Vol 17 · Issue 1 · Fall 2018

ps

ps addiction: an
ps

ps
interview with
Dr. henry
ps
Kransler
Developing page 29
drugs: Women
in clinical ps ps
trials
page 26 ps

elecrochemical
oxidization for
renewable energy
conversion and
storage
page 33
page 31

Drugs
from development to public health
PENN SCIENCE
FALL 2018 VOL. 17 ISSUE 1
PennScience is a peer-reviewed journal of undergraduate
research and related content published by the Science and Technology Wing at
the University of Pennsylvania and advised by a board of faculty
members. PennScience presents relevant science features,
interviews, and research articles from many disciplines, including
the biological sciences, chemistry, physics, mathematics,
geological science, and computer science. PennScience
is funded by the Student Activities Council. For additional
information about the journal including submission guidelines,
visit www.pennscience.org or email pennscience@gmail.com.

EDITORIAL STAFF
Mia Fatuzzo
editors-in-chief
Jenny (JiCi) Wang

writing managers design manager technology manager

Kenny Hoang Roshan Benefo Rounak Gokhale
Darsh Shah
editing managers communications business managers
Billy Hasley managers Donna Yoo
Kathy Wang Rachel Levinson Catherine Ruan
Aaron Zhang

faculty advisors Dr. M. Krimo Bokreta student advisor Grace Ragi

Dr. Jorge Santiago-Aviles

writing editing design business

Emily Lo Abraham Frey Farhaanah Mohideen Alexander Massaro
Andrew Lowrance Daniel Rodriguez Felicity Qin Glen Kahan
Michelle Paolicelli Brian Song Julia Davies Angela Yang
Pranshu Suri Emma O’Neil Amara Okafor Helen Jiang

communications
Hiab Teshome Ken Jiao Jessica Tan
Tamsyn Brann Lily Zekavat Julia Yan
Neelu Paleti Sumant Shringari Kaitlyn Thayer
Roshni Kailar Mimi Lu Abi Szabo Jasmine Chen
Rose Nagele Brian Zhong Olivia Myer Celia Zhang
Asha Dahiya Kelly Liang Arjun Jain
Amanda Paredes Zhiqiao Jiang
Charles Rothkrug
Joshua Kim
Natasha Chity-Guevara
David DeVaro
Shriya Beesam
Lynn Ahrens
Eric Teichner
 Tab
Co le of
nte
nts

interview
29 with dr.
the future of henry
6 immunotherapy kranzler
hydrogels: the end interview
9 of daily medication with dr.

mental illness
31 reagan
12 wetherhill
treatment
oxytocin: a
hormone of the
33
15 body, a love from electrochemical oxidation
within ourselves of formate on a PdNI/C
nanoparticle catalyst for
renewable energy conver-
18 the opioid epidemic sion and storage

digital therapeutics:
the doctor that
20 fits in your pocket 38 ps

Cannibis Oil: A modifying reaction

diffusion: a numerical
23 health trend to model for turing
weed out? morphogenesis,
ben-jacob patterns,
developing drugs:
and cancer growth
26 women in clinical
trials
A LETTER
FROM THE EDITORS

D
ear Reader,
We are thrilled to present the fall issue of the seventeenth volume of
the PennScience Journal of Undergraduate Research. We are incredibly
grateful for the members of PennScience who worked diligently all semester
to assemble this journal, the students who submitted their research findings
for publication, and the Penn community who attended our events and en-
gaged in scientific discourse on campus. In this issue, Hiab Teshome examines
the future of immunotherapy in treating cancer. Michelle Paolicelli discusses
the potential of targeted drug delivery using hydrogels. Roshni Kailar reviews
the current treatment options for mental illnesses from multiple perspectives.
Andrew Lowrance takes a closer look at oxytocin, a hormone that drives
human interconnected behavior. Pranshu Suri investigates the opioid epidem-
ic and its implications for public health. Neelu Paleti explores the emerging
intersection between drugs and technology. Finally, Rose Nagele provides a
detailed look at the complicated role of women in clinical trials. We are also
proud to present the original research of two students – Sai Mamidala and Kai
Trepka.
We have greatly enjoyed our semester leading PennScience, and we would
like to extend a sincere thank you to the many groups and individuals who
have made PennScience possible. First, we would like to thank our incredible
journal staff – the members of our writing, editing, design, business, and com-
munication committees – for their hard work, dedication, and enthusiasm. Our
publication is entirely student-run and relies on the efforts of our scientifically
curious undergraduate members. We would also like to recognize the stu-
dents on campus who shared their experiences with us at our research panel,
as well as Dr. Henry Kranzler, who was interviewed for our journal by writing
committee member Tamsyn Brann. We owe our funding to the Science and
Technology Wing of the King’s Court College House and the Student Activi-
ties Council. Thank you also to our faculty mentors, Krimo Bokreta and Jorge
Santiago-Aviles, for their constant guidance and support. Finally, we would
like to thank you for reading PennScience – enjoy our latest issue!
Sincerely,
Mia Fatuzzo (C’19)
Jenny (JiCi) Wang (C’19)
Co-Editors-in-Chief
 Looking for a
chance to
publish your
research?
Penn Science is accepting Research in any scientific field will
submissions for our spring 2019 be considered, including but not
issue! limited to:
Submit your independent study
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Spring 2018 Spring 2017

 Features

THE
TUR
U
F

E
O

y
f r a

p
Im e
muno th
By Hiab Teshome
Designed by Farhaanah Mohideen

T raditionally, metastatic melanoma cancer has been targeted with

chemotherapy, but new immunotherapies can use the bodies defenses to
attack this cancer. These immunotherapies work by developing antibod-
ies in the lab that can be used as a targeted therapy [1]. By tagging these
cancer cells, the antibodies signal to the immune system to destroy them,
or act as immune checkpoint inhibitors to regulate many of the body’s
immune system checkpoints.

Scientist have been studying two types of immunotherapy drugs, spe-

cifically for metastatic melanoma. First, small-molecule inhibitors target
the MAP kinase pathways that regulate many different types of cellular
activities. Second, immune-checkpoint inhibitors reactivate suppressed
antitumor immune responses by removing blinders on cancer cells
that once prevented the immune system from recognizing the cells as
cancerous [2]. Both treatments increased the survival rates of patients

6 PENNSCIENCE JOURNAL | fall 2018

with metastatic melanoma. This progress in cancer im-
munotherapy has shown great promise in activating the
Tumor Cell Features
immune system against cancer.

These drugs target two biochemical pathways, the

MAPK and ERK pathway. The MAPK, or mitogen-ac-
tivated protein kinase, pathway is critical for human Drug
cancer cell survival [3]. Errors in this pathway have been immunotherapies
shown to alter cell regulation, leading to cancer. MAP have allowed
kinases work with extracellular signal regulated kinases researchers to
(ERK), which are a chain of proteins that relay signals target tag tumor
from receptors outside of the cell to genes inside of cells, using
the nucleus. ERKs communicate with a family of Raf antibody signalling
PD-L1 to destroy them.
Antigen By destroying
Both treatments increased the pathways that have
survival rates of patients with PD-1 allowed tumor cells
metastatic melanoma. to be
T Cell Receptor unrecognizable to
T-cells, the growth
proteins which are a series of kinases that are involved in rate of cancer can
the proliferation, differentiation, and apoptosis of cells be diminished.
[4]. In immune cells, activated Raf is also a component Immunotherapies
of the innate response in different steps of the inflamma- target the PD-1/
PD-L1 pathway to
tory cascade, increasing the expression of tumor necrosis
target cancer cells.
factor alpha (TNF-α) and inducible nitric oxide synthase
T-Cell
(iNOS), which are both signalling proteins involved in
systemic inflammation in order to coordinate an immune
response [5].
Tumor Cell
Because of Raf ’s and ERK’s important role in the Death
immune pathway, studies were carried out to explore if
the MAP pathway can be a potential target for antican-
cer drugs. The most common mutation of the Rafs and
ERK involves the BRAF gene, which dictates the proper
protein formation of these proteins. Recent studies have
involved identifying selective BRAF inhibitors in order
to reduce the production of mutated Rafs and ERKs.
Selective BRAF inhibitors, such as vemurafenib and
dabrafenib, extended the median cancer progression free
survival of patients for more than 7 months [6]. Both
of these drugs inhibit the protein synthesis of mutated
BRAF which results in abnormal growth of cells, and PD-L1
inhibition of the immune system to regulate cancer cells.
Although BRAF inhibitors have had clinical benefits, Anti PD-L1 Antigen
drug resistance is very frequent making these inhibitors Anti PD-1
limited in their ability to destroy cancer cells In addition,
these inhibitors sometimes incorrectly activate MAP T Cell Receptor
kinase pathways in BRAF wild-type cells driving tumor PD-1
growth [7]. As a result, due to some of the failings of the
BRAF inhibitors, researchers began to study immune
system checkpoints, and possible drugs to alter and reac-
tivate these systems. MAP kinase pathway immunothera-
pies inhibit the production of mutated proteins.

However, another very commonly used immuno- T-Cell

fall 2018 | PENNSCIENCE JOURNAL 7

 Features
therapy is through using drugs to block immune checkpoints to
allow the body’s’ natural immune system to destroy cancer cells
Researchers are trying to better
understand how tumors can escape
immune cell recognition by inhibiting
the ability for T cells to respond to
antigen and co-stimulatory signals.
without regulation. The major cell involved in mediating im-
munity against cancers are T cells. The activation of T cells to
perform its anti tumoral function requires two signals. Signal one
is an antigen-specific signal to the T-cell receptor. These specific
signals are expressed on many cells including cancer cells. The
second required signal is a co-stimulatory signal provided by B7
and other co-stimulatory molecules that assist in T cell activation
[8]. The successful balance of activating and inhibiting T cells
determines the surveillance and cancer eliminating function of
T cells. Researchers are trying to better understand how tumors
can escape immune cell recognition by inhibiting the ability for
T cells to respond to antigen and co-stimulatory signals. Under
normal conditions, immune checkpoint molecules serve to reg-
ulate T-cell responses, which is necessary to avoid uncontrolled
destruction. However, tumor cells use these intrinsic ‘brakes’ of
the immune system as immune escape mechanisms by inducing
functionally exhausted T-cells which can no longer respond to
antigens [9].
Anticancer drugs targeting these ‘immune checkpoints’ on
T-cells are termed ‘checkpoint inhibitors’[9]. These check-
point molecules are extremely important, as they help the body
to discriminate between ‘foreign’ and ‘self ’. Numerous drugs
have been developed to intercept tumor control of the immune
system by specifically targeting these checkpoint molecules on
T-cells by blocking inhibitory checkpoints to restore immune
system function, however they were not as successful at increas-
ing the lifespan of patients. Recently, two drugs were approved
by the FDA to block immune checkpoint molecules, ipilimumab
and atezolizumab. These drugs target checkpoint proteins on T
cells, such as CRLA-4 and PD-1, that can switch off T cells to
keep it from attacking other cells in the body [9]. These drugs
can identify and inhibit these targets in order to activate the
immune system to destroy cancer cells that it did not once recog-
nize. However, the danger in using this form of immunotherapy
is that by blocking inhibiting checkpoints, there is no longer a
mechanism for immune cells to recognize foreign cells and self
cells.
Cancer immunotherapy is a blossoming field in the medical
field. Researchers are currently developing drugs that target
more inhibitory molecules, and creating drugs that can blockade
for more than one inhibitory molecules. However, by globally
suppressing the inhibitory molecules, many individuals under-
going these therapies develop serious autoimmune diseases due
to the drug’s widespread blocking activity. Researchers therefore
are moving to a more “personalized” approach to combina-
tion immunotherapy; in that scenario, tumor biopsies would
be interrogated for a series of addressable checkpoints, then a
personalized checkpoint blockade cocktail administered [10]. An
even more promising field in cancer immunotherapy is studying
how different strategies for inhibiting the brakes on the immune
system can be used in the treatment of cancer. This year’s Nobel
Prize winners in Physiology or Medicine, James P. Allison and
Tasuku Honjohe, discovered a new protein pathway that when
blocked was a promising strategy in the fight against cancer. Re-
sults were dramatic, leading to long-term remission and possible
cure in several patients with metastatic cancer, a condition that
had previously been considered essentially untreatable [11]. For
more than 100 years scientists have been attempting to use the
immune system in the fight against cancer. Checkpoint therapy
has now revolutionized cancer treatment and has fundamentally
changed the way we view how cancer can be managed.

References
[1] Cancer.Net. (2018). Understanding Immunotherapy. [online] Available at: https://www.cancer.net/navigating-cancer-care/how-cancer-treated/immunotherapy-and-vaccines/understand-
ing-immunotherapy [Accessed 4 Nov. 2018].
[2] Turajlic, S. and Larkin, J. (2018). Immunotherapy for Melanoma Metastatic to the Brain. New England Journal of Medicine, 379(8), pp.789-790.
[3] De Luca A, Maiello MR, D’Alessio A, Pergameno M, Normanno N. The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for
therapeutic approaches. Expert Opin Ther Targets. 2012;16(Suppl 2):S17–27.
[4] Hagemann, C. and Rapp, U. (1999). Isotype-Specific Functions of Raf Kinases. Experimental Cell Research, 253(1), pp.34-46.
[5] Arthur, J. and Ley, S. (2013). Mitogen-activated protein kinases in innate immunity. Nature Reviews Immunology, 13(9), pp.679-692.
[6] K.T. Flaherty, I. Puzanov, K.B. Kim, A.Ribas, G.A. McArthur, J.A. Sosman, et al. (2010). Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med, 363, pp. 809-819.
[7] Sanchez-Laorden, A. Viros, M.R.Girotti, M. Pedersen, G. Saturno, A.Zambon, et al. (2014). BRAF inhibitors induce metastasis in RAS mutant or inhibitor-resistant melanoma cells by
reactivating MEK and ERK signaling. Sci Signal, 7, p. Ra30
[8] Shi, T., Ma, Y., Yu, L., Jiang, J., Shen, S., Hou, Y. and Wang, T. (2018). Cancer Immunotherapy: A Focus on the Regulation of Immune Checkpoints. International Journal of Molecular
Sciences, 19(5), p.1389.
[9] Greil, R., Hutterer, E., Hartmann, T. and Pleyer, L. (2017). Reactivation of dormant anti-tumor immunity – a clinical perspective of therapeutic immune checkpoint modulation. Cell
Communication and Signaling, 15(1).
[10]Li, X., Shao, C., Shi, Y. and Han, W. (2018). Lessons learned from the blockade of immune checkpoints in cancer immunotherapy. Journal of Hematology & Oncology, 11(1).
[11] Nobelprize.org. (2018). [online] Available at: https://www.nobelprize.org/uploads/2018/10/press-medicine2018.pdf [Accessed 4 Nov. 2018].

