Leukemia Research 25 (2001) 179–181

Open forum

What the human genome project will not tell us: the role ofmicro-organisms in disease

Azra Raza *Pre-Leukemia and Leukemia Program, Rush Uni6ersity, Suite 108, 2242 West Harrison Street, Chicago, IL 60612-3515, USA

Received 14 July 2000; accepted 22 July 2000

Keywords: Human genome project; Microorganisms; Eukaryotes

www.elsevier.com/locate/leukres

The sum of living organisms, or biota that existwithin �5 miles above and below the earth’s surface ismainly composed of microscopic life-forms, the vastmajority of which have yet to be characterized. Bacte-rial cells that lack a nucleus, also referred to asprokaryotes, are the simplest and the smallest possibleliving creatures that are capable of independent exis-tence, and make up the bulk of biota. After life origi-nated on earth, prokaryotes alone existed for more thantwo billion years, until their mergers and combinationseventually led to the formation of eukaryotes or unicel-lular organisms that contain a nucleus. Proof thateukaryotes emerged as a result of symbiotic unionbetween bacterial cells comes from finding three typesof intracellular structures within these eukaryotic cellswhose origins can be traced to a prokaryotic ancestor.The first is mitochondria, once independently existingbacteria that are the source of energy for most eukary-otic cells, in return for a permanent abode. Second, thegreen plastids called chloroplasts, which synthesize foodfrom water and sunlight are present in plant cells, andare also thought to have existed previously as indepen-dent blue–green cyanobacteria. Finally, the whip likeundulipodia on the surface of motile cells, share incred-ible structural uniformity, whether they exist as cilialining the respiratory passages, or as flagella in spermtails, and appear to be derived directly from one of thefastest moving bacteria called spirochetes. Thus, eu-karyotic cells in the form of unicellular organismscollectively referred to as protists, emerged as a confed-

eracy of bacteria �1.6 billion years ago. Transforma-tion of prokaryotic cells into nucleated eukaryotesappears to be the single most dramatic event in biologysince this became the blueprint for the design of the restof the four kingdoms that include protists, plants,animals and fungi. Further evolution of the unicellularprotists into multi-cellular organisms was an accidentwaiting to happen, even though it took another fewhundred million years.

During those early years, the lonely inhabitants ofthe earth were not mere silent spectators. Rather, theselowly bacteria defined the basic rules for cooperativeexistence thereby laying down the foundations for thebirth and proliferation of all the incredible life formsthat we witness today. In addition to their parental roleas our ‘founding mothers’, there is increasing evidencethat the earth’s environment as we know it now, owesits gaseous composition and precise temperature regula-tion directly to the activities of these microscopic formsof life. In other words, rather than being passivehostages, subservient to the whims of an indifferent,pre-determined environment, these diverse and interact-ing life forms profoundly influence the atmosphere,making and remaking its composition, and determiningthe conditions for our survival. If our earth is to beviewed as a self-sustaining meta-organism, then the leadrole for maintaining homeostasis must be assigned tothe symbiotic and cooperative operations of our micro-scopic ancestors and fellow passengers. Disruption ofthis symbiotic balance for any reason would result inthe elimination of selective micro-organisms and theprovision of an undue growth advantage to others* Tel.: +1-312-4558474; fax: +1-312-4558479.

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eventually affecting the chemical composition and tem-perature of the lower atmosphere. This brings us to thefirst conclusion of the present thesis:

Toxic chemicals may be responsible for global warm-ing by directly perturbing the symbiotic existence ofmicro-organisms.We can now apply this model to the human body.

While some prokaryotes may have been subdued intolosing their identity and becoming an integral part ofthe eukaryotic cell, others continue to maintain theirindependence by learning to live in symbiosis with bothunicellular and multi-cellular organisms. The extent ofthis phenomenal cooperative existence can be appreci-ated somewhat by reiterating a few simple facts. Thenumber of pathogens is ten times greater than thenumber of cells in the human body. In fact, bacteriamake up �10% of our total dry weight. There aremore bacteria in one individual’s mouth than the num-ber of humans that ever lived on earth. Since we havemore bacteria in our bodies than we have cells, it isunrealistic to think that they are innocent bystanders.Rather, they represent a collection of pulsating, throb-bing, interdependent lives that are intimately involvedin maintaining the integrity and normal functions ofour bodies. In fact, it appears that every organ in thebody comes with its own set of symbiotically existingmicro-organisms, referred to as its ‘normal flora’. Or,germs are us. The fact that germs play an equallyimportant role in maintaining our health as they do incausing our diseases is critical to a better understandingof the factors which control our survival on earth. Oneway to determine the profound contribution of micro-bial agents towards maintaining physiologic homeosta-sis is to examine what happens if their normalsymbiotic state within our bodies is perturbed. Anobvious example is the appearance of diarrhea follow-ing prolonged antibiotic usage, caused by a redistribu-tion of proliferative advantage within the normalintestinal flora. Another example relates to the conversesituation where chronic intestinal inflammation of thegut has been successfully treated by oral administrationof the worm T. sui to patients with Crohn’s disease.Inflammation is apparently subdued as a result of theworm’s role in resetting of the intestinal flora back toits normal state. Worms won where several othermodalities of treatment, including chemotherapy, hadfailