SYNAPSE...PENN’S UNDERGRADUATE MEDICAL CONNECTION SYNAPSE Theranos How a promising idea ended in...

PENN’S UNDERGRADUATE MEDICAL CONNECTION SYNAPSE

TheranosHow a promising idea ended in

criminal charges 32

The Human Cord Blood IndustryUntapped potential 8

Can a watch save your life?Detecting atrial fibrilation with

the new ECG Apple Watch 22

SPRING 2019

Coca-Cola and Life-Saving MedicinesAn unlikely pairing 20

PHarma & biotech

EXECUTIVE BOARD

GENERAL BOARDSAssociate EditorsMaya Abdel-MegidLynn Ahrens Sanaea Bhagwagar Kaitlyn BoyleLucy CaoChloe ChoYouvin ChungKeely DouglasEric Hsieh

Design Staff Lynn AhrensAlicia GoSabina London Brian Song

Business Staff Robin Hu

ADVISORY BOARDKent Bream, MD: Assistant Professor of Clinical Family Medicine and Community Health, Hospital of the University of PennsylvaniaPhyllis Dennery, MD: Chief of Neonatology and Newborn Service, Children’s Hospital of PhiladelphiaJohn Heon, PhD: Professor of English and Writing, College of Arts and Sciences Lisa Mitchell, PhD: Assistant Professor of South Asian Studies, College of Arts and SciencesBrendan Maher: Features Editor, NatureMark Pauly, PhD: Bendheim Professor of Healthcare Management, The Wharton SchoolPhilip Rea, PhD: Professor of Biology, College of Arts and SciencesHarvey Rubin, MD, PhD: Professor of Medicine, Penn School of MedicineMichael Topp, PhD: Professor of Chemistry, College of Arts of SciencesNicholas Wilcox: Founder of SYNAPSE

FEATURED SPEAKER SPRING 2019Laura Bessen, M.D.

MANY THANKS TO

Scott Massa, Victoria Siu Tiberiu MihailaMahip GrewalChloe Cheng, Saitej Guttikonda, Ryan Leone, Vaishnavi Sharma Raveen Kariyawasam, Emily XuMary Lin, Phyllis Parkansky

Editors-in-ChiefExternal VPInternal VP

Executive Editors

VP DesignVP Finance &

Marketing

Dear Readers,

Sitting unassumingly in your medicine cabinet are products from one of the leading industries worldwide. Pharmaceutical and biotech companies drive innovation in medications, therapeutic treatments, diagnostics, and other types of medical technology. Pharmaceuticals include small chemical drugs, while biotechnology, or biotech, utilizes large molecules derived from living organisms. This continually expanding field crosses many aspects of medicine with boundless possibilities, but also brings into question the public perception of the industry and ethical dilemmas behind business practices. The Spring 2019 edition of SYNAPSE seeks to approach the topic of pharmaceuticals and biotech through the areas of biomedicine, public health, and business.

This semester, our feature articles focus on unconventional sources of treatment and unique medication distribution methods with promising potential to advance healthcare. In addition, the articles forewarn the necessity for ethical practices behind the pharmaceutical and biotech industry. Among these articles, we explored the therapeutic applications and research potential behind human umbilical cord blood. We shined a spotlight on the unique partnership between health-based organizations and Coca-Cola to expand access to and distribution of essential medicines. We also reviewed the meteoric rise and dramatic downfall of Theranos, a health technology corporation doomed by its leadership’s public deception. Finally, our infographic explains the mechanisms behind the revolutionizing CRISPR-Cas9 gene editing tool and explores the potential for research and therapy behind the innovative method. In all, we hope that this edition informs the readers with a grounded perspective on the pharmaceutical and biotech industry.

In this nineteenth installment of SYNAPSE, we would like to sincerely thank all our writers and members of the Editorial, Design & Layout, and Finance & Marketing teams for their contributions this semester and over their collegiate careers. Without the dedication and hard work of our team, the creation of this issue would not have been possible.

Sincerely,Scott Massa and Victoria SiuEditors-in-Chief

Robin HuAlice LiuJoan LimMary LinEmily LoPeter MaAris Saxena Brian Song

EXECUTIVE BOARDBACK (L TO R): PHYLLIS PARKANSKY, RYAN LEONE, SCOTT MASSA, VICTORIA SIU

FRONT (L TO R): EMILY XU, MAHIP GREWAL, CHLOE CHENG, RAVEEN KARIYAWASAMNOT PICTURED: MARY LIN, VAISHNAVI SHARMA, SAITEJ GUTTIKONDA, TIBERIU MIHAILA

2 | SYNAPSE | SPRING 2019 SPRING 2019 | SYNAPSE | 3

Interested in writing for SYNAPSE?Go online to www.upennsynapse.com or email [email protected] for

more information.

CONTENTS

THE HUMAN REFERENCE GENOMEA Work in Progress

Saagar Asnani

4Biomedicine

ON THE COVERThis issue’s cover is a representation

of the pharmaceutical industry and the large impact that business and society

have on the industry.

Designed by Raveen Kariyawasam and Emily Xu.

INDUCED PLURIPOTENT STEM CELLSBiological Alchemy of Stem Cells

Sydney Lee

6

THE HUMAN CORD BLOOD INDUSTRYUntapped Potential

Eric Hsieh

8

THE GROWING MICROBIOME SECTORA Promising Therapeutic Avenue

Ila Sethi

10

VACCINE HESITANCY & MEASLES OUTBREAKS IN THE U.S.The Importance of Debunking Myths

Sarah Devlin

12PUblic health

PRESCRIPTION AND PERCEPTIONDisparities in the Prescription of Mental Health Medication

Isabel Buckingham

14

HARNESSING TECHNOLOGY TO EXPAND PALLIATIVE CAREMaking it the Norm, Rather Than an Exception

Christeen Samuel

16

COCA-COLA AND LIFE-SAVING MEDICINESAn Unlikely Pairing

Aris Saxena

20

REGULATION OF PRESCRIPTION DRUGS A Problem Concerning the Biotech and Pharma Industries\

Rohan Vemu

24

business

DRUGS AND DEFENSEThe Military Funds Disease Solutions that Pharma Won’t Address

Ryan Leone

26

ADVANCEMENTS IN HOSPITAL PRICE TRANSPARENCYOvercoming a Barrier in Healthcare

Jessica Tang

28

FUNDING INNOVATION The Biotech Startup Environment

Charitha Moparthy

30

THERANOSHow a Promising Idea Ended in Criminal Charges

Evan Jiang

32

INFOGRAPHIC 18

CAN A WATCH SAVE YOUR LIFE?Detecting Atrial Fibrillation with the New ECG Apple Watch

Isabella Wang

22

Revolutionizing Genomic Research: CRISPR-Cas9

Raveen Kariyawasam and Victoria Siu


On April 2003, the Human Genome Sequencing Consortium published the first blueprint of the human body. The Human Genome Project’s fifteen-year journey culminated in the release and publication of the human genome, presenting a sequence of approximately three billion bases as the foundation of who and what we are.1 Despite this groundbreaking discovery, it was only the first step on a long path to truly understanding the genetic code. Released in December 2013, the Genome Reference Consortium human build 38 (GRCh38) is the most up-to-date version of this genome, containing fewer than one thousand gaps in the sequence, which is a huge improvement from the original version.2

The human genetic sequence is crucial to biomedical research and has led to advances in medicine and biological understanding. Indeed, many experiments attempting to better understand the workings of the human body require the manipulation of standard genome forms. The use of genetic therapies and gene-targeted treatments is particularly important to the field of precision medicine, where the specific information garnered from a patient’s genetic sequence can suggest drugs that are tailored exactly to that patient’s needs. For example, research on patient-specific genetic information for organ transplantation is now looking towards the development of “organoids,” small tissue cultures grown from patients’ stem cells in order to replicate a specific Patient’s own organs that may even be modified in order to mitigate the effects of a particular disease.3 Nonetheless, gaps in the most recent versions of the

genome pose challenges to scientists looking to understand questions like that of “missing heritability” of diseases. Certain maladies, like schizophrenia, have recently been the subject of genome-wide association studies with the aim of pinpointing their heritability and genetic basis. However, the genetic link for these illnesses is still unclear, and the current gaps in the human genome could be a potential source for the DNA involved in the expression of these diseases.4 There is still ample information about the human genome that has yet to be discovered.

T h e r e i s s t i l l a m p l e i n f o r m at i o n a b o u t t h e h u m a n g e n o m e t h at h a s y e t t o b e d i s c o v e r e d.

Sample size and diversity are considerations which complicate the process of cataloguing the human genome. The first human genome in 2003 was compiled with DNA from less than twenty volunteers living near the laboratory where it was first generated,5 encapsulating only a small fraction of total human diversity.6 However, recent estimates place genetic variation between humans to be, on average, equal to about 0.1% of the genome, or roughly 3 million base pairs.7 Newer versions of the genome have even made efforts to account for this general variation. As of 2017, nearly 300 alternate scaffolds, addendum patches that account for variation, were added to the original version.8 However, the problem with this approach is that it does not properly account for heterogeneous populations.

It also doesn’t account for large differences in the number of base pairs in the genomic code.

In an era where DNA sequencing is gaining a larger role in diagnostics and preventive care for individuals around the world, the incompleteness and biases inherent to the current reference genome are hindrances to it being a fully functional tool.

Relying on the reference genome has drawbacks. As DNA sequencing has become more accessible, its failure to account for genetic variation has left large gaps in its usefulness for many people not represented by the reference genome.9 A paper by John Hopkins Medicine, written in response to recent studies on the genetic heterogeneity of human populations, states the necessity for the creation of multiple human reference genomes to better account for large-scale genetic variations between ethnicities.10 Therefore, there is a need to continue adding to the current reference genome to help advance the field of precision medicine. The genetic variation between various human populations is not yet properly understood, so it is difficult for researchers to determine exactly which genetic sequences code for phenotypes that are benign and which may result in illnesses.

Most interestingly, DNA’s inherent tendency to include large sections of repeats, especially near the centromeres and other non-coding regions of chromosomes, creates one of DNA sequencing technology’s biggest limitations. The earliest DNA sequence technology relied on the presence of short priming strands of DNA to target the area of sequencing -- this made it difficult to get accurate readings in areas with large amounts of repeated DNA. Next-generation sequencing technologies, which are widely used today for sequencing large-scale projects like The Human Reference

BY Saagar Asnani

The Human Reference Genome

A Work in progressBiomedicine

4 | SYNAPSE | SPRING 2019 SPRING 2019 | SYNAPSE | 54 | SYNAPSE | SPRING 2019 SPRING 2019 | SYNAPSE | 5

Genome, operate by breaking the DNA into many small pieces and then reassembling the sequence like a using overlapping portions of the sequenced DNA as guides. However, the presence of repetitive DNA makes it difficult to determine exactly where and how long pieces of DNA sequences are are, which has resulted in the 875 gaps present in the current version of the human genome.11

In 2010, it was found that the genomes of Asian and African individuals contained an extra five million base pairs that did not correlate to anything in the Human Reference Genome.12 This finding suggested that while over 80% of these “novel sequences” appeared to correlate to gaps in the genome, the rest of the sequences seemed to be specific to individuals and populations and therefore likely implicated in gene transcription. This study by Li et al (2010) introduced the idea of genomes of different populations varying not only in terms of DNA substitutions, deletions, or rearrangements but also in the size of the actual genome. Here, the first steps were taken towards creating a human “pan-genome,” or a sort of “master” genome that would include all non-redundant base pairs found in diverse human populations, with the possibility of increasing in size as more novel sequences are found. Since then, there has been an increased interest on studying the genetic variations present within specific populations. A study

SCAN FOR REFERENCES

that sequenced one thousand Japanese individuals found approximately twenty-one million single nucleotide polymorphisms (SNPs), of which twelve million were specific to this particular subgroup and are not accounted for in the original reference genome.13 A smaller scale study conducted on people of South Asian descent found ten million SNPs, of which about twenty percent were novel.14 While neither of these

studies found significant variations in the size of the genomes, they do call into question the actual amount of variation between human populations, especially across different ethnicities.

Despite this groundbreaking discovery, it was only the first step on a long path to truly understanding the genetic code.