8 PENNSCIENCE JOURNAL | fall 2018

 Features

Hydrogels:
The End of Daily
Medication
By Michelle Paolicelli
Designed by julia yan

S cientists
today are creating
materials with amazing
capabilities on a microscopic scale
in an effort to improve the human
experience. Our ancestors first realized
that the objects around us could be manipulated
to better suit our needs about two and a half million years ago,
and since then the field of materials science has continuously
evolved. Today, so-called “smart” materials are being designed stages. During the drug delivery
to respond to specific and distinct environments. One emerging process, the drug and hydrogel
field is targeted drug delivery using hydrogels. Hydrogels are are cross- linked before the resulting complex
versatile substances predominately made up of water, and they is taken into the body orally [3]. When hydrated,
have received great attention because of their biocompatibility, hydrogels become a soft rubbery material that can be easily
easy manipulation, and unique physical properties [1]. molded to create an internal drug reservoir, and they
serve as a barrier between the drug and the human body.
Hydrogels have a multitude of applications in medicine. From
contact lenses to synthetic wound dressings, they serve as the Depending on the properties of the hydrogel packaging, the
ideal material for use in the human body [2]. Although hydrogels boundary between drug and body will only break under
are well established in contact lens technology, their use in specific physiological conditions —such as a specific pH [3]—
pill capsules for targeted drug delivery is still in its formative or when the gel reaches a certain state related to swelling

fall 2018 | PENNSCIENCE JOURNAL 9

 Features

HYDROGELS
are versatile
substances
predominantly
Drug resevoir made up of
water.
hydrogel
From contact
lenses to syn-
thetic wound
dressings, hy-
drogles serve
as the ideal and anatomical conditions. This is beneficial for patients
material for use suffering from morbidities specific to a particular body system
in the human or in need of continuous relief. Traditional medications use
body.
rudimentary and slow release techniques that limit their
efficacy in providing the patient with satisfactory results
because the medication must be frequently re-administered.
Drug resevoir
To encompass numerous delivery parameters, many
proposals for the use of hydrogels in drug delivery rely on a
hydrogel
diffusion-controlled release mechanism. Hydrogel capsules
contain a central drug reservoir surrounded by a hydrogel
membrane to create a concentration gradient that allows for
a constant release rate of the drug. Some diffusion-controlled
applications also incorporate a swelling-controlled aspect. This
The progression of hydrogel degrada- refers to the swelling response of a hydrogel when it comes
tion in the body. Drug diffusion occurs in contact with a bio-fluid. Once expanded to the critical
from the core through the hydrogel point, the drug within begins to diffuse into the body [2].
membrane.

Currently, there are only a few commercial products that

employ hydrogels as a means of drug delivery, but that is likely
to change in the coming years. Dr. Kinam Park, a professor
Hydrogels of biomedical engineering at the Purdue University School
of Pharmacy, has dedicated his decades-long career to the
have a study of the applications of biomaterials in drug delivery.
He has proposed that hydrogels be used to create an orally
administered drug that can be retained in the stomach for
multitude of twenty-four hours [2][4]. This allows for a slower release of
medication, and grants the patient a greater period of relief
applications for each dosage taken. This method would be applicable for
any drugs currently treated with pills. Dr. Park explains his
in medicine. research approach using an analogy of the digestion of food:
if a large piece of meat is swallowed, it will sit in the stomach
until its volume has been reduced enough to allow passage
into the rest of the digestive tract. Similarly, the larger a dose
of orally administered medicine, the longer it will take for the

10 PENNSCIENCE JOURNAL | fall 2018

medicine to become small enough to pass into the small intestines. Features
Park also notes that a physical pill capsule must be small enough
to be easily swallowed. This underscores the need for a dynamic
vessel like a hydrogel capsule that can change size based on the
level of hydration. Park’s research employs the use of hydrogels to
induce swelling of the pill capsule to an extent that it cannot pass
into the small intestine from the stomach. However, such pills need
to be eliminated by the body eventually, requiring the hydrogels
to not only swell, but also be enzyme-digestable [4]. According
to Park’s concept of the hydrogel, a patient would ingest a dried
hydrogel-drug complex in the form of a capsule about the size
of a Tylenol pill. The pill would then swell in the stomach and
be broken down over time by the interaction of pepsin in the
stomach and the susceptible hydrogel boundary, releasing the drug
at a controlled rate [4]. Park hopes to one day create a targeted early research
drug delivery mechanism specifically for cancer treatment.

Certain limitations exist when working with hydrogels due to

suggests that
the limited scientific knowledge of the diffusion of enzymes
through gels. This gap poses an obstacle when predicting the
hydrogels can be
diffusion rate of enzymes into hydrogels, and thus the rate of
release of the drug itself. More generally, ensuring the complete used to encapsulate
and natural removal of the hydrogel casing from body has
been the primary focus of scientists [5]. Also, further research drugs for slow
is necessary to assess the possible side effects of hydrogel use as
well as the nature of the gels’ degeneration. Lastly, hydrophobic
drugs, including certain antitumor drugs, pose a serious obstacle
release in the body.
to to incorporation into the hydrophilic hydrogels [5] [6].
Despite ongoing limitations to the practical applications of
hydrogels for targeted drug delivery, early research has shown
how hydrogels can be used to encapsulate drugs for slow-release
in the body. Scientists like Dr. Kinam Park are focused on
improving the reliability of current hydrogel applications within
drug delivery as well as expanding the number of compatible
medications [7]. The biocompatibility and tunable release
mechanisms of hydrogels make them ideal for slow-release drug
delivery. With continued developments in hydrogel technology,
perhaps the era of daily medication will soon be behind us.

References:
[1] Kopeček, J. (2007). Hydrogel biomaterials: A smart future?. Biomaterials, 28(34), pp.5185-5192.
[2] Caló, E. and Khutoryanskiy, V. (2015). Biomedical applications of hydrogels: A review of patents
and commercial products. European Polymer Journal, 65, pp.252-267.
[3] Peppas, N. (1997). Hydrogels and drug delivery. Current Opinion in Colloid & Interface Science,
2(5), pp.531-537.
[4] Park, K. (1988). Enzyme-digestible swelling hydrogels as platforms for long-term oral drug delivery:
synthesis and characterization. Biomaterials, 9(5), pp.435-441.
[5] Hoare, T. and Kohane, D. (2008). Hydrogels in drug delivery: Progress and challenges. Polymer,
49(8), pp.1993-2007.
[6]Schwendener, R. and Schott, H. (2009). Liposome Formulations of Hydrophobic Drugs. Methods in
Molecular Biology, pp.129-138.
[7] Pàmies, P. and Stoddart, A. (2013). Materials for drug delivery. Nature Materials, 12(11),
pp.957-957.

fall 2018 | PENNSCIENCE JOURNAL 11

 Features

Mental
Illness
treatment
By Roshni Kailar
Designed by Kaitlyn Thayer

Currently, most drugs used to treat

mental illness target neurotransmitters
in the brain. Too high or low levels of
neurotransmitters are often the cause of
Disclaimer: This article discusses treatments
symptoms associated with mental illness.
of mental illnesses from multiple per-
For example, low levels of serotonin
spectives but is in no way a comment
and norepinephrine are correlated
on what an individual with a men-
with depression and anxiety. Pre-
tal illness should do. As always,
scription drugs bring these levels
you must consult a professional
back to normal, thus alleviating
regarding any form of treatment.
symptoms. Common classes of

D
drugs include selective serotonin
epression is one
reuptake inhibitors (SSRIs) and
of the leading
selective norepinephrine reuptake
causes of disabil-
inhibitors (SSNIs), both of which
ity throughout the world
increase the amount of serotonin
estimated to affect 1 in 5
in the synaptic space. However,
adults [1]. Compared to
SSRIs and SSNIs don’t work
1 in 6.6 people in the US
for all patients and have several
who reported smoking or 1
associated side effects. For example,
in 37 people in the US who
patients can have seizures or other
have a stroke, it is clear that
cerebrovascular complications. Anoth-
mental health is a very pressing
er complication is serotonin syndrome
public health issue to be con-
which causes autonomic instability,
sidered which is only expected to
gastrointestinal issues, and neuromuscu-
increase in incidence [2, 3]. In re-
lar hyperactivity [4]. In addition to the
sponse to this concerning trend, this
side effects of drugs like SSRIs, another
article hopes to provide a review of
problem is that two-thirds of patients
current treatments, with a focus
on recent advancements,
for those with mental
illness.

12 PENNSCIENCE JOURNAL | fall 2018

with depression do not respond to the first Features
drug they are prescribed [5]. This implies
that a majority of patients diagnosed with
depression effectively go without treatment
for quite some time.

An alternative for these traditional treat-

ments is new pharmaceutical drugs, in
development, that hopefully will not have
SSRIs and SSNIs
the same side effects. Some new targets for
treatment include glutamate and ion chan-
don’t work for all
nel receptors. Glutamate is an excitatory
neurotransmitter that activates receptors
patients and have
on neurons, such as the NMDA receptor. several associated
Elevated glutamate levels have been ob-
served in patients with depression and oth- side effects.
er mood disorders. Novel antidepressant
drugs like NMDA receptor antagonists,
which block the function of receptors,
have shown significant behavioral effects
in rats. In a 2008 study, a single dose
caused rapid and sustained antidepressant Presynaptic
effects that lasted for up to one week in Cell

rats. By blocking glutamate from binding

to the NMDA receptor, the drug alleviates
symptoms associated with high glutamate
levels [6].

An effective alternative to drug treatments

is exercise. Research conducted by Duke
University found that between 40-45%
of people with depression can overcome
their symptoms through exercise alone
[5]. This research suggests that there are SSRI
natural ways to try to combat mental
illnesses. Although it is unclear specifically
how exercise is able to alleviate mental
illnesses, some hypotheses do exist. One
theory is that exercise may be involved in
the hypothalamic-pituitary-adrenal (HPA)
axis via an increase in blood flow to the
brain, which allows for the reduction of Seratonin Seratonin channel
stress. Another potential way that exercise
can help a patient with depression is by
Seratonin receptor
facilitating social interaction and provid-
Postsynaptic Cell
ing a distraction from harmful thoughts.
People often exercise in groups and meet
The addition of SSRI’s block the re-uptake of
new people through exercise; exercise can
therefore help patients by allowing them
seratonin by the presynaptic cell.
to form new social relationships, which are
generally therapeutic in terms of mental
illnesses. Thus, potential alternative treat-
ments suggested by this research are to use
exercise or a combination of exercise and

fall 2018 | PENNSCIENCE JOURNAL 13

 Features involves 4 stages, in which patients develop their coping
mechanisms. The first stage is stabilization of thoughts,
the second stage involves stabilization of behaviors, the
third stage promotes happiness, and the fourth stage
develops skills to allow for fulfillment. DBT differs from
CBT in developing mindfulness skills whereas CBT
involves focusing on reasoning and rationality. Also,
medications [7].
DBT fosters therapy in a group setting whereas CBT is
generally one-on-one. According to data by Bohus et al.
Another way to treat mental illnesses is through behav-
patients who underwent DBT improved at a greater rate
ioral therapy. The main form of behavioral therapy is
than those who didn’t, and DBT was effective at helping
cognitive behavioral therapy (CBT). CBT targets both
every factor except anger in mentally ill patients [10].
cognitive and behavioral factors involved in mental
illnesses. CBT involves strategizing with a psychologist
Overall, there are two main treatments for mental illness:
about how to deal with certain situations by identify-
prescription drugs and behavioral therapy. The obvious
ing misconceptions or wrong assumptions which lead
question based on the two very different types of treat-
to harmful thoughts [8]. Patients then monitor their
ments is that of efficacy. Since every person is different
thoughts and substitute any harmful thoughts arising
and both forms of treatment involve very different ways
from misconceptions with more realistic thoughts. CBT
of targeting the condition, it is difficult to say if one is
also develops methods to deal with negative thoughts and
generally better than the other. A possible consideration,
behaviors. Current research suggests CBT is just as effec-
however, in the comparison of efficacies of drugs and
tive as, if not better, at dealing with depressive symptoms
psychotherapy is patient compliance in terms of listening
compared to prescription drugs for symptoms associated
to treatment prescribed by the psychologist or psychia-
with bipolar disorder. However, research has suggested
trist. Another great alternative involves the simultaneous
that the efficacy of CBT is dependent on the condition.
use of both prescription drugs and behavioral therapies
For example, CBT is not very effective at controlling
together. Current research has already suggested that
aggression in patients with schizophrenia. Thus, the com-
optimized treatment would involve both methods, but
parison between drug treatments and CBT still needs to
this idea is perhaps one that can be researched further in
be considered [9].
the future. Since the two methods target different aspects
of mental illness, namely behavior and chemistry, the
A similar method of behavioral therapy that is based on
eventual goal is to help all patients and reduce, if not
CBT is dialectic behavior therapy (DBT) which involves
eliminate, mental illnesses.
developing acceptance and change strategies. DBT

References
[1] Nami.org. (2018). Mental Health By the Numbers | NAMI: National Alliance on Mental
Illness. [online] Available at:
https://www.nami.org/Learn-More/Mental-Health-By-the-Numbers [Accessed 4 Nov. 2018].
[2] Adaa.org. (2018). Treatment | Anxiety and Depression Association of America, ADAA.
[online] Available at: https://adaa.org/understanding-anxiety/depression/treatment
[Accessed 4 Nov. 2018].
[3] Benjamin, E., Virani, S., Callaway, C. et al, (2018). Heart Disease and Stroke
Statistics—2018 Update: A Report From the American Heart Association. Circulation, 137(12).
[4] Haddad, P. and Dursun, S. (2007). Neurological complications of psychiatric drugs: clinical
features and management. Human Psychopharmacology: Clinical and Experimental, 23(S1), pp.S15-S26.
[5] Adaa.org. (2018). [online] Available at:
https://adaa.org/sites/default/files/SomberQuestions_Antidepressants.pdf [Accessed 4 Nov. 2018].
[6] Dang, Y., Ma, X., Zhang, J., Ren, Q., Wu, J., Gao, C. and Hashimoto, K. (2014). Targeting of
NMDA Receptors in the Treatment of Major Depression. Current Pharmaceutical Design, 20(32), pp.5151-5159.
[7] Sharma, Ashish et al. “Exercise for mental health” Primary care companion to the Journal of
clinical psychiatry vol. 8,2 (2006): 106.
[8] Gettingunstuck.com. (2018). [online] Available at:
http://www.gettingunstuck.com/cpu/PSY412/Overhead/COGNITIVE%20BEHAVIORA
L%20THERAPY%20OH.pdf [Accessed 4 Nov. 2018].
[9] Hofmann, S., Asnaani, A., Vonk, I., Sawyer, A. and Fang, A. (2012). The Efficacy of
Cognitive Behavioral Therapy: A Review of Meta-analyses. Cognitive Therapy and Research, 36(5), pp.427-440.
[10] Dialectical behavior therapy: current indications and unique elements. Psychiatry
(Edgmont). 2006;3(9):62-8.

