In contribution to our overall grant, our most recent publication, led by Dr. Parvesh Sharma and myself, investigates the development of biocompatible nanoparticles, capable of imaging damaged murine muscle. Methodically, we've developed biocompatible nanoparticles that are able to be associated with Indocyanine Green (ICG), which are passively taken up into damage mouse muscle. Importantly, the particles protect the optical fluorescent properties of the ICG, allowing for imaging long after administration compared to raw ICG. These developments lay the exciting groundwork for developing a safe, longitudinal, reliable, and inexpensive way to optically image damaged and dystrophic muscle.
As quickly as it started, it ended. Just one year ago, when the PhD concluded, I briskly, and wildly underprepared, ventured back into the clinical world of medicine as an M3. My "doctor" title, granted from the PhD was as meaningful as the points from "Whose line is it Anyway" in this new foreign territory. My expertise with animal surgeries and operating various different imaging apparatuses refined by years of lab work poorly translated to better history taking or physical exam skills. To call me petrified was an understatement during this metamorphesis. Thanks to the calm patience from several attendings and understanding residents, I soon started to grasp the modus operondi of the clinic. By the end of the year, I was comfortable managing numerous patients with multiple co-morbidities on an inpatient floor simultaneously.
Medical school is a terribly wild and unruly roller coaster ride of experiences and emotions. Generally, our residents and attendings embraced a "mother-bear" protective attitude towards us students, not allowing us to take some of the more callous patients or those with poor terminal diagnoses. The worst experience for me was having to inform a patient that his headaches and shortness of breath / cough were likely caused by lung cancer that had metastasized to the brain. Nothing in my training could have prepared me for that. Another particularly lugubrious experience was being the student who received and transferred a grossly premature baby from the obstetrics team to the NICU team. It was smaller than the palm of my hand when I received it and I still do not know how that baby faired out. Lastly, and not unique to any specific patient, but too frequently did we encounter inappropriate discharges for patients that were unable to receive the drug rehabilitation they requested or the physical/occupational therapy needed to restore their health, due to insurance denials. Insurance companies dictating medical decision making is utterly inappropriate and detrimental to patients' wellbeing.
For the most part, the 3rd year was filled with heartwarming experiences more freqeuntly than the negative troughs. The greatest highlight of the year came when I actually skipped clinic to meet up with an old MDA camping buddy of mine to receive the first ever commercially approved treatment for Duchenne Muscular Dystrophy. Another highlight during surgery was helping drill burr holes into skulls, assisting with Deep Brain Stimulation surgery (under very watchful scrutinizing eyes). Naturally, delivery babies during the OB-GYN clerkship synthesized unforgettable memories as well. One particular experience that was rewarding was when I had the opportunity to take care of a mother who was having pregnancy complications, and then several months later, saw the family with a +1 in tow in the pediatric ED. The family happy-cried seeing me take care of their baby (who turned out to be just fine)! Lastly, many tears were shed with several families whose lives were turned upside down because of diagnoses to their children. While these situations certainly can be seen through negative lights, we made sure that the families and children knew that we were all on the same page with them, whether it was to provide the highest remaining quality of life possible and helping them leave legacies, or to help guide them through difficult chemotherapies seeking remission of the diseases. The final positive experiences that we had was to help plan for "good" deaths with palliative medicine and hospice for terminally ill patients and their families.
In all, I cannot believe the year is over. I still do not know how I survived the sleep deprived surgery residents and attendings, to the interminable rounds of medicine. Through it all, my patients were the best teachers that I had, allowing me intimately into their lives during their most fragile and vulnerable times. It's a sacred communion that few other occupations have the privilege to experience. Moving forward, I've assisted with surgeries that I'll never again perform; I'm not planning to ever deliver another baby again; and I'll never have to spend hours as a statue battling accumulating lactic acid in my weakened muscles and increasingly distressed detrusor muscles retracting bladders during multi-hour surgeries, but would I trade it for anything? No. It was the opportunity of a lifetime composed of unexpected daily adventures with people that I'll never forget.
A large barrier currently exists between the common public and the ivory tower that frequently isolates scientists. Because of this divide, there is a misunderstanding of the importance of science in the community, and its ever present impact is often overlooked. Given the recent proposal to decrease NIH funding by nearly 20%, I felt compelled to try and reach out and inform the public about the impact that science (resulting from NIH funding) has had on everyone's daily lives.