Interestingly, in November of 2018, it was found that doing “deep sequencing” of nearly a thousand individuals of African descent revealed an extra 300 million base pairs present in their genomes.15 Deep sequencing is a technique that involves repeatedly sequencing small portions of the genome to verify the accuracy of a given sequence, especially in regions of repetitive DNA.16 Given that the average size of a human chromosome is about 100 million base pairs in size, this study may even point to the existence of

a large chromosome’s worth of genetic information about which we know very little.17 In an era where DNA sequencing is gaining a larger role in diagnostics and preventive care for individuals around the world, the incompleteness and biases inherent to the current reference genome are hindrances to it being a fully functional tool.

Looking forwards, the end goal for this research would be to construct a pan-genome, or a whole genome set, for the human species. This would give researchers the complete toolset that they would need in order to conduct more thorough research and to study diseases that may only affect certain populations of humans. However, the scope of these endeavors is just as daunting as the initial Human Genome Project was and it may be quite a long time before the human genetic information available to the public will be as thorough as possible.

GRAPHIC/WIKIMEDIA COMMONS

Genome reference consortium human build 38 (grch38)

4 | SYNAPSE | SPRING 2019 SPRING 2019 | SYNAPSE | 54 | SYNAPSE | SPRING 2019 SPRING 2019 | SYNAPSE | 5

Alchemy

laboratory instead of inside the female body.1 Second, there are also adult stem cells that are used for repair and replacement of damaged tissue in specific areas.1 Although they are called adult stem cells, they are present in infants and children as well. These cells lack the pluripotent potential of embryonic stem cells. Finally, the third type of stem cells, which was discovered by Shinya Yamanaka, are induced pluripotent stem cells (iPSCs).

Using adult stem cells and adjusting them to become cells in an embryonic stem cell-like state can evade ethical concerns regarding the use and destruction of human embryos.

Induced pluripotent stem cells are specialized adult cells that are genetically reprogrammed to be in an embryonic stem cell-like state. Essentially, adult stem cells are edited to resemble the first type of stem cell, embryonic stem cells. These iPSCs, therefore, can potentially differentiate into all cell types in the body.

Biologicalof Stem Cells

HISTORY OF STEM CELL RESEARCH

Prior to stem cell research, the prevailing view was that cellular differentiation was unidirectional and thus non-reversible.2 As a result, as cells continued to divide, they were thought to become increasingly specialized and ultimately lose their pluripotency, or their ability to transform into different cell types. For many years, it was thought that adult cells were unable to revert to a non-differentiated state. However, in 1962, John B. Gurdon discovered that adult cells still contain the necessary genetic information to recover pluripotent capacity.3 In 2006, Yamanaka took skin cells from adult mice with a virus and introduced them to 24 embryonic stem cell transcriptional factors crucial to the characteristics of embryonic stem cells.3 44 years following Gurdon’s research, Yamanaka demonstrated that fully specialized adult cells could be revised to a pluripotent state that can develop into any cell type in the body.

Life begins as one cell — the fertilized egg — which divides to make new, identical cells. As the cells continuously divide, they gradually vary in their type through differentiation, a process which allows cells to acquire specific functions in different tissues.1 However, there are stem cells that have not been differentiated but retain the ability to divide and turn into various types of cells. Throughout the timeline of stem cell research, stem cells have been the topic of both hope and controversy. However, the birth of induced pluripotent stem cells has engendered excitement among researchers and the general public because these cells could potentially be applied clinically without raising ethical concerns. STEM CELLS AND DIFFERENTIATION

There are many types of stem cells, each with distinct purposes. First, there are embryonic stem cells, which have the ability to potentially develop into any type of cell. Production of these cells requires in-vitro fertilization, which involves fertilizing an embryo in a

By Sydney Lee

GRAPHIC/PIXABAY


CIRCUMVENTING ETHICAL CONCERNS

Although adult stem cells (iPSCs) do not pose any ethical problems, embryonic stem cells may raise some ethical concerns, especially in how they are harvested. During this procedure, a fertilized embryo is destroyed.3 Opponents of embryonic stem cell research argue that an embryo is a human being and has rights that should be protected. On the other hand, proponents reason that an embryo is not yet a human being and that zygotes made through in-vitro fertilization would be disposed whether or not they are used for research purposes.4 However, the discovery of iPSCs lessened the demand for research using stem cells harvested from human embryos and thus bypassed many ethical concerns. Using adult stem cells and adjusting them to become cells in an embryonic stem cell-like state can evade ethical concerns regarding the use and destruction of human embryos. STEM CELLS TO TREAT DISEASES

There are benefits associated with iPSCs. Researchers have speculated the possibility of personalized therapy through iPSCs. For instance, a person’s skin cells can be reprogrammed into iPSCs that can grow into any other type of cell, such as neurons, liver, or blood cells.5 This therapy method would be ideal not only ethically but also clinically; for example, iPSCs can circumvent the risk of immune rejection resulting from transplantations of other individuals’ organs.

With their possibility of creating an unlimited supply of human tissues to meet the demands of research, iPSCs are regarded as significantly valuable instruments for investigation and modeling of human diseases and drug discovery.8

Since the discovery of iPSCs in 2006, iPSC therapies have been tested in clinical trials for their regenerative potential. The health ministry of Japan already allows the use of iPSCs for treatment of rare eye disease by transplanting retina cells that were grown from iPSCs.6 In 2014, researchers at the RIKEN Center for Developmental Biology conducted

the first transplant of retinal cells that were iPSC-based.6 In October 2018, neurosurgeons from Kyoto University implanted iPSCs into a patient’s brain to treat Parkinson’s disease, which is a neurodegenerative disorder that affects dopamine-producing cells. The iPSCs were reprogrammed from peripheral blood cells of a donor and transferred into dopaminergic precursor cells, with the goal of heightening dopamine levels to alleviate symptoms.7 In February 2019, Japan approved the testing of iPSCs for treating spinal cord injuries. With this approval, a research team from Keio University plans to inject two million iPSCs into the damaged areas of patients who have lost mobility and sensory functions resulting from a spinal cord injury and review the outcome over a year.6 This approach has been tested in a paralyzed monkey, who gained the ability to walk after the treatment. SHIFTING FOCUS AND UNRESOLVED CHALLENGES

Despite the progress in clinical trials, major clinical advancements through these cells have proved to be incredibly challenging. Rather than using them in clinical settings, researchers started to look into iPSCs’ potential in research laboratories. With their possibility of creating an unlimited supply of human tissues to meet the demands of research, iPSCs are regarded as significantly valuable instruments for investigation and modeling of human diseases and drug discovery.8 These cells have been especially useful for studying neurological diseases and human development.9 Researchers can collect patients’ skin cells, derive iPSCs out of the skin cells, and differentiate the cells into the affected types of cells in vitro. Using this procedure, a disease can be replicated and modeled in a Petri dish and to help identify new drugs to treat the disease.10 Some researchers have even succeeded in creating organoids, such as mini-livers and mini-guts. Furthermore, researchers from the Salk Institute for Biological Studies used iPSCs in their generated cancer model in human organoids. iPSCs used in the study became invasive and destroyed surrounding organoid structures by initiating tumors.5 This finding could offer some platform to investigate the natural progression of cancer.

Nevertheless, iPSC research faces difficulties and complications. For instance, the four transcriptional factors that are crucial for maintaining the embryonic stem cell-like state were found to be oncogenic, causing tumor formation, in studies with mice.11 Also, the use of viruses for gene insertions risks occurrence of insertion mutations in cells. In addition, the inserted transgenes that are silenced after the reprogramming can be reactivated unintentionally; this reactivation risks cells growing into tumors.12 In response to these difficulties, researchers sought to develop some nongenic methods, such as reprogramming proteins and interfering with signaling pathways.13 As research progresses, there are inevitable obstacles that lie ahead. Beyond their potential in personalized medicine, iPSCs could be banked to create off-the-shelf treatments.7 If this is possible, iPSC therapies could be more accessible to patients economically. However, research efforts could be hampered because grown human cells for research could be incompatible with populations with a diverse genetic makeup. Although there are drawbacks that should be considered, the discovery of induced pluripotent stem cells is nonetheless a prominent scientific breakthrough for regenerative medicine.

SCAN FOR REFERENCES


Wrapping him in a soft white blanket and placing a tiny cap on his head, the nurse gingerly carries the newborn baby over to his awaiting mother. The new mother cries tears of joy as she holds her baby in her arms and stares into his eyes for the first time, beginning her journey into parenthood. In the back of the room, out of sight, the phlebotomist injects a needle into the detached umbilical cord, drawing blood into a collection bag using gravity. After filling the bag, the phlebotomist places it into a biohazard container and readies it for shipping. Depending on the instructions dictated by the mother, the collected cord blood is either donated to a public bank or stored privately for future use.1

This procedure, while simple and risk-free, has only been a recent development. Human umbilical cord blood (UCB) has long been regarded as a waste product of birth and subsequently discarded along with the placenta. It was only in 1978 that UCB was recognized as a rich source of progenitor and stem cells.2 Despite this breakthrough, it was another decade before the first cord blood transplant was performed in a clinical setting.3 Today, there is an entire industry surrounding the collection, banking, and use of UCB, with more than 450 companies involved in the process worldwide.4 However, UCB remains a largely untapped resource as over 9 the United States every year.5

WHY CORD BLOOD?

All stem cells are extraordinary in their abilities to divide and renew themselves, as well as to specialize into different cell types. Stem cells can be isolated from almost every stage of life, ranging from human embryonic and fetal tissues to the bone marrow and peripheral blood of a fully grown adult.5 Embryonic stem cells are pluripotent, meaning they can become

any cell type within the body. However, despite its numerous potential medical applications, the sourcing of embryonic stem cells is subject to immense ethical and political controversy.6 On the other hand, stem cells isolated from a fully grown adult are often difficult to obtain. A bone marrow donation requires surgery under general anaesthesia and peripheral blood donation is a multi-day process with a collection period of up to eight hours long.7 These limitations highlight the promise of UCB.

UCB is rich in populations of hematopoietic stem cells, which can develop into blood cells, as well as mesenchymal stem cells, which can grow into bone, cartilage, and fat.8 What makes UCB so promising is that it possesses numerous functional and practical advantages over peripheral blood and embryonic stem cells, representing a balance between these other stem cell sources.

Firstly, cells in cord blood have greater proliferative capabilities than their peripheral and bone marrow counterparts. For example, UCB has more than eight times the amount of HPP-CFC cells, which are cells with high proliferative potential and are capable of forming cell colonies. Furthermore, UCB contains a higher proportion of hematopoietic stem cells than bone marrow and peripheral blood, and these stem cells are more primitive, thus allowing for more versatility when differentiating into different cell types.9

UCB stem cells also possess unique functional advantages over adult stem cells for stem cell transplants. UCB stem

cells have a lower risk of transmission of infection and a lower chance of graft versus host disease, which is a serious complication where white blood cells from the donor can attack the recipient.10 Lastly, UCB does not suffer the same ethical quandaries as embryonic stem cells because they can be collected at no harm to the mother or baby. Consequently, it is no wonder that an entire industry grew around this biological resource with its ethical, scalable sourcing and its far-reaching applications.

Private Cord Blood Banking

A large sector of the human cord blood industry revolves around banking services, with some of the most prominent players being Cryo-Cell, Viacord, and LifeBankUSA. In the third trimester of pregnancy, an expecting couple may learn about cord blood banking on the internet or through their OB/GYN. If they decide to use cord blood banking services, the bank will collect, process, and cryopreserve the stem cells, with the couple paying a fixed initiation fee and then an annual fee for however long they decide to store the cells.11 Typically, health insurance will not cover the costs of banking, but some plans do reimburse families if the storage is deemed medically necessary, such as banking for a family with a history of leukemia or other blood diseases.12

Many banks sell their banking services to expecting parents as a type of insurance policy. Diseases like blood cancers, inherited immune disorders, and inherited metabolic disorders may

UNTAPPED POTENTIAL

THE HUMAN CORD BLOOD INDUSTRY

BY ERIC HSIEH


SCAN FOR REFERENCES

require the patient to receive a stem cell transplant. These patients can sometimes use their own stem cells, an autologous transplant, but more often than not, they must rely on a public donation. These allogeneic, or foreign, donations may be hard to acquire, especially for minority groups, since certain human leukocyte antigen (HLA) markers must match.13 In this way, some parents may want to bank their cord blood stem cells in order to have a repository of stem cells to use if needed.