14 PENNSCIENCE JOURNAL | fall 2018

 T
here is an inevitable crossroad between our sub-
Features
jective desire for interconnectedness and the sci-
entific understanding of that desire — the drive
to understand the fundamental basis from which we
are drawn to one another. At the heart of our de-
(1) Lee, H. J., Macbeth, A. H., Pagani,
sire? Oxytocin (OT): the neurochemical argu-
J. H., and Young W. S. (2009). Oxyto-
cin: the great facilitator of life. Prog- ably responsible for feelings ranging from self-actualization to codependency. The
understanding of OT is fundamental to the work of neuroscience researchers
ress in Neurobiology 88, 127-151.

(2) Insel, T. R., and Fernald, R.D. (2004).

How the brain processes social informa-
tion: searching for the social brain. Annu-
and enthusiasts alike. From the psychological compulsions of the mind, to the
al Review of Neuroscience 27, 697-722. neurobiological explanations of the body, the generality of oxytocin is hard-
(3) Feldman, R. (2015). Sensitive peri-
ods in human social development: new
ly insignificant.
insights from research on oxytocin, syn-
chrony, and high-risk parenting. Develop-

In simple terms, OT is a peptide secreted by the hypothalamus

ment and Psychopathology 27, 369-395.

(4) Bartz, J. A., Zaki, J., Bolger, N., and Ochs-

ner, K. N. (2011). Social effects of oxytocin
in humans: context and person matter.
and transported to the posterior lobe of the pituitary gland where
Trends in Cognitive Sciences 15, 301-309. neurochemical interactions give rise to its flagship sense of at-
(5) Kosfeld, M., Heinrichs, M., Zak, P. J., Fisch-
bacher, U., and Fehr, E. (2005). Oxytocin in-
tachment [1]. Though an understanding of the psychologi-
creases trust in humans. Nature 435, 673-676.
cal, behavioral, and neurochemical determinants of OT
should be conveyed for a thorough picture of its overall
(6) Cho, M. M., DeVries, A. C., Williams,
J. R., and Carter, C. S. (1999). The ef-
fects of oxytocin and vasopressin on
partner preferences in male and female
prairie voles (Microtus ochrogaster). Be-
effects on the developing mind, an understanding of
havioral Neuroscience 113, 1071-1079. its biological implications is sufficient for practical
(7) Windle, R. J. (1997). Central oxytocin
administration reduces stress-induced
deliberation of its importance.
corticosterone release and anxiety behav-
ior in rats. Endocrinology 138, 2829-2834.

(8) Baumgartner, T., Heinrichs, M., In recent years, researchers looked to the
Vonlanthen, A., Fischbacher, U., and Fehr,
E. (2008). Oxytocin shapes the neu-
ral circuitry of trust and trust adapta-
amygdala for an understanding of hu-
tion in humans. Neuron 58, 639-650. man interconnective behavior. Sci-
(9) Kirsch, P. (2005). Oxytocin mod-
ulates neural circuitry for social cog-
entists have demonstrated that the
nition and fear in humans. Journal
of Neuroscience 25, 11489-11493. component of fear that underpins
(10) Kumsta, R., Hummel, E., Chen, F. attachment is explained by the
S., and Heinrichs, M. (2013). Epigene-
tic regulation of the oxytocin receptor
gene: implications for behavioral neu-
process of neurochemical
roscience. Frontiers in Neuroscience 7. activation from the hypo-
thalamus, particularly
for infants and their
maternal figures
[2]. Persistent
se paration,
within a
level of
cogni-

X
t i ve

OXYTOCIN
A Hormone of the Body, the Love from Within Ourselves
By Andrew
Lowrance
Designed by
Felicity Qin

fall 2018 | PENNSCIENCE JOURNAL 15

 Features

growth,
impairs the development
of basic psychological cues, illustrat-
ed by the release of OT. This region of time
concerning perpetual psychological neglect, as
within a child’s early years, is most commonly aligned
with the notion of sensitive periods (SP), where basic
physical and psychological phenomena play a greater
role in shaping our sense of consciousness and well-being
[3]. Studies have demonstrated a statistically significant
link between the perpetuation of SP’s and the promul-
gation of neural plasticity, with OT playing a key role in
the reconciliation of this emotional advancement to a
state of psychological equilibrium.
To effectively delineate the process by which
the SP impacts infants, scientists looked to the
neurochemical basis by which OT diffuses.
Experiments have been conducted to un-
derstand the relationship between OT
and psychological codependency us-
ing both human and non-human
subjects. However, attempts
by researchers to correlate
the human sense of
close interaction and
the neurochemi-
cal basis from
which that
euphoria
is de-
rived
using non-human brains
will arguably produce less conclusive
results; contextualization is a critical factor to
be considered when understanding the behavior
of humans, as opposed to non-human subjects [4].
However, for ethical and financial reasons, scientific
experiments involving human subjects are often not fea-
sible. Non-human testing has therefore been utilized by
the scientific community for decades in the pursuit of
greater neurobiological understanding. These studies
demonstrated linear* relationships between the release
of OT throughout the hypothalamus and the corre-
sponding sense of apparent emotional attachment
[5]. Although these experiments were conducted
on animal models, comparative physiology has
demonstrated the remarkably similar composi-
tion and function of human and non-human
brains. That is, similar patterns of OT dif-
fusion within non-human subjects pro-
vide insight into the possibilities of
understanding the chemical basis
of human behavior.
For instance, non-hu-
man variables, such
as rats, were used
for investigat-
ing OT’s
socio-bi-
ologi-
cal

* (for purposes of practical understanding,

linear in this context refers to the direct link between two given factors within a degree of statistical certainty, without significant consideration of outlying factors)

16 PENNSCIENCE JOURNAL | fall 2018


com-
ponents and
how it heightens the
nociceptive (pain) thresh-
olds, thereby reducing relative
anxiety levels within an organism [6].
An analytical approach was considered in
devising a breakdown of the fundamental effects
of OT in rats through varying dosages to determine
the associative behavioral and neurochemical attributes
of the additional peptide, thereby assessing the hypothal-
amo-pituitary-adrenal (HPA). Measurable changes in neu-
rochemical balances within the amygdala were recorded,
with a coexistent shift in characteristic behavior toward a re-
duced state of anxiety [7]. Similarly, a study concerning the
internasal, double-blind administration of OT within human
test subjects, subsequently analyzed by an fMRI, found asso-
ciative trust adaptations linked to the administration of OT.
The amygdala, midbrain region, and dorsal striatum were
specifically activated in subjects receiving OT [8]. Thus,
the link between OT increase and certain be-
havioral outputs, like trust, signifies a
corresponding shift in the dif-
fusion rate
o f
Features
O T
through targeted neu-
ral pathways.
Likewise, from the funda-
mental link between human and
non-human testing, OT reveals an as-
sociation between the complex emotional
states derived from subjects and consequent
chemical distribution. More particularly, there is
a symmetry between the human brain and OT’s
connection to attachment, social recognition, and
aggression in non-human mammals: strong evidence
conveys the perpetuation and modulation of OT within
the amygdala, as in the instance of SP’s with younger sub-
jects. A study concerning 15 healthy males after double-blind
crossover intranasal application of OT and a placebo illustrat-
ed the possible mediation of the amygdala by OT. Thus, de-
spite the non-linear relationship between OT diffusion and
consequent behavior, a practical understanding of OT’s im-
plicative characteristics refines the bridge between human
and non-human testing [9].
The mind-brain symmetry that concerns psychological be-
havior unravels a necessary beauty to the universe, a uni-
verse that could be sought within the lives of individuals
and the interconnectedness of their minds. More partic-
ularly, with respect to the continuity of time, human
evolution necessitates the precision with which this
“love drug” reshapes the human sense of
desire and the innate
composi-
tion of
the
self.
fall 2018 | PENNSCIENCE JOURNAL 17
 Features

the
M T W T F S

By Pranshu Suri P I O I D
By Pranshu Suri
epidemic
Designed by Amara Okafor

M
ore people in the U.S. die every day from opi-
oid overdoses than car accidents [1]. This fact
may strike some as surprising, but, to those
who are close to the rampant opioid epidemic, it is a trag-
ic reality. Deaths resulting from opioid painkillers have been
steadily increasing in the U.S. over the past 20 years, so it
is imperative that we are informed about this sphere of
public health. Despite all of the coverage on the opioid ep-
idemic, many Americans report still not knowing exactly
what an opioid is and why they are so uniquely addictive.
Opioids are prescription narcotics that act to relieve pain [2].
The most common trigger event for long-term addiction seems
to be a prolonged use and/or misuse of prescription pain-
killers such as Oxycontin, Percocet, and Vicodin [3]. When
someone consumes an opioid drug, the drug molecules rapidly
enter into their bloodstream; from there, they travel through
the body to the brain and bind to individual proteins called
m-opioid receptors that exist on the surface of opioid-sensi-
tive neurons [3]. Specifically, these neurons and receptors
are interconnected with the reward pathways in the human
brain. These reward pathways run through a region called the
limbic system, which is located in the center of the brain [3].
The limbic system has many functions ranging from the regu-
lation of emotions and sensory processing to the formation of
memories [4]. The aforementioned opioid-sensitive neurons
Illustration of a brain not on drugs versus a brain
of a person who regularly uses. Opioids prompt an
increase in neurotransmitters like serotonin, dopa-
mine, etc. This creates feelings of pain relief and
euphoria.
are found in a region of the limbic system called the ventral
tegmental area (VTA) [4]. Thus, when a person takes an opioid
painkiller, the opioid-sensitive neurons in the VTA release do-
pamine, the “feel-good” neurotransmitter, into the surround-
ing regions [3]. Under normal circumstances, the feelings of
pleasure caused by this dopamine release serve to counteract
any pain one might be feeling at that given time; however,
when the person consuming the drug is not feeling any pain to
begin with, the limbic system’s essential functions are disrupted
[5]. Opioids can make the user feel extremely happy, content,
and relaxed; because the limbic system is also responsible for
the formation of memories, the brain associates each subse-

18 PENNSCIENCE JOURNAL | fall 2018

quent drug consumption with this
skewed perception of reality [4].
Addiction plagues millions across
the country, for whom there is
currently no discernible solution.
For years, lawmakers have debat-
ed various policy ideas to amelio-
rate this pervasive epidemic, to no
avail. With tens of thousands of
opioid-related deaths each year,
the economic toll on the U.S. has
Features
Besides this, drug companies
heavily market their opioid prod-
ucts to the general public, which
makes people more predisposed
to turn to opioids when they are in
pain, even if such highly addictive GABA
drugs are not necessarily needed
[8]. Although it may seem coun-
terintuitive, the government’s
Morphine
attempt to limit the number of
prescriptions that physicians are GABA
Opioids

accumulated to over $1 trillion allowed to write for opioid drugs

and is only expected to increase in
coming years [6]. Despite the in-
creased use of registries and alter-
native or holistic therapies to limit
the over-prescription of painkill-
ers, the opioid epidemic in Amer-
ica persists, which arguably indi-
cates deeper underlying issues that
cannot be solved simply by limit-
ing the number of prescriptions
doctors are allowed to write [7].
may actually be contributing to
the problem rather than solv-
ing it. Because of this policy, in
recent years, prescription drugs
have become harder to acquire
and some individuals reliant on GABA Receptors
prescription opioids turned to
illegal drugs such as heroin and DOPAMINE
fentanyl [7]. Almost half of the
deaths linked to opioids in 2016
were due to these illicit drugs [7].

As it turns out, the opioid crisis
that America faces today can-
not be traced to just one origin;
it is a complex and multifaceted
issue that has many underlying
causes. More often than not, ad-
diction typically arises from tak-
ing a higher-than-normal dosage
in order to control pain. People
In many cases, those prone to Dopamine
addiction are not aware of other
treatment options for their pain
and instead select prescription
painkillers, which are not always
necessary. Learning about and
spreading knowledge of the opi-
oid crisis—even down to how
these drugs interact with our Dopamine Receptors

who overdose on opioids to curb
their pain often aren’t aware
of other treatment options and
rehabilitative services for pain,
so they default to opioids [8].
bodies biochemically—is crucial Opioids and morphine hyper polarize GABA
in order to ensure that we are neurons which then suppress the release of
making informed decisions and GABA. Usually, GABA inhibits the release
is the first step to effectively man- of Dopmaine– opioids, however, supress
aging this public health epidemic. GABA which then inceases the release of
Dopmaine.

references
[1] Durkin, E. (2018). US drug overdose deaths rose to record 72,000 last year, data reveals. The Guardian.
[2] (2018). Opiate Addiction/Opioid Addiction. (https://www.therecoveryvillage.com/opiate-addiction/#gref)
[3] Kosten, T., and George, T. (2002). The Neurobiology of Opioid Dependence: Implications for Treatment. Science & Practice Perspectives 1, 13-20.
[4] Poot, M., Yuska, B., and Tolen, L. (2018). Drugs and the Limbic System.
[5] Nabipour, S., Ayu Said, M., and Hussain Habil, M. (2014). Burden and Nutritional Deficiencies in Opiate Addiction- Systematic Review Article. Iranian Journal Of
Public Health 43, 1022–1032.
[6] Mangan, D. (2018). Economic cost of the opioid crisis: $1 trillion and growing faster. CNBC.
[7] Hellmann, J. (2018). What caused the opioid crisis?. The Hill.
[8] (2018). The Origin and Causes of the Opioid Epidemic. (http://www.georgetownbehavioral.com/node/2013)

fall 2018 | PENNSCIENCE JOURNAL 19

 Features

Digital
Therapeautics:
The Doctor
that Fits in
Your Pocket

By Neelu Paleti
Designed by Jessica Tan

20 PENNSCIENCE JOURNAL | fall 2018

T he first picture that comes to mind when one
thinks about pharmaceuticals is a doctor pre-
scribing a chalky white pill. Yet, this picture may
change quite significantly in the near future, where a touch
Features

of a button on your smartphone could replace the need for

that doctor. From apps about birth control to opioid addic-
tion, there are a range of digital tools that are beginning
to change the way we interact with drugs on a daily basis.
This emerging intersection between drugs and technology
is shifting the power of medical decision-making from doc-
tors to the apps and their users. Each of these applications,
with its new range of accessible, personalized treatments, is
poised to have an unprecedented impact on the way patients
receive care.
administration is diabetics who must track insulin dosage.
Whenever it is time for an insulin shot, patients must cal-
culate how much insulin to inject. Apps such as mySugr,
PredictBGL, and Diabetes:M fulfill this function through a
device that sits under the skin. The connected apps project
the predicted blood glucose levels and allow users to visu-
alize these trends. Additionally, the apps serve as daily logs
where users can input information about diet and exercise
to yield more accurate projections of blood glucose level [4].

