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The Ofcial Journal of theW. Montague Cobb Research Laboratory
Winter 2015 • Spring 2Volume 2 Iss
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Cover page credit: We thank Amanda D. Strong for access to this photo of a cadaver from the W. Montague Cobb Research Lab.
The BackboneOFFICIAL JOURNAL OF THE W. MONTAGUE COBB RESEARCH LABORATORY, HOWARD UNIVERSITY
ISSN (Online): 2373-3934
ISBN (Print): 2373-3926
Editor -in-Chief: Fatimah Jackson, Ph.D.
Production Editor: Nicholas Guthrie
Copy Editor: Amanda D. Strong
The Backbone is published twice a year by the W. Montague Cobb Research Laboratory at Howard University. Thisonline, open-access journal accepts original articles, short biohistories, and recent abstracts on scientific considerationsof broad aspects of the African diaspora. Manuscripts for publication consideration, comments on the journal, and otherinquiries should be sent to: [email protected]
Howard University © All Rights Reserved
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Contents
Editorial
Resilience Through Research and PublicationFatimah L.C. Jackson ………………………………………………………………………………………………………………………………... 1
Full Articles
Chronic Kidney Disease and its Sequelae within the Cobb Collection: Osteological Manifestations
and Clinical Record of Evidence Amanda D. Strong, Uzaomaka Nqaogwugwu, M.D., Christopher Cross, M.S., Fatimah Jackson, Ph.D.………..……………………………. 2
Analysis of Potential Treatments for Sickle-Cell Anemia, or Drepanocytosis, in AdultsCameron D. Clarke …………………………………………………………………………………………………….……………………………… 10
Genetic Behavioral Evidence for Autism in the Cobb CollectionJayla Harvey , Fatimah Jackson, Ph.D.……………………………………………………………………………………………………..…….… 16
A Review: Evolutionary Theories of the Pathogenesis of SchizophreniaNichelle Jackson….……………………………………………………………………………………………………………...……………….……. 19
How might the genetic identification of mental disorders vary across geographical spaces, cross
culturally and though time?
Sedera Moore ……………………………………………………………………………………………..…………………………………………… 26
Prevalence and Anatomical Evidence of Treponemal Infection in the Cobb CollectionNicholas Guthrie ………………………………………………………………………………………………………..……………………………… 31
Biohistories
The Story of CC18Theodore Meadough, Jermain E. Robertson ……………………………………………………………………………………………………..… 35
The Story of CC112Turquoisia McNabb, Whitley Hatton ……………………………………………………………………………………………………………….… 39
The Story of CC312Christine Okaro, Christopher Wilson ………………………………………………………………………………………….………………………42
The Story of CC315James M. Bryne III, Lopriela Seabrook ………………………………………………………………………………...…………………………… 46
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The Story of CC331Jordan Mitchell, Jordan R. Howard ……………………………………………………………………….……………….………………………… 49
The Story of CC437Rachel Davalos, Mariela A. Martínez …………………………………………………………………………………..…………………………… 52
The Story of CC459Jasmine Mack, Ambra Palushi ……………………………………………………………………………….……………………………………… 55
Recent Abstracts from W. Montague Cobb Research
Laboratory Validation of Cobb Collection Biohistories
Davlyn Hollie …………………………………………………………………………………………………………………...……………………… 58
How the Cobb Research Lab succeeds in increasing the number of STEM and STEM-affiliated
StudentsSherese Taylor ………………………………………………………….…………………………………………………………………...………… 59
Investigation of the Cobb Collection, A Statistical ApproachNicholas Guthrie ……………………………………………………………………………………………………………………………………..… 60
Overview of the Interface of the Cobb Research Laboratory and the Robert Wood
Johnson Summer Medical and Dental Education Program (SMDEP) at Howard University Donna Grant-Mills, RDH, M.Ed., DDS ………………………………………………………………………………………….…………………… 61
Comparative Analysis of DNA Extraction Techniques on DNA yield from Ancient TeethLatifa Jackson Ph.D….………………………………………………………………………………………………………………………………… 62
Geospatial Assessment o Residential and Work Sites for Cobb Collection IndividualsHasan Jackson ………………………………………………………………………………………………………………………………………… 63
Minimally Invasive Method to extract DNA from Dentition using Cobb Collection Human Skeletal
Remains Alexis Payne, Christopher Cross, M.S., Latifa Jackson, Ph.D, John Harvey, D.D.D., Fatimah Jackson, Ph.D. …………………….……… 64
Trends and Causes of African-American Osteoarthritis and Osteoporosis within the Cobb Collection Sierra Williams ………………………………………………………………………………………………………………………………….……… 65
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Evidence for Arthritis and Specifically Osteoarthritis in the Cobb CollectionMaimouna Traore ………………………………………………………………………………………………………………………...…………… 66
Biohistorical Analysis od Cardiovascular Disease in the Cobb CollectionJameshisa Alexander …………………………………………………………………………………………………….…………………………… 67
Historical Trends of Hypertension and Cardiovascular Disease within the Cobb CollectionJanet Mansaray …………………………………………………………………………………………………..………………….………………… 68
The Prevalence and Biohistory of Congestive Heart Failure in the Cobb CollectionKayla Bedeau ………………………………………………………………………………………………………………………………..………… 69
The Correlations between African-American Life Experiences and Type 2 DiabetesWhitney Griffith ………………………………………………………………………………………………….…………………...………………… 70
Prevalence of Cerebrovascular Accident within African Americans of the Cobb CollectionNatalia Christian …………………………………………………………………………………………………………..…………………………… 71
Assessment on the Resurgence of Rickets and Scoliosis on African AmericansKhristian Ifill ………………………………………………………………………………………………………………………..…………………… 72
Identifying the effects and treatment of Alzheimer’s disease in African Americans Youngho Jung ………………………………………………………………………………………………………….……………………………… 73
Lead in Teeth: Reconstructing Environmental Biohistory and Health at the New York African
Burial Ground Using Laser Ablation-Inductively Coupled Plasma-Mass Spectrometry (LA-ICP-MS)Joseph L. Jones, Ph.D. …………………………………………………………………………………………..…………………………………… 74
Profile and initial elemental determination of soil samples collected rom the New York African Burial
Ground RemainsCandice Duncan, Ph.D. ……………………………………,,,………………………………………………………………………………..……… 75
Analysis of Grave Soil Samples Found in the New York African Burial GroundKeely Clinton …………………………………………………………………………………………………………………………………………… 76
Enhancing Public Access to Recent Research on the African Burial Ground Materials: Grave Soil and
Oral Microbiome AnalysesFatimah Jackson, Ph.D. …………………………………………………………………………………………………………….………………… 77
Announcements/Advertisements
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Resilience is the process of adapng well in the face of adversity, trauma,
tragedy, threats or signicant sources of stress. Wring about AfricanAmerican history, studying human biology, and interpreng the past are all
acvies that can contribute to our resilience as individuals and as a naon.
We become vulnerable when we are unfamiliar with our past, when we
cannot reconstruct the successes of our ancestors, when we cannot learn
from their mistakes and misjudgments. Resilience is primarily a learned
aribute. Stress smulates resilience to subsequently stressful episodes,
parcularly when it is mild in magnitude and controllable by the individual
(Ashokan et al 2016) Research on African American health and lifeways can
provide a kind of “stress inoculaon” by familiarizing us with what has occurred in the past and how it wasresponded to. This, in turn can facilitate our psychological adaptaons, social connecons, life meaning and
planning, and ulmately physical wellness. Researching and wring about scienc aspects of the African
Diasporas, parcularly its transatlanc components, can begin to heal the longstanding wounds of that
experience and its sequelae by changing the social context within which these historical facts are
understood. The social context is the third pillar linking individual genec suscepbility, a traumatogenic
event, and the phenotypic expression of stress (see Auxéméry, 2012).
This issue of The Backbone contains arcles on various clinical condions evident in the Cobb Collecon as
well as theorecal papers on aspects of human evoluonary biology. As a new feature of The Backbone, we
feature a diverse set of short biohistories on specic individuals of the Cobb Collecon. These were
researched and reconstructed by Summer Medical and Dental Educaonal Program (SMDEP) student
scholars during the summer 2015 research program held at the Cobb Research Laboratory (see Cobb
Research Lab News 2(3) Summer 2015). This issue concludes with a urry of recent abstracts on a range of
scienc topics from the Cobb Research Laboratory. These abstracts include topics aliated with our
research on ancient human DNA and our historical studies of health disparies. The abstracts will be given
as research papers on April 12, 2016 during a special symposium during Howard University’s Research
Week 2016.