A growing trend within the cord blood banking industry is banking companies partnering with genetic testing companies, evident through the partnership of LifeBankUSA and Human Longevity. Cord blood banking companies may also launch their own genetic testing services, as shown by Viacord’s provision of a genomic sequencing option to their clients. The purpose of these partnerships is that through genetic testing and genome sequencing, parents are not only armed with the knowledge of the risks of future diseases, but they also have the tools to face them through stem cells.14

THE POWER OF THE PLACENTA

While much of the attention is focused on UCB, another valuable biological resource is discarded in the millions each year: the placenta, a maternal-fetal organ that supplies the fetus with oxygen and nutrients. Along with the pioneering work of Dr. Robert Hariri, a landmark 2009 study found the placenta to be another source of stem cells that could be harvested through a placental perfusion process.15 Therefore, along with cord blood, the placenta is a non-invasive source for valuable hematopoietic stem cells.16 This discovery led to the creation of new companies, the foremost being Dr. Hariri’s Celularity, a spin-out from the biotech giant Celgene.

Other than the placental blood, the placental tissue itself has numerous applications. For example, the amnion, the inner placental membrane, and the chorion, the outer placental membrane, can be harvested and processed into cell grafts. These cell grafts can be used to heal wounds from surgery, diabetic foot ulcers, and even full-thickness burns. The grafts consist of growth factors,

cytokines, chemokines, proteases, and key proteins like collagen, fibronectin, and laminin. Acting as scaffold for native cells to attach to, these grafts promote healing and reduce scar tissue.17

Promising cellular therapies and future directions

Biotech companies are also using cord blood and placental derived stem cells for cellular therapies, with the most exciting application being in cancer treatments. Immunotherapy utilizes the body’s natural defense mechanism, the immune system, in the fight against cancer. After receiving cord blood or placental blood from donors, researchers can isolate the stem cells and then grow them into different kinds of white blood cells, particularly natural killer cells, which are specialized lymphocytes that can recognize and kill cancer cells.

What makes this so remarkable is that these natural killer cells do not have to be matched to a specific patient. As recent studies have shown, these genetically foreign or allogeneic cells can be infused into a patient without infusional toxicities or graft-versus-host disease. Furthermore, one cord blood or placenta donor’s stem cells could potentially be used to treat multiple patients. This “off-the-shelf” model for immunotherapy means that providers can avoid the cost problems currently plaguing the CAR-T cell platform, which costs upwards of $475,000 for a single treatment. Specifically, instead of having to draw a patient’s own blood, modify it, and then re-infuse it, as in the CAR-T cell treatment, providers can simply inject pre-packaged cells into a patient.

While there is still a long way to go with regards to the applications of cord blood and placenta, these resources undoubtedly have the potential to revolutionize not only how we treat cancer, but also how we approach things like organ regeneration and functional regeneration. In all, these vastly underutilized resources should be more widely used in the lab, in the clinic, and beyond.

GRA

PHIC/G

OO

DFREEIM

AG

ES


GRA

PHIC

/RAV

EEN

KA

RIYA

WA

SAM

When we think of causes of human disease, our genetics and environment most readily come to mind. Yet, our bodies contain almost ten times more bacterial cells than human cells, most often in symbiotic relationships with each other.1 These bacterial cells are collectively referred to as a microbiome that exists in our skin, mouth, nose, urogenital tract, and feces and present a key area of research that will allow us to further understand human disease mechanisms and pathology. Gut microbiota is often a specific focus due to its immense diversity and variability, even amongst identical twins. In fact, researchers estimate that the human gut contains about 160 different bacterial species.

Microbiome Based Therapeutics

While the gut microbiome is necessary for survival, it also provides key insights into human health. Abnormal colonies in the gut have been associated with Crohn’s disease, colon cancer, and nonalcoholic liver disease. Different gut compositions are linked to different vitamin production and disease susceptibility. Microbiome-based therapies play key roles in lowering occurrences of autoimmune disorders and chronic diseases such as diabetes and cardiovascular disease, as well as combating antibiotic resistance and central nervous system based disorders. One of the most promising treatments is the fecal microbiome transplant to treat C.dificile infection in antibiotic-resistant cases.1

The Growing Microbiome

SectorBy Ila Sethi

10 | SYNAPSE | SPRING 201910 | SYNAPSE | SPRING 2019

scan for references

Research efforts focused on microbiome-based therapies have only accelerated recently. While under 250 PubMed publications referred to “human microbiome” in 2003, there were nearly 4000 publications about the topic in 2013.2 This increase may be a response to the rising prevalence of chronic conditions and antibiotic resistance, both of which are targets of microbiome therapeutics.3

The Growing Microbiome Market

Interestingly, this upward trend in research and scientific output in the microbiome field is directly correlated to a rise in microbiome-based patents.4 Furthermore, according to Mordor Intelligence, the global microbiome market is currently worth nearly $273.40 million, and it is expected to reach a value of $757.26 million by 2025 with a compound annual growth rate (CAGR) of 23.08% during this period.3 Like the microbiota itself, its global market is incredibly diverse, with groups targeting a wide array of ailments such as obesity, diabetes, autoimmune disorders, cancer, gastrointestinal disorders, central nervous system disorders, and depression. Active companies and partnerships have increased exponentially over the last five years. For example, Enterome, a Paris based startup focusing on developing gut-based microbiome therapies, has partnered with Johnson & Johnson Innovation, Jannsen BioTech, Takeda, Bristol-Myers Squibb, Mayo Clinic, and Geisinger hospitals.3 Venture capital investment has increased in tandem, with larger investments in later stage funding.4 AOBiome, for instance, is now a private company that has created a skincare product that uses ammonia-oxidizing bacteria. These bacteria are able to treat acne, eczema, and diabetic ulcers by restoring the skin’s natural biome.5 Funding transcends normal venture capital and incubators — even the United States Department of Defense is funding a microbiome-based startup named Azitra. Azitra focuses on developing skin-safe bacterium to secrete proteins missing from the skin’s microbiome in disease patients to target eczema and staph infections.6

A number of startups that harness biotechnology to offer personalized

therapies coupled with increased consumer engagement have also emerged. For example, Ubiome, a Series C funded startup, makes genomic sequencing publically available with products such as SmartGut, a microbiome sequencing test for patients with chronic gut conditions such as inflammatory bowel disease and irritable bowel syndrome. They have also expanded beyond the gut with their women’s microbiome screening test, SmartJane, to screen for 19 different strains of human papillomavirus.8

Further, a startup called Thryve not only uses custom testing for tailor-made probiotics using a monthly subscription service but also provides a platform for individuals with microbiome based therapeutics to connect and share their illness narratives.9

Remaining Barriers

There remain significant barriers towards a comprehensive understanding of the human microbiome including the diversity of human genetic composition, global dietary patterns, and geographical variability. The scale of the human microbiome is immense and difficult to study in isolation. Currently, no translational models exist that successfully model the microbiome’s complexity.4 While the Human Microbiome Project is definitively a step in the right direction, research in this field needs continual growth and innovation.

Key challenges also remain in terms of microbiome-based therapies. Although some products have entered Phase 3, there is an overall lack of microbiome therapies that have been approved for human use by the FDA. According to leading researchers in this sector, increasing the strength of research models and reproducibility of work will enable the translation of research into approved products for human use.4

Nonetheless, microbiome-based products have promising therapeutic potential, align with the shift towards personalized treatment, and represent a quickly expanding healthcare sector. The microbiome represents a sphere of innovation, from research laboratories to start-ups, that will bring new meaning to the adage “you are what you eat.”

SPRING 2019 | SYNAPSE | 11

Before vaccines, infectious diseases ran rampant in the Unit-ed States and worldwide. In 1918, the Spanish flu killed 500 million people throughout the world. Polio took the lives of 3,145 people in the United States during the 1952 epidemic. As early as the 6th century, smallpox ravaged human popula-tions, killing one in three infected.1 Today, dangerous diseases such as polio have been eradicated in the US. Smallpox only exists in laboratories. Thanks to vaccines, diseases such as mea-sles, diphtheria, pertussis (whooping cough), tetanus, rubella, mumps, varicella (chicken pox) and Hepatitis B can all be pre-vented.2

MAD ABOUT MEASLES

In recent years, however, a growing opposition to vaccines has allowed outbreaks of preventable diseases to return. Today’s parents do not remember consequences of diseases such as po-lio and rubella. Measles cases in the United States hit a 20-year peak in 2014.3 From December 2014 to February 2015, there was an outbreak of measles, linked to 125 cases of the disease, which originated in Disneyland, California. Of these cases, 45% were unvaccinated, 43% had unknown or unfound vacci-nation records, and only 1% had all three rounds of MMR vac-cination. 12 of these patients were too young to be vaccinated.4

Since then, there have been other minor outbreaks in the US. In fact, one is currently ongoing in Clark County, Oregon. 63 cases of measles have been confirmed as of February 20, 2019. 55 of these children have never been vaccinated against the measles. There are over 23 potential exposure sites including two elementary schools and two daycares.5,6

HOW VACCINES ARE MADE

A vaccine is a substance that strengthens the body’s immune system against certain microbes and is made of a weakened form of a microbe, its toxins, or its surface proteins. These an-tigens stimulate the body’s immune system to recognize the pathogen as foreign and respond effectively if it is encountered again.7

It is important that everyone who can get vaccinated does, es-pecially children. Children’s immune systems have not been exposed to as many pathogens as those of adults. The first time someone’s immune system encounters an infectious agent, it takes longer to respond.

Not everyone is able to get vaccinated. People with compro-mised immune systems (such as cancer patients) and babies cannot be vaccinated. Pregnant women cannot receive the measles, mumps, and rubella (MMR) vaccine. Herd immunity protects these individuals.

Herd immunity, which is also known as community immunity, is “a situation in which a sufficient proportion of a population is immune to an infectious disease to make its spread from per-son to person unlikely.”8 The percentage of vaccination nec-essary for herd immunity to be effective is different for each disease. According to the NIH at least 96% of the population

Vaccine Hesitancy & Measles Outbreaks in the U.S.BY SARAH DEVLIN

GRAPHIC/UNSPLASH

public health


sion about vaccines with their healthcare providers. Healthcare providers should reach out to parents about their concerns. Sometimes, parents are open to vaccines but are worried about the pain of injection or the fever that might follow vaccination.3 Healthcare providers can teach the parents that these are mi-nor risks.

State laws also play an important role in vaccination adherence. Vaccination coverage varies with stringency of state laws. Cali-fornia’s senate passed a new bill in 2015 in hopes of increasing vaccination compliance. This bill phased out the religious and philosophical exemption for vaccines that is necessary for chil-dren to go to school. In the first year after the bill’s approval, vaccination rates for kindergarten students increased by 2.8%. In 2014, state officials of Michigan created a policy requiring parents seek vaccination exemption for non-medical reasons to receive vaccination education.13 In Vermont, there has been no option for personal belief exemption from vaccines since 2016.14,15 Overall, Vermont is close to the CDC’s recommended vaccine coverage at 94%. However, there are areas of the state with much lower coverage, and a higher chance of outbreaks.15 Since the elimination of the personal belief exemption, the amount of kindergarten students with a non-medical exemp-tion decreased by 1.8%.

With the possibility of each measles case causing up to 12 addi-tional cases (in a completely unvaccinated population), MMR vaccination rates are undoubtedly important. But when there is such a divide in what parents want for their children, policy makers and healthcare professionals face an urgent challenge and ethical dilemma. What is more important: the individual rights of parents or the health of an entire community? Ac-cording to the CDC and the American Medical Association, vaccinations for all children who can get them are crucial to avoiding the dangers of preventable diseases.15

Despite the evidence of safety of vaccines, there is no sign that anti-vaxxers are changing their minds any time soon. As long as there are outbreaks and disagreement, this issue will remain in headlines. If it is the goal of the medical and public health com-munity to keep the population safe, there is work to be done on educating and convincing them about vaccines.

SCAN FOR REFERENCES

must be vaccinated in order to ensure herd immunity protec-tion from the measles.3

VACCINE HESITANCY SPECTRUM

People have varying degrees of belief in the importance of vac-cines. “Vaccine rejecters” are people who are firm in their an-ti-vaccine beliefs. Others may have concerns about one specific vaccine. “Vaccine resisters” do not currently endorse the use of vaccines, but are open to learning more information about them. Therefore, this is group of people that education should be targeted towards.3 Vaccine hesitancy, on the other hand, is defined as “delay in acceptance or refusal of vaccines despite availability of vaccination services.”6 This allows a distinction to be drawn between parents who choose not to vaccinate their children and parents who lack have access to healthcare ser-vices. Parents may be hesitant to vaccinate their children due to the abundance of misinformation about vaccines that per-meates the internet.3

VACCINE HESITANCY IS DEFINED AS “DELAY IN ACCEPTANCE OR REFUSAL OF VACCINES DESPITE AVAILABILITY OF

VACCINATION SERVICES.”