The Gainesville Sun recently published my first Op-Ed, highlighting the importance of public funding for science.
Over the last two months, I've had the opportunity to venture through the exciting and exhilarating world of Pediatrics. Having started with a vested interest in pediatrics, the entire M3 year has been building up to this clerkship, and it most certainly did not disappoint. From the inpatient services (heme-onc, general, neurology, nephrology, and endocrinology) to general outpatient, ED, and newborn nursery, everyday was a new and exciting day.
A phrase frequently preached is that "children are not little adults", and for all of the right reasons this is true. The kiddos we took care of are naive and innocent without self inflicted harm that may have caused their morbidity. They are frequently tougher with less complaints than adults and their innocent nature was truly refreshing, making their care that much more meaningful.
Pediatrics also provided a unique sense of longitudinal care. One of my more favorite attendings preached how fixing their illnesses in youth potentially provided them 60+ years of health, which is truly unique to this specialty. Unique to this specialty too was that on newborn nursery and outpatient clinic, we saw more healthy patients than sick individuals. It really goes to emphasize the cost saving long term strategy of preventative medicine rather than retrograde disease treatment.
All in all, this was a tremendous experience, and cemented my yearning to become a Pediatric Neurologist, allowing myself the opportunity to tie together research that will redefine our management of neuromuscular diseases in pediatric populations.
Several of our colleagues have developed magnetic resonance microscopy (MRM) to image at the cellular level (such as large neurons), repeatedly defying the boundaries of resolution on how small we can image. In collaboration with them, we attempted to image individual myofibers with MRM using both optical and MR contrast agents in our most recent manuscript. We found that this is possible, achieving resolution as little as 6 um, allowing us the ability to image individual myofibers. In the bigger picture, this will allow us to study MR properties of healthy and myopathic muscle cells. Furthermore, using nuclei tagged with optical and MR gene markers, we may find this useful for cell lineage MR studies.
It has been an absolute whirlwind of a few weeks in the DMD world, capped by the approval of Eteplirsen, the first drug to combat DMD. Just last week, the first ever administration of eteplirsen took place at UF Health, a moment that I'll remember and cherish forever.
For years, the DMD community of families, patients, scientists, and clinicians have defied boundaries and pushed forward to advance research and treatment options for DMD. Though dystrophin was originally identified by Dr. Kunkel and colleagues in 1987, treatments still eluded researchers. Treatments were initially limited to symptomatic management of the disease, rather than attacking the root cause of the disease. A huge turning point occurred in 2001, with the approval of the MD CARE Act, which provided the impetus of funding for vast amounts of research of muscular dystrophies. Interestingly, around the time that the MD-CARE Act was initiated, survival of DMD rarely extended into the 20s, but by 2010, survival from DMD reached the 30s. This single understanding of the prolongation of quality life demonstrates how powerful and necessary research is in these diseases.
However, all has not been smooth during the process to approve Eteplirsen. Several potent obstacles were faced throughout the evolution of clinical trials for all drugs in DMD. First, though DMD is more common than other muscular dystrophies, it is still a rare disease, and no two mutations are identical, making for a very difficult time for researchers to adequately power clinical trials. In April 2016, a split vote by the FDA recommended against the approval of eteplirsen, showing how controversial the approval of this drug is. The FDA raises fair concerns that Eteplirsen may not be as effective as studies show, and that it's approval is premature. Patient advocates and scientists argue that the alternative to the drug is inevitable death without any therapy, and that this "questionable" drug is better than nothing. Debate continues following Eteplirsen's approval, and approval was only given contingent on follow up studies of efficacy to be performed.
The approval of Eteplirsen has been a momentous triumph for patient advocates. Not since the advocates of HIV/AIDS have we seen such a potent community of advocates for a particular disease. While facing immeasurable obstacles, their efforts certainly have been rewarded with the recent approval of Eteplirsen. Led by the PPMD and MDA, patients, families, scientists, and physicians have rallied around our boys to help find a cure for this devastating disease.
While this approval has caused a lot of excitement in the muscular dystrophy world, the first is certainly not over. In fact, eteplirsen only treats 13% of the DMD population, but the hope is that this approval may lead to approval of similar drugs, extending the treatment to a greater proportion of the population.