“
By awarding points to anything from logging carbs to mak-
the emerging intersec- ing a periodic endocrinologist appointment, PredictBGL
formas its interface as a game involving healthy competi-
tion between drugs and tion between users [5]. Eventually, this can maximize pa-
technology is shifting the tient independence and efficiency, offering users a seamless
power of medical deci-
sion-making from doctors
to the apps and their
users.
“
12:00 PM

Touted to be the first FDA-approved digital birth control app,

Natural Cycles represents a new form of individualized birth
control directly available on a phone. Using daily basal tem-
perature measurements and monthly menstrual cycle data,
the application’s algorithm analyzes trends to show whether
or not the user is fertile. This algorithm observes an array of
metrics such as sperm survival, cycle length, ovulation day,
and temperature fluctuations to produce results; it displays a
red light to indicate fertility and a green light otherwise [1].
This application mainly serves to collect the necessary data
and notify users of when to take further measures to prevent
pregnancy. According to a study conducted by the European
Journal of Contraception and Reproductive Health Care,
this app is shown to be 93% effective, and by adding more
data such as luteinizing hormone test results, this app can
be more accurately tailored to the user [2]. Despite its high
success rate, Natural Cycles depends on consumer compli-
ance in recording basal temperatures five times a day for
best results. Additionally, this app’s algorithms depend on
previous body patterns; any sudden hormonal imbalances
could lead to incorrect results. Yet, amidst such drawbacks,
this app serves as an addition to the toolbox of birth control
methods, thereby reducing the necessity for doctors in wom-
en’s pregnancy and health with a smartphone [3].

Another patient population where technology can aid drug

fall 2018 | PENNSCIENCE JOURNAL 21

 Features
incentive to keep their diabetes under control through
self-monitoring. Furthermore, Diabetes:M is able to collect
data on diet and daily patterns of blood glucose or insulin
activity and send them directly to doctors, further bridging
the gap between patients and healthcare providers [6]. The
blood glucose levels that once required careful examination
at periodic checkups can now be sent remotely within mo-
ments, yet another advantage of these newer drug technol-
ogies.
In addition, smartphone apps are now able to utilize the
efficient and customizable features of the digital space to
treat a population of users coping with drug abuse and ad-
diction recovery. One such app, Triggr, can not only help
prevent cravings and relapse but also use data from screen
engagement, texting patterns, phone calls, and sleep trends
to predict an episode of relapse and provide necessary inter-
vention [7]. By initially inputting a user’s drug preferences,
relapse history, trigger words, and other personalized data,
the app’s algorithms are able to implement machine learn-
ing techniques to search for trends and alert a recovery team
member or a user’s specific care team. This offers care pro-
viders a user-friendly platform to consistently track high-risk
patients and prevent relapse and overdose with 92% accu-
racy right from their smartphones [7]. Similarly, Reset, the
References:
[1] (2018). FDA allows marketing of first direct-to-consumer app for contracep-
tive use to prevent pregnancy. U.S. Food & Drug Administration. https://www.
fda.gov/newsevents/newsroom/pressannouncements/ucm616511.htm
[2] Our research. Natural Cycles. https://www.naturalcycles.com/en/science/
research/
[3] Wakeman, J. (2018). FDA approves controversial birth control app.
Healthline. https://www.healthline.com/health-news/fda-approves-contro
versial-birth-control-app
[4] Huckvale, K., Adomaviciute, S., Prieto, J. T., Leow, M. K. S., and Car, J.
(2015). Smartphone apps for calculating insulin dose: a systematic analysis.
BMC Medicine 13.
[5] Ward, J. (2017). PredictBGL is a diabetes management app predicting fluctua-
tion in blood sugar levels. Startup Daily. http://www.startupdaily.net/2017/06/
predictbgl-diabetes-management-app-fluctuations-blood-sugar/
[6] The ultimate way to understand and manage your diabetes. Diabetes-M.
https://www.diabetes-m.com/
[7] Byrnes, N. (2017). Treating addiction with an app. MIT Technology Re-
view. https://www.technologyreview.com/s/604085/treating-addiction-with-
an-app/
[8] (2017). FDA permits marketing of mobile medical application for substance
use disorder. U.S. Food & Drug Administration. https://www.fda.gov/NewsEv-
ents/Newsroom/PressAnnouncements/ucm576087.htm
[9] Singer, N. (2018). Take this app and call me in the morning. New York
Times. https://www.nytimes.com/2018/03/18/technology/take-this-app-and-
call-me-in-the-morning.html
[10] Loy, J., Ali, E. E., and Yap, K. Y. (2016). Quality assessment of medical apps
that target medication-related problems. Journal of Managed Care & Specialty
Pharmacy 22, 1124-1140
22 PENNSCIENCE JOURNAL | fall 2018
first FDA-approved health app to target substance abuse,
can track triggers including hunger, anger, loneliness, social
pressures, and other situations to report results back to the
user’s doctor.8 Providers can then track the trends of these
triggers and cravings to either reward the user or prescribe
them further treatment.
A typical 30-day inpatient treatment costs insurers and gov-
ernment agencies, such as Medicaid, an average of $17,000
per person [9]. Furthermore, the cost of treating hepatitis
C, a disease highly associated with injection drug abuse, is
around $5 billion per year [9]. In addition to preventing
such costs, these drug technologies could spare a portion of
the expenditure spent towards rehabilitation visits and pe-
riodic doctor appointments. Using a customizable and ac-
cessible approach, these digital therapeutics could offset the
traditionally time-consuming aspects of healthcare required
“
While drug technologies
can offer a range of new
treatment possibilities,
the road to definitive dig-
ital treatments is not yet
“
complete.
for this population of substance abuse patients.
The rise of digital therapeutics offers an accessible, remote
way of interacting with drugs without the constant need for
doctor-patient interaction. However, it is imperative to con-
sider the downsides to user-based treatment avenues. Many
of these apps and the corresponding treatments rely heavily
on user compliance and the accurate input of information.
A slight mistake while logging blood glucose data or a us-
er’s failure to consistently feed data on substance abuse trig-
gers can yield incorrect results from these machine-learning
based apps [10]. In addition, such apps are often used with-
out proper medical supervision, which could cause users to
misinterpret the results. For example, insulin injections may
be taken at unnecessary times if patients misunderstand the
app’s data. This also raises the question of liability between
the app, doctors, and patients if treatment steps are taken
without proper guidance. Furthermore, treatment is lim-
ited to the patient population with access to smartphones.
While drug technologies can offer a range of new treatment
possibilities, the road to definitive digital treatments is not
yet complete. Digital therapeutics has pushed the image of
pharmaceuticals far past that of a doctor and a pill, and this
path to effective, accessible treatments continues to unfold
with the introduction of newer innovative technologies each
day.
 Features

Cannabis Oil

“C
annabis” is a term that perhaps leads
you to conjure the image of a pop pop-
ular yet illicit five-leaf plant known
for its psychoactive effects on the brain. The

A Health Trend characteristic high that marijuana induces can be

attributed to tetrahydrocannabinol (THC): the
primary active ingredient in cannabis that binds

to Weed Out? to the human brain’s cannabidiol-1 (CB1) recep-

tor and interferes with neurotransmitter signal-
ing. Yet today, cannabis also garners increasing
By Emily Lo attention from non-prescriptive drug consumers
who believe the substance could hold promising
Designed by Abi Szabo anti-inflammatory properties. They are interested
in cannabidiol (CBD), marijuana’s second most
prominent cannabinoid (chemical constituent of
cannabis), which can be contained in an insoluble
liquid extract known as cannabis oil [1].

Unlike THC, CBD does not bind to CB1 and is

fall 2018 | PENNSCIENCE JOURNAL 23

 Features
in fact legal and non-intoxicating. People use canna-
bis oil to treat conditions ranging from acne to colds,
some even speculating that it could address cancer
and Alzheimer’s Disease [2]. Major companies such as
Coca-Cola have also taken note of the substance’s in-
creasing popularity and are exploring the possibility of
incorporating CBD into “functional wellness beverages
[3].” Yet, despite recognition of cannabis oil’s potential
THese results suggest that
cannabis oil has the ability
to alleviate the frequency
of seizures among Epileptic
patients in a dose-dependent
manner.
medicinal value by researchers, industry leaders, and
average consumers alike, the product also attracts skep-
ticism as its benefits have yet to be fully characterized
and understood.
As the market for cannabis oil continues to expand on
an international scale, many are encouraged by exist-
ing evidence that the substance could improve the lives
of those suffering from specific chronic and debili-
tating illnesses. Much of this proof is anecdotal--for
instance, this past June, a story about Billy Caldwell,
a severely epileptic twelve-year-old boy from Britain,
made headlines [4]. Cannabis oil was able to alleviate
his life-threatening seizures, which intensified when
his CBD was confiscated at an airport. Following the
controversy spurred by this high-profile case, United
Kingdom Home Secretary Sajid David announced on
October 11th that medical cannabis oil will be ap-
proved for prescription use starting November 1st [5].
In addition, earlier this year on June 25th, the Federal
Drug Association (FDA) approved Epidolex, “an oral
solution of cannabis oil,” to address severe forms of
epilepsy such as Lennox-Gastaut syndrome (LGS) and
Dravet syndrome (DS), both of which are challenging
to address using other medications [6]. This followed
three phase 3 randomized double-blind, placebo-con-
trolled clinical trials that showed Epidolex decreased
24 PENNSCIENCE JOURNAL | fall 2018
the frequency of seizures when taken concurrently with
other medications by human patients [7].
The most recent of the three studies, published this
past May in the New England Journal of Medicine,
examined the efficacy of a CBD solution by collecting
data from 225 patients. Non-placebo patients were oral-
ly dosed with CBD at either 10 mg/kg of body weight
or 20 mg/kg of body weight. The researchers found
that patients treated with CBD experienced a greater
percent reduction in drop-seizure frequency compared
to the placebo group [7]. These results suggest that
cannabis oil has the ability to alleviate the frequency of
seizures among epileptic patients in a dose-dependent
manner. Furthermore, this correlation highlights the
substance’s potential to combat symptoms of epilepsy
and provide relief.
“Lennox-Gastaut is one of the most difficult epilep-
sy conditions to treat,” notes Dr. Elaine Wirrell, the
director of Pediatric Epilepsy at the Mayo Clinic and
a contributor to the aforementioned study. She adds,
“Having another treatment that holds promise to sig-
nificantly reduce drop seizures is important [7].” How-
ever, in all three Epidolex studies, adverse effects such
as sleepiness, elevated liver enzymes, and diarrhea were
also noted. Given the benefits and risks of cannabis
oil that have been uncovered thus far, Epidiolex
researcher Dr. Jacqueline French notes that
its use would need to be monitored by
a physician [7].
As CBD has yielded prom-
ising results when used
to address epilepsy and
psychological conditions, it
continues to attract inter-
est and spark hope among
patients, doctors, and
researchers seeking effective
solutions to various medical
conditions. Nonetheless,
there remains concern re-
garding the substance’s nov-
elty and the adverse effects tied
to cannabis oil. According to Marcel
Bonn-Miller, faculty at the Perelman
School of Medicine, “It’s important to know
that the research in this area is in its infancy, partly

because we haven’t really understood much about CBD
until relatively recently [9].” Scientific evidence regard-
ing the benefits of cannabis remains limited, and many
currently question the substance’s inconsistent physi-
ological impact on consumers. Considering that there
are many varieties of CBD oil with differing concen-
trations and chemical compositions, it is imperative for
future research to explore the nature of this compound
so that consumers are aware of proper dosage and
potential side effects. As Martin Lee, director of Proj-
ect CBD, remarks, “There really is a scientific basis for
understanding why CBD can work, but we’re still really
a long way of mastering the hows [1].”
As studies and success stories fuel the world’s growing
fixation on cannabis oil, the substance is likely to retain
its popularity for the time being. It may be that the
assessment of the safety and efficacy of cannabis oil
continues to pose a challenge to the scientific communi-
ty. The liquid extract also attracts increasing skepticism,
and its popularity has created the demand for scientific
proof validating its status as a billion-dollar industry
and an ever-growing health trend [1]. Yet, one thing is
certain: there is
Features
more to be discovered about this substance’s properties
and value in the medical world. While the emergence
of CBD indeed holds great promise, only time and
additional research can truly dictate how and when this
compound should be used in our lives.
References:
[1] Snyder, C. (2018). What is CBD oild and how did it become a $1 billion industry?
Business Insider. https://www.businessinsider.com/what-is-cbd-oil-how-made-marijua-
na-cannabis-plant-health-2018-8
[2 Johnson, J. (2018) Everything you need to know about CBD oil. Medical News
Today. www.medicalnewstoday.com/articles/317221.php
[3] (2018). Coca-Cola eyes cannabis oil market. Web MD. www.webmd.com/diet/
news/20180918/coca-cola-eyes-cannabis-oil-market.
[4] (2018). Billy Caldwell ‘could die’ unless given cannabis oil, says mum. BBC News.
https://www.bbc.com/news/uk-44504142
[5] Tobin, O. (2018). Medicinal cannabis oil will be available on prescription by next
month, Sajid Javid says. Evening Standard. https://www.standard.co.uk/news/uk/
medicinal-cannabis-oil-will-be-available-on-prescription-by-next-month-sajid-javid-
says-a3959866.html
[6] (2018). FDA approves first drug comprised of an active ingredient derived from
marijuana to treat rare, severe forms of epilepsy. U.S. Food & Drug Administration.
https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm611046.htm
[7] Ellis, F. J. (2018). FDA approves oral cannabidiol for Dravet and Lennox-Gastaut
Syndromes. Neurology Today. https://journals.lww.com/neurotodayonline/blog/
breakingnews/Pages/post.aspx?PostID=740
[8] Stern, C. A. J., and Gazarini, L., Takahashi, R. N., Guimarães, F. S., and Bertoglio,
L. J. (2012). On disruption of fear memory by reconsolidation blockade: evidence from
cannabidiol treatment. Neuropsychopharmacology 37, 2132-2142.
[9] Hickock, K. (2018). What is CBD oil, and does it really work? LiveScience. https://
www.livescience.com/63452-what-is-cannabis-oil.html
really work? LiveScience. https://www.livescience.com/63452-what-is-cannabis-oil.
html
fall 2018 | PENNSCIENCE JOURNAL 25
 Features