FACT OR FICTION?

Misinformation includes the claim that vaccines are unsafe and big pharma is poisoning children with aluminum and an-tifreeze. The reality is that aluminum is present only in small quantities and is used as an adjuvant- meaning it increases the body’s response to the vaccine. Antifreeze is not in vaccines.3

Vaccines are safe and their benefits outweigh potential side effects. Vaccines can cause some discomfort including pain, redness, and tenderness at the site of injection.10

A common misconception is that vaccines cause autism. In 1998, Andrew Wakefield and colleagues published articles in Lancet proposing that the MMR vaccine predisposes chil-dren to autism. The “research” evaluated a sample size of 12 children who had developmental delays.10 Susan Wakefield, a writer for psychology today and a former anti-vaxxer says, “Wakefield’s theory made so much sense to me… it gratified my instinctive feelings that autism was unfair for what it did to kids, and that we as a society are so careless with our medica-tions!” 12 Soon after this publication, more research was done to evaluate his findings, which were deeply flawed. Correlation is not causation. Young children get MMR vaccines around the age that they are diagnosed with autism. Additionally, the team chose to study children who would fit the pattern of their data. In 2010, Lancet retracted Wakefield’s publications.10

STRATEGIES TO IMPROVE RATES OF VACCINATION

About 80% of the population regularly searches the internet to find health information, but few talk about their apprehen-

12 | SYNAPSE | SPRING 2019 SPRING 2019 | SYNAPSE | 13SPRING 2019 | SYNAPSE | 13

GRAPHIC/UNSPLASH.COM

Capable of processing information to control emotion, sensation, and movement, the brain is the most complex structure in the human body. The struggle to provide adequate treatment for mental illness reflects the challenges of comprehending the organ’s formation and function. Despite medical advancements pertaining to many physical diseases, those with mental disorders continued to suffer in asylums and hospitals into the 20th century.

With the advent of modern technology and medicine, our understanding of mental illnesses has improved dramatically, creating a burgeoning pharmaceutical market for psychiatric treatment. This growth is essential because neuropsychiatric disorders account for the greatest disease burden in the United States, surpassing every other disease category including cardiovascular disease, cancer, and diabetes.1 Recent estimates indicate that 18.7% of the total U.S. population over the age of

18 suffer from such conditions.2 Furthermore, 70% of suicides result from mental health illnesses such as Major Depression or Bipolar Disorders.3

Although the prevalence and gravity of mental illness in the United States is better understood today than in the past, current mental health treatments are not equally accessible by all, with growing disparities between ethnic and socioeconomic groups.

The Financial Burden of Psychiatric Medicine

Advances in medical knowledge have extended into the field of psychiatry, producing a more informed definition of mental illness and a plethora of pharmaceutical treatment options for patients. Examples of these medications include antidepressants, anti-anxiety medications, and antipsychotics.

BY ISABEL BUCKINGHAM

GRAPHIC/UNSPLASH


The benefits of improved psychotropic treatment options are tempered by inflated health care costs and health inequities. Given the increased utility of complex technology and multiple medications in diagnosis and treatment, the price of healthcare has risen. 40% to 50% of the annual increase in health care spending can be attributed to the augmented prices of biotechnology and medication. The result of these ballooning costs is a higher rate of uninsured U.S. residents.4 11% of Blacks, 19% of Hispanics, and 22% of American Indians do not have health insurance, as opposed to 7% of White Americans.5

Therefore, minority groups in the United States carry the majority of the burden of rising health care costs. A lack of insurance is a substantial obstacle to accessing health care, especially pertaining to the stigmatized arena of mental health medication prescription.

Disparities and Barriers in Mental Health Treatment

In addition to overall health equity being an unavoidable issue in the general health care system, the gap between race and ethnicities in mental health treatment is especially significant. This rising disparity is a result of increased pharmaceutical treatment usage to address mental health options among white — but not minority — populations.8 The root of this burgeoning gap lies in the fact that minorities have considerably less access to medical care. The association between minority status, lack of insurance, and poverty is a valid, and often cited, factor for this discrepancy.8,10

However, even when the socioeconomic status variable was controlled, studies have found that those who were white accessed mental health treatment more often than non-whites.5 For example, three black men for every ten white men will seek or receive relevant treatment.8 The seeking of treatment is a crucial step to access. Black and Asian populations in the United States are less likely to not only receive treatment, but to also pursue it in the first place.5, 7, 8, 10 While blacks cite higher severity and persistence of mental illness, research respondents appeared to rely on alternate treatments involving spirituality, religion, and therapy.8

The rates of reporting mental illness, seeking treatment, and using psychotropics are the lowest for the Asian population in the U.S. in comparison to every other race and ethnicity.11 This issue is rooted in cultural differences and stigma against mental illness. In traditional Chinese and Malay culture, mental illness is perceived as social punishment, spiritual weakness, or a lack of self-worthiness. The discrepancy between cultural values and medical science causes misconceptions; 80% of surveyed east-Asian patients made incorrect claims concerning the role and use of psychotropics, such as medication should only be taken when the patient is symptomatic.11 When seeking care, Asians frequently understate their symptoms8 or rely on alternatives such as meditative or herbal remedies.11

Despite the act of seeking care, disparities may still persist. Minority patients are statistically more likely to be misdiagnosed or underdiagnosed for their conditions, with Asians being the most likely to be misdiagnosed as “problem free.” This has been attributed to discrepancies in reporting, as detailed above, and a lack of cultural awareness and competency in medical providers.9 Other minorities such as Hispanic and

Black populations are also underdiagnosed at a significant rate in comparison to Whites, resulting in a lower prescription rate of medications that could significantly improve their health.8,9,12

The association between mental health and poverty is complex yet clearly cyclical. An individual with mental illness may lapse into poverty due to an inability to function productively. Social dysfunction precipitates consequences such as less educational and/or career advancement opportunities, vulnerability to further mental or physical harm, societal exclusion and isolation, and residential instability. Conversely, an individual in extreme poverty is more likely to develop mental illness due to the same environmental factors. Once in poverty, illness is compounded by a lack of access. Given the aforementioned links between minority status and poverty in the United States, the vicious cycle involving low socioeconomic status and mental illness could potentially impact minority individuals, their communities, and entire populations.8,13

Solutions

The era of enhanced medical technology and pharmaceuticals has the potential to impact and improve the lives of millions with psychoneurological conditions. However, access and attitudes towards psychotropics remain unequal across the bounds of race and ethnicity. Financial constraints, cultural values, physician misdiagnoses, and stigma towards medicating mental illness have all contributed to this growing issue. As pharmaceutical treatment options continue to improve, it is imperative to promote equal access to such medications while also publicizing accurate information surrounding mental health and illness.

Studies have suggested immediate and multidimensional approaches to decreasing, and eventually eliminating, the racial and cultural obstacles that cause disparities in psychotropic prescription disparities. Such strategies include various educational campaigns geared toward specific minorities that inform them of the ways they could access and benefit from treatment. These efforts would also correct common misconceptions concerning psychiatric diagnoses and the utility of medications. At the medical level, healthcare providers can offer cultural competency trainings with a specific focus on recognizing depression and other disorders. At the political level, lawmakers can increase insurance and general healthcare access by allocating funding for continued research, public health measures, and infrastructural development that would cater to the needs of individuals with mental health challenges.8,9

Whether through informative campaigns, continued education of healthcare providers, or policy solutions, prescriptions for mental health must be normalized and made accessible for every individual. In order for the U.S. to progress towards equity in the healthcare sphere and beyond, it is essential for all citizens, regardless of race or income, to have the opportunity to access medications and resources that promote a healthy body and mind.

SCAN FOR REFERENCES


Harnessing

Technology to

Expand Palliative

Care

PALLIATIVE CARE IN A NUTSHELL Unlike most medical approaches, the field of palliative care does not address the underlying disease process. It targets symptoms directly to enhance a patient’s qual-ity of life, regardless of the cause. Symptom management, psychosocial-spiritual support, and assistance in medical decision-making comprise three core aspects of palliative care. Traditionally, palliative care has been associated with those who are dying, but in recent years, the scope has been broadened such that palliative care is offered in earlier stages of disease trajectory.

BENEFITS OF EARLY ACCESS TO PALLIATIVE CARE

Palliative care can be an option for any patient with a chronic life-limiting illness who is burdened by pain and undergoes treatments such as chemotherapy, renal dialysis or oxygen therapy. In contrast, hospice care, which only targets quality of life, is for patients who are no longer receiving curative treatments or have a max-imum of a six-months prognosis. Palliative care is an umbrella term under which hospice and end-of-life care fall when the focus of care shifts according to disease progression. The need for integrating palliative care early after a diagnosis may help dismantle the trend that “modern medicine is good at staving off death with aggressive interventions—and bad at knowing when to focus, instead, on improving the days that terminal patients have left.” Moreover, the medical and palliative care teams can collaborate to monitor changes in a patient’s well-being to avoid execut-ing medical procedures that are doing more harm than good.

By Christeen Samuel

GRAPHIC/PIXABAY


SCAN FOR REFERENCES

Unfortunately, due to the misconception that palliative care is only for end of life or cancer patients, many patients with chronic illnesses, such as heart disease, lung disease, or dementia suffer more than necessary. Palliative care is a holis-tic approach to care that promotes a pa-tient's ability to remain active in import-ant activities and relationships despite a difficult diagnosis. Therefore, in offering early palliative care, primary care provid-ers not only help their patients cope with their conditions, but also maximize their qualities of life.

BARRIERS TO ACCESS TO PALLIATIVE CARE

Americans in rural and underserved ar-eas often struggle to access palliative care.4, 5 A study by Fink et al. found that in 236 Rocky Mountain-area rural hos-pitals, while 99% were familiar with the concept of palliative care, only 56% had access to it. One major reason is that there is a dearth of healthcare profes-sionals with specialized training in palli-ative practices in rural areas.3 Palliative care often involves the use of painkill-er drugs, such as opioids, which have a dosage regimen that constantly needs adjustment as therapeutic goal changes. Furthermore, there is increasing opio-phobia in rural areas, as opioid misuse can lead to addiction.6 Therefore, there is a need to enrich both providers and patients’ understanding and access to frontline knowledge of palliative practic-es, especially related to use of palliative medications.

TELECOMMUNICATION & THE COMING OF AGE OF RURAL PALLIATIVE CARE

How do we achieve the tipping point whereby palliative care advances are widely propagated across both urban and rural settings? Telecommunication has been proposed as a potential solution. For example, a project called ECHO (Extension for Community Health Out-reach) was founded in the University of New Mexico to de-monopolize front-line specialist knowledge and amplify the capacity to provide quality palliative care for rural and underserved people.

Through the use of multisite teleconfer-encing technology, Project ECHO links specialists from a main “hub” with clini-cians in local communities with limited palliative care resources —the “spokes” of the model. Together, the hub and spokes participate in regular video con-ference “teleECHO” sessions that allow for knowledge sharing and mentoring.

Such sessions could cover controversial topics such as the use of haloperidol for nausea and vomiting, the adminis-tration of methadone as an analgesic, and the management of opioid-induced sedation. In other words, “teleECHO” sessions could help new palliative prac-titioners navigate the use of medications with highly-variable and patient-specific pharmokinetic profiles. Altogether, tele-medicine could help promote democra-tization of medical knowledge to ensure that more providers engage in cutting edge palliative practices, regardless of their location or population demograph-ics. EXTENDING IMMEDIATE SYMPTOM MANAGEMENT OUTSIDE HOSPITAL WALLS Another important component of deliv-ering effective palliative care is ongoing symptom assessment and appropriate adjustment of medication doses, which is currently difficult to achieve in homes and outpatient settings. Fortunately, a new movement to use remote symptom monitoring technology shows promise.

Advanced Symptom Management Sys-tem in Palliative Care (ASyMSp) is a mo-bile phone-based symptom assessment technology that allows patients to record information electronically on a range of palliative symptoms. Patients send this information in real time directly to the clinical site, where it can be monitored by expert palliative health professionals. This technology improves patients’ ac-cess to palliative self-care advice from health professionals, helping them avoid drug abuse when they encounter dis-tressing symptoms. McCall et al. (2008) suggests ways to refine this new technol-

ogy, such as including diagrammatic rep-resentation to indicate sites of pain(s) with further ability to record each pain in terms of level of severity.7 In this vein, remote reporting and monitoring facili-tates more nuanced recommendations for pain management, ensuring that pa-tients are able to remain at their homes for as long as possible while receiving optimal care.

