the backbone volume 2 issue 1

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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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CobbResearchLab.com/TheBackbone Winter 2015•Spring 2016 Volume 02 Issue 01

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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CobbResearchLab.com/TheBackbone Winter 2015•Spring2016 Volume 02 Issue 01

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


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


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


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

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2003;14:2902 –2907.

6. Tareen N, Zadshir A, Marns D, et al. Chronic kidney disease

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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,

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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,

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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.



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The Backbone

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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FULL ARTICLES Potential Treatments for Sickle-CThe Backbone

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


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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FULL ARTICLES Evidence for Autism in the CThe Backbone

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.


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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FULL ARTICLES Evidence for Autism in the CCThe Backbone

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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FULL ARTICLES Evidence for Autism in the CThe Backbone

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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The Backbone

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.


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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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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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

the backbone volume 2 issue 1

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