Ashokan A, Sivasubramanian M, Mitra R. 2016 Seeding Stress Resilience through Inoculaon. Neural Plast. 2016;2016:4928081.
doi: 10.1155/2016/4928081. Epub 2016 Jan 5. Accessed February 10, 2016
Auxéméry Y. 2012 [Posraumac stress disorder (PTSD) as a consequence of the interacon between an individual genec
suscepbility, a traumatogenic event and a social context]. Encephale. 2012 Oct;38(5):373 -80. (in French) doi: 10.1016/
j.encep.2011.12.003. Epub 2012 Jan 24. Accessed February 10, 2016.
Editorial
Resilience through Research and Publication
Fatimah L.C. Jackson, Ph.D.
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Chronic Kidney Disease (CKD) has plagued the African American (AA) community as a frequent result of severe
hypertension and diabetes, both diseases that may be insgated by environmental factors or hereditary factors suchas genecs. CKD is an ailment that causes a dangerous imbalance of vital minerals and ions, and can cause waste to
build up throughout the major organs of the body. In contrast to its prevalence, there is an underrepresentaon of
CKD when parcipang in cadaver dependent research; this is the result of major consequences of CKD, such as
cardiovascular or neurological symptoms being pronounced the cause of death. The Cobb Research Laboratory ’ s (CRL)
invesgaon within chronic kidney disease will involve the examinaon of cadaver skeletons whose deaths have been
notably caused by CKD. With the informaon gathered from these invesgaons, the CRL team is opmisc for
anatomical clues le behind by the disease in the hopes of diagnosing other unknown cases within the Cobb
Collecon for further research. With the ndings of more cases it will be possible to examine the genes that are linked
to CKD as well as nd explanaons that could assist in research on the preventave progression of the disease.
GENETICS & EPIDEMIOLOGY
Chronic Kidney Disease and its Sequelae within the CobbCollection: Osteological Manifestations and Clinical Recordof Evidence
Amanda D. Strong1,2
Uzoamaka Nwaogwugwu, M.D.3
Christopher Cross, M.S.,1,4 Fatimah Jackson, Ph.D.1,21W. Montague Cobb Research Laboratory, Howard University
2Department of Biology, Howard University3Department of Medicine, College of Medicine, Howard University
4Department of Anatomy, Howard University
FULL ARTICLES Chronic Kidney Disease and its Sequelae within the Cobb Coll
Introduction
In the United States, the AA community constutes
approximately 13% of the enre populaon, yet 32% of
all paents receiving treatment for kidney failure are
AA,1 this leads to an overall kidney failure rate that is
over three mes larger than that of our Caucasian
counterparts. It has also been shown that AAs require
dialysis or transplantaon at younger ages.6,7
Chronic
kidney disease most oen leads to end-stage renal
disease (ESRD) in which the kidneys can no longer
funcon at the level necessary to remove all of the waste
and excess water from the body.2 AAs have greater
incidence rates of ESRD at each decade of life compared
with any other racial/ethnic group.6,7
The likelihood for
the development of chronic kidney disease is determined
by the relaonship and interacons between genes and
the environment.3 It is key to understand both the
genec and environmental factors so that nove
treatments and therapies can be developed. Most
importantly, understanding the underrepresentaon of
CKD and why it plagues our community will aid in
developing the preventave measures needed to
FIGURE 1: RISK FACTORS FOR CKD5
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improve our stascal status on the maer. Socio-
environmental, behavioral, biomedical, and predisposing
factors all work together towards parcular health
outcomes. Once all taken into consideraon, real
progress can and will be made.
Background ResearchAs reported by the Naonal Kidney and Urologic
Diseases Informaon Clearinghouse (NKUDIC) and
displayed in Figure 1, African-Americans (red circles)
have the highest occurrence of ESRD incidents and well
as the highest exponenal increase since the year of
1980. In second lead, incidents in Nave Americans (blue
diamonds) began to rise up unl 1999 when a decrease
began. Asians (yellow squares) and Caucasians (green
triangles) have shown the slightest increase in
comparison with the others. Compared to the other
ethnic groups analyzed and to the overall average of
those groups, AA’s have, and have always
had, the highest rate of CKD incidents.
African Americans and Nave Americans share many
social environmental stressors that may have aided in
their correlaon up unl 1999. The quickly accelerang
progression of the disease has oen be aributed to risk
factors such as diabetes, hypertension and obesity;
however, this has not been able to explain the elevated
rate of CKD progressing into ESRD among AAs and other
groups with low socioeconomic status.8 Unfortunately,
the consequences of the social environment is too oen
over-looked as a contribung element. Through
behavioral science studies, it has been established that
there are psychological and physiological consequences
dependent on the environment in which one works and
lives.9,10 Social environmental stressors such as poverty
and discriminaon are proven to adverse the bodies
psychological funconing as well as prompt response in
regards to the nervous and vascular systems; these
complicaons place individuals at greater risk for
developing CKD and cause a lesser ability to prevent the
progression towards ESRD.8 From Figure 3, it can be seen
that social environmental factors are the beginning of a
chain of risk factors that can contribute to other high risk
factors such as psychosocial and behavioral that lead tonegave eects in pathophysiological
mechanisms. Social issues such as economic struggle and
discriminaon oen lead to psychological manifests of
anxiety, depression and stress. Alone, the psychological
state can impact the physiological funcons of the body;
however, the situaon is heightened double-fold when
these psychological factors insgate poor habits such as
drug use, poor diet and lowered physical acvity. Many
studies have focused on the eect of racialdiscriminaon and instuonalized racism.
It has been suggested that the excess risks for chronic
diseases such as CKD among groups such as African
Americans (and Nave Americans) are a funcon of
economic deprivaon. However, racial disparies in the
prevalence and progression of kidney disease connue
to persist even when the socioeconomic posion at the
FULL ARTICLES Chronic Kidney Disease and its Sequelae within the Cobb Colle
FIGURE 2: INCIDENT RATES OF ESRD BY RACE4
FIGURE 3: CKD RISK FACTOR FLOW CHART8
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individual and community level is improved and
stable.11,12,13
The main concern given by Figure 1 is in
regards to the connuaon of an exponenal rise in
ESRD in African-Americans that dierenates them from
others of same or lower socioeconomical status. These
results lead us to examine the genec factors as the only
key to understanding why the dierence among AAs
occurs. It is a fact that AAs14
have the highest risk
associated with family history, as do Nave Americans15
and Hispanic Americans;16
however, it is observed in case
studies across the United States that AAs are the only
racial group to have a nine-fold higher risk of developing
ESRD if they already have a rst degree family member
on dialysis.17
Some studies have concluded racially
variable suscepbility rate is due to familial clustering of
those with CKD in certain racial groups,3 but other
research has indicated a correlaon among AA
individuals who have a mutaon at the locaon of the
PKD1 gene.3,18
From newer studies a posive correlaon
between similar genec mutaons and familial clustering
has been found, thus combining the two previous
theories.
In Kidney Internaonal studies, it was shown that the
locaon of the PKD1 gene mutaon is directly correlated
with the severity of renal disease and the onset of
ESRD.18
In studies regarding rodent renal failure a
correlaon was noced in the Rf -1 gene, the rodent
analog of the human chromosome10
To assess any
possible linkage between markers on chromosome10
and
ESRD potenal, a linkage analysis was performed in
African American sibling-pairs. It was shown that in AAs
with nondiabec eologies of ESRD, there was strong
suggesve evidence for linkage on chromosome 10p,
specically.3 Curiously, this is near the D10S1435 marker
that is conrmed to have a consistent presence in
diabec families.19
For AA families with a history of type
2 diabec nephropathy, a genome wide scan on sibling
pairs showed evidence for linkage on chromosomes 3q,
10q, and 18q.20
Notably, the type 1 diabec nephropathy
locus was at the 3q peak in the chromosome.21
Studying
the close proximity of these chromosomal markers and
loci may help to explain the connuous relaon between
diabetes and renal disease beyond the physiological level
and allow for a genec perspecve. This informaon is
extremely useful in determining the cause of CKD
underrepresentaon in the AA community. Essenally,
there is a considerable amount of evidence that supports
family history of renal disease, as well as familial
clustering of ESRD, as contribuon to the pathogenesis
of chronic kidney failure.3 Idencaon of causave
elements located within the genome may enlighten the
development of innovave gene therapies.3
Osteopathic Research
According to Dr. Uzoamaka Nwaogwugwu, MD and
DaVita expert, renal osteodystrophy is the most common
bone disease associated with kidney failure. This disease
causes signicant imbalances in calcium, parathyroid
hormone, phosphorus and acvated vitamin D. The
condion further develops to aect the balance of
osteoclast and osteoblast development and
producon.22
When the calcium levels in the blood begin
to drop a signicant amount, the body begins to over
acvate the parathyroid glands to produce the
parathyroid hormone. This hormone will begin to extract
calcium from the skeletal system and into the
bloodstream in order regain calcium equilibrium. As the
calcium is being stripped from the bones they begin to
weaken and the texture becomes chalky, rather than the
natural sturdy form.22
Secondly, kidney disease causes an
extremely high amount of phosphorous levels in the
FULL ARTICLES Chronic Kidney Disease and its Sequelae within the Cobb Colle
FIGURE 4: OSTEOMALACIA ON BONE23
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blood. Because calcium and phosphorous share a
symbioc relaonship, the body will begin to draw
calcium from the bones into the blood to create
equilibrium between calcium and phosphorous.22
Of
course, this causes the same side eect of low blood
calcium and diminishes the bone. The kidneys serve an
ulmately vital funcon of acvang the vitamin D that
courses through our blood to form calcitriol. Calcitriol is
acts to assist the body in absorbing calcium and
maintaining normal parathyroid hormone levels.22
Unfortunately, when the kidneys begin to fail, they are
no longer able to convert vitamin D into calcitriol and the
body is no longer able to absorb dietary calcium
properly. Again, the body aempts to fulll its calcium
need by stealing from within the bones.