MAKING PAIN MANAGEMENT SAFER FOR PALLIA-TIVE PATIENTS

In 2016, the Centers for Disease Con-trol and Prevention classified prescrip-tion drug overdose as the leading cause of injury death. To ensure safer drug use among palliative patients, research-ers have been developing abuse-deter-rent opioid drugs, called prodrugs such as Hydrocodone and Tramadol, which are chemically modified such that they eliminate or reduce euphoria associated with opioid intake.8 Such pharmacologi-cal innovation is meant to prevent drug misuse and to ensure the adherence to treatment by patients receiving palliative care, especially ones in home or out-pa-tient settings. Protecting palliative pa-tients from the risks of drug misuse or addiction is essential to the core premise of palliative care in promoting a patient’s overall well-being.

MAKING PALLIATIVE CARE THE NORM RATHER THAN AN EXCEPTION

Advances in telecare and pharmaceu-tics have the potential to make palliative care accessible across the nation. This is a critical step in making palliative care an integral component of standard care delivery, such that it is the norm rather than an exception. As a society, we will hopefully be able to appreciate that palli-ative care is a multifaceted approach that can range from spiritual support provid-ed by a chaplain to remote monitoring that connects patients to their healthcare providers from the comfort of their homes.


GRAPHIC/WIKIM

EDIA COMM

ONS

Although many mechanistic and ethical questions remain to be addressed, the use of CRISPR-Cas9-based genome technologies will expand our understanding of disease processes and their treatment in the near future. This field is undoubtedly revolutionizing research in our current era and may open new avenues in the treatment of fatal genetic disease.

The gene editing tool CRISPR-Cas9 has revolutionized medical research and created a buzz in the scientific community. It has long been understood that creating a change in a gene, either in a cell line or a whole organism, allows for the possibility to study the effect of that change to understand gene function.1 In the past, geneticists utilized chemicals or radiation to cause mutations. However, they had no control over where the mutation would occur in the genome. The development of CRISPR-Cas9 as a gene-targeting method allows for simple, versatile, and precise genetic manipulation.

Clustered regularly interspaced short palindromic repeats (CRISPR) is an RNA mediated adaptive immune mechanism found in bacteria and archaea. This natural defense system prevents viruses and plasmids from invading these organisms.2 Specifically, Cas9 is an enzyme from the Type II CRISPR system that has drawn the most attention from researchers. Cas9 encodes a guide RNA (gRNA), forms a direct binding to target DNA with the base pairing and promotes its cleavage.2 The host cell responds to this double-strand break with two different mechanisms: (a) nonhomologous end joining (NHEJ) and (b) homology-directed repair (HDR) which lead, respectively, to insertion/deletion and frameshift mutation in target DNA and HDR that offers a donor DNA as template for homologous recombination.1 Cas9 has many applications in genetic engineering such as gene editing, gene expression, and gene functional studies. On the basis of these characteristics, Cas9 has become an attractive potential treatment method of many diseases caused by mutations, including cancer.3

Revolutionizing Genomic ResearchCRISPR-Cas9

WHAT’S NEXT?

By Raveen Kariyawasam and Victoria Siu

18 | SYNAPSE | SPRING 2019

THE PROCESS

MORE CONTENT

Scan to access Augmented Reality (AR) contentUsing the zappar app

GRAPHIC/US National Library of medicine


One of the biggest challenges facing global access to essential medicines is the lack of efficient delivery from one location to another. Every year, pharmaceutical companies subsidize their products so that those in dire need of treatments can receive them. However noble these efforts may be, many of them ultimately fail due to an inability to access remote regions where those most in need of care live. According to a study by the United Nations, the lack of supply chain infrastructure is why over two billion people lack access to essential medicines globally.1 This distribution dilemma, dubbed “the last mile” challenge, is one that nearly any company that deals with the developing world must face. Yet, while most corporations have given up hope, there is one unlikely company that has thrived: Coca-Cola. With over seventy million customers in developing countries, Coca-Cola has succeeded in providing their products to rural regions across the globe.2 As the saying goes, in some places, it’s easier to get access to Coca-Cola than drinking water. If Coca-Cola can be delivered all across the developing world, why can’t essential medicines? That is

the question that governments, public health organizations and pharmaceutical companies are attempting to answer.

ColaLife and The Beginning of a Productive Partnership

Any discussion of Coca-Cola’s impact on healthcare delivery must begin with ColaLife. Almost twenty-five years ago, Simon Berry, the founder of an organization known as ColaLife (an independent organization with no legal association with Coca-Cola), hoped to tackle diarrhea in South Africa.3 To do this, he created the “Kit Yamayo”, or “Kit of Life”, a packet which contained oral rehydration solutions, zinc soap, and educational material. After experimenting with some clever design strategies, Berry was able to create a product that could fit on top of crates of Coca-Cola that were to be distributed globally. In 2012, ColaLife began supplying their kits in Zambia, South Africa, a region where one in four children die of diarrhea annually. In one year, almost 45 percent of the children who needed the kits got access to them.3


In 2013, the kit was featured in the United Nations General Assembly as one of the top ten breakthrough innovations in mother and child health.4 However, when Berry began fleshing out his business model, he soon realized that transporting kits using Coca-Cola crates was too limiting to be applied in the long run. Instead, ColaLife seeked to emulate Coca-Cola’s secret ingredient in distribution: their investment in people.

Coca-Cola directly employs 68,000 people in Africa, but works with up to 10 times more, including independent bottlers, wholesalers, distributors, and shop owners.3 Most of their independent partners are the people who deliver the product the last extra mile. ColaLife has begun creating these same partnerships by signing contracts with local distributors and hiring more locals to inform them about the best methods of getting to specific regions.

Project Last Mile

Organizations worldwide took notice of ColaLife’s success and sought to emulate it on a larger scale. This desire manifested itself into Project Last Mile. Project Last Mile, which launched in 2010, is a groundbreaking public-private partnership among the Coca-Cola Company, USAID, the Global Fund, and the Bill & Melinda Gates Foundation.5 Through this collaborative project, the governments of developing countries can draw from over eighty-five years worth of distribution expertise, marketing experience, and business knowledge that Coca-Cola has accrued to get critical supplies to those who need it. Thus, instead of simply taking Coca-Cola’s supply chain and using it as their own, governments are instead able to leverage Coca-Cola’s expertise to build a supply chain of their own. While the project is currently focused in Tanzania and Ghana, the partnership plans to invest over twenty millions dollars to expand their efforts to over ten countries in the next five years.6

The results thus far have been astounding. In Tanzania, before the project was launched, the government’s Medical Stores Department (MSD) was delivering supplies to 130 medical supply centers at district level and did not facilitate distribution beyond that point.5 As a result, some 30% to 40% of orders from health centers ended up being unfilled.6 By leveraging the expertise of Coca-Cola, however, the Tanzanian government has improved how drugs are supplied. Interventions included training for MSD staff members through courses from the Accenture Supply

Chain Academy. Furthermore, Coca-Cola has facilitated the outsourcing of delivery to third parties that were already shipping goods to remote areas by connecting medical suppliers with local distributors across the nation. Additionally, drugs now reach rural areas through more unconventional means of transportation such as by boat in the rainy season. According to a case study from the Yale Global Health Leadership Institute, while the Tanzanian government’s distribution system doesn’t reach Coca-Cola-like efficiency, it has vastly improved.5 Delivery times have been cut from thirty days to just five.5 In addition, 80% of patients now have access to vaccination, up from 50% just two years ago.5 The availability of medicines have increased by 23% and Tanzania’s distribution system has expanded from 9 zonal and about 400 district drop-off points to direct delivery to more than 5,500 Last Mile health facilities.4

The Future

While Project Last Mile’s success in Tanzania is a great start, there is still much potential for similar partnerships to form elsewhere across the globe. As information regarding Coca-Cola’s supply chain disseminates further and to a greater variety of actors, soon it will be easy for governments and other organizations to gain access to this novel method of supply chain management without necessarily having to work with Coca-Cola themselves. For example, South Africa has launched a project focused on developing pick up points in stores where people could easily and reliably pick up medication orders.3 In Mozambique, outsourced delivery of drugs to third party organizations has helped to supply remote areas with goods. Furthermore, while current initiatives are focused on large-scale collaborations between governments and NGOs, independent pharmaceutical companies may soon jump on board as well in order to extend their global reach. The surprising and unorthodox partnership between health-based organizations and one of the largest private corporations in the world has shed light onto the potential for collaborations between disparate entities. It has taught us lessons that public health has to learn from business practices. This revolutionary model has set the groundwork for future partnerships between the public and private sector in order to make real social change in the world. The progress that has been made up to date is remarkable and an idea of this magnitude has the potential to shift global healthcare delivery on a much larger scale.

GRAPHIC/UNSPLASH.COM

SCAN FOR REFERENCES


Wearable technology, or wearables, refers to all smart electronic devices that can be attached to the body as an accessory or article of clothing.1,2 Despite the origins of wearable technology dating over twenty years, it was not until the current decade that technological evolution further enabled the design of higher-functioning smartwatches with more elaborate interfaces.3 In 2014, several tech giants including Google, Apple, and Samsung unveiled groundbreaking new smartwatches.2 Many of their latest innovations enhance the growing field of digital health by integrating digital technologies and healthcare to enable better health outcomes.4 More specifically, smartwatches are incorporating functions that monitor medical conditions as a preventative measure to combat health risks and potentially save lives.

Atrial Fibrillation

One such health risk is atrial fibrillation (AF). AF manifests itself as an irregular, and often rapid, heart rate as a result of uneven and chaotic beating of the atria. During an episode, an afflicted patient may experience heart palpitations, shortness of breath, confusion, and overall weakness. AF can lead to complications including blood clots in the heart, heart failure, and stroke. If left untreated, AF doubles the risk of heart-related death and increases the risk for stroke five-fold; nonetheless, only about 33% of patients consider AF a serious

condition.5,6 Diagnosis of AF relies on the results of a standard electrocardiogram (ECG) during a suspected episode. Thus, it can often be difficult to confirm the diagnosis during the limited time frame of a physician visit. Moreover, a significant portion of patients who do not show any symptoms and only face sporadic episodes are likely to be unaware of their condition unless a physician discovers it by chance or following an AF episode that induces obvious or life-threatening complications.7

Detecting AF with the Apple Watch

To improve early detection and diagnosis of AF, we need new devices that can conveniently conduct an ECG without the presence of a physician. In comparison to readily available, portable heart rate monitors, new smartwatches have an advantage in internet connectivity that enables easy transfer of locally collected health data to doctors. The Apple Watch Series 4, launched in September 2018, features an on-demand active ECG monitor in addition to the passive heart rate monitor from the older generations.8,9 The titanium electrode at the Digital Crown of the Watch and the sapphire crystal at the back can read the electrical heart impulses in the wearer’s fingertip and wrist, respectively.10 To start taking an ECG, the wearer needs only to touch the Digital Crown for 30 seconds. If the electrodes detect an irregular heart

rhythm, the ECG app immediately alerts the wearer. Moreover, the Apple Watch automatically stores all ECG readings, waveform classifications, and related data in the Health app on the user’s iPhone. The user can then easily share the data with any doctor and receive pertinent medical advice.11

In January 2019, about one month after the new Apple Watch’s ECG app and irregular heart rhythm notification went live,12 Johnson & Johnson (J&J) announced a collaboration with Apple. Together, the two companies have planned to launch a multi-year research project in 2019 to assess the effectiveness of the Apple Watch Series 4 and an accompanying patient engagement app developed by J&J in detecting and diagnosing AF to improve cardiovascular outcomes.13,14

Excitement and Pioneer Studies

The partnership between Apple and J&J is not the first time that Apple has teamed up with medically-focused organizations to participate in consumer-based research on the role of the Apple Watch in health monitoring. In late 2017, Apple launched a joint r e s e a r c h study,

CAN A WATCH SAVE YOUR

DETECTING ATRIAL FIBRILLATION

WITH THE NEW APPLE WATCH

LIFE?BY ISABELLA WANG

22 | SYNAPSE | SPRING 2019 SPRING 2019 | SYNAPSE | 2322 | SYNAPSE | SPRING 2019

SCAN FOR REFERENCES

named the Apple Heart Study, with Stanford Medicine to assess whether an already developed app could accurately detect irregular heart rhythms and notify wearers experiencing AF. Unlike the most current model that has electrodes inserted into the Watch’s Digital Crown, the older model tested in this study read and calculated heart rate and rhythm by emitting LED light from the back sensor and detecting the amount of blood flowing through the wearer’s wrist.15 The study began in 2017, entered its final phase of data collection in late 2018, and was projected to conclude by January 2019.16,17 Because the passive monitoring technology under assessment is still used in Series 4 to assist AF detection, findings from this study will still have significant and relevant implications.