This is certainly something worth celebrating over, but is only a temporal victory. We still have a lot of research and work to do!
As important as treatments are to mitigate pathology within muscle, the ability to assess such treatment is just as critical. Previously, our lab has developed magnetic resonance imaging / spectroscopy techniques to assess and quantify the state of muscle health in pathologic states. We've built upon those findings, developing a new technology, near infrared optical imaging, to assess the state and health of muscle through a well controlled injury model.
In our first manuscript in this realm, we delve into the potential of NIR optical imaging as a feasible modality to measure injury and recovery of non-dystrophic muscle, as a foundation for future experiments!
For the last several months, I've spent trying to relearn what it means and takes to be a medical student after a brief research hiatus. Bluntly put, it's an entirely different atmosphere and attitude than that of the graduate school years.
First, the appreciation of time is entirely different. In medical school, we are told the hour that we are to graduate, during our orientation four years prior. In graduate school, we are told to figure out where we'll be in ten years. Clinicians are always seemingly in a rush and hurry to do something, while researchers gain comfort from methodically picking apart a problem, frequently to excess.
Comparing the stresses of graduate to medical school is like comparing apples to oranges. Weeks, months, even years can be spent in graduate school stressing over single experiments, and future opportunities and jobs can be made or broken by the success of such experiments. Life becomes endless pipettes, beakers, dishes, and time course experiments that you hope to be able to one day make a story/dissertation from. In medical school, stress is caused by the immediate situation of a human life at stake in front of you, which (with all due respect to animals) is more stressful than working with cells, nematodes, or even mice. The stresses are simply different in their own ways.
Appearances matter, in med school at least. No one cares much at all what you look like (so long as you're EH&S and IACUC compliant), and that is perfectly okay. In med school, we frequently have to 'fake it till we make it' and one of the ways of faking it is to appear the part of a doctor. More than just a physical barrier from the cesspool of pathogens that we're exposed to in clinic, the white coat serves as a metaphorical shield to hide behind when our own clinical skills become questioned.
The public reception of both realms is frequently also misunderstood. In graduate school, the most common question to receive is "When will you be done?" while in medical school, it is "What are you going into?" In this odd dual degree situation that I've finagled myself into, it most frequently is "What the heck were you thinking?"
This past week, I earned my PhD from the Interdisciplinary Program within the College of Medicine at the University of Florida.
From the bottom of my heart, thank you everyone for the kind words over the last few days as we've finished up this PhD. To me, the PhD is much more than more initials after my name (I certainly already have enough letters in my name), but rather a small checkpoint in this arduous trek through life.
As a teenager, I gained impetus for this journey by seeing the inadequacies of clinical management for the muscular dystrophies affecting my friends. Our journey is far from over, and there's much work to still do, but ultimately it's going to be our combined research efforts that end muscular dystrophy.
My friends and family are my stalwart bedrock, and without them, I would not be here today.
As much of the DMD community is already aware, yesterday Sarepta Therapeutics went in front of the FDA, seeking approval to sell Eteplirsen within the US.
Unfortunately, the FDA voted against this 7-3, with 3 votes abstaining.
If approved, Eteplirsen would have been able to treat ~13% of the DMD population, based on specific mutations. Despite 12+ hours of hearings, including patient and advocate testimonials, the FDA found the trial to be too poorly designed with not enough concrete outcome evidence, thus the denial. The FDA went so far to state that “anecdote and emotions don’t change the data.”
While blame is easy to turf, and hindsight is 20/20, I think we (as advocates and health care professionals), have a lot we can learn from this to better prepare for the next proposal. I believe that there is a fair amount of short-sightedness in the clinical trial design (with understandable reasoning) in that many companies hope and expect a drug to work in 6-24 months (all companies included), while these diseases take a lifetime to affect boys. In this limited timeframe, mitigation of disease is subtle with current outcome measures. Overall, it would be more cost efficient to run a single successful large randomized control trial for a longer time, rather than multiple failed trials.
In all, it makes me appreciate what ImagingDMD does, using quantitative, longitudinal, and objective outcome measures like MRI, to assess the state of health.
I'm a current MD-PhD candidate, working hard to help treat and manage muscular dystrophies