Developing Drugs:
Women in
Clinical Trials
By Rose Nagele
Designed by Julia Davies

I
n 1977, Andrea Goldstein filed a lawsuit against drug manufacturer Eli Lilly and
Company. The drug in question, diethylstilbestrol, or DES, had been prescribed to
Goldstein’s mother, Mrs. Schwartz, while she was pregnant in 1953. [1] At the time,
DES was commonly prescribed to pregnant women to prevent miscarriages. During the
1970s, it became clear that the drug was not only ineffective, but also detrimental to the
resulting children. The DES prescribed to Mrs. Schwartz caused abnormalities in the de-
velopment of Goldstein’s uterus, leading to complications with pregnancy, miscarriage, and
eventually infertility. Determining accountability for the harms of a drug prescribed and
manufactured a generation ago, however, is hardly straightforward. Eli Lilly and Company

26 PENNSCIENCE JOURNAL | fall 2018

battled the lawsuit against Andrea Goldstein for a decade as her
symptoms developed. Goldstein was only one of many women,
called DES daughters, calling for restitution for the harm caused
by DES manufacturers like Lilly. As recently as 2013, Lilly faced
yet another DES lawsuit, brought by four sisters, each of whom
had developed breast cancer in their 40s.
The fallout surrounding DES treatments illustrates the compli-
cated history of the under-representation of women in clinical
trials. DES was one of several problematic medications offered
to pregnant women in the 1950s and 60s, including thalidomide,
an anti-nausea drug that caused severe limb malformations in
newborns. These cases brought to light the differential respons-
es of men and women to certain compounds. While much has
changed in the conduct of medical research to address these nu-
ances, issues of safety and representation in drug development
continue to this day.
Every drug approved by the FDA undergoes three phases of
clinical trials that investigate both the efficacy of a drug at
treating a specific condition and the drugs safety (see figure).
Drugs are first tested on animal models before they are moved to
human subjects in clinical trials. Phase I is focused on ensuring
there are no extreme side effects and involves a small number of
patients. With each phase, the sample size becomes larger and
the questions more nuanced. This process is intended to min-
imize risk to human subjects while developing the drug. While
healthy subjects are usually used in early trials when the effects
of the drug are still hazy, in order for the drug to effectively treat
a specific illness, subjects with that condition must be included in
developmental studies.
A number of factors cause differences in the way individuals
respond to drugs. The genetic and societal differences between
men and women is just one example. Some molecular, physi-
ological, and behavioral differences between men and women
impact their susceptibility to disease their response to treatment.
Whether a person has an XX or XY genotype impacts the com-
position of hormones and chemicals in the bloodstream, organ
development, metabolism, and other physiological processes.
For example, women (XX) produce more of the hormone
estrogen, while men (XY) produce more androgens. These
hormones are thought to account for many sex-specific respons-
es to treatments such as quinidine, a drug used to treat irregular
heart rhythms. Women who are given quinidine are more likely
to have a potentially lethal reaction called “torsades de pointes”
than men who are prescribed the same drug. The different
physiological responses to quinidine among men and women
demonstrate that treatments marketed to both men and women
should undergo clinical trials that account for those differences.
The DES crisis did not immediately result in efforts to safely
include women in the drug development process, however.
Instead, the FDA implemented policies that restricted women
Features
from participating in clinical trials on the basis of protecting a
vulnerable population. In 1977, the FDA released “General
Considerations for the Clinical Evaluation of Drugs,” a guide-
line that effectively excluded women from early phase clinical
trials. In order to protect “the fetus from unanticipated expo-
sure to potentially harmful drugs,” all women “of childbearing
potential” were to be excluded from Phase I and II trials, unless
they had a life-threatening condition. A woman of childbearing
potential” was defined as a “premenopausal female capable
of becoming pregnant,” which meant that even women who
had no plans to become pregnant were excluded. This policy
received criticism for its paternalistic denial of the “autonomy
and decision-making capacity” of women. Moreover, it did
little to actually improve the quality of medications available
to pregnant women. Medical professionals had to assume that
the drugs they prescribed female patients would have the same
effectiveness and side effects as they had on men. And since
the effects on a developing fetus were virtually unknown, many
pregnant women were advised to stay off medications altogeth-
er.
The predominately male composition of the research field in
the twentieth century also biased clinical trial design. In 1978,
about 20% of medical school graduates were female. This was
up from about 6% in 1950. Roughly the same ratios existed for
students earning science related doctorates. When men are the
ones planning and carrying out research, men are more likely to
be the study subjects. Men are innately more likely to assume
the male form as a suitable model of human physiology.
Quantifying the degree to which women are disadvantaged
due to regulatory and social restrictions, however, has not
been simple. A 1994 committee on “Ethical and Legal Issues
Relating to the Inclusion of Women in Clinical Studies” stated
that determining “whether women have been disadvantaged
by policies and practices regarding their participation or by
a failure to focus on their health interests in the conduct of
research, are hindered by a scarcity of reported data.” The lack
of data, however, may have only served to reinforce the demand
for changing practices. In the 1990s, the FDA began to address
both the regulatory and social restrictions of women in clinical
trials. The 1977 restrictions were finally loosened in 1993 with
the “FDA Guidance Study and Evaluation of Gender Differ-
ences in the Clinical Evaluation of Drugs.” A Special Report
on the new guidances acknowledged that “it is possible to re-
duce the risk of fetal exposure through protocol design” without
excluding women from early clinical trials.
To ensure that those possibilities would be pursued, however,
fall 2018 | PENNSCIENCE JOURNAL 27
 Features
the FDA needed to address the bias of the male dominated
research field. An advisory group called the Office of Women’s
Health formed at the FDA in 1994 to advise officials on wom-
en’s health, recommend policy and initiatives, and promote the
inclusion of women in clinical trials. A parallel office opened at
the National Institutes of Health (NIH), the organization that
oversees the distribution of federal funds for health and science
research. The Office of Research on Women’s Health at the
monitors the inclusion of women in clinical trials and the alloca-
tion of federal grants for research on women’s health. Perhaps
the most effective way to reduce bias, however, is to increase the
diversity of those carrying out the research. An increasing num-
ber of women are entering scientific and medical professions,
and experimental designs are changing to reflect the populations
they come from.
In the early 2000s, a number of studies on the presence of
women in clinical trials indicated that representation may have
improved following these institutional changes. A 2003 review
of the inclusion of sex and gender in medical studies noted
a shift in perspective among researchers. While historically
“the research agenda” for women’s health was limited to their
reproductive capacity, research has expanded to include more
nuanced concerns for sex-based variation in disease. The au-
thor identified sex-based variation in the prevalence, symptoms
experienced, and responses to treatment for numerous diseases,
including HIV, type-2 diabetes, irritable bowel syndrome, chron-
ic fatigue, autoimmune diseases, and heart disease. Though the
literature on women’s health has grown, more research can be
conducted, as a review published in Pharmacy Practice in 2016
points out. The biological differences between men and women
are complex, with implications on cellular, physiological, and
morphological scales. The life experiences and external pres-
sures facing men and women--which are related to but distinct
from their genetic makeup--also impact their health.
While women are generally seeing more representation in
clinical trials, the issues surrounding inclusion of pregnant
women are still unresolved. Women with chronic conditions,
like multiple sclerosis, diabetes, hypertension, and psychiatric
disorders, face the decision of whether to continue taking drugs
while pregnant. There is little research on how these drugs may
interact with the physiological changes brought on by pregnancy,
but stopping treatment can pose significant risk to the mother. In
April 2018, the FDA released a draft guidance titled “Pregnant
Women: Scientific and Ethical Considerations for Inclusion in
Clinical Trials.” The document, which “contains nonbinding
recommendations,” acknowledges that “development of accessi-
28 PENNSCIENCE JOURNAL | fall 2018
ble treatment options for the pregnant population is a significant
public health issue.” Whether the guidance, which permits the
inclusion of pregnant women in clinical trials provided certain
conditions are met, results in an improved body of knowledge
regarding the effects of medications in pregnant women is yet to
be seen.
All clinical trials must balance the risk imposed on the study
subjects with the need to produce new and effective treatments.
While no drug can ever be 100 percent safe due to the complex-
ity and variation of human biology, careful adjustments to study
design can go a long way to improving treatment. The past few
decades have seen improved representation of women in clinical
trials as a result of policy changes and the recognition of women
themselves as capable researchers. This improvement exempli-
fies how equitable regulations as well as diversity in the medical
field results in the development of more effective treatments. In
order for women as well as other underrepresented populations,
such as ethnic minorities or gender-nonconforming individuals,
to have access to effective treatment, they must have a presence
in the research process.
References:
[1] Silbersweig, S. E. (1980). Payton vs. Abbott Laboratories: an analysis of the Massachusetts DES
class action suit. American Journal of Law and Medicine 6, 243-282.
[2] Rheingold, P. D. (1977). Litigation involved DES. Women Health 1, 26-27.
(2013). Settlement reached in Eli Lilly pregnancy drug linked to breast cancer case. CBS News. https://
www.cbsnews.com/news/settlement-reached-in-eli-lilly-pregnancy-drug-linked-to-breast-cancer-case/
[3] Institute of Medicine (US) Committee on Ethical and Legal Issues Relating to the Inclusion of
Women in Clinical Studies. (1994). Women’s participation in clinical studies. In Women and Health
Research. Mastroianna, A. C., Faden, R., and Federman, D., ed. (Washington DC: National Acade-
mies Press).
[4] (2017). Investigational new drugs: FDA has taken steps to improve the expanded access program
but should further clarify how adverse events data are used. U.S. Government Accountability Office.
https://www.gao.gov/products/GAO-17-564
[5] Benton, R. E., et al. (2000). Greater quinidine-induced QTc interval prolongation in women.
Clinical Pharmacology & Therapeutics 67, 413-418.
[6] (1977). General considerations for the clinical evaluation of drugs. U.S. Food & Drug Administra-
tion. (Rockville, MD: U.S. Department of Health).
[7] (2010). Diversity in the physician workforce: facts and figures 2010. Association of American Medi-
cal Colleges. https://www.aamc.org/download/432976/data/factsandfigures2010.pdf
[8] Staff Care: an AMN Healthcare Company (2015). Women in Medicine: A Review of
Changing Physician Demographics, Female Physicians by Specialty, State and Related Data (Irving,
Texas).
[9 ] National Center for Science and Engineering Statistics (2018). TABLE A-2. Citizenship status,
race/ethnicity, and sex of Ph.D.s, by field of doctorate: 1975–99 total and 5-year cohorts from 1975.
[10] Mastroianni, A., Faden, R., and Federman, D. (1994). Women and Health Research: Ethical and
Legal Issues of Including Women in Clinical Studies: Volume I. (Washington, D.C.: National Academy
Press).
[11] McCarthy, L., Milne, E., Waite, N., Cooke, M., Cook, K., Chang, F., and Sproule, B. (2017). Sex
and gender-based analysis in pharmacy practice research: A scoping review. Research In Social And
Administrative Pharmacy 13, 1045-1054.
[12] (2018). Regulations, Guidance, and Reports related to Women’s Health.
[13] Merkatz, R., Temple, R., Sobel, S., Feiden, K., and Kessler, D. (1993). Women in Clinical Trials of
New Drugs -- A Change in Food and Drug Administration Policy. New England Journal Of Medicine
329, 292-296.
[14] (2018). Office of Women’s Health.
[15] Miller, M. (2001). Gender-Based Differences in the Toxicity of Pharmaceuticals—The Food and
Drug Administration’s Perspective. International Journal Of Toxicology 20, 149-152.
[16] (2018). Medical scientists, & life scientists, all other.
[17] (2018). Physicians & surgeons.
[18] National Science Foundation (2018). Survey of Doctorate Recipients; Survey Year 2015.
[19] Pinn, V. (2003). Sex and Gender Factors in Medical Studies. JAMA 289, 397.
[20] Liu, K., and DiPietro Mager, N. (2016). Women’s involvement in clinical trials: historical perspec-
tive and future implications. Pharmacy Practice 14, 708-708.
[21] Wizemann, T., and Pardue, M. (2001). Exploring the biological contributions to human health
(Washington, D.C.: National Academy Press).
[22] Lyerly, MD, MA, A. (2018). Should pregnant women be included in clinical trials?.
[23] McCormack, S., and Best, B. (2014). Obstetric Pharmacokinetic Dosing Studies are Urgently
Needed. Frontiers In Pediatrics 2.
[24] Office of Communications, Division of Drug Information, Center for Drug Evaluation and
Research, Food and Drug Administration (2018).
[25] Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials Guidance
for Industry.