Amidst the excitement, prospective wearers should remain cautious about the watch’s detection accuracy and conclusions. In one study with more than 580 participants, for nearly 10% of all trials conducted, the app was unable to read the heart rhythm recordings conclusively. Nonetheless, at other times, the app reported the correct result whether or not the user had AF, 98% of the time for people previously diagnosed with AF and 99.6% of the time for those without AF.18 The first peer-reviewed study that used an app installed on the Apple Watch to detect AF found that the algorithm of the app was 97% accurate in identifying AF episodes.19

Concerns and Skepticism

Although several pioneer studies have

demonstrated the app’s high accuracy, some question the usefulness of ECG examinations for asymptomatic patients. While such practice has become a regular feature of annual physicals, the U.S. Preventive Services Task Force released a statement in June 2018 pointing out the poor cost-effectiveness of mass ECG screening to prevent cardiovascular diseases (CVD) in asymptomatic adults at low risk and thus recommended against it. The Task Force also reported that data regarding ECG screening in CVD prevention, even for people with high- or intermediate-risk, are still insufficient to prove the practice’s cost-effectiveness.20 Two months later, in a separate statement focusing specifically on AF, the Task Force reached a similar conclusion: the existing evidence was inadequate for proper evaluation of the net benefit of ECG screening for AF prevention.21 Despite skepticism from some medical experts, very few studies have investigated the cost-effectiveness of extensive ECG screening in detail.

Other concerns have been raised about the vast difference between the age distribution of people with AF and that of wearable technology users. In the U.S., while adults younger than 55 make up over 90% of all users of wearables like the Apple Watch,22 the prevalence of AF in this age group is only 0.1%, as

compared to 3.8% among those 60 years or older and 9.0% among those 80 years or older.23 Therefore, most existing Apple Watch users, who are at low risk for AF, would likely receive limited benefits from the watch’s on-demand ECG capabilities.

Looking Towards the Future

Despite current doubts, leading technology firms and pharmaceutical companies remain optimistic about the life-saving potential of the new ECG-equipped Apple Watch. “I believe, if you zoom out into the future, and you look back, and you ask the question, ‘What was Apple’s greatest contribution to mankind?’ it will be about health,” said Apple CEO Tim Cook during an interview on CNBC in January 2019. While much more research is needed, it is clear that wearable technology will continue to gain increasing importance in health care. As exciting partnerships form between innovative technology firms and pharmaceutical companies, collaborations will blend the disciplines of health, technology, and medical informatics.

DETECTING ATRIAL FIBRILLATION

WITH THE NEW APPLE WATCH


GRAPHIC/BRIAN SONG

Advent of the Debate on Regulation of Pharmaceuticals

Imagine attending a doctor’s appointment in the United Kingdom (U.K.) and receiving a prescription for Cymbalta at $46 per month to treat your chronic depression. The following week, you try to redeem the same prescription in the United States (U.S.), but now the cost of Cymbalta is $194, more than four times the price you had paid in the U.K.1 This discrepancy in prices has led to great debate in the U.S. and has pushed the public to question why the government is not involved in the regulation of pharmaceutical prices.2 Comparisons to the drug markets of other first world countries make many question why the U.S. does not regulate drugs as a public utility and aim to make treatment accessible to everyone. How the U.S. market deals with pharmaceuticals and

how potential regulation could directly and indirectly affect the biotech and pharma industries provide an important area of study.

Introduction to the US Market

One of the largest questions facing U.S. pharmaceutical companies revolves around balancing the prices of current, accessible drugs with investments in research to develop new medications to help future generations. Advancing medical science remains a priority for millions, but what happens when the products of this research slowly become less and less accessible to the general population due to the decreasing revenue of pharmaceutical companies? Allowing unregulated access to prescription drugs and medical aid has proven to be a difficult task, even for the most developed nations such as the U.S. Finding this equilibrium between innovation and affordability is an ongoing debate.3

Currently, the U.S. market imposes no regulations on the prices of drugs. The prices of drugs are determined solely between pharmaceutical companies and insurance providers.4 However, the power in this two-way negotiation often lies in the hands of the pharmaceutical companies. Consequently, prices soar for prescriptions drugs.

Drug prices are higher in the United States than in other industrialized countries because the U.S. healthcare system allows drug manufacturers and

overarching corporations to fix their own price for a given commodity.5

To effectively understand the inability to negotiate prices in the U.S. healthcare system, we should consider how prices are regulated by insurance companies and individuals under Medicare and Medicaid. When dealing with Medicare, the public health insurance provider for the elderly, insurance companies are required to incorporate prescriptions across the spectrum, from antidepressants to immunosuppressants, but are unable to negotiate prices at the federal level. With Medicaid, the government’s universal healthcare insurer for low-income groups, there are previously mandated discounts already instituted.6

In contrast to the U.S. system, the entire U.K. is subject to a universal regulated system, an assigned, delegated body that negotiates drug prices or rejects coverage of products if the price demanded by the manufacturer is excessive in light of the benefit provided.7

Recent Examples Affecting the Market

“If the drugs are so expensive that you can’t afford them, that’s functionally the same thing as not even having them on the market.” --Aaron Kesselheim, an associate professor of medicine at Harvard Medical School12

By rohan vemu

A Problem Concerning the Biotech and Pharma Industries

Regulation of Prescription Drugs

GRAPHIC/UNSPLASH

GRAPHIC/EMILY XU

Business

24 | SYNAPSE | SPRING 2019 SPRING 2019 | SYNAPSE | 2524 | SYNAPSE | SPRING 2019

In recent history, two products have instigated large backlash at the U.S. market’s lack of regulation: Sovaldi in 2013 and Humira in 2015. Sovaldi’s manufacturer Gilead, like many other drug companies, set an extremely high price of over $80,000 for this revolutionary hepatitis drug.8 Similarly, Humira, a medicine prescribed to treat arthritis and psoriasis, was marked up to $2,300 in the US alone. Humira is one of the most commonly prescribed medications and the lack of regulation has brought it to the forefront of criticism.9

Effect on the Pharmaceutical and Biotechnology Industries

“As you decrease the potential profits I’m going to make from pancreatic cures, I’m going to shift more of my investment over to apps or just keep the money in the bank and earn the money I make there,” --Craig Garthwaite, a professor at Kellogg School of Management12

Due to the backlash directed by the public towards large pharmaceutical companies because of high-priced drugs like Sovaldi and Humira, the negative implications of government regulation on the pharmaceutical and biotechnology industries are frequently overlooked.

By fixing their own high prices, pharmaceutical companies can maximize their profits and revenue. However, with government regulation and markdown of these prices, the pharmaceutical companies would earn lower revenues. Often, the profits accumulated from selling other products are channeled into the research and development divisions of a large company.10 Without these regulations, more money would be invested into developing drugs, prompting the question of whether the general populace is partially misguided by their preference for immediate, inexpensive health care that limits the possibilities of future innovation.

Consequently, with this lack of money entering the R&D sector, biotechnology investors would have minimal significant economic incentives and remain reluctant to invest their money and time into these private companies. In addition SCAN FOR REFERENCES

to disincentivizing investors, potential startups seeking to market their new drug technologies would be hesitant to enter the public market, knowing that their revenue will be throttled by government regulations on their product.

Every policy decision comes with benefits and drawbacks, a fact that rings true in the debate over the regulation of prescription drug prices. If the United States started to put price controls on drugs, medications would become universally less expensive and more accessible, but with a significant drawback: the potential for future innovation declines.

Potential Solutions

American health care providers and pharmaceutical companies are taking advantage of the American public because of our extremely fragmented healthcare system. Nevertheless, it seems difficult to propose an effective solution to combat the problem of inflated prescription drug prices. The U.S. could potentially look towards the healthcare systems and modes of regulations in the U.K. and Australia as an alternative to the current system. However, ingrained in U.S. culture is the need and obligation to continue innovating and finding new solutions regardless of its effects on the current market and attempting to impede this progress and strike a balance between innovation and reason will prove more costly than beneficial for the general U.S. population.

GRA

PHIC/U

NSPLA

SH

24 | SYNAPSE | SPRING 2019 SPRING 2019 | SYNAPSE | 25SPRING 2019 | SYNAPSE | 25

approved along the way.2,3,4 This reality is undeniably unfortunate for sufferers of rare diseases, which do not promise large financial returns for their drug de-velopment.

In order to keep their profits high, pharma companies target diseases that will have large drug markets and generate massive returns to recoup the initial investment costs. Despite the fact that pharmaceu-tical companies have the infrastructure and expertise to successfully produce drugs for many infectious diseases, they often enter more profitable markets with large populations of patients, such as HIV and hepatitis C.7 With the lengthy clinical trial process, companies spend an average of 12 years developing a drug af-ter identifying its target, so they are pres-sured to pick products that will provide profits that compensate for years of re-turn-less investment.6 Additionally, there are several other financial disincentives associated with antibiotics in particular. The population of people who are affect-ed by drug-resistant infections is small, there is intense competition with generic products that cost far less, and antibiot-ics are categorized as extra costs rather than reimbursable ones by the Diagnosis Related Groups classification.16

The U.S. spends an enormous amount of time and money working to improve hu-man health through research and devel-opment (R&D). In 2016, $171.8 billion was put into medical health research by private industry, the federal government, universities, foundations, and other or-ganizations.1 Over half of that, however, came from the biopharmaceutical indus-try (“pharma”), which sponsored 52.3% of spending compared with 21.9% spent by the U.S. government. While great strides have been made in improving treatments for diseases such as cancer and cardiovascular disease, financial disincentives have typically dissuaded pharma from focusing on rare infectious diseases or antibiotics research. Conse-quently, R&D surrounding these mala-dies is often spearheaded by government agencies such as the U.S. military.

The reasons for pharma’s limited spend-ing in these sectors are sensible financial-ly. Massive pharmaceutical companies want to maximize revenues and mini-mize costs to generate optimal profits. Although leading pharma companies generate annual revenues exceeding $50 billion, the cost of producing one singu-lar approved product is approximately $2.6 billion and companies face a 90% risk that a given drug product will not be

In addition to the financial risk, there are logistical complications that make rare infectious diseases and bacterial in-fections less desirable targets. For one, these diseases are prominent in devel-oping countries that are unlikely to have the proper infrastructure to distribute pharmaceutical products.8 The sup-ply chains in these countries often lack proper economies of scale, struggle to overcome long procurement timelines, and face information gaps between local pharmacies and distributors at the top of the chain, which impacts forecasting needs. Pharma companies also know that patients affected by these diseases or in-fections may not be able to pay for these interventions and are likely in conditions of poor sanitation and nutrition.9

Such realities have prompted shifts in the industry. Major players like Novartis, AstraZenica, Allergan, and Sanofi have all exited the antibacterial and antiviral space, the goal of which was to develop antibiotics to address current and future threats of a “superbug” disease.10 This reduced focus on antibiotics, in addi-tion to undiversified infectious diseases research, could have severe global con-sequences. While it’s important to note that companies like Merck have contrib-uted cures for diseases like river blind-

The Military Funds Disease Solutions that Pharma Won’t Address

Drugs and Defense

BY RYAN LEONE


ness and that other companies have put some work into researching malaria, tu-berculosis, and leishmaniasis, these few examples of them taking on “unprofit-able” diseases are not enough to develop widespread solutions.19,22

Fortunately, another source that surpris-es most people has put funds towards this work: the U.S. military.

The U.S. Department of Defense (DoD) provides medical care for over 9.4 mil-lion beneficiaries, accounting for ap-proximately $50 billion, or 8% of its overall budget.13 With the responsibility to care for so many people, it becomes less surprising that the DoD would put money towards medical research. But why would the military choose infectious diseases and antibiotics to be areas of re-search?