The typical symptoms for degradaon of the bone
include: bone and joint pain, bone deformaon and
fractures, as well as poor mobility.22
In the case of this
research, bone deformaon is the key component. When
having suered from long-term renal failure or chronic
kidney disease, evidence of the disease is le behind on
the skeletal structure. Osteodystrophy, osteomalacia,
uremia and metabolic bone disease all alter the visual
integrity of the bone. Bone lesions, porousness, thinning
or thickening, and the abnormal curving of the bone areall potenal signs that the skeletal system was being
robbed of essenal minerals and ions.
In Figure 4, the abnormal curvature and slight protrusion
towards the ps of the bone can be seen. When
describing osteomalacia, Dr. Nwaogwugwu described
how the bone matrix weakens and the bone begins to
are up towards the joints, where majority of the
damage occurs. Figure 5 shows the lack of mineral
density near the joints when suering from renalosteodystrophy. Renal osteodystrophy has been viewed
using an X-ray, even when being viewed as a deeshed
cadaver. The symptoms most suitable for observaon in
the laboratory are related to lesion formaon. Lesions
can be seen on the bone without using tools, however,
this can cause an issue when aempng to dierenate
natural deterioraon from mechanical damage due to
FULL ARTICLES Chronic Kidney Disease and its Sequelae within the Cobb Colle
FIGURE 7: X-RAY OF BONE LESIONS26
FIGURE 5: RENAL OSTEODYSTROPHY X-RAY24
FIGURE 6: EXAMPLE OF LYTIC BONE LESION25
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processing. Fortunately, an X-ray picture of the bone
lesions can reveal its true nature and will not be
confused with mechanical damage.
Methods and Procedures
Extensive research was done on what types of
osteological symptoms would be present in order to
truly piece together our analysis of cadaver skeletons
from the Cobb collecon. The beginning step was to
completely review the digital Cobb Collecon les, with
the assistance of our director, Dr. Famah Jackson, for all
paents whose cause of death was related to kidney
malfuncon or kidney disease. The exact cause of death,
age, race and body number was noted. It was then that
some of the noted bodies were pulled with guidance of
our assistant curator and student of anatomy,
Christopher Cross. The enre anatomy of a carefully
chosen, deeshed cadaver was laid out on the laboratory
table and recongured for organizaon and easy access,
as shown in Figure 8.
Beginning with the bones that survive the most
tension and pressure through the lifeme, as well as the
highly sensive joints, we aempted to nd signs of
lesioning, porosity and abnormal morphology on the
femurs. This task became dicult as we faced quesons
that had not yet posed an issue. During the retrieval of
many skeletons from the African Burial Ground (New
FULL ARTICLES Chronic Kidney Disease and its Sequelae within the Cobb Colle
FIGURE 11: FEMURS FROM #693FIGURE 8: DEFLESHED CADAVER #693
FIGURE 9: JOINT (1) FROM #693
FIGURE 10: JOINT (2) FROM #693
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York), many of the bones were damaged through
mechanical digging and treang.
As can be seen in Figure 9 and in Figure 10, it is dicult
to categorize the damage on the bone under a specic
cause. While it is possible that the damage to the bone
could be the result of deterioraon, it could also be
damage inicted from machinery or rough handling
during transportaon.
Figure 11 is an example of how normal dierences in
midsagial skeletal structure can be mistaken for the
thinning or improper curving of the bone. The
le femur, on the boom of the gure, appears thinner
with slightly more curvature than its le counter part. It
is expected for the skeletal anatomy to dier slightly
when analyzing midsagial pieces. The queson that
arises is whether or not this dierence is signicant
enough to note it as an osteopathic symptom. In the lab,
we also noced a dierence in the texture and color of
the two bones, yet determinaon of the cause was not
enrely clear. All fragments in queson were
photographically captured for future comparison.
Conclusion
Ulmately, we were not able to determine as much
as had been ancipated through the physical laboratory
analysis due to the uncertain observaons; however, the
aws in our expectaons have been led us to new
venues, methods, and resources to connue our hunt for
answers. To eliminate mispercepon between natural
deterioraon of bone and mechanical damage done to it,
we have proposed x-ray scanning. By using a
radiographically produced image (Figure 5 and Figure 7),
it would allow us to see beyond the outer surface of the
bone and deeper into its matrix; for example, dark areas
within the bone matrix will indicate signicant
deterioraon, as in renal osteodystrophy whereas patch-
like spots on the bone will indicate bone lesions have
formed. Ulizing the Howard University Hospital Crical
Image and Photo department will allow the W.
Montague Cobb Research laboratory access to x-ray
machines as well as bone biopsy processes. Bone
biopsies will allow us to insure consistent results by
conrming osteopathic symptoms that appear similar
also have similar chemical and molecular makeup. This
will be helpful in proving the exact mineral composion
that results from these pathological processes. Along
with Dr. Nwaogwugwu, we hope to make a connecon
with the Howard University Hospital Pathology
department in order to gain a more complete
understanding of the bone pathologies in this focus. To
assist in dierenang what is appropriate for expected
anatomical dierence in the bone versus signicant bone
curvature or loss (Figure 11), the Howard University
Hospital Osteology department will be able to analyze
measurements taken in the lab as well as photographs.
In the proceeding research, we will use the
informaon gain to nd more cases of osteopathic
symptoms represenng CKD in the Cobb Collecon.
Specically, we will do this by examining deeshed
cadavers that have causes of death most oen
associated with CKD (i.e., diabetes, cardiovascular
disease, nuerological disorders). Not only will this add
more sources to our research, but will allow for the W.
Montague Cobb Research Laboratory to have a more
detailed record for causes of death. Having an extended
collecon of deeshed cadavers specically marked forCKD would also allow us to collect DNA samples from a
variety of sources in order to analyze the genes and
aempt to nd common markers and genec clues.
Potenally, nding a common genec factor amongst all
CKD cases in the Cobb Collecon could allow for a
starng point for gene therapies. We can then extend
the research to verify whether CKD is prominent in a
certain sex, age or lifestyle (i.e., profession, family size)
within the AA community. By comparing locaon ofdeaths, a crude idea of how the social environment
impacted the progression of CKD can be
composed. Being that the Cobb Collecon contains
African remains dang back to the 17th century, we also
hope to nd a posive correlaon between rising CKD
levels and me spent in what is now the United States.
We are hoping to nd clues that will allow us to
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hypothesize in regards to why AA specically have
developed predisposions for chronic disease that is not
common of our ancestry.
Discussion
In all, this research is guided towards to the awareness
and understanding of how and why chronic kidney disease
aects the African American populaon at an exponenal
rate. Our research could potenally serve as a foundaon
of knowledge for a disease that is highly neglected on the
preventave and treatment level in our community. If we
improve our understanding of what factors place African
Americans at risk for chronic kidney disease, we will be
beer equipped to avoid those scenarios as preventave
measure.
Acknowledgements
I would like to thank our director, Dr. Famah Jackson,
PhD, for allowing us to be apart of the amazing experience
of the W. Montague Research Cobb Laboratory. We would
also like to thank our curator, Christopher Cross, MS, for
his helpful instrucon when analyzing the anatomy of the
cadaver skeletons in the Cobb Collecon. Finally, I would
like to thank Mahew Calhoun for his ideas and
construcve conversaon toward the research.
References
1. "African Americans and Kidney Disease." The Naonal
Kidney Foundaon. N.p., Apr. 2014. Web.
2. Miller, Sco, MD, and David Zieve, MD, MHA. "End-stage
Kidney Disease: MedlinePlus Medical Encyclopedia." U.S
Naonal Library of Medicine. U.S. Naonal Library of
Medicine, 2 Oct. 2013. Web.
3.
"Kidney Disease Stascs for the United States." KidneyDiseases Stascs for the United States. Naonal Kidney
and Urologic Diseases Informaon Clearinghouse (NKUDIC),
June 2012. Web.
4. "3 Risk Factors and Causes of Chronic Kidney Disease."
Australian Instute of Health and Welfare. N.p., n.d. Web.
5. Hsu C-Y, Lin F, Vingho E, et al. Racial dierences in the
progression from chronic renal insuciency to end-stage
renal disease in the United States. J Am Soc Nephrol.
2003;14:2902 –2907.
6. Tareen N, Zadshir A, Marns D, et al. Chronic kidney disease
in African American and Mexican American populaons.
Kidney Int. 2005;68(supplement 97):S137 –S140.
7. Bruce, Marino A., Bena M. Beech, Mario Sims, Tony N.
Brown, Sharon B. Wya, Herman A. Taylor, David R.
Williams, and Errol Crook. "Social Environmental Stressors,
Psychological Factors, and Kidney Disease." Journal of
Invesgave Medicine : The Ocial Publicaon of the
American Federaon for Clinical Research. U.S. Naonal
Library of Medicine, 18 Feb. 2010. Web.
8. Fremont A, Bird C. Social and psychological factors,
physiological processes, and physical health. In: Bird C,
Conrad P, Fremont A, editors. Handbook of Medical
Sociology. Upper Saddle, NJ: Prence Hall; 2000. pp. 334 –
352.
9. Seeman T, Mcewan B. Impact of social environment
characteriscs on neuroendocrine regulaon. Psychosom
Med. 1996;58:459 –471.
10. Norris K, Nissenson AR. Race, gender, and socioeconomic
disparies in CKD in the United States. J Am Soc Nephrol.
2008;19(7):1261 –1270.
11. Tarver-Carr ME, Powe NR, Eberhardt MS, et al. Excess risk of
chronic kidney disease among African Americans versus
white subjects in the united states: a populaon-based
study of potenal explanatory factors. J Am Soc Nephrol.
2002;13:2363 –2370.
12. Volkova N, McClellan W, Klein M, et al. Neighborhood
poverty and racial dierences in ESRD incidence. J Am Soc
Nephrol. 2008;19(2):356 –364.
13. Freedman, BI, Soucie, JM, McClellan, WM: Family history of
end-stage renal disease among incident dialysis paents. J
Am Soc Nephrol 1997 8:1942 –1945.
14. Pe, DJ, Saad, MF, Benne, PH, et al: Familial
predisposion to renal disease in two generaons of Pima
Indians with type 2 (non –insulin-dependent) diabetes
mellitus. Diabetologia 1990 33:438 –443, 10.1007/
BF00404096.
15. Pugh, J: Diabec nephropathy and end-stage renal disease
in Mexican Americans. Blood Purif 1996 14:286 –292.
16. Freedman, BI, Spray, BJ, Tula, AB, Buckalew, VM: The
familial risk of end-stage renal disease in African Americans.
Am J Kidney Dis 1993 21:387 –393.
17. Rose, S, Burton, S, Strmecki, L, et al: The posion of the
polycysc kidney disease 1(PDK1) gene mutaon correlates
with the severity of renal disease. J Am Soc Nephrol 2002
13:1230 –1237, 10.1097/01.ASN.0000013300.11876.37.
FULL ARTICLES Chronic Kidney Disease and its Sequelae within the Cobb Colle
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25. Museum of London - Cross Bones Burial Ground Photo-
graphs." Museum of London - Cross Bones Burial Ground:
Centre for Human Bioarchaeology. N.p., 2005. Web.
26. "Orthopedic Teaching: Bone Lesions Case 2 Answer." Bone
Lesions Case 2 Answer : : Feinberg School of Medicine:
Northwestern University. Northwestern University Feinburg
School of Medicine, n.d. Web
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This research paper discusses the clinical and evoluonary history of sickle -cell disease, also known as sickle-cell anemia, or
drepanocytosis. It noted the genec causes and physiological eects of sickle -cell disease, and the evoluonary and
environmental factors involved in the disease’ s emergence, nding that its proliferaon was likely the result of a selecve sweep
of an adaptaon of the red blood cells that had a secondary protecve eect against malaria in heterozygous individuals. This
also menoned two of the possible treatment methods that could be used to eliminate or migate sickle -cell disease and its
symptoms. The rst treatment method analyzed was therapy of a paent with sickle -cell disease to increase the producon of
healthy red blood cells containing fetal hemoglobin. The second involved a bone marrow transplant to replace the defecve bone
marrow. It was found that while both treatments are eecve in reducing the severity of sickle -cell disease, only a bone marrow
transplant has been conclusively shown to be able to cure the condion, and even then, has only undergone trial tesng among
children. However, there is currently preliminary clinical research being conducted on gene therapy to promote the body ’ s
connued producon of fetal hemoglobin, prevenng sickle-cell hemoglobin S from even developing, and curing sickle-cell disease
GENETICS & EPIDEMIOLOGY
Analysis of Potential Treatments for Sickle-Cell Anemia, orDrepanocytosis, in Adults
Cameron D. Clarke1,2 ,3
1W. Montague Cobb Research Laboratory, Howard University2Department of Biology, Howard University
3Department of Health, Human Performance and Leisure Studies,, Howard University
Clinical BackgroundSickle cell disease, also known as sickle-cell anemia or
drepanocytosis, is a hereditary blood disorder,
characterized by a genec mutaon in the gene thatcodes for hemoglobin in the red blood cells of the body.
Hemoglobin is an iron-based metalloprotein that binds
to molecules of oxygen in the capillaries of the lungs, and
then carries them through the bloodstream, releasing
the oxygen molecules into the somac cells, and binding
to carbon dioxide, which is released back into the lungs
with each exhalaon.1
This paper will discuss three (3)
disnct variees of hemoglobin: Hemoglobin A (HbA),
the normal adult form of hemoglobin; hemoglobin S
(HbS), the diseased variety of hemoglobin; and
hemoglobin F (HbF), fetal hemoglobin. Sickle cell disease
occurs as a result of a mutaon at a single nucleode (A
to T) of the β-globin gene, which results in glutamic acid
being substuted by valine at posion 7 (posion 6
under the historic nomenclature. This causes the protein
to form Hemoglobin S (HbS) in its nal conformaon,
instead of Hemoglobin A (HbA), normal adult
hemoglobin. Under normal condions, the mutaon is
generally benign, causing no apparent eects on the
secondary, terary, or quaternary structures of
hemoglobin in condions of normal oxygen
concentraon. Under condions of low oxygen
concentraon, however, this mutaon allows for the
polymerizaon of the HbS itself. When HbS is in
condions of low oxygen saturaon, the hydrophobicresidues of the valine (formerly glutamic acid) at posion
7 of the beta chain in hemoglobin are able to associate
with the hydrophobic patch, causing hemoglobin S
molecules to aggregate and form brous precipitates
(Figure 1). These precipitates form long, interlocking
strands within the blood cells, elongang and distorng
its shape, and causing them to take on the disncve
malformed “sickle-like” shape that gives the condion its
name. These “sickle” cells are far less ecient in carrying
oxygen than the ordinary rounded cells, addionally,
aer a cell is sickled, it loses much of its elascity,
becoming much more inexible. This rigidity makes the
cells much more likely to become trapped in the small
openings of the capillaries and narrow blood vessels. As
cells accumulate in the blocked vessels, they can cause
ischemia (oxygen deprivaon) and cell death in the
aected areas, a complicaon called a sickle-cell crisis.
Sickle-cell crises are oen extremely painful, and
potenally fatal if the obstrucon occurs around a vital
organ and causes organ damage or failure. Addionally,
the deformaon of the cells by the hemoglobin bers
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reduces the integrity of the cell membrane, making the
cells much more likely to lyse. This damage is severe, to
the extent that while healthy red blood cells may
typically funcon for 90 –120 days, sickled cells only last
10 –20 days before lysis.2 This rapidly accelerated rate of
hemolysis is from where the condion derives its
designaon as an anemia; although the bone marrow
creates red blood cells at increased volume compared to
healthy humans, it is simply unable to compensate for
the rate of cell destrucon. Paents are oen le with
lower-than-normal levels of erythrocytes, and can
exhibit symptoms common to general anemia suerers,
including feeling red, weakness, shortness of breath, or
a poor ability to exercise.3
Evolutionary BackgroundSickle-cell disease is an allelic disorder, located on the
chromosome 11, at 11p15. It has an autosomal recessive
paern of inheritance, in that the condion will only
present itself when the allele for sickle-cell disease is
passed from both parents during reproducon. In
individuals that are heterozygous for sickle-cell disease
(one copy of the diseased allele), also called “carriers,”
the sickle cell load is greatly reduced, and symptoms
generally only appear aer prolonged oxygen
deprivaon, or severe dehydraon. Evoluonarily, the
emergence and proliferaon of the sickle-cell allele are
likely linked to the disease’s protecve eect against
malaria, a far more expansive and lethal disease, found
in a similar range (Figures 2 & 3).