H
ow would you de-
fine addiction?
I should preface this by
saying that addiction is, to
some people, a dirty word.
Some people view it as a
pejorative term, yet it remains
widely used and recognized. In
fact, our center is the Center
for Studies of Addiction. Thus,
I’ll use the term addiction
because it remains useful. My
definition of addiction is im-
paired control over a behavior.
Substance addiction, such as
drug and alcohol addiction, is
impaired control over the use
of such substances. I empha-
size impaired control because
simply using a substance is not,
by definition, addiction. It’s
the need to actively seek and
continue to use the substance
despite knowing that its use
has adverse consequences that is the
essence of addiction.
How can precision medicine
add to the research already
being done about addiction?
Precision medicine aims to match
treatment to the characteristics of
the individual and the disease being ment research, I study the genetics
diagnosed and treated. Pharma-
cogenetics is relevant both to the
therapeutic effects of a drug and
the adverse effects of a drug. A
genetic variant, for example, could
predict who’s going to respond well
to a medication in terms of the
treatment response but it can also
predict who’s going to suffer adverse The same is true for other drugs
consequences of that medication.
If the potential adverse effects are
severe, knowing who’s at risk is very tors, which are also both genetic
important clinically.
interview
developing a substance use
disorder. However, the notion
of an “addictive personality”
is too simplistic; the origin of
substance use disorders is quite
complex.
Dr. Henry Kranzler
Interview by Tamsyn Brann In regard to the opioid
epidemic: do you think the
Henry Kranzler, M.D. is the Benjamin Rush Pro- problem can be ameliorat-
fessor of Psychiatry and Director of the Center for ed through further re-
Studies of Addiction at the University of Pennsyl- search, or are other kinds
vania’s Perelman School of Medicine. He research- of efforts required?
es the genetics and pharmacology of the treatment
of substance abuse disorders, with a specific focus As with substance use disor-
on precision medicine (the identification of specific ders, the opioid epidemic, does
medical treatments that match the characteristics not have a simple solution, as
of individual patients). His work has appeared in it is complex and multiply-de-
over 500 journal articles and other publications termined. A big contributor
and he is the Editor of the journal Alcoholism: to the epidemic has been the
Clinical and Experimental Research. sharp increase in prescribing
of opioid pain relievers by
physicians, which was promot-
ed by pharmaceutical compa-
nies and advocates for more
aggressive treatment of pain. How-
ever, there’s been a drop in the rate
Are there risk factors in a of prescription of opioids in the
person’s genome that predis- past few years. Physicians have been
pose him or her to an addictive made aware of the problem, and
disorder? Is there such a thing there are state prescription moni-
as an addictive personality? toring programs – such as in Penn-
sylvania – that require that, before
In addition to conducting treat- I prescribe an opioid to a patient, I
look up their opioid treatment his-
of substance use disorders, that is, tory, including whether they’ve been
the genetic variation (differences prescribed opioids by different doc-
in DNA sequence) that predisposes tors, which would suggest that they
people to develop a substance use may be “doctor shopping.” Solu-
disorder. It’s very clear, for exam- tions like these are new, and they
ple, that alcohol dependence is 50 have begun to reduce over-prescrib-
percent heritable, which means that ing of these drugs. A troublesome
it’s also 50 percent environmental. trend that has contributed to the
continued rise in the opioid over-
as well, including opioids, cocaine, dose death rate is that many people
and cannabis. Psychological fac- who first became dependent on pre-
scribed opioids have turned to using
and environmental, contribute to illicit opioids – heroin and the much
fall 2018 | PENNSCIENCE JOURNAL 29
 interview
more potent synthetic opioid fentanyl.
What made you pursue this particular branch
of research?
I started by doing research on medications to help
treat alcohol use disorder. There are three medications
that have been approved to treat the disorder, and I
participated in some of those development efforts.
However, the medications have comparatively modest
treatment effects. The reasons for that include the fact
that alcohol (unlike opioids or nicotine, for which there
are specific binding sites, which multiple medications
target) has no specific receptors that can be targeted for
treatment. Thus, it is much harder to find a drug that’s
likely to exert a large treatment effect in patients with
an alcohol use disorder. Around the time that I began
conducting treatment research, I began collaborating
with a colleague at Yale on the genetics of alcohol use
disorder, which then progressed to studies of cocaine,
opioid, and cannabis use disorders. Those efforts led us
to identify genetic variants that appeared to predict the
response not only to drugs of abuse but also to thera-
peutic drugs.
Is pharmacogenetics the same as precision
medicine?
Pharmacogenetics is a major component of precision
medicine. Another approach involves animal models
that can be used to inform precision medicine research
in humans. However, one problem with animal stud-
ies is that the findings may not generalize to humans.
Although humans and rodents, for example, are mam-
mals, there are some big species differences. For exam-
ple, most animals won’t self-administer alcohol, so there
are procedures that have been developed to facilitate
alcohol self-administration studies in animals.
Have you worked with animal models before?
Not directly, but I collaborate with animal research-
ers. I am currently working with Mariella De Biasi, a
neuropharmacologist here at Penn. Her laboratory is
researching a topic that is of particular interest to me
and is related to pharmacogenetics. It is a study of an
experimental medication that blocks GluK1-containing
kainite receptors, a specific kind of glutamate receptor.
Glutamate is the most abundant excitatory neurotrans-
mitter in the brain. We chose to look at this receptor
subtype because, in a prior study of the medication
topiramate in humans, we found that variation in the
30 PENNSCIENCE JOURNAL | fall 2018
gene encoding the GluK1 subunit implicated it as a
key target for reducing heavy drinking. Dr. De Biasi’s
lab has followed up on that human finding in a mouse
model of alcohol drinking to determine the mechanism
of the pharmacogenetic effect.
Do you find that between the work you’ve done
peripherally with animal models and your own
work with humans that there’s a specific advan-
tage with using human models?
I have chosen to work with humans because I am
interested in improving the human condition, and it’s
much more direct to do that by working with humans.
That said, a lot of what we know about human genet-
ics and pharmacology has been gained through animal
research and it’s a very useful way to identify molecular
mechanisms of effects seen in humans.
What is the focus of your current research?
About 20 years ago, I began looking for an easily mea-
sured genetic moderator that can be used to identify
people who are likely to respond well to a medication
to reduce heavy drinking. This ultimately led to a study
of topiramate, which we completed and published, and
which enabled us to obtain funding to do a replication
study. That study, which were doing at Penn, should be
finished in the next year. To date, we have randomized
nearly 150 patients to treatment with topiramate or
placebo based on their genotype to see whether we can
validate our initial findings. I am also conducting two
other pharmacogenetic trials, one to treat alcohol use
disorder and the other smoking cessation in pregnant
women. Finally, I am conducting multiple studies of
the genetics of alcohol and drug use disorders.
What advice would you have for undergraduates
looking to get into the field of research?
Start early. Give yourself time to find out what you
really like because you have to have a passion for re-
search to enable you to stick with it. It requires a lot of
commitment and there will be disappointments along
the way, but if it excites you and satisfies a burning
curiosity, it’s a wonderful career option. To sustain a
research career, you have to get research funding, which
is difficult, and if you don’t have a “fire in the belly,”
as they say, you’re going to lose interest. It’s best to find
out early whether research excites you. If you love it,
it’s worth the effort. That said, however, what you find
exciting early in your college career may not excite you
later, so it’s hard to predict where your interests may
take you. My bachelor’s degree waas in anthropology,
and I thought I was going to do anthropological field
work, but I ended up doing much more biologically-ori-
ented research. The bottom line, though, is that you
should pursue your passions and see where they lead
you.

W
hat is your area
of research?
My research focuses on iden-
tifying the neural features that
predict and/or maintain sub-
stance use or relapse, as well
as the consequences of alco-
hol and substance use on the
brain. This research involves
integrating several research
approaches, including genet-
ics, neuroimaging, neuropsy-
chological assessments, and
clinical trials.
What does your research
suggest about the differenc-
es between addiction in men
and women?
Men and women are different,
not surprisingly. Males typical-
ly initiate substance use at an
earlier age, but women escalate
use more quickly. Females are
also at greater risk of negative
Features
Dr. reagan
wetherill
Interview by Asha Dahiya
From a biological
Dr. Reagan Wetherill is an Assistant Professor and perspective, how
Licensed Clinical Psychologist at the Center for does substance
Studies of Addiction in the Department of Psy- addiction affect the
chiatry at the Perelman School of Medicine at the brain?
University of Pennsylvania. Dr. Wetherill’s training
and research experience encompass both basic and From the perspective
clinical neuroscience, and her program of research of a neuroscientist,
integrates genetic and neuroimaging approaches to there are stages of
help elucidate the etiology of alcohol use disorder, addiction with brain
cannabis use disorder, and nicotine use disorder processes that under-
and to optimize pharmacological treatments. lie each stage. The
limbic area, or reward
network, is the key
network underlying
health-related consequences. addictive behaviors,
For example, female smokers and as such, plays a role in all
are at greater risk of developing stages of addiction. The first
lung cancer, death from chronic stage is often described as the
obstructive pulmonary disease, binge/intoxication stage. Anoth-
and so on. There are hormones er side of addiction is when the
at play there, particularly estro- drug is not present in the brain
gen. Substance use is harmful and we see a heightened state of
to everyone, but for women, the negative affect and stress. Over
effects of use seem to be more time, the changes that go on in
severe. the brain because of repeated
use leads to tolerance and crav-
fall 2018 | PENNSCIENCE JOURNAL 31
 Features
ing. These stages culminate into preoccupation when
the person spends a great deal of time thinking about,
obtaining, using and recovering from using.
You have conducted research on cannabis, nic-
otine and cocaine. What are the differences be-
tween how addiction develops for each of these
substances?
Each drug works on a different receptor system, but all
of them affect dopamine, which is the primary neu-
rotransmitter for the limbic system. Those that directly
hit the dopamine system, such as cocaine, have a much
quicker and more powerful effect than, say, marijuana,
which affects the endocannabinoid system. These drugs
still work along the same neural networks, but through
different processes.
What kind of pharmacological treatments exist
to treat substance addiction, and how do these
treatments work?
Essentially, there are agonists and antagonists that can
either mimic or block the drug from causing their usual
effects. What we do here [at the Treatment Research
Center] is try to find the best fit for the individual.
One of the studies Dr. Kranzler, the Center Director,
and I are working on now is a prospective examination
of whether a genetic polymorphism in a specific SNP
[single nucleotide polymorphism] moderates treatment
response to Topimarate (which is not yet approved for
alcohol use disorder), but has been shown to reduce
heavy drinking days in individuals with alcohol use
disorder. Foreseeable, we could one day have a person
come in, screen them, and then match them to the
medication that works best for that individual. In gener-
al, research suggests that treatment response to phar-
macotherapy for alcohol and substance use disorders
is modest, which pushes the drive towards precision
32 PENNSCIENCE JOURNAL | fall 2018
medicine.
You have conducted research on drinking
among college-aged students and on the link
between drinking, sexual activity and perceived
risk. What kind of drinking patterns are pres-
ent in this demographic, and what is their so-
cial and behavioral impact?
That’s a big area of research that I’ve spent quite a lot
of time in. Essentially, the type of drinking behaviors
that we see quite often among college-age individuals is
the binge-drinking or heavy episodic drinking pattern;
drinking large amounts of alcohol over short periods.
An area of research I have worked on is alcohol-in-
duced blackouts. That is, memory loss for all or part of
a drinking episode. Alcohol-induce blackouts have been
reported by 40-50% of college students who consume
alcohol.
Do you find that these patterns are indicative
of addiction later in life?
It’s an interesting thought. Research suggests that
people mature out; that is that once a person leaves the
college environment and takes on more responsibilities,
the lifestyle of drinking doesn’t fit well with managing
and maintaining adult roles, such as having a career,
spouse, or children, so many individuals stop engaging
in binge-drinking behavior. However, there is a sub-
set that continues on and maintains the high level of
alcohol consumption regardless of life changes. Several
factors likely contribute to maintaining that type of
behavior.
In your opinion, what are the most critical sci-
entific questions surrounding substance addic-
tion that have yet to be answered?
One of the big topics that is underway right now is
identifying the brain structures and behaviors that
influence neurodevelopment and contribute to alcohol
and substance use before a person initiates use. It could
and will hopefully provide information that we need to
improve prevention and treatment efforts.
Another big area of interest would be finding a treat-
ment that works for the masses. That is why we do what
we do and try to help as many people as we can until
we get there.
 RESEARCH

Electrochemical Oxidation of
Formate on a PdNi/C Nanoparticle Catalyst for
Renewable Energy Conversion and Storage
Sai Mamidala
Center for Automation Technology, Drexel University, Philadelphia, PA, USA
Acknowledgments: This research was conducted from June 20 to September 1, 2017 at the Center
for Automation Technology at Drexel University under the guidance and mentorship of Dr. Joshua
Snyder.
Abstract:
Rising global temperatures are increasingly being attributed to excess CO2 in the Earth’s atmosphere,
commonly generated by the use of nonrenewable energy sources such as coal and natural gas. Address-
ing the large disparity between peak energy demand and peak energy production by renewable sources
requires the development of reliable methods/devices for the storage and conversion of the generated
power. This study examines the utility of formate as an electrochemical fuel through the assessment of
the activity and mechanistic progression of the half-cell electrooxidation of formate. We show that a
catalyst composed of palladium-nickel alloy nanoparticles supported on high surface area carbon is both
active and operationally stable during extended polarization as assessed by metrics including peak current
density, rate of decay, and intrinsic activity. Pd-Ni/C exhibits clear performance superiority to more tra-
ditional materials including Pd/C and Pt/C. We also assess mechanistic shift in the reaction progression
for alloy catalysts, including any changes to a rate determining step, by determining the kinetic isotope
effect through the comparison of formate oxidation activity of regular and deuterated formate. The exact
mechanisms of formate oxidation on the three catalysts (Pt/C, Pd/C, Pd-Ni/C) are also discussed here;
the slightly different properties and compositions of each of the catalysts analyzed in this study prove to
have a visible effect on the mechanisms and therefore the performance metrics of the catalysts themselves,
as relevant to the formate oxidation reaction.

Intro/Background: organic compounds such as methanol and formic acid has

While Earth’s current climate change crisis can be traced
back to a variety of factors, the abundance of “greenhouse
gases” in the atmosphere is cited as contributing signifi-
cantly.18 The increase in both rate and quantity of CO2
released into the atmosphere is a confluence of multiple
events and processes; the burning of fossil fuels is arguably
the most detrimental. Nonrenewable energy sources ac-
count for about 85.1% of the United States’ annual energy
production, and over 5.1 billion metric tons of CO2 was re-
leased by the US energy sector in 2016 alone.15 The prob-
lem is not limited to the United States; coal, a nonrenew-
able energy source, is responsible for 41% of the world’s
electricity needs, while renewable sources account for just
21%.14, 10 This disparity underscores why research into
new energy storage and conversion devices is necessary; the
development of technologies to either capture atmospheric
CO2 or limit its continued release into the atmosphere.20
The reaction of electrochemical CO2 reduction to small
recently been a popular area of research as it presents a
possible method of renewable energy storage in the form
of chemical bonds.22 Renewable sources such as solar or
wind power can be used to power these reduction reac-
tions.22 Oxidation of these reduced fuel molecules in a
fuel cell device can then extract the stored energy to power
devices and processes during off-peak hours. Following
this rationale, a combined system if devised in the future
may function as a device to both generate and store pow-
er. The formate oxidation reaction, a method of power
generation, would be coupled with the reverse reaction,
CO2 reduction, a potential technique for storing energy.
Such a device, for which many further developments are
necessary, would have a number of practical applications
in addition to increasing the viability of energy production
through renewable sources. For example, in a submarine or
spacecraft, where hostile outside conditions prevent crews
from being able to utilize a large amount of resources, the