The answer is that these areas have im-plications for national security. With troops in dozens of countries around the world, American lives are put in the same circumstances as local civilians within those developing nations. If ser-vice members were to become afflicted by a rare infectious disease or a drug-re-sistant infection, the DoD would want to be able to treat them effectively, so that their ability to protect our nation at home and abroad is not comprised.14 Additionally, some contagious or deadly pathogens could be utilized in biological warfare attacks.15

Historically, the military’s research has led to a variety of critical developments. Beginning in 1777 with its work to devel-op a vaccine for smallpox, the military has brought forth treatments or vaccines for yellow fever, typhoid, hepatitis A, adenovirus, Japanese Encephalitis, and rubella.12 Today, it continues to lead the way in research, addressing illnesses like malaria, Zika virus, and Ebola.11 From using recombinant proteins to target malaria parasites to testing tetravelent recombinant attenuated vaccines for dengue and conducting early phase trials of vaccines for enteric diseases, the mili-tary has continuously worked to develop solutions to a variety of conditions.5

With this proven track record of success, the military is poised to continue finding solutions to global health problems. It

conducts this research through an over-arching program, the Military Infectious Disease Research Program (MIDRP), which has over 300 researchers work-ing to develop preventive measures and treatments for diseases.18 Within MID-RP, a variety of centers exist, including the U.S. Army Medical Research In-stitute of Infectious Disease, which has served as the “birthplace of medical bio-defense” since its inception in 1969, and the Walter Reed Army Institute of Re-search, which was founded in 1893 and has its own Center for Infectious Disease Research.17,20 Beyond these centers, the Defense Advanced Research Projects Agency has a Biological Technologies Office with a budget of nearly $300 mil-lion that works to provide grants which subsequently de-risk early investment in disease or biotechnology research for other companies.21

Despite this expansive array of research institutions, the military can’t do this all on its own. For example, the Army leads the way in these research areas and receives $70 million in funding, which is less than 2% of the budget the NIH puts towards infectious disease and im-munology research.18 Pharma must be willing to sacrifice some of its profits to benefit those in need, something it can do by heightening its collaboration with the military.

While it’s unfortunate that large phar-maceutical companies are incentivized to prioritize profit over impact in the case of products like antibiotics and in-ternationally-focused vaccines, it is reas-suring to see that the military has worked relentlessly to bridge the gap. Whether its intentions are to care for deployed soldiers, to protect against domestic ep-idemics, or to provide a strictly humani-tarian service, the efforts of the U.S. mil-itary to research interventions for these widespread diseases are commendable. Going forward, it is crucial that phar-maceutical companies work on expand-ing public-private partnerships with the military to share their expertise and re-sources for the betterment of patients world-wide.

GRAPHIC/PIXABAYSCAN FOR REFERENCES


Advancements in hospital price transparencyBY SARAH DEVLIN

BY JESSICA TANG

Most people at some point have encountered the frustrating obscurity of hospital billing. Hospitals often cannot provide cost estimates before a scheduled visit or procedure, only sending bills afterwards that can be surprisingly high even to patients with health insurance. A recent JAMA Internal Medicine study, in which researchers posed as grandchildren seeking information for a grandparent about a primary hip replacement, a common procedure, found that only 21% of hospitals surveyed could provide a complete price estimate.1 In an effort to address the issue of hospital price transparen-cy, the Centers for Medicare and Medicaid Services (CMS) mandated that after January 1, 2019, all hospitals publish price lists, also known as “chargemasters,” for every proce-dure, service, and medication offered.

The mandate is just one part of the CMS’s greater effort to increase healthcare cost transparency. Other regulations pro-posed by the CMS have targeted drug pricing, both requiring pharmaceutical companies to disclose the list price of drugs in direct-to-consumer ads, and health insurance plans to in-clude drug pricing information and formulary alternatives in the explanation of benefits.2 Last August, at a press release announcing the hospital price transparency mandate, the CMS stated that the policy will “further advance the agency’s priority of creating a patient-centered healthcare system by achieving greater price transparency...so that patients have what they need to be active healthcare consumers.”3

THE ROAD TO TRANSPARENCY

There has been a growing demand for healthcare price trans-parency. In 2014, the Government Accountability Office re-leased a report calling on the CMS to take action towards improving cost information for patients.4 Several states, in-cluding California and Colorado, have preceded the federal initiative by requiring hospitals to disclose prices for common services.5 Private companies that market price transparency tools have also noticed a window for business, although these rapidly growing organizations have their own transparency issues.6

The demand has been partly driven by shifting attitudes about convenience and control in the digital age. Whereas people can readily find cost information online for many oth-er types of products and services, patients have limited ability

to shop for healthcare quality and value due to the lack of transparency.

The key drivers for price transparency, however, have been rising healthcare costs and the closely intertwined trend to-wards a market-based healthcare system. In a 2014 JAMA editorial, Princeton political economist Uwe E. Reinhardt explained how in order to “gain better control over the growth of their health spending, employers have of recent resorted to a technique long recommended to them by the market devotees among health economists, namely, putting the patient’s ‘skin in the game,’ as the jargon goes.”7

Placing the responsibility of utilizing healthcare services cost-efficiently on patients has meant insurance structures like high-deductible health plans, which require patients to pay more out-of-pocket health costs before the insurance coverage kicks in.8 High-deductible health plans are often coupled with health savings accounts, which let patients pay out-of-pocket costs with pre-tax dollars, in employer-spon-sored market and insurance exchanges. The Affordable Care Act, by emphasizing insurance “marketplaces” (also known as exchanges) has set the country “firmly on the path to a new paradigm of healthcare commerce.”9 In order for pa-tients, or consumers in this new paradigm, to make informed purchasing decisions, they have to be armed with more trans-parent cost information.

IMPLEMENTING THE MANDATE

Although the need for transparency is clear, the CMS mandate has its shortfalls. First, it requires that chargemaster rates be pre-sented in machine-readable Excel spreadsheets that would be difficult for any layperson to interpret. The spreadsheet posted by the Hospital of the University of Pennsylvania, for example, contains more than 14,000 entries of eight-digit procedure codes associated with abbreviated procedure names and the charges.10

Additionally, the chargemaster rates are often not what patients, particularly those with insurance, are liable for at the end. Earlier in 2018, the American Hospital Association (AHA) released an issue brief warning that upfront pricing information has limited utility, as patients have different levels of insurance coverage and receive hospital care tailored to their individual needs.11


The shortfalls of the CMS mandate may also increase discussion about one cause for the obscurity of hospital billing - the hospi-tal insurance negotiation process. Healthcare billing expert and professor at Lehigh University, George Nation, has suggested that instead of posting chargemasters, hospitals should publish prices that reflect the average reimbursement they accept from insurers.12 However, private insurers work with hospitals to ne-gotiate lower rates from the chargemaster set point, and those negotiated rates are generally viewed by hospitals as a trade se-cret.

MOVING FORWARD

The chargemaster is only the starting point for improving healthcare cost transparency. Among healthcare stakehold-ers and policy analysts, there are many perspectives on the next steps that should be taken.

For hospital and health system leaders, the CMS mandate has highlighted the need to educate their providers and staff on how to discuss healthcare costs as information becomes more accessible to patients. In a 2017 survey, over one-third of providers reported that they never talked with patients about their ability to pay before delivering healthcare ser-vices.13 Physician inexperience with having conversations about cost can hinder hospitals’ efforts to increase price transparency.

For policy analysts, hospital cost transparency brings up questions concerning the amounts that hospitals are actually charging. Kaiser Health News examined the price lists of the largest acute care hospitals in several large cities, including Los Angeles, New York, and Atlanta. They found that pric-es vary widely, even for some basic services in nearby hos-pitals in the same city. The price of a complete blood count with differential could range from $59.86 to $525.46, and the price of a semi-private room could go from $1,910.00 to $9,375.00.14 Many hospitals have pages on their websites ex-plaining what goes into a price, such as administrative, equip-ment, and technology upgrade costs. Growing awareness of the variations in price may lead to increased public scrutiny of hospitals with higher price listings.

Economists and healthcare policy experts at the Federal Trade Commission have also noted that greater transparency cannot be a substitute for competition in healthcare.15 En-abling patients to better shop around for healthcare services may help to promote savings and quality improvement, but only if meaningful competition already exists and the mar-ket for healthcare is not monopolized. Given the rising levels of industry consolidation, and mounting evidence showing that consolidation leads to higher prices, the benefits of cost transparency may be limited.16

BROADER IDEOLOGICAL CONCERNS

From a broader standpoint, the issue of price transparency brings up ideological questions. Although most people de-

sire greater transparency, there are differing views on the type of healthcare system in which it should feature. For Seema Verma, CMS administrator for the Trump admin-istration, increasing cost transparency in a market-based healthcare system would help “activate patients to be con-sumers,” whereas universal healthcare in the form of a pro-posed Medicare-for-All system would be the antithesis to pa-tient-centric care, “giving the government complete control over the decisions pertaining to your care, or whether you receive care at all.”17 For others, the nomenclature shift from “patient” to “healthcare consumer” is an ethical issue. “A patient deserves healthcare as a right,” Leana Wen, current president of Planned Parenthood, wrote in Psychology To-day, “But does a consumer?” These proponents of univer-sal healthcare would argue that cost transparency should go hand-in-hand with a more socialized system of healthcare, as it does in other countries like Sweden and France.

At the end of the day, increased healthcare price transpar-ency is an important step towards improving the quality and value of healthcare, but as a country we will have to decide which type of healthcare system it would work best in.

Price Range of a Semi-Private Room

Los Angeles

new york

Atlanta

keck hospital of usc

kaiser permanente -los angeles

cedars-sinai medical center

grady memorial hospital

new york presbyterian hospital

$2,858

$3,407

$8,534

$1,910

$9,375

SCAN FOR REFERENCES

GRAPHIC/ALICIA GO


GRAPHIC/PIXABAY

Financial capital is the umbilical cord of the biotech industry. As bioscience innovation accelerates faster than ever before, the ability to effectively fund innovation is growing into a monumental concern. With venture capital (VC) firms changing their investing patterns, limited funds are affecting stakeholder interactions with startups and creating a shift in the approaches founders are taking to obtain necessary capital.

All things considered, we are in a new period of the biotech startup revolution—parallel to the mid-1970s that was spurred on by the founding of Genentech and Cetus, now a part of Novartis.1 However, recovery after the market crash in 2008 proved to be difficult for startups with investments dropping in the 2008-2012 period. This drought period transformed market interactions and the business to investor relationship, ultimately opening the industry to greater public engagement. Due to the rapid rate and powerful impact of biotech innovation, analysts at Grand View Research, Inc. expect the global biotechnology market to reach $727.1 billion by 2025 with an annual growth rate of

7.4%.2 The prospects for the industry look promising, but it is crucial to look beyond surface statistics and analyze the impact that investment trends have on the delicate balance between innovation and capital.

THE BIOTECH STARTUP

Biotech startups are distinct from those in other industries. Firstly, biotechnology is a high-risk, high-reward business, and the market is notorious for operating under a boom and bust cycle. Unlike software development or engineering startups where prototypes can be built with limited funds, a viable biotech product requires years of research and development with large upfront costs. Furthermore, very few products pass stringent regulatory hurdles, meet consumer demand, and gain market access.3 This challenge applies greatly to medical biotechnology products, including drugs, as analysts estimate that 85% to 95% of all prospective new drugs fail to reach approval.4 The lean startup approach, which is based off of shorter product development cycles and iterative product releases, also cannot be used in the context of biotech startups,

as products need to be fully developed before entering the market.5

Financing Paradigms

Venture CapitalFrom the private sector, startups generally rely on a variety of funding mechanisms from university grants to venture capital. Venture capital (VC) firms are institutions that invest high risk capital into companies they believe have growth potential in exchange for equity. VCs receive a sizable portion of a company’s ownership, granting them influence over operational decisions.

Biotech startups observed a record breaking investment from VCs in 2017 with global VC backing reaching $10 billion. 8 months into 2018, VC investments in biotech surpassed that number with $11.47 billion: more than the total capital invested in global biotech in 2012, 2013, and 2014 combined.6

Despite the grandiose numbers and trends, Bains et al. (2014) claim that biotech startups looking for early funding

Funding InnovationTHE BIOTECH STARTUP ENVIRONMENT

By Charitha Moparthy

30 | SYNAPSE | SPRING 201930 | SYNAPSE | SPRING 2019

SCAN FOR REFERENCES

GRA

PHIC/RAVEEN

KARIYAW

ASA

M

can expect little support from VCs in the future.7 While VCs are pouring more funds into biotech, it appears that they are writing substantial checks to a smaller number of companies.8 Mega- rounds, fundraising rounds of $100 million or more, have grown 39% since 2017 resulting in the drastic increase of VC investment.9 The rise in VC investment is also attributed to a strategy where large investments are made into a company before an initial public offering (IPO) in order to raise the company’s valuation on the market. Analogous to the biotech industry itself, these trends can be described as high risk and high innovation. If VCs are pouring more capital into startups, select companies will have greater capacities to develop products and start projects. Nonetheless, because fewer companies have been receiving these opportunities, the vast majority of startups are not reaping larger investments and therefore lack a critical driver for innovation.

