Table Of ContentEvolution’s Clinical
Guidebook
Evolution’s Clinical
Guidebook
Translating Ancient Genes into
Precision Medicine
Jules J. Berman
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Other Books by Jules J. Berman
About the Author
JulesJ.Bermanreceivedtwobaccalaureatedegreesfrom
MITinMathematicsandinEarthandPlanetarySciences.
HeholdsaPhDfromTempleUniversity,andanMD,from
the University of Miami. His postdoctoral studies were
completed at the US National Institutes of Health, and
his residency was completed at the George Washington
UniversityMedicalCenterinWashington,DC.Dr.Berman
served as Chief of Anatomic Pathology, Surgical Patho-
logy, and Cytopathology at the Veterans Administration
Medical Center in Baltimore, Maryland, where he held
jointappointmentsattheUniversityofMarylandMedical
CenterandattheJohnsHopkinsMedicalInstitutions.In
1998, he was transferred to the US National Institutes of
Health as a Medical Officer and as the Program Director for Pathology Informatics in
the Cancer Diagnosis Program at the National Cancer Institute. Dr. Berman is a past
presidentoftheAssociationforPathologyInformaticsandthe2011recipientoftheAsso-
ciation’s Lifetime Achievement Award. He has first-authored more than 100 journal
articles and has written numerous science books. His most recent titles, published by
Elsevier, include:
Taxonomic Guide to Infectious Diseases: Understanding the Biologic Classes of
Pathogenic Organisms,1st edition (2012)
PrinciplesofBigData:Preparing,Sharing,andAnalyzingComplexInformation(2013)
Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common
Diseases (2014)
Repurposing Legacy Data: Innovative Case Studies (2015)
Data Simplification: Taming Information with Open SourceTools (2016)
Precision Medicine and the Reinvention of Human Disease (2018)
Principles and Practice of Big Data: Preparing, Sharing, and Analyzing Complex
Information, 2nd edition (2018)
Taxonomic Guide to Infectious Diseases: Understanding the Biologic Classes of
Pathogenic Organisms,2nd edition (2019)
xi
Preface
Everythinghasbeensaidbefore,butsincenobodylistenswehavetokeepgoingback
and beginningall overagain.
AndreGide
In 1973, Theodosius Dobzhansky, a distinguished geneticist and the awardee of the US
National Medal of Science, delivered an influential essay entitled “Nothing in biology
makes sense except in the light of evolution” [1]. In this essay, he argued that we need
the theory of evolution to explain paleontology, zoology, and the biomedical sciences.
Thereasonforthisisthatalloftheobservablephenomenaofliving(oronce-living)organ-
ismsdevelopedstepwise,overvaststretchesoftime.Itisthroughthetheoryofevolution
thatscientistsunderstandbiologicalobservations.Withoutevolution,biologicalobserva-
tions arereducedto merefactoids.
AssumingthatDr.Dobzhanskywascorrectandthatallbiologicalobservationsmustbe
interpreted within the framework of their evolutionary origins, then we would surmise
thatanyoneinterestedinbiologywouldbehighlyencouragedtostudythefieldofevolu-
tion, as well as the complementary fields in which the steps of evolution are directly
expressedinanimals(i.e.,embryology,histology,anatomy,microbiology,andphysiology).
Thesefivefields,theformermainstaysofmedicaleducation,havefallenbehindthetwo
relatively new fields of molecular biology and bioinformatics. Progress in the fields of
molecular biology and bioinformatics, over the past three decades, has been so rapid
andsoexcitingthatwecanhardlyfaultstudentswhochoosetoconcentratetheiratten-
tion on these twonew areas.
Asapointoffact,advancesinthegeneticsofhumandiseaseshavevastlyoutpacedour
abilitytoanalyzeandunderstandourdata.Wehavenowidentifiedthousandsofgenevar-
iants that arethe putative root causes of rarediseases, without achieving a deep under-
standing of the biological mechanism whereby the variant gene leads to the clinical
expression of disease [2]. In the case of the common diseases of humans, particularly
in the case of cancers, we have collected thousands of gene variants that are associated
withsubsetsofaffectedindividuals,butweseldomhaveaclearunderstandingofthebio-
logical roles these genes play in the development or progression ofdisease[3].
Wenowknowthatdiseasesdevelopthroughasequenceofbiologicalstepsthateven-
tuallyleadtotheappearanceofaspecificclinicalphenotype(i.e.,cellularpathologyand
consequentsymptoms).Aspecificdefectinaparticulargenemaylieattherootcauseof
the disease, but identifying a “causal” gene seldom tells us much about the subsequent
stepsthatoccuroverdaysormonthsoryears,leadingtodisease.Inmanycases,knowing
xiii
xiv PREFACE
those steps may be more important than simply identifying the root causal gene; the
reason being that the most effective way to prevent, diagnose, or treat a disease may
involve targeting those subsequent events and pathways. Furthermore, knowledge of
theeventsandpathwaysthatleadtothedevelopmentofaspecificdiseasemaybedirectly
applicable to otherdiseases, including subsets of common diseases[4].
At this point, you might be wondering how issues concerning disease development
mightrelatetothetopicofevolution.Asithappens,thepathwaysleadingtothedevelop-
mentofdiseaseareconservedcellularpathways,allofwhichcameintoexistencethrough
evolution, at particular moments in the development of ancestral species. If we want to
understandthepathwaysthatleadtodisease,wemightwanttolookathowandwhythese
pathwaysevolved,thefunctionstheyserveatparticularstagesinanorganism’sdevelop-
ment, and the particularcellsin which those pathways areexpressed.