This is due to the sickling of the cells interfering with
the complex lifecycle of the parasite that causes malaria,
Plasmodium malariae. Plasmodium reproduces within
the erythrocytes. In a carrier for sickle-cell disease, the
presence of the malaria parasite causes the red blood
cells with defecve hemoglobin to ruptureprematurely,
FIGURE 1: DIAGRAM OF SICKLE CELLS CAUSING VASO-OCCLUSIVECRISIS
FIGURE 2: MALARIA DISTRIBUTION
FIGURE 3: SICKLE-CELL DISTRIBUTION
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making the Plasmodium parasite unable to reproduce.
Further, the polymerizaon of the hemoglobin aects
the ability of the parasite to digest hemoglobin in the
rst place. This reduced ecacy of Plasmodium leads to
shorter and less severe infecons among sickle-cell
carriers. Therefore, in areas with endemic malaria,
chances of survival actually increase amongheterozygotes. However, this protecve eect does not
extend to sickle cell homozygotes, or people with the
disease, since the premature lysis of infected cells is a
common cause of sickle-cell crises. The heterozygote
advantage, however, is enough to account for the
persistence of sickle-cell disease in areas with high
endemic malaria. Analysis of the disease’s genec
history via restricon endonuclease analysis found that it
most likely arose spontaneously in several dierent
areas, with a dierent variant of the mutaon emerging
in each one. These variants are known as Cameroon,
Senegal, Benin, Bantu, and Saudi-Asian. This evidence
also supports the hypothesis that the mutaon that
causes sickle cell arose and proliferated as a result of the
widespread malaria that is endemic to the regions.
Fetal Hemoglobin TreatmentIn addion to corroborave evidence of evoluonary
pressure for the emergence of sickle cell, the restricon
endonuclease analysis of the disease also found that in
some regions, including Senegal and Saudi-Asia, the
sickle-cell mutaon has variants that are correlated with
increased and persistent producon of hemoglobin F,
also known as fetal hemoglobin (HbF).4,10
Fetal
hemoglobin is the type of hemoglobin that is produced
in the human fetus during the last seven months of
development in the uterus. Funconally, fetal
hemoglobin diers lile from adult hemoglobin, apart
from the fact that it has a slightly higher oxygen anity,
and bonds more ghtly, but sll temporarily, to the
oxygen molecules in the capillaries of the lungs.5 This is
due to the mixture of oxygenated and deoxygenated
blood in the maternal blood that is delivered to the fetus
via the umbilical vein. Generally, within six months of
birth, humans stop producing fetal hemoglobin, and
begin producing adult hemoglobin (HbA) (Figure 4).In
most cases, the switch from fetal hemoglobin to adult
hemoglobin is relavely inconsequenal. However, since
the structure and genecs of fetal hemoglobin dier
from those of adult hemoglobin, it is not aected by the
same genec mutaons that govern the producon of
adult hemoglobin. When fetal hemoglobin producon is
switched o aer birth, normal children begin producing
adult hemoglobin (HbA). Children with sickle-cell disease
instead begin producing a defecve form of hemoglobin
called hemoglobin S (Figure 5). However, among children
with the sickle-cell trait, where fetal hemoglobin remains
the predominant form of hemoglobin aer birth, the
frequency and severity of sickle-cell crises decrease
relave to those where fetal hemoglobin producon has
ceased. This protecve eect was observed in variants of
the sickle-cell mutaon in Senegal and Saudi-Asia, where
it is believed to be a secondary adaptaon, blunng
some of the acute complicaons of sickle cell disease.
FIGURE 4: HEMOGLOBIN A
FIGURE 5: HEMOGLOBIN S
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Fortunately, much progress has been made in a clinical
applicaon for this phenomenon.
In a landmark study in the New England Journal of
Medicine, it was found that not only did treatment of
paents with hydroxycarbamide (hydroxyurea), an
anneoplasc (tumor-inhibing) drug, increase the
quanty of fetal hemoglobin in erythrocytes, but that it
also appeared to break down cells that were likely to
sickle, further decreasing the risk of vaso-occlusive sickle
-cell crises. Addionally, a second study discovered that
the treatment of sickle-cell disease with a combinaon
therapy of hydroxycarbamide and recombinant
erythropoien (a hormone involved in red blood cell
synthesis) further increased levels of HbF, and further
reduced the frequency of acute sickle-cell
complicaons.6 Even more signicant, this treatment
method was found to have no major adverse side
eects, and so would likely signicantly improve paent
outcomes and quality of life.
Important to note, however, is that the study was only
conducted on adults, so it is not currently clear how
much the success would translate to intervenons in
children. Addionally, hydroxyurea treatment has only
been shown to reduce the frequency of sickle-cell crises,
not prevent them enrely. As such, it is only a parallyeecve treatment, not a cure. It also has not been
tested in an aempt to resolve a currently occurring
sickle-cell crisis, and so cannot be recommended as an
emergency intervenon. Finally, the researchers
involved with the study noted that “there is concern that
long-term hydroxyurea therapy may be carcinogenic or
leukemogenic, because some other anneoplasc agents
have such eects.”7 As with any medicaon, addional
research is necessary in order to more completelyunderstand the mechanism of hydroxyurea therapy’s
funcon in prevenng crises, and its long-term eects on
individuals and their children. However, this treatment is
already in use in paents suering from sickle-cell
disease, and so far has seen widespread success.
On the horizon, researchers have begun tesng
whether gene therapy to smulate permanent
producon of HbF in humans is feasible in order to more
permanently treat, or even cure, sickle-cell disease.
Preliminary studies have already found that it is possible
to completely cure mice of a variant of sickle-cell disease
by using gene therapy, and studies in humans have
shown promising results, to the extent that gene therapy
has moved on to the early stages of clinical trials as a
permanent cure for sickle-cell disease.8,9,11
Hematopoietiec Stem Cell TransplantaionFor all of the promising research on the horizon,
however, a cure for sickle cell disease already exists.
Hematopoiec stem cell transplantaon (HSCT), also
known as bone marrow transplantaon, has been shown
to permanently cure children of sickle cell disease when
it is successful. Allogenic bone marrow transplants, thetype used in sickle-cell procedures, are a high-risk
procedure, usually involving two people: the (healthy)
donor and the recipient (paent). In the procedure, the
donor and the recipient must both be tested to
determine if they have similar or idencal variants of the
human leukocyte angen (HLA) system. This network of
genes is responsible for an individual’s immune response
to foreign cells and molecules. If the two individuals are
incompable, or too dissimilar, the transplantaon willfail, as the recipient’s immune system will either aack
the donor’s stem cells, or the donor’s stem cells will
cause an infecon in the recipient’s ssues, a condion
called gra-versus-host disease . Even if the HLA paerns
of the individuals match, in order to minimize the
possibility of a rejecon, the paent must be subjected
to immunosuppressant treatment to destroy their
immune response system. This immunosuppression is
part of what makes the procedure so high-risk; paents
with compromised immune systems are extremely
vulnerable to infecon, such that even a relavely
mundane disease such as the common cold can be fatal.
Once the recipient is immunosuppressed, the donor is
placed under general anesthesia, and the hematopoiec
stem cells are removed from a large bone of the donor,
typically the pelvis, through a large needle that reaches
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the center of the bone. This technique is referred to as a
bone marrow harvest (Figure 6). The cells are then
implanted into the paent’s own bones, and aer a few
weeks to allow the cells to mulply, the paent is
removed from immunosuppressants, and the procedure
is completed.
Although HSCT, due to its relavely high risk, is
generally only aempted in people with condions that
are extremely life-threatening, recent advances in the
safety and standardizaon of the procedure have made
it safe
enough to aempt in individuals with less-threatening
condions, such as sickle-cell anemia. In such cases,
however, studies have only been conducted among
children. A recent study by the New England Journal of
Medicine found that of 22 paents upon whom bone-
marrow transplants were performed, 20 survived the
procedure itself, and 16 were found to be free of sickle-
cell disease in the months following the procedure,
survival and event-free survival at four years of 91
percent and 73 percent, respecvely. Although these
results are promising, a mortality rate of 9%, and withonly a 10% mortality likelihood by age 20 is clearly
unacceptable, so more advancements must be made,
both in the calculaons of the likelihood of rejecon, and
in the safety of the procedure itself, before
hematopoiec stem cell transplantaon can be
considered a viable and ecacious treatment for sickle-
cell disease.