fall 2018 | PENNSCIENCE JOURNAL 33

 research
CO2 reduction reaction could be used to store energy,
remove CO2 from the enclosed atmosphere, and generate
O2 gas. The formate oxidation reaction could then be used
in situations when emergency power generation capabilities
are necessary.
Over the last few decades, extensive work on for-
mate/formic acid electrochemical oxidation has outlined
the predicted mechanisms of the reaction and explored the
process’s properties, advantages, and limitations on various
electrocatalytic materials.5 Formic acid oxidation, which is
analogous to the formate oxidation reaction, can take place
through one of two distinct mechanisms. One pathway goes
through an active intermediate, not only producing current
but also leaving the active site cleanly and efficiently for the
next molecule of reactant to be catalyzed into product
(direct pathway). The second pathway goes through an
alternate intermediate which tends to adsorb strongly onto
the metal surface, severely blocking the number of available
active sites on the catalyst (indirect pathway).23, 3 This
dual-mechanism proposal is frequently discussed in the
literature and generally accepted in the field of electrocatal-
ysis.24, 25 CO was effectively identified as the likely poison
intermediate in the second pathway, but finding, definitively,
the active intermediate and its subsequent relevant mecha-
nism has proved challenging due to the short lifetime of the
intermediate species during the reaction.3
However, it is known that formate oxidation occurs slightly
differently on different catalysts because of each catalyst’s
unique properties.2 A small change in the composition of
a catalyst can have large effects on the resulting maximum
current density, rate of decay, etc when tested for the for-
mate oxidation reaction, which is why a study of different
metals and their behaviors as catalysts is necessary. A widely
accepted and mathematically rigorous hypothesis which
helps predict how certain metals may function as cata-
lysts using thermodynamics is Density Functional Theory
(DFT), which was employed to create an “activity volcano”
predicting binding strengths for metal catalysts. This is
especially important for the design of catalysts because it
translates the complex compromising of binding strengths
of key reaction intermediates (binding too strongly leads
to catalyst poisoning, while binding too weakly inhibits the
progress of the reaction itself) into a simple one-dimension-
al optimization problem with an ideal catalyst being near
the top of the volcano. DFT and the activity volcano have
been historically fairly accurate when making inferences
about specific catalysts’ binding strengths, and we predict
that our alloy catalyst, Pd-Ni/C, will yield more optimal
34 PENNSCIENCE JOURNAL | fall 2018
results than plain Pd and Pt, which are already at a high
position on the volcano.7
This paper will include a thorough discussion of the Pd/C,
Pt/C, and Pd-Ni/C catalysts, their properties, and overall
performance metrics in various solutions, with accompa-
nying graphs. We will also provide evidence for the differ-
ence in the mechanisms for the formate oxidation reaction
on the Pd/C and Pd-Ni/C catalysts, which will increase
our understanding of how the formate oxidation reaction
proceeds on different surfaces. We aim for these conclusions
to assist in the future design of catalysts to be used in formic
acid/formate fuel cells.
Experimental:
The Pd/C and Pd-Ni/C nanoparticles were synthesized
using a solvothermal process. Catalytic electrodes were
made through drop-casting of a catalyst ink. Transmission
electron microscopy and scanning TEM were performed
to visually characterize the microstructure of the nanopar-
ticles; energy-dispersive X-Ray spectroscopy was used to
measure Ni and Pd fractions.
Results & Discussion:
(1) Material Characterization
In this study, commercially-made Pt catalyst and our as-
made Pd catalyst serve as respective controls to compare the
relative functionality of the Pd-Ni/C catalyst. Pd-Ni/C, a
catalyst carrying the properties of an alloy into the elec-
trochemical testing, was chosen to benefit from both the
inherent advantage of using Pd as the parent metal over Pt
and that of another metal bonded into the lattice structure
of the metal. While its potential as an effective catalyst for
CO2 reduction has been recently examined, an assessment
of its performance for the formate oxidation reaction was
necessary.9
(2) Electrochemical Characterization
Although the mechanism of the formate oxidation process
is not completely certain, some probable conjectures do
exist.26 Research done previously concerning formate/
formic acid oxidation points out that certain characteristics
of Pd based catalysts give them higher current densities
than Pt based catalysts. The high activity of Pd for hetero-
geneous hydrogenation reactions has been anecdotally tied
to its ability to adsorb as well as absorb hydrogen.27 With a
H/Pd ratio near 0.7, Pd readily forms a hydride at electro-
chemically relevant conditions.4 This is in contrast to Pt,
which can only form surface adsorbed H and cannot form
a hydride. It has been proposed that this hydride behavior
partly contributes to the differences in formic acid/formate
oxidation between Pd and Pt.1 The formate oxidation
reaction on a Pt catalyst proceeds via a dual mechanism
(indirect pathway), with one pathway utilizing an active in-
termediate, likely COO2-, and the other pathway allowing
the formation of a strongly adsorbed intermediate species,
CO, which most likely CO.4 This CO poisons active sites
of the catalyst, decreasing the electrochemically active area
over time and eventually resulting in complete deactivation.
It has been purported that formic acid/formate oxidation
on Pd progresses through a direct mechanism, avoiding the
formation of CO and resulting in faster rates and greater
operational stability, lower degree of intermediate poison-
ing.22
for adsorbed formate and the recorded oxidation current,
evidence of the effects of differing Figure 2 contains the
format oxidation CVs for Pt/C and Pd/C where the cur-
rents have been normalized by the electrochemically active
surface area (ECSA) of the electrodes. ECSA is calculated
from the charge due to the oxidation of a surface layer of
adsorbed hydrogen. In Figure 2, it is evident that Pd/C
exhibits both higher oxidation currents as well as a lower
potential separation between the anodic and cathodic peaks
which is an indication of the superior poisoning tolerance/
avoidance of the Pd/C catalyst.
The Pd-Ni/C catalyst was synthesized as a 75/25 at. %
alloy of Pd and Ni, respectively. A core-shell structure is
formed upon annealing in H2/Ar where the surface is pas-
sivated in several atomic layers of Pd with a high concentra-
tion of Ni in the underlying atomic layer, as has been shown
for other platinum group metal alloys.9 Formation of this
Pd-skinned structure results in a change in the surface
lattice parameter the valence electronic structure of the sur-
face atoms.3 In addition to their strong adsorption of CO,
Pd and Pt bind the active intermediates of formic acid/
formate oxidation too strongly.26 The modification of the
valence electronic structure of the surface through alloying
effectively weakens the adsorption strength of both poison-
ing species and active intermediates, improving reaction
rates for a range of electrochemical reactions.26 Nørskov et
al. have used ‘d-band theory’ to model changes in surface
reactivity due to alloying as well as provide a metric for pre-
dicting the activity of different materials.12 The chief prin-
ciple underlying the theory is that the binding energy of an
RESEARCH
adsorbate to a (pure or alloy) metal surface is largely depen-
dent on the electronic structure of the surface itself.11 This
model uses the d-band center (εd) shift, with respect to the
reference, or Fermi, level as a measure of tracking the vari-
ation of electronic structure, binding strengths, and corre-
sponding changes in the catalytic activity.5 εd is controlled
and affected by a variety of factors, including shape of the
d-band, how full the d-orbital is, and the distances between
the atoms of the lattice. In addition, the type of metal that
Pd is alloyed with determines the degree and sign of strain
that the surface metal atoms experience.1, 28 The position
of εd is known to have an approximately linear correlation
with the binding energy of adsorbed intermediates, chiefly
those composed of hydrogen or oxygen, and consequently
the catalytic activity with respect to electrochemical formate
oxidation.7 Depending on whether the second metal has
a larger or smaller lattice constant, which is the physical
parameter of unit atoms in the lattice, than the parent, εd
will shift up or down, the d-band will become narrower
or broader, and the overlap between the d-orbitals of the
parent and second metal decreases or increases, respective-
ly.16 This shifting of the d-band center and charge trans-
fer affects the corresponding binding energy of reaction
intermediates, with a higher εd resulting in stronger bond-
ing and a lower one resulting in weaker bonding of organic
molecules to a metal surface.5 Pd-Ni alloys fall into the
latter case: Ni, the metal being alloyed with its parent, Pd,
has a smaller lattice constant than Pd (352.4 pm for Ni >
389.1 pm for Pd). Therefore, this leads to a compressive
strain effect that facilitates the overlap of the d-orbital of
Pd, lowering εd, which we speculate ultimately leads to
an optimal adsoption/desorption balance during formate
oxidation. The d-band center may also be shifted down by
a phenomenon known as the ligand effect, in which, ac-
cording to calculations from Density Functional Theory, the
electrons from less noble metals such as Ni tend to shift to
more precious metals such as Pd.5 Alloying palladium with
other non-precious metals lowers εd, by both altering the
electronic structure and introducing a degree of irregularity
into the palladium lattice, which in turn causes the resulting
alloy to bind oxygen or other small organic compounds
more weakly than pure palladium would. It is established
that this effect lowers the binding energy for adsorbed
poison intermediates, most prevalently CO in this case.
This, therefore, allows for not only a lower rate of decay,
as poison intermediates will not be permanently adsorbed
as easily or as quickly, but also higher current densities
relating to the formate oxidation reaction because less of
fall 2018 | PENNSCIENCE JOURNAL 35
 RESEARCH
the catalyst active sites will be taken up by adsorbed poison
intermediate species.16 This is important because it points
out the potential advantages of a metal alloy catalyst, more
specifically Pd-Ni, over a pure metal catalyst. Ni was chosen
here because when alloyed with Pd, it decreases the adsorp-
tion strength of intermediates, in addition to producing a
homogenous alloy in the specified ratio.6 Verification of
the hypothesized comparison of peak current densities can
be found in Figure 3: the ECSA normalized peak current
densities produced by a Pd-Ni/C catalyst are significantly
higher than those produced by a pure palladium or even a
pure platinum catalyst. We propose that this difference is
due to the weakened interaction between the Pd-Ni/C and
the active adsorbed intermediate, increasing the rate of the
reaction propagation as a function of applied potential.
As previously considered, a catalyst’s rate of decay is also
a useful method of characterization. The rate of decay,
when normalized by the initial current for each catalyst to
create an accurate standard of comparison, gives a measure
of the catalyst’s operational durability and is obtained by
potential holding and observing the behavior of the cata-
lyst’s decaying activity (overall/initial speed of decay, time
taken for activity to fully diminish, etc.). Figure 4 shows
the current transient for the Pd/C and Pd-Ni/C during a
constant potential hold at 0.3 V vs RHE. Although some
poison species builds up on both the Pd/C and Pd Ni/C
catalysts, it is evident that the rate of decay is much slower
for Pd Ni/CSince it is clear that some poison species does
build up on both the Pd/C and Pd-Ni/C catalysts, they
both exhibit some degree of decay in activity over time.
However, it is evident that the rate of decay is much slower
36 PENNSCIENCE JOURNAL | fall 2018
for Pd-Ni/C. We purport that this difference is due to the
weakened interaction between Pd-Ni/C and intermediates
including CO as well as other active, oxidized species. This,
again, is reflective of the fact that the Pd-Ni/C catalyst does
not bind poison intermediates as strongly as Pd/C; stronger
binding of poison intermediates during the reaction would
lead to quick buildup of adsorbed poison on the available
active sites on the catalyst and consequently a faster initial
rate of decay.
To gain more insight into any potential mechanistic
shifts, including any changes to the rate determining step of
the reaction mechanism as a consequence of alloying, we
measured the kinetic isotope effect (KIE) for formate oxida-
tion on Pd/C and Pd-Ni/C. We probed the relative impor-
tance of the first dehydrogenation step...Comparing the rel-
ative current densities for the oxidation of HCOO- versus
DCOO-, we can probe the relative importance of the first
dehydrogenation step, HCOO-/ DCOO- —> H+/D+ +
COO2-. Replacing H with D deliberately introduces a slow
step as D is a heavier isotope and generally reacts with slow-
er rates than the lighter H.8 For Pd/C, a clear KIE exists
where significant decrease in oxidative current is observed
for DCOO- in comparison to HCOO-, Figure 5. As shown
in Figure 6, however, no KIE is observed for the Pd-Ni/C
electrocatalysts. The oxidative current densities on Pd-Ni/C
when tested in 0.1 M KHCO3 + 0.01 M NaHCOO and
0.1 M KHCO3 + 0.01 M NaDCOO solutions are nearly
identical, showing that this catalyst’s mechanism is not as
drastically affected by the heavier hydrogen atom. From
these observations we are able to draw some conclusions.
Since the deuterated formate solution affected the behav-
ior of the Pd/C but not the Pd-Ni/C catalyst, the formate
oxidation mechanisms must differ on each catalyst such that
the dehydrogenation step is the rate-limiting step on Pd/C
catalyst but not Pd-Ni/C. This result gives insight into the
properties of the formate oxidation reaction’s mechanism
on an alloy such as Pd-Ni/C, especially when compared to
pure metals such as Pd. By better understanding the pro-
gression of this mechanism, more active and stable catalysts
can be designed for improved device power and efficiency
as well as reduced cost. Future work will focus on further
elucidation of the exact elementary reaction steps that gov-
ern formate oxidation of Pd alloy nanomaterials.

Conclusions:
In this study we examined the properties of Pd-Ni/C cat-
alyst with respect to the formate oxidation reaction. These
properties were evaluated by comparing to two control cat-
alysts, Pd/C and Pt/C. We consistently see the advantages
of using a Pd-Ni/C alloy nanoparticle catalyst. In the cyclic
voltammogram depicting a test in a 0.1 M KHCO3 + 0.01
M NaHCOO electrolyte, the Pd-Ni/C catalyst outperforms
both Pd/C and Pt/C in peak current density. The potential
hold experiment at 0.3 V makes evident the decreased rate
of decay for the Pd-Ni/C catalyst in comparison to Pd/C.
The reasons for these results can be traced back to the fact
that Pd-Ni is an alloy, and its structure brings the properties
unique to alloys, such as modified electronic structure, to
the overall catalyst. These properties are proven here to
have a positive impact on the formate oxidation reaction by
optimizing the binding strength of key reaction intermedi-
ates while eluding the negative effects of strongly adsorbed
poisons. In addition, a further experiment designed to test
one part of the formate oxidation mechanism, the dehy-
drogenation step, revealed that it is the rate determining
RESEARCH
step of the reaction on Pd/C but not on Pd-Ni/C, which is
not significantly affected by the heavier H isotope. All these
results provide important insight that may be used for the
design of next generation formic acid/formate oxidation
electrocatalysts for application to efficient, reversible renew-
able energy storage and conversion.
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pendent Statistics and Analysis.” What is U.S. electricity generation by energy source? - FAQ - U.S. Energy
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16 Witte, Jon. “D-Band Theory - ORR Catalysis with Pt-based CSNPs.” ORR Catalysis with Pt-based
CSNPs. December 13, 2011.
17 Leahy, Stephen. “Hidden Costs of Climate Change Running Hundreds of Billions a Year.” National
Geographic. September 27, 2017.
18
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“Climate change causes: A blanket around the Earth.” NASA. August 10, 2017.
Harvey, Chelsea. “Scientists Can Now Blame Individual Natural Disasters on Climate Change.”
Scientific American. January 02, 2018.
20 London Battersea Power Station. “Promising technologies to reduce power plant emissions - Horizon
2020 - European Commission.” Horizon 2020: The EU Framework Programme for Research and Innova-
tion. June 01, 2017.
21 “Greenhouse Gases Explained: Where Greenhouse Gases Come From.” US Energy Information
Administration. July 7, 2017.
22 Kortlever, Ruud, Collin Balemans, Youngkook Kwon, and Marc T.m. Koper. “Electrochemical CO2
reduction to formic acid on a Pd-based formic acid oxidation catalyst.” Catalysis Today244 (2015): 58-62.
23 Markovic, N. “Structural-effects in electrocatalysis Oxygen reduction on the gold single crystal elec-
trodes with (110) and (111) orientations.” Journal of Electroanalytical Chemistry 165, no. 1-2 (1984): 121-33.
24 Climent, Vı́ctor, Enrique Herrero, and Juan M. Feliu. “Electrocatalysis of formic acid and CO oxida-
tion on antimony-modified Pt(111) electrodes.” Electrochimica Acta 44, no. 8-9 (1998): 1403-414.
25 Vidal-Iglesias, F. J., J. Solla-Gullón, E. Herrero, A. Aldaz, and J. M. Feliu. “Formic acid oxidation on
Pd-modified Pt(100) and Pt(111) electrodes: A DEMS study.” Journal of Applied Electrochemistry 36, no. 11
(2006): 1207-214.
26 Min, Xiaoquan, and Matthew W. Kanan. “Pd-Catalyzed Electrohydrogenation of Carbon Dioxide
to Formate: High Mass Activity at Low Overpotential and Identification of the Deactivation Pathway.”
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fall 2018 | PENNSCIENCE JOURNAL 37
 research

Modifying Reaction Diffusion: A Numerical Model for

Turing Morphogenesis, Ben-Jacob Patterns, and Cancer
Growth
Kai Trepka
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA

Abstract:
Modeling the development of organisms and diseases has been of interest for decades. Often, complex
systems of development or signaling pathways can be explained and modeled to a high degree of accu-
racy with only a few simplifying assumptions. Complex systems such as pattern development, bacterial
growth, and tumor formation can be modeled numerically using a reaction diffusion model with relatively
few factors and still give accurate results, allowing exploration of equilibrium and non-equilibrium solu-
tions. Here, applications of such an approach to a few model problems are presented – morphogenesis,
bacterial growth, and cancer treatment.