Now we come to the premise of this book. We’ll take Dobzhansky at his word, that
“Nothing in biology makes sense except in the light of evolution,” and we’ll extend it to
assert that “nothing in the field of Precision Medicine makes sense except in the light
of evolution.” Evolution’s Clinical Guidebook: Translating Ancient Genes into Precision
Medicine is an exploration ofthisassertion.
Howto read this book
This book is primarily written for anyone who is searching for a clear, logical, and
informedexplanationoftherelationshipbetweenevolutionaryprocessesandthescience
of modern medicine.On a verysimplistic level, evolutionarytheorycan be coveredin a
fewparagraphsofamiddleschooltextbook,leavingstudentswithacredibleaccounting
ofhowancientanimalsmayhavegivenrisetoallthespeciesofanimalsthatinhabitour
planettoday.Ifwewanttounderstandexactlyhowparticulardiseasesmayhaveevolved
andhowwemightuseourunderstandingofevolutionaryhistorytodevelopandtestnew
and effective treatments for human diseases, then we must be prepared to think very
deeplyandtointegratetheseeminglyunrelateddisciplinesofembryology,biochemistry,
paleontology, comparative anatomy,molecular biology, bioinformatics, and pathology.
Needless to say, it is impossible for anyone to absorb all the subjects covered in this
book.Settingasidethemanynewconceptsthatwillbediscussed,theburdenofmastering
theterminologiesofhalfadozenscientificfieldsistoooneroustobear.Accordingly,the
book is organized to eliminate the need for rote memorization, while permitting the
readerto focus onthe fundamentalconceptsexplained in each sectionofeach chapter.
Insomesense,thebookisacollectionoflogicalarguments.Thefactsinthebookappear
forthesolepurposeoflegitimizingthearguments.Ifyouareacuriouslayman,thecon-
ceptsthataredevelopedthroughoutthebookwillsatisfyyourcuriosity.Ifyouareamed-
ical researcher, then you can always returnto the book and readit a second time for its
factualcontent.
Thereareabout800referencesincludedwiththetextandthisshouldkeeptheserious
scholaroccupiedforyearstocome.Inaddition,eachchapterisaccompaniedbyaglos-
sarycontainingmanyofthediscipline-specifictermsappearinginthetext.Thereare,in
toto, over 300 glossary terms. Along with term definitions, most of the glossary items
Preface xv
expand upon the concepts covered in the text, providing additional references and
instructiveexamples.Readerswholackastrongbackgroundinthebiologicalormedical
sciences are encouraged to read the chapter glossaries, before proceeding to the subse-
quent chapters.
References
[1] Dobzhansky T. Nothing in biology makes sense except in the light of evolution. Am Biol Teach
1973;35125–9.
[2] Berman JJ.Rarediseasesandorphandrugs:keystounderstandingand treatingcommondiseases.
Cambridge,MA:AcademicPress;2014.
[3] BermanJJ.Neoplasms:principlesofdevelopmentanddiversity.Sudbury:Jones&Bartlett;2009.
[4] Berman JJ. Precision medicine, and the reinvention of human disease. Cambridge, MA: Academic
Press;2018.
1
Evolution, From the Beginning
OUTLINE
Section1.1IntheBeginning ...........................................................................................................1
Section1.2BootstrappingParadoxes .............................................................................................5
Section1.3OurGenes,fortheMostPart,ComeFromAncestralSpecies .................................12
Section1.4HowdoMetabolicPathwaysEvolve? .......................................................................15
Section1.5CambrianExplosion ....................................................................................................21
Section1.6AftertheCambrian:CoexistenceandCoevolution ..................................................25
Glossary ..........................................................................................................................................29
References ......................................................................................................................................44
Section 1.1 In the Beginning
The beginningsandendings of all human undertakings are untidy.
JohnGalsworthy
Every story has a beginning. Inthe case of life on planetEarth, thereis no one who can
speakwithanygreatauthorityonthesubject.Ithappenedtoolongago,onaworldthat
wasverydifferentfromtheworldwelivein.Nonetheless,thebeginningoflifeonEarthisa
topic that invites thoughtful speculation. The purpose of this chapter is to discuss how
biological processes begin, in general terms. If nothing else, the chapter provides us an
opportunity to explore fundamental concepts that will surface throughout the book:
enzymes, pathways, natural selection, and evolution.
Abiogenesis
Abiogenesisisthecreationoflifefromnonlivingmatter.Forthousandsofyears,themys-
teryoftheoriginoflivingorganismshaschallengedphilosophers,theologists,andscien-
tists.Inthissection,we’lltrytoshowthatlifeisverysimpletocreate,ifwejustacceptthe
following threeassumptions:
–1. Alllivingthingsarecomposed ofnonliving things.
Lifeonearthconsistsofcells,andcellsarejustbagsofchemicals.Ithappensthatthese
bagsofchemicalscanreplicatethemselves(i.e.,self-replicate),accountingforwhythere
aresomanycellsontheplanet.Becausealllivingmatteriscomposedentirelyofnonliving
matter, we can guess that life may have gotten its start from some process involving
nonlife.
1
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