Discussion
Of the methods described, as a praccal soluon for
paents with mild to moderate sickle-cell disease, with
only occasional, infrequent vaso-occlusive crises, the
combinaon therapy of hydroxyurea and recombinant
erythropoien seems to be the ideal currently available
treatment, both in terms of relave safety and likelihood
of success, and in terms of eecveness. Of course, as
elaborated, all of the treatments require further
research to conclusively determine their long-term
health risks and benets, but currently the risks of
hydroxyurea are the most widely studied and well
known. The most promising of the treatments, however,
remains gene therapy, which, unlike hydroxyurea
therapy, promises to completely cure sickle-cell disease,
and without the complex surgery and high-risk
immunosuppression of hematopoiec stem cell
transplantaons. Unfortunately, as this method is sll in
its earliest stages of clinical trial, it may be years before it
becomes available to the average sickle-cell paent.
Sickle-cell disease is a sgmazed, misunderstood, and
life-altering condion, but it is no longer the death
sentence it once was. Hopefully, with addional study,
evoluonary and clinical research, and public healthoutreach, we can make sickle-cell disease no more than
a nuisance, instead of a potenally debilitang condion.
References1. Maton, Anthea; Jean Hopkins; Charles William
McLaughlin; Susan Johnson; Maryanna Quon Warner;
David LaHart; Jill D. Wright (1993). Human Biology and
Health. Englewood Clis, New Jersey, USA: Prence Hall.
ISBN 0-13-981176-1.
2. Maakaron, J. (2014). Sickle Cell Anemia. Medscape.
Retrieved April 14, 2015, from hp://
emedicine.medscape.com/arcle/205926-overview
3. Stedman's medical diconary (28th ed. ed.). Philadelphia:
Lippinco Williams & Wilkins. 2006. p. Anemia. ISBN
9780781733908.
4. Lanzkron S, Strouse JJ, Wilson R et al. (June 2008).
"Systemac review: Hydroxyurea for the treatment of
FIGURE 6: BONE MARROW HARVEST
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adults with sickle cell disease". Annals of Internal
Medicine 148 (12): 939 –55. doi:10.7326/0003-4819-148-
12-200806170-00221. PMC 3256736. PMID 18458272
5. Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th edion.
New York: W H Freeman; 2002. Secon 10.2, Hemoglobin
Transports Oxygen Eciently by Binding Oxygen
Cooperavely.
6. Rodgers GP, Dover GJ, Uyesaka N, Noguchi CT, Schechter
AN, Nienhuis AW (January 1993). "Augmentaon by
erythropoien of the fetal-hemoglobin response to
hydroxyurea in sickle cell disease". The New England
Journal of Medicine 328 (2): 73 –80. doi:10.1056/
NEJM199301143280201. PMID 7677965.
7. Charache S, Terrin ML, Moore RD et al. (May 1995).
"Eect of hydroxyurea on the frequency of painful crises
in sickle cell anemia. Invesgators of the Mulcenter
Study of Hydroxyurea in Sickle Cell Anemia". The NewEngland Journal of Medicine 332 (20): 1317 –22.
doi:10.1056/NEJM199505183322001. PMID 7715639
8. Pawliuk R, Westerman KA, Fabry ME, Payen E, Tighe R,
Bouhassira EE, Acharya SA, Ellis J, London IM, Eaves CJ,
Humphries RK, Beuzard Y, Nagel RL, Leboulch P (2001).
"Correcon of Sickle Cell Disease in Transgenic Mouse
Models by Gene Therapy". Science 294 (5550):2368 –71.
doi:10.1126/science.1065806. PMID 11743206.
9. Wilson, Jennifer Fisher (18 March 2002). "Murine Gene
Therapy Corrects Symptoms of Sickle Cell Disease". The
Scienst – Magazine of the Life Sciences. Retrieved 17
December 2014.
10. Green NS, Fabry ME, Kaptue-Noche L, Nagel RL (Oct 1993).
"Senegal haplotype is associated with higher HbF than
Benin and Cameroon haplotypes in African children with
sickle cell anemia". Am. J. Hematol. 44 (2): 145 –6.
doi:10.1002/ajh.2830440214. ISSN 0361-8609. PMID
7505527.
11. St. Jude Children's Research Hospital (4 December 2008).
"Gene Therapy Corrects Sickle Cell Disease In Laboratory
Study". ScienceDaily. Retrieved 17 December 2014.
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1 in 88 children in the United States are diagnosed with ausm; this number has grown exponenally over the past couple of
years, primarily due to raised awareness of this disorder. The denion of ausm as we know it today didn ’ t come about unl
1980. Prior to that, ausm was dened as schizoid personality disorder aributed fundamentally to a lack of maternal
warmth. Mental health issues, in general, in African Americans have not been extensively studied and are frequently under -
diagnosed. Dierenal expression of mental disease likely stems from the mul -generaonal inhumane eects of the
transatlanc slave trade, segregaon, racism, and discriminaon. As a result, the literature is scant on explicit descrip ons of
ausm for the African American populaon. However, new scienc advances are suggesng that ausm is genecally linked by
clusters of DNA markers. Since African American’ s rich diversity is not widely represented in either genec or behavioral studies,this research will search for evidence of mental disease in specic individuals within the Cobb Collecon try to develop a bri dge
between the behavioral expression of mental disease and the presence of genec suscepbility genes for ausm. This study w ill
focus on African American adults from the District of Columbia, Maryland, and Virginia area who died in the 1930s, 40s and 50s
and for whom clinical reports and other clinical and demographic clues suggest evidence of mental disease. Advanced
bioinformac approaches will be expended to idenfy likely ausm gene clusters in the targets of study.
GENETICS & EPIDEMIOLOGY
Genetic Behavioral Evidence for Autism in theCobb Collection
Jayla Harvey1,2
Fatimah Jackson, Ph.D.1,21W. Montague Cobb Research Laboratory, Howard University
2Department of Biology, Howard University
IntroductionMany of the paents conned at St. Elizabeth’s
Hospital in Washington, D.C between the decades of
1930s through 1950s were instuonalized because they
were unable to funcon in society.1
This inability to
assimilate into the general public may be a consequence
of an undiagnosed mental illness. Ausm Spectrum
Disorders (ASD) were not characterized separately from
schizophrenia at this me, therefore it is possible that
some paents that were being held at St. Elizabeth’s
Hospital because they didn’t exhibit ‘normal’ behavior
and suered from an ASD.14
Latest genec research
shows that ASD can be shown through a connecon of
many mutated genes.2
These mutaons can be
eologically eected by the environment the paent was
subjected to. African-Americans of this me period
would likely be more suscepble to these mutaons due
to the immense stressors of living in a me of
segregaon, Jim Crow Laws, post slavery traumac
syndrome, and poverty.
Methods and ResultsThe genes that will be studied in this experiment are
various genes that have been linked to ausm over the
past couple years. The genes have been grouped into
three categories: mutated genes, deleted or copied
genes, or genes with methylaon changes.
Mutated genes either show single nucleode
polymorphisms (SNPs) or frameshi mutaons. The
mutated genes being studied are Dopamine Receptor D2
(DRD2: Gene ID1813), Protein phosphate1, regulatory
inhibitor subunit 1B (PPP1R1B: Gene ID 84152), and
Neuroligin4, X-linked (NLGN4X: Gene ID57502). DRD2
encodes for the D2 subtype of a dopamine receptor
which has roles in postsynapc neurons and
autorecpetor mediang dopamine synthesis and
neurotransmission. The receptor inhibits adenylyl cyclase
acvity, which catalyzes the conversion of ATP and cyclic
adenosine monophosphate (cAMP) and pyrophosphate.3
cAMP is important because it is used in the intracellular
signal transducon. In ASD, the DRD2 gene shows an
over transmission of the T allele, which causes the gene
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to be incorrectly, negavely eecng how cells send
signals to each other.4
The PPP1R1B gene encodes for
DARPP-32, a bifunconal signal transducon molecule,
expressed in dopaminocepve neurons and mediates the
eects of D1 and D2 dopamine receptors. In ASDs, this
gene shows an over transmission of the C allele, which
can show decreased release of dopamine.
