new agent once one of the test arms graduates, ready for Phase III trials that (theoretically) have a might higher chance for success, with fewer patients (2, 3). The trial has been engineered to make cancer drug trials quicker and less expensive, and more information can be found here.
The I-SPY2 trial is co-directed by Laura Esserman, who gave an illuminating talk at the UCSD Moores Cancer Center last week. Most targeted therapies are tested in clinical trials in heavily pre-treated patients in the metastatic setting, and often without molecular biomarkers. Agents tested in the metastatic setting often see a 2-4 year knowledge turn, while those in the adjuvant setting often come with a 6-9 year knowledge turn. This is simply too slow (and uses too many patients and is too expensive) to realize the vision of personalized oncology.
In the neoadjuvant setting (pre-surgery, chemo-naive patients) the turnaround can be much faster. Instead of disease recurrence, the trial readout is volumetric change in tumors. Tumor samples are subject to panomic (genomic, proteomic, methylomic, etc) analysis before and after neoadjuvant therapy, enabling post-therapy clues to efficacy or failure of tested agents. While this sounds straightforward, this is not the norm for current oncology clinical trials, especially ones for targeted therapies. The reasons for this are beyond the scope of this post. There has been an extreme paucity of information for why certain drugs do not work, and very limited information on what –omics background produce responders.
While pre-operative administration could permit greater organ conservation in the patient, I am also interested in this approach for two additional reasons:
1) Chemotherapy-naive patients might be less susceptible to drug resistance out of the gate. Many drug resistance mechanisms are shared, and patients will not have been weakened from systemic chemotherapy in the neoadjuvant setting (4, 5).
2) Surgery is a highly invasive procedure that damages tissue, releasing cytokines and growth factors that can promote inflammation and tumor growth (6).
The neoadjuvant is a better stage to test for agent efficacy, and opens the door to glimpses of tumor biology that might enable more curative approaches. The neoadjuvant drug administration combined with panomics approaches could be a boon for the emerging “Rapid Learning Precision Oncology” paradigm proposed as part of “Personalized Oncology 3.0″ by Shrager and Tenenbaum (7). Eventually, it may be possible to consider each patient encounter as an experiment, with each additional “experiment” better informed than the last.
I-SPY2 has already graduated two agents to Phase III trials: the small molecule dual HER2 and EGFR inhibitor Neratinib, and the PARP inhibitor Veliparib. The speed at which they passed through Phase II trials is encouraging. Because the trial actively adapts with genotype efficacy, it’s anticipated that Phase III trials will have a greater chance of success. I will be watching this with great anticipation, and at this point in time I am skeptically optimistic about I-SPY2. We need more bullets, big or small, and every new target and every new agent adds another small step toward realizing the vision of personalized oncology.
1. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013 Oct 17;502(7471):333-9. PubMed PMID: 24132290. Epub 2013/10/18. eng.
2. Berry DA. Adaptive clinical trials in oncology. Nature reviews Clinical oncology. 2012 Apr;9(4):199-207. PubMed PMID: 22064459. Epub 2011/11/09. eng.
3. DeMichele A, Berry DA, Zujewski J, Hunsberger S, Rubinstein L, Tomaszewski JE, et al. Developing safety criteria for introducing new agents into neoadjuvant trials. Clinical cancer research : an official journal of the American Association for Cancer Research. 2013 Jun 1;19(11):2817-23. PubMed PMID: 23470967. Epub 2013/03/09. eng.
4. Junttila MR, de Sauvage FJ. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature. 2013 09/19/print;501(7467):346-54.
5. Lord CJ, Ashworth A. Mechanisms of resistance to therapies targeting BRCA-mutant cancers. Nature medicine. 2013 Nov;19(11):1381-8. PubMed PMID: 24202391. Epub 2013/11/10. eng.
6. Costanzo ES, Sood AK, Lutgendorf SK. Biobehavioral influences on cancer progression. Immunol Allergy Clin North Am. 2011 Feb;31(1):109-32. PubMed PMID: 21094927. Pubmed Central PMCID: PMC3011980. Epub 2010/11/26. eng.
7. Shrager J, Tenenbaum JM. Rapid learning for precision oncology. Nature reviews Clinical oncology. 2014 Feb;11(2):109-18. PubMed PMID: 24445514. Epub 2014/01/22. eng.
18 February 2014
It’s been a busy month! Well, most months are busy, but this one has been especially so, and I have some good news to show for it:
1) I am pleased to announce that my review article “Caspase-8 as a Regulartor of Tumor Cell Motility” has been published in Current Molecular Medicine and is available on PubMed.
2) About a week ago I had my pre-thesis defense meeting with my Thesis Committee. After a grueling two hour meeting my Committee Chair gave their verdict: “We are pleased with your progress, we accept your proposed graduation timeline and would like a draft of your dissertation in six weeks’ time.” Looks like I’ll be defending my thesis in the spring! I have not yet set a date, but it’s most likely going to be mid-May.
3) On top of all of that excitement I have been in the midst of my Med Into Grad program. It’s hard to appreciate the nuances and challenges of clinical oncology from the lab bench, and there are so many things that I see on a daily basis that could be aided with new technology. Often, the applications are not groundbreaking or miraculous or ideas that come down from the sky on sunbeams with chariots of angels singing a chorus; they are often subtle, but the sum of all of small innovations will aid modern oncology.
For instance, today I heard a surgeon describe being mid-surgery deep in the peritoneal cavity, his patient open on the operating table. He came across a lesion that looked very much like fibrosis, but was later revealed to be tumor after analysis of biopsy that he sampled just to be sure. A team of physicians then discussed how to move forward on the patient, who was still recovering from surgery with residual tumor cells remaining.
In another instance, a minor stir almost ensued when a patient was staged (via histology) as having a low-grade primary ovarian tumor, when it was more low-ish. The distinction matters tremendously, as the high grade (and more common) tumors will receive systemic, and sometimes preoperative, chemotherapy along with surgery, while the low grade tumors will be treated with surgery alone. The decision to give systemic chemotherapy is not taken lightly by clinical oncologists, and they absolutely need the most un-ambiguous information possible to do be the most effective with the least amount of harm.
I want to find out how subjective and reproducible the measures are that are currently used for diagnosis and guidance of treatment. I want to find means for emerging technology to help remove ambiguity in diagnosis and aid treatment. Could the emerging sequencing technologies and avenues like liquid biopsy provide a better means to asses tumor burden, extent of vascular invasion and prognostic response to existing and emerging therapies? Could this provide a more precise means of who needs what therapy?
In less than a week I’ll be starting my clinical rotations with histology. I’ll be observing how pathologists grade tumors and what sort of clinically relevant information is gleaned from microscopic observation of tumor samples, and how precise and / or subjective such measures are. It should be fun!