Equity CrowdfundingWith the launch of Kickstarter in 2009, the popularization of equity crowdfunding has enabled startups to launch campaigns to a broader groups of investors. Biotech startups, in an attempt to rely less on VCs, are launching crowdfunding campaigns like Capital Cell, which focuses exclusively on biotech.

Many question the effectiveness of equity crowdfunding in attracting investors and raising large quantities of funds due to the high risk and long-term nature of biotech products. However, the faster rate at which capital is raised can catalyze the progress of startups just beginning their journeys. Investigations by Kaminski et al. (2019) even indicate that there is a long-running correlation between crowdfunding and VC investments, as successful crowdfunding campaigns on Kickstarter have resulted in increased VC investments.10

Impact InvestingWith investors like the Gates Foundation entering the biotech realm, startups are being encouraged to utilize private technology to tackle public problems concentrated in developing countries or amongst vulnerable populations. Investors make contributions known as impact investments, harnessing capital

that is injected into companies with the intention of generating social impact alongside financial return. In 2017, the Gates Foundation committed $167 million to 14 biotech investments to increase the chances of a hit on vaccines and drugs for diseases such as malaria, HIV, and typhoid.11 These investments are controversial amongst venture capitalists, who are disinclined to support biotech startups that divert resources from potential blockbusters towards products for which no developed world market exists.

Balancing FInancial risk and Innovation

Changes in VC financing and growth in the biotech market leave startups with space for immense growth, but with limited funds and a hypercompetitive environment, companies will need to employ innovative means to achieve their goals. In the first half of 2018, the biotech startup environment saw rigorous consolidation with 247 mergers and acquisitions deals accumulating to $175.9 billion with Takeda Pharmaceutical’s $62 billion agreement to acquire Shire headlining news.12 Mergers and acquisitions decrease research and development costs along with competition, but may also slow down progress. Acquisitions create enormous debt for companies, often translating to a reduction in operating costs and the laying off and termination of duplicate projects.

From a business standpoint, a merger secures a startup's financial status, but there is a conflict of interest with accelerating growth. However, some may argue this is beneficial as innovation is outpacing investment of financial capital. The inconsistent goals of stakeholders such as consumers, businesses, and governments add an additional layer of repulsion between balancing risk and nurturing novel biotechnologies. The biotech environment has yet to establish a symbiotic relationship between finance and innovation, but with a growing market and new forms of investment, we are approaching a new horizon with endless possibilities.


Imagine an arm patch that could painlessly draw blood through the skin using microneedles, analyze that blood to determine how much of a particular drug to deliver, and communicate those results to a patient’s doctor.1 This seemingly far-fetched idea became the genesis for the biotech, Theranos. The company’s technology enticed investors and retail partners so much that it was valued at more than $9 billion dollars at its peak.1 However, everything came crashing down when investigative journalists revealed a glaring problem: the technology didn’t work.3

THERANOS

By the start of the 21st century, Apple had revolutionized personal computing and the tech industry. Silicon Valley was not only abuzz with interest in Apple products but also its founder Steve Jobs’ unique backstory and personality: a college dropout with an intense fixation on quality and perfection. Elizabeth Holmes was one of the many inspired by Jobs, but one of the few that could achieve his level of success. Like Jobs, Holmes dropped out of college, leaving Stanford in 2003 to start Theranos. Theranos, a combination of the words “therapy” and “diagnosis”, received initial success through Holmes’ ability to entice family connections

and venture capitalists to invest in the company.1 One year later, Holmes had raised nearly $6 million and Theranos’ scientists directed their attention to transforming Holmes’ idea into a real product.

The Technology

Holmes and her team quickly realized that her original idea for an adhesive patch that could perform the wide array of diagnostic tests she wanted bordered on scientific fiction.1 Looking for a more realistic goal, they scrapped the patch idea in favor of a cartridge-reader system, similar to the

How a Promising Idea Ended in Criminal Charges

By Evan Jiang

Image/PEXEL

graphic/raveen kariyawasam

32 | SYNAPSE | SPRING 2019

handheld blood glucose monitors of the time. Patients simply needed to prick their finger and place a small sample of blood on a cartridge the size of a thick credit card.1 The cartridge would be inserted into the reader and blood would be pumped through the machine and analyzed through various tests within the machine itself.1 The reader would then be able to send those results wirelessly to the patient’s doctor, who could then adjust the patient’s medication in real-time.1 Everything Theranos envisioned for its blood testing machine was theoretically possible: all the technology they needed already existed, they simply needed to make it smaller. However, this meant Theranos scientists would need to miniaturize not one, but dozens of pieces of lab technology. If this wasn’t enough trouble, Holmes’ insistence on some aspects of the machine’s design made development even more challenging for scientists. Holmes’ original idea for this blood-testing system supposedly stemmed from a childhood fear of needles, thus motivating her immovable stance that the machine require only a small amount of blood to function.1 This made life hard for the scientists. For the instruments in the machine to do their job , a certain volume is required to produce a reading.1 Thus, in order to meet this requirement, the small amount of blood inserted had to be significantly diluted, resulting in inaccurate readings.1 Furthermore, Holmes prioritized the machine’s size over how the individual components functioned, frustrating some Theranos scientists who saw this as “putting the cart before the horse”.1 Overall, as Theranos continued to grow in revenue, the product that it marketed could only be described as “a work in progress”.

The Culture

As Theranos scientists continued to be stumped by trying to resolve the accuracy of their readings with Holmes’ unwavering demands, another storm was brewing within the company. While many investors were captivated by Holmes’ drive and ambition, her attitude towards employees and leadership in the company

bordered on autocratic. Information was on a need-to-know basis and only Holmes and her business partner, Ramesh “Sunny” Balwani, seemed to know all the secrets.1 Communication between closely related departments like the chemistry and engineering teams was discouraged, which not only decreased productivity but also didn’t sit well with many employees.1 This wasn’t even the worst aspect of Holmes and Sunny’s management style. Any employee who was deemed not one hundred percent dedicated to the company was alienated and eventually fired. The revolving door of Theranos

So where did Theranos and Holmes go wrong?

ushered in new recruits and pushed away long-time employees at an incredible rate, with many employees leaving because they either could not stand the toxic culture of Theranos anymore or they incurred the wrath of Sunny or Holmes.1 The most startling case is that of Ian Gibbons, one of first scientist Holmes hired when Theranos launched back in 2003.1 By 2010, Gibbons had become frustrated with Holmes’ demands, management style, and “loose relationship with the truth”, and complained to a colleague.1 However, what was meant to be a private conversation was reported to Holmes and Gibbons found himself fired the next day.1 Surprisingly, other colleagues managed to convince Holmes to reconsider and Gibbons managed to keep his job but was demoted from his position as the chief scientist.1 Unfortunately, Gibbons took this demotion hard and in the ensuing years, he fell into a deep depression and ended up committing suicide.1 Although not every former employee of Theranos has such a dramatic story, many would agree that Holmes and Sunny created a toxic culture that aided in Theranos’ downfall.

The Downfall

A decade after its inception, Theranos had already courted many pharmaceutical

companies and retail partners but had yet to deliver on its revolutionary blood-testing device.1 Despite the company’s growing net worth, Holmes’ deception and discontent from current and former employees eventually reached a tipping point. In 2015, John Carreyrou of The Wall Street Journal received a tip to investigate Theranos.1 Bringing his perspective as a health care reporter, Carreyrou went on to publish series of articles that highlighted the company’s deception and faulty technology.3 Although Theranos denied the allegations, the articles led to investigations by the FDA and other organizations resulting in the shutdown of most of the company’s operations in 2016. By 2017, Holmes and Sunny were facing multiple lawsuits leading to the eventual shutdown of the company in 2018.3

So where did Theranos and Holmes go wrong? Holmes’ crime was not pitching an incomplete product, after all many budding Silicon Valley startups debug as they go along.4 The “fake it until you make it” mentality seemed to be Holmes’ mantra but applying this maxim to a medical product with patients’ lives at stake was Holmes’ first mistake.4 Furthermore, even if Holmes remained insistent on the iterate and debug methodology, her second mistake was refusing to admit that what her business partners expected from her and what her company had managed to develop were not even remotely close. It’s pointless to speculate what was running through Holmes’ mind, but her policy of pushing out dissenters undoubtedly allowed her to travel far down the path of deception since no one was willing or able to stand up against her.2 Even beyond Holmes’ deception, board members and many business partners got swept up in the moment and failed to do their due diligence, allowing Holmes’ to gain autonomous control of the whole system.2 As the SEC continues to investigate Holmes, Theranos stands as a reminder to entrepreneurs and investors of how a business can begin with promise and end with criminal charges.

SCAN FOR REFERENCES

SPRING 2019 | SYNAPSE | 33SPRING 2019 | SYNAPSE | 33

Laura Bessen, M.D.

Vice President, Head of U.S. Medical,Bristol-Myers Squibb

Our speaker for this semester’s Synapse Launch Event is Dr. Laura Bessen-Nichtberger. Dr. Bessen-Nichtberger retired from her career at Bristol-Myers Squibb (BMS) as the Vice President and Head of U.S. Medical, where she was responsible for successfully launching medicines and making decisions for the U.S. market. Prior to this role, she spent time serving as the Vice President, Global Medical Affairs and as the leader of the Immunoscience and Neuroscience areas within U.S. Medical for BMS. Throughout her incredible career, Dr. Bessen-Nichtberger has helped manage and develop products like Atripla, Reyataz, and Sustiva for HIV, and Orencia for rheumatoid arthritis.

Before entering the pharmaceutical industry full-time, she was a practicing clinician and researcher. She was previously Physician-in-Charge for the AIDS Clinical Trial Unit at Beth Israel Medical Center, where she carried out both industry and NIH sponsored clinical trials, and was an Assistant Professor of Medicine at the Albert Einstein College of Medicine.

Dr. Bessen-Nichtberger is a Phi Beta Kappa graduate of Binghamton University and an Alpha Omega Alpha graduate of the New York University School of Medicine. She completed her clinical training in internal medicine at Mount Sinai Med-ical Center and completed a fellowship in Infectious Diseases at Albert Einstein College of Medicine.

SYNAPSE is excited to continue running our blog! The blog is a medium through which students share articles relating to current news or topics that are of interest to them. Blog posts are written in about 400 words, retaining the same structure and citation style as our full-length articles in print. We look forward to sharing our upcoming blog posts on a diverse array of topics. The blog writers and editors have enjoyed working on these blog posts and hope that readers enjoy them as well! We encourage everyone to check out our blog feature at upennsynapse.com.

SYNAPSE BLOG

Spring 2019 speaker


Get involved!Our Teams

Editorial Team Design & Layout

Finance & Marketing Committee

What We Do:

1. Design graphics and format articles by collaborating with

writers and editors

2. Learn how to use the Adobe Creative Cloud Suite

(InDesign, Photoshop, Illustrator, etc..)

What We Do:

1. Organize the magazine launch event

2. Organize and allocate funds to support semesterly

publication and launch event

What We Do:

1.Work 1-on-1 with writers to develop their pieces into

finished products throughout the semester

2. Develop leadership and critical writing skills as an editor

Want to be a part of SYNAPSE’s new blog

format? We are currently accepting ideas. Submit them

here! bit.ly/SynapseBlogApp

Blog

Interested in writing for or contributing to SYNAPSE in some way next semester? Look forward to the opening of our applications at the very beginning of the semester!

Send us an email ([email protected]) with your name and email if you are currently not on our listerv.

SYNAPSE


For more SYNAPSE, visit our website: www.upennsynapse.com

SYNAPSE...PENN’S UNDERGRADUATE MEDICAL CONNECTION SYNAPSE Theranos How a promising idea ended in...

Documents

Transcript of SYNAPSE...PENN’S UNDERGRADUATE MEDICAL CONNECTION SYNAPSE Theranos How a promising idea ended in...