Altered levels
of the DARPP-32 molecule displays impaired reversal
learning. Mutated DRD2 and PPP1R1B genes addively
predispose ASDs and are only found in male
paents. The decreased dopamine acvity in the medial
prefrontal cortex is also a sign of ASD.5
The NLGN4X gene
eects cell adhesion molecules localized at the CNS
synapse. It is sll being studied, about the exact
variaon of this gene sequence that predisposes ASD,
but it has been suggested that the defect in this gene
negavely aects synaptogenesis.12 Therefore, when this
gene is mutated, neurons in the CNS have trouble
communicating with each other due to the fact that they are
unable to create proper synapses.
Certain genes have deleted or copied sequences that
cause either a lack of or overproducon of specic
proteins. The deleterious or copied genes in this study
are Fragile X mental Retardaon 1 (FMR1: Gene ID2332),
CD38 molecule (CD38: Gene ID952), Ca2+-
dependentsecreon acvator 2 (CADPS2), and protocadherin alpha
cluster 10, complex locus (PCDHA10: Gene
ID56139). FMR1 is a very well studied gene that encodes
for the Fragile X mental retardaon 1 protein. In the
brain, the protein may play a role in the development of
the connecons between nerve cells at the synapse.6
The
protein also regulates synapc plascity. Synapc
plascity is the ability of synapse to adapt over me in
response to experience.13 Synapc plascity plays a role
in learning and memory. In Fragile X syndrome, which
has features of ASD, 200+ CGG repeats causes the gene
to be unstable and in consequence to be silenced,
making lile to no protein. Fragile X syndrome is a
precursor for Ausm. The CD38 gene encodes for a
transmembrane protein, CD38, which regulates oxytocin
secreon. Oxytocin is described as the ‘bonding
hormone.7
It also promotes ethnocentric behavior,
incorporang the trust and empathy of in-groups with
their suspicion and rejecon of outsiders. In ASDs, there
is reduced to no expression of the CD38 protein due the
fact that the gene is mutated or deleted. The CADPS2
gene encodes for calcium binding proteins that play a
major role in exocytosis of neurotransmiers and
neuropepdes into the synapse and of dense core
vesicles in neuroendocrine cells.8 This gene also
regulates neurotrophin release from granule cells
leading to regulate cell dierenaon and survival during
cerebellar development. CADPS2 is deleted in ASD. The
gene PCDH10 deals with the establishment and funcon
of cell to cell connecons in the brain at the
synapse. This is also one of the largest deleons in ASD.9
The absence of this gene negavely aects the cells to
create synapses and communicate with each other.
Methylaon changes on a DNA sequence alters how
the gene or protein is expressed without changing the
actual sequence. The genes with epigenec changes
that may predispose ausm that are being studied in this
research are Nuclear Receptor Subfamily 3, group C,
Member 1 (NR3C1: Gene ID2908) and Methyl CpG
Binding Protein 2 (MECP2: Gene ID4204). NR3C1 gene
encodes for a glucocorcoid receptor that regulates
transcripon factors.
Glucocorcoids are involved in
inammatory responses, cellular proliferaon and
dierenaon in target ssues. In ASD, it has been
found that suppressed methylaon on hippocampal DNA
may be due to deprived maternal care during
infancy.10
This methylaon suppression at the NR3C1
gene leads to a decreased number of the glucocorcoid
receptors needed to regulate transcripon. The MECP2
gene encodes for the methyl-CpG binding protein 2. This
gene is located on the X chromosome at Xq28; it is an X-
linked dominant mutaon that is only found in females,
due to the fact that it is lethal in males. MECP2 is
idened with Res Syndrome, a precursor to ausm.11
De novo mutaons at CpG dinucleode causes
epigenec change of deacylaon of core histones, which
changes the chroman architecture and leads to
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transcriponal repression. This repression show low
levels of gene transcripon.
Conclusion
Ausm is a heterogeneous neuro-developmental
syndrome with a complex genec eology. Unifying
principles among cases of ausm are likely to be at the
level of brain circuitry at the synapse. All of the genes in
this study eect the synapc transmission of informaon
in some way. The idea that ASD can be aected or
caused by environmental factors is reinforced by the
characterisc called synapc plascity, in which a
synapse can change and adapt by either strengthening of
weakening over me in response to increases or
decreases in acvity or because of an alternaon in the
number of neurotransmier receptors on the
synapse. Conclusively, ASD is likely to be a synapc
disorder.
In the future we plan to extract DNA from the selected
specimen and rst look for the group of genes that
would have been deleted or copied, then mutated
genes. Lastly, we will look for possible methylaon
changes on the previously highlighted genes. If a paent
exhibits more than 3 mutated genec factors then we
will pull their archived records and compare their
psychiatric records with genec evidence found on their
genome and possibly, tentavely change their
psychiatric records with genec evidence found on their
genome and possibly, tentavely change their diagnoses
to an ASD.
References
1. Barak Goodman, J. M. (Director). (2010). American
Experience: The Lobotomist [Moon Picture].
2. Geschwind, D. H. (2008). Ausm: Many Genes, Common
Pathways. CellPress, 391-395.
3. NCBI. (2015, April 5). DRD2 dopamine receptor D2 [ Homo
sapiens (human) ]: Gene ID 1813. Retrieved from NCBI
Gene Summary: hp://www.ncbi.nlm.nih.gov/gene?
cmd=Retrieve&dopt=full_report&list_uids=1813
4. J. Reece, N. C. (2002). Biology. San Francisco.
5. Joe A Henger, X. L. (2012). DRD2 and PPP1R1B (DARPP -
32) polymorphisms independently confer increased risk
for ausm spectrum disorders and addively predict
aected status in male-only aected sib-pair families.
Behavioral and Brain Funcons.
6. U.S Naonal Library of Medicine. (2012, August). FMR1
Gene. Retrieved from Genecs Home Reference: hp://
ghr.nlm.nih.gov/gene/FMR1
7. Heon-Jin Lee, A. H. (2009). Oxytocin: the Great Facilitator
of Life. Progressive Neurobiology.
8. Declan J. James, a. T. (2013). CAPS and Munc13: CATCHRs
that SNARE Vesicles. Froners in Endocrinology , 817.
9. Eric M. Morrow, S.-Y. Y.-K.-S. (2008). Idenfying Ausm
Loci and Genes by Tracing Recent Shared Ancestry.
Science.
10.L J van der Knaap, H. R. (2014). Glucocorcoid receptor
gene (NR3C1) methylaon following stressful events
between birth and adolescence. The TRAILS study.
Translaonal Psychiatry .
11. Lam CW, Y. W. (2000). Spectrum of mutaons in the
MECP2. J Med Genet.
12.Jamain, S. (2003). Mutaons of the X-linked genes
encoding neuroligins NLGN3 and NLGN4 are associated
with ausm. Nature Genecs 34, 27-29.
13.Sarah R. Gilman, I. I. (2011). Rare De Novo Variants
Associated with Ausm Implicate a Large Funconal
Network of Genes Involved in Formaon and Funcon of
Synapses. CellPress: Neuron, 898-907.
14.(2013). The Evoluon of Ausm. Retrieved from The
History of Autsim: hp://ct-educaonadvocates.com/
informaon/ausm/the-evoluon-of -ausm/
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FULL ARTICLES Evolution of the Pathogenesis of Schizophre
Evoluonary theories suggest schizophrenia, and other psychiatric disorders, are uniquely human disorders that coevolved during
evoluon of the human brain. As brain size and complexity, relave to body mass increased, the energec demand required for
advancements in cognion, language, and execuve funcon increased. Currently, a variety of techniques using rodent models
and comparave genecs are used to invesgate the pathophysiology and therapeuc targets of schizophrenia while simultane-
ously placing this disorder into an evoluonary perspecve. Theories regarding the cause of schizophrenia range from gene-
environment interacons to dierences in brain chemistry and structure. Much research has been done to idenfy the role of sin-
gle gene mutaons and neuronal mitochondrial dysfuncon in the onset schizophrenia.
GENETICS & EPIDEMIOLOGY
A Review: Evolutionary Theories of the Pathogenesis ofSchizophrenia
Nichelle Jackson1,21
W. Montague Cobb Research Laboratory, Howard University2Department of Biology, Howard University
IntroductionThroughout history, individuals with psychiatric
disorders were sgmazed, dehumanized, and separated
from the community. During the Middle Ages, individuals
aicted by an illness were thought to be either
possessed by demons or punished by gods. To “cure”
these disorders, individuals were subjected to blood-
lengs, exorcisms or burned at the stake. By the 19th
century, psychiatric disorders were sll not understood,but illnesses were viewed as a sickness rather than an
evil or divine punishment. During this me, the mentally
ill were placed in asylums and prisons where they
received inhumane and insucient care. Emil Kraepelin
was the rst to described the symptoms of schizophrenia
in 1896. Kraepelin used the term demena praecox, to
characterize a disnct form of demena marked by poor
mental funcon in addion to reoccurring delusions and
hallucinaons.2
In 1911, Eugen Bleuler renameddemena praecox to schizophrenia (‘schizo’=split;
‘phren’= mind) and further characterized the disorder by
nong the incidence of posive and negave symptoms.