Mathematical Background and Model:

The Diffusion Equation
Given a collection of small particles (for example
bacterial nutrients, or oxygen in water) and a hetero-
geneous concentration profile, over time the particles
will be pushed by random thermal fluctuations into a
more homogeneous (i.e. uniform) profile. This gives
us a flux, j, that scales with the diffusion constant, D,
and the concentration gradient.
System Validation: Gaussian Fitting
As a basis for this model, I wrote a 2D Laplacian
operator in Matlab and verified that the concen-
tration profile of a diffusing point source fits to the
appropriate Gaussian (as it should – we see Green’s
function gives a Gaussian concentration profile.) The
concentration profile after 1000 timesteps is shown in
Figure 1.

This tells us that the flux of particles is higher near

“pointier” places in the concentration profile (caus-
ing us to expect fractal-like growth in certain sys-
tems). Plugging this into Fick’s law, we obtain the
final diffusion equation of a collection of particle
concentrations C over time, i.e.

Figure 1: System Validation

38 PENNSCIENCE JOURNAL | fall 2018


Animal Morphology:
Model: Small Fluctuations around Equilibri-
um
How do animals get their shapes? At a biochemical
level, various complicated signaling pathways are in-
volved (Fgf, Bmp, Hedgehog, and Notch, for example
[1]). However, Alan Turing proposed that complex
pattern formation can be described by a reaction
diffusion system with at least two factors, with minor
random or directed fluctuations from a homogeneous
equilibrium resulting in a very heterogeneous final
distribution, for example leopard spots and zebra
stripes [2]. Turing solved this system by linearizing
around the steady state, which yields interesting pat-
terns in and of itself, but has important limitations in
that we can’t know the behavior at long timeframes.
To model this numerically, I adopted the following
system using two dummy morphogens (factors that
affect animal growth) A and B:
Suppose the diffusion coefficients of A and B are 0.5
and 4.5, respectively, in arbitrary units. Also sup-
pose that the change in concentrations over time are
defined by
Initialize a uniform system at a steady state (i.e. with
no perturbations, there will be no changes). Consider
the case
Define the numerical value of a small fluctuation
(this represents random perturbations from the envi-
ronment),
Randomly generate pairs of fluctuations (these
represent elements being thermally bounced “back
and forth”,) where the first element in the pair has
concentrations A1, B1, and the second has concen-
trations A2, B2, where
RESEARCH
I then investigated the behavior by varying a-d, as
well as the locations of pairs relative to each other
(i.e. are the points in the pairs right next to each oth-
er, one apart from each other, or in totally random
locations entirely).
Results and Conclusions
Varying the values a-d results in changes in the
density of heterogeneous defects/lines in the steady
state – higher (absolute) values of coefficients result
in more dense patterns (see Figure 2). This means the
difference between an animal with very complicat-
ed patterns everywhere and one with larger spots/
defects may be varying reaction rates based on local
concentrations.
Figure 2: Steady state patterns of systems with 1000 random-
ly located point pairs. In the left image, a = 100000,
b = -100001, c = 100001, d = -1000002. In the right
image a = 5, b = -6, c = 6, and d = 7.
Pair location has little effect – if each point is ran-
domly located (i.e. each point is not next to its cor-
responding point, A1 defect is not next to the A2
defect), it produces the same patterns as if each point
in the pair is one apart (i.e. A1-normal-A2 in a row).
However, if each pair is right next to each other, i.e.
the point with the A1 defect is directly adjacent to
the point with the A2 defect, the changes, the defects
end up canceling each other out in the long-run,
resulting in homogeneity.
This is just one example of the failure of the linear-
ization approximation (i.e. long-term stability even
with predicted short-term non-equilibrium pertur-
bations). Turing’s approximation is useful for some
patterns, but over time some smaller aspects of these
fall 2018 | PENNSCIENCE JOURNAL 39
 research
patterns disappear – this is why it is useful to numer-
ically model the full timescale of pattern formation
so we know the behavior at equilibrium, rather than
just the behavior after short-term perturbations (see
Figure 3).
Figure 3: Short-term (linear) approximation (left) vs long-term
steady-state (right)
Future Directions
We have shown it is possible to numerically model
Turing pattern formation, the effects of tweaking
parameters such as number of defect and governing
constants, and potential developmental relevance. To
improve on this model and understand arbitrary pat-
terns, it would be useful to consider increased num-
bers of morphogens (rather than just using Turing’s
simplified system with two morphogens linearized
around the steady state), as well as considering more
complicated reactions.
Modeling Bacteria in Non-Equilibrium
Growth Model:
Adding Growth
While reaction diffusion on its own leads to inter-
esting patterns and conclusions, it is instructive to
incorporate growth into the model, given that cells
do not exist in a static environment and are constant-
ly considering whether to synthesize a new copy of
their DNA and divide of the conditions are right.
Ben-Jacob observed interesting growth regimes when
growing bacteria on agar with different peptone con-
centrations (see Figure 4) [3,4]. Our goal was to see
if we could simulate and obtain the same patterns
40 PENNSCIENCE JOURNAL | fall 2018
mathematically, using reasonable physical constants.
Figure 4: Bacterial Patterns from [6] (Empirical). Peptone
concentrations of 0.1, 1, 3, and 10 g/l, respectively (a-d).
To model bacterial growth, we assumed each pix-
el represents one bacterium – a bacterial radius is
about 5 um, so a pixel is about 10x10 um, and each
pixel is one bacteria. Each bacterium has a certain
uptake rate of nutrients, and will divide when the nu-
trient concentration inside exceeds a certain thresh-
old, and each resulting bacterium will have half the
nutrients of the initial bacteria. In this model, there
is no diffusion of bacteria themselves, and no death
if a nutrient threshold is passed.
In addition, recall that
<Δx^2> =2nDΔt
For reasonable physical constants, we have D = 10-7
cm2/s, and delta x is 10 microns, so the timestep we
use is dt = 5 seconds. Additionally, let the amount of
nutrient a bacterium needs before division be 3*10-
12 g/bacterium (which is per pixel). Finally, we run
through a range of nutrient (peptone) concentrations
from 10-6 to 2*10-6 g/cm2.
Results and Conclusions
Figure 5: Bacterial Patterns (modeled). Peptone concentra-
tions of 10-6, 1.25*10-6, 1.5*10-6, and 2*10-6 g/cm2,
respectively (a-d).
Using even this simple model of growth, we can
roughly reproduce the four growth regimes observed
by Ben-Jacob’s groups – at low peptone concentra-
tion, there is a circle in the center, and some small
radial branching. At intermediate peptone concen-
tration, there is radial branching and fractal-like
growth on these branches. At high peptone concen-
tration, there is radial “finger” growth, and at very
high peptone concentrations, there is just a bacterial
blob.
In other words, we have shown numerically that bac-
terial growth is diffusion limited and can be modeled
as such, in very close agreement with reported exper-
imental data. One interesting thing to note is these
fractal-like patterns emerge because the flux through
points is locally higher than the flux through a large
surface, resulting in increased growth and branching
from branches that already exist rather than from the
center.
The utility of this result is we can determine what
patterns we expect based on certain nutrient concen-
trations and rates of growth, compare it to empirical
patterns, and use this to determine the accuracy of
our constants. Additionally, this has applications to
other fractal-like processes, such as crystal growth via
physical vapor deposition at high temperatures (flux
is highest through points).
Future Directions
To improve the model and give even more accurate
patterns, we should consider the doubling time of
bacteria (which is 1500 seconds for all 4 stages of
the cell cycle, rather than the 5 second timesteps we
used), account for bacterial motility (for example
swarming or the “run and tumble” model), and add
a parameter for cell death if nutrient concentration
around the bacteria is too low for cell maintenance.
Reaction Diffusion and Cancer Model:
Incorporating Multiple Factors
One particularly interesting application of reaction
diffusion models is diffusion-limited cancer growth
[5]. For example, the following tumor morphologies
from [5] can be roughly modeled using a reaction
diffusion model. Cancer cells are often mutated such
that growth factor networks are out of control – they
require less growth factor than normal cells to divide,
and can often produce more, resulting in a positive
feedback loop of growth and risks metastasis [6,7].
Cancer cells also kill surrounding tissue, either by
outcompeting it for nutrients or secreting a “death
factor” that kill surrounding WT cells [8].
RESEARCH
We will model cancer cells by considering a system
in which there are a network of blood vessels that
constantly replenish nutrients (especially since the
speed of blood, 0.1 m/s, is much faster than the
speed of oxygen diffusion through tissue, which is
under 10-4 m/s, so we can say the vessel locations
constantly replenish all nutrients in each timestep.)
Nutrients diffuse from the blood vessel, cells grow if
above a certain nutrient threshold and no surround-
ing cells (if WT) or even through surrounding cells
(if a cancer cell), cells die below a certain nutrient
threshold, cells produce and consume growth factors
at certain rates, and growth factors and nutrients dif-
fuse according to the diffusion equation. Cancer cells
have a lower threshold of growth factor to divide in
all of our models, as found in [6,7]; however, we also
set the model so that cancer cells produce far less
growth factor than normal cells, effectively depend-
ing on normal cells for their own division. We then
investigate a variety of starting conditions (possibility
of detachment from basal lamina, effect of different
nutrient demands and uptake from cancer cells, ef-
fect of cancer cells making more growth factors, and
growth along different blood vessel locations.
Figure 6: Simulation Results - Steady State Profiles of Cancer
Cells
Results and Conclusions
Above are the images of cancer cell steady state
locations for different initial parameters. Note that
in each of them, there were 50 randomly generat-
ed cancer cells at different points, and certain ones
survived and then grew into the above morphologies.
For figures 9a-9d, there are 7 parallel vertical blood
vessels; for 9e, there is a grid of such blood vessels
instead. For most simulations, cancer cells can diffuse
across the nutrient source; for 9a, they cannot (pre-
fall 2018 | PENNSCIENCE JOURNAL 41
 research
sumes basal lamina provides some protection against
metastasis).
From this, we can see that diffusion can limit tumor
growth – these models reached a steady state past
which the cancer cells could no longer grow. This
has relevance for therapies that attempt to prevent
formation of blood vessels in tumors in order to
starve them of nutrients. Furthermore, differences in
rates of growth factor production have a huge influ-
ence on whether a tumor stays benign or undergoes
a feedback expansion.
Future Directions
To improve this model, more realistic rather than
arbitrary diffusion and reaction coefficients could be
used, as well as a 3D generalization, and considering
different initial locations of blood vessels and cancer
cells. Further questions to be investigated via similar
means include comparing a nutrient competition vs
death factor secretion model, as well as modeling
drugs that inhibit growth factors as a method to treat
tumors and what expected morphology changes are.
Conclusions and Future Directions:
Conclusions
Often, complex systems of development or signaling
pathways can be explained and modeled to a high
degree of accuracy with only a few simplifying as-
sumptions – we don’t need to understand every gene
expressed in every pathway to get a good idea of
what will happen. Complex systems such as pattern
development, bacterial growth, and tumor formation
can be modeled numerically and with relatively few
factors and still give interesting and roughly accurate
results, which obviates the need for a lot of compli-
cated math and lets us find the eventual t=∞ solu-
tion.
Although not very optimized as presented here, a
reaction-diffusion-growth model of cancer is partic-
ularly interest. If you can set up an accurate system
(i.e. appropriate diffusion coefficients, rates of growth
factor production/consumption, blood vessel loca-
42 PENNSCIENCE JOURNAL | fall 2018
tions), you can predict how you expect cancer to
grow normally. Further, you can predict how certain
diffusion-limited treatments (chemotherapy) should
affect tumor morphology, and compare predicted
results to MRI to see if we understand drug mecha-
nism.
Outside of biology, this work has interesting applica-
tions in determining non-equilibrium or interesting
steady-state solutions to physical systems such as fluid
flow and the heat equation.
Future Model Improvements
To improve on the work presented, the model could
be expanded to 3D (which is not very challenging
conceptually – it’s just setting up a different Lapla-
cian and tracking across a 4D rather than 3D array,
but is annoying with edge cases and visualization),
and compared to the continuous case (where we use
Green’s function convolved with the distribution at
each step, rather than just discretizing the Lapla-
cian).
Further, models of cells should consider cell motility,
as well as allow for arbitrary factors and cell types.
The challenge is to determine the appropriate con-
stants to use, as well as which factors are relevant
– for any given pathway, there could be dozens of
genes involved, but the morphology of the result can
be predicted with far fewer components in the model
(as we showed in the case of bacterial growth).
Acknowledgements
Kai Trepka would like to acknowledge Dr. Adam
Cohen for his assistance in the planning and execu-
tion of this model during Chem 163 at Harvard.
References
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[3] Ben-Jacob, Eshel, and Peter Garik. “The formation of patterns in non-equilibrium
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[5] Ferreira Jr, S. C., M. L. Martins, and M. J. Vilela. “Reaction-diffusion model for the
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