Within the last century, knowledge of the neurological
basis and associated therapies of schizophrenia have
improved. Paents with schizophrenia are no longer
subjected to crude forms of therapy as researchers
search for long-lasng anpsychoc medicaons.
Currently, schizophrenia is understood as a highly
heritable and debilitang psychological disorder with a
world-wide incidence of approximately 1%. Despite
medical advancements, the cause of schizophrenia is sll
unknown. Many individuals aicted with this disorder
become dependent on family members and medical
professionals and unable to live a normal life. Instead,
these individuals are. The economic costs associated
with the symptoms of schizophrenia total an upwards of
$63 billion dollars in the United States alone.23
If the
suering of paents and families is not enough
movaon to fund schizophrenia research, the economic
burden should be.
Paents aicted by schizophrenia exhibit a variety of
posive, negave and cognive symptoms that vary
among individuals. Posive symptoms are characterizedby psychoc behaviors not seen in healthy individuals.
Such symptoms include, hallucinaons, delusions,
thought disorders (disorganized thinking, thought
blocking, neoglisms) and movement disorders
(stereotyped movement, catatonia). Flat aect and lack
of pleasure in everyday life are considered negave
symptoms because they are qualies that disappear in
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FULL ARTICLES Evolution of the Pathogenesis of Schizophre
individuals presented with the disorder. Finally, cognive
symptoms are characterized by a decits in working
memory, execuve funconing and aenon.19
Symptoms of schizophrenia typically manifests during
adolescence and early adulthood, between the ages of
16 and 30. Childhood onset of schizophrenia is rare, but,
does occur. However, symptoms of schizophrenia do not
manifest once middle age is reached. Sexual dimorphism
of this disorder, exists as males tend to experience
symptoms sooner and more severely than females.
Addionally, males are more likely to be diagnosed with
schizophrenia while females are more likely to be
diagnosed with schizoaecve disorders.
Though the precise cause of schizophrenia is unknown,
genec and environmental factors have been found to
play an important role in the incidence of schizophrenia.
As previously menoned, schizophrenia occurs in 1% of
the general populaon. For second-degree relaves of
individuals diagnosed with schizophrenia, the genec
risk is greater than 1% and for rst-degree relaves, the
risk is around 10%. Idencal twins have the highest risk
of developing schizophrenia if one twin has the disorder
(40-65%).19
However, since the risk of idencal twins
developing schizophrenia is well below 100%, sciensts
believe there are environmental factors that contributeto greater vulnerability to.
Alternavely, dierences in brain chemistry and
structure may play a role in schizophrenia. Schizophrenia
has been consistently associated with enlarged
ventricles, and an overall reducon in brain size
especially in the hippocampus, thalamus, and frontal
lobes.21
Neuroimaging and immunohistochemistry of
post-mortem brains of schizophrenic paents were
marked by neurological abnormalies, parcularly in thehippocampus and neocortex, when compared to normal
controls. Neurons in these regions were also smaller with
abnormal dendric arborizaon and synapc
organizaon. Moreover, immunohistochemistry found a
marked decrease in biomarkers for GABAergic inhibitory
interneurons.24
Taken together, this disorder is
characterized by a reducon in synapc organizaon and
connectedness coupled with decreased expression of
GABAergic interneurons. These structural changes are
correlated with decits in the formaon, maintenance
and orchestraon of synapses that disrupts normal brain
funcon.
Genetic and Environmental FactorsFamilial studies implicate a strong genec component
to the suscepbility of schizophrenia, and several
candidate genes have been idened. Disrupted-in-
schzophrenia-1 (DISC1), Neuregulin (NRG1), Nuclear
receptor related 1 protein (Nurr1), and Dystrobrevin
binding protein 1 (DTNBP1) are a few of the top
candidate genes that display posive selecon for genes
associated with schizophrenia.13,25
However, since the
risk of developing schizophrenia decreases as the degree
of genec relatedness decreases, and twins do not have
a 100% risk of developing the disorder if one twin is
diagnosed, environmental insults have been suggested
to exert some degree of inuence on the suscepbility to
schizophrenia. Therefore, schizophrenia is theorized to
be the result of genec and environmental interacons.
Environmental factors such as maternal stress, social
isolaon, immune acvaon and pharmacological
interference have been found to mimic or exacerbatesymptoms of schizophrenia when combined with
individuals predisposed with genec risk factors.
DISC1, is among the most characterized gene
implicated in schizophrenia. This gene was originally
discovered in a Scosh family with a high prevalence of
schizophrenia and psychoaecve disorders including:
schizoaecve disorder, bipolar disorder, major
depression, adolescent conduct disorder and ausm
spectrum disorders.
13,18
Dysfuncon of this scaoldingprotein is characterized by a balanced translocaon
between chromosomes 1 and 11 that has been linked to
the development of psychosis. Addionally, DISC1
interacts with other proteins important to funcons of
intracellular signaling, neurodevelopment and
synaptogenesis.8
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FULL ARTICLES Evolution of the Pathogenesis of Schizophre
Evolutionary Perspective of SchizophreniaHuman evoluon is predominantly characterized by
the transion to bipedalism and the evoluon of brain
size. The evoluon of brain size led to increased
cognion and execuve funconing, in addion to, more
complex forms of language. The increase in brain size
was marked by increased development of the neocortex,
with a signicant increase in size and complexity of the
prefrontal cortex (PFC). Increases of the PFC led to
advantages in emoonal processing, motor control, and
regulaon of behavior in response to environmental
smuli.25 One theory suggests genec changes that
caused these enhancements occurred over 50,000 years
ago when Homo sapiens transioned from precursor
hominid species.5 Addionally, these enhancements may
have occurred when H. sapiens adapted to live in biggersocial groups forced to forage for sustenance. In these
condions, individuals evolved to cooperate, empathize
and access the emoonal states of others with cognive
adaptaons.12,7
In order to perform these energecally
demanding tasks, a balance between brain size and
energy demand was established. To meet the energec
demands imposed by evoluon of brain size, researchers
believe species could have increased energy intake and
producon and/or reduced the amount of energy usedby other bodily funcons.
In order to obtain the energy necessary to maintain
basal funcon, the brain depends on oxidave
phosphorylaon. At rest, the human brain uses
approximately 20% of total body oxygen consumpon.
This can be compared to apes that use 13% and other
vertebrate mammals that need 2-8%, but are considered
to be less intelligent.16 The amount of total body oxygen
consumed only increases when performing energecallydemanding tasks. Glucose metabolism is an important
source of energy within neuronal mitochondria that are
needed for oxidave phosphorylaon and intracellular
Ca2+ regulaon to maintain homeostasis. Moreover,
mitochondria that move within neurons are essenal for
processes that contribute to neurogenesis and neural
plascity including: neuronal dierenaon, neurite
outgrowth, neurotransmier package and release, and
dendric modeling.4
Comparave genomics suggests
mitochondrial genes coevolved with increased metabolic
processes and neuronal acvity. Mitochondria adapted
to produce more ecient means of electron transport
during oxidave phosphorylaon thereby increasing
energy levels necessary to maintain brain funcon. This
is thought to have coevolved with increased gene-
expression levels of genes associated with energy
metabolism and synapc connecvity in the human
neocortex compared to non-human primate relaves.10
Schizophrenia is thought to be a human specic disease
because its clinical symptoms indicate dysfuncon
among genes and/or pathways involved in human brain
evoluon.25 In parcular, changes in metabolic pathways
have been implicated in disorders like schizophrenia that
impact cognive abilies.
Methods and Materials
Animal Models of Schizophrenia
To study schizophrenia, researchers must study the circuitry
and molecular mechanisms of human brain. However, because
the organ is so vital to human life, obtaining the necessary
samples is dicult and impraccal. Tissue donated from post -
mortem paents has led to several advances in
neuroanatomical dierences observed in the disorder, but
physiological informaon cannot be obtained from dead
ssue. Addionally, studying post-mortem brains does not
provide insight needed to determine whether structural
changes are the cause or result of the disorder. Instead, animal
models are used because basic brain circuitry and molecular
mechanisms are conserved among many species throughout
evoluon.27
Tradionally, gene mutaons idened from
paent samples have been isolated and then genecally
modied in mice. Mice exhibit validity if (1) there is a mutaon
in the gene that has been supported by human literature, (2)
physical or behavioral phenotypes associated with the
disorder are displayed, and (3) mice exhibit similar phenotypic
response to therapy seen in humans. Despite construct
validity, cauon must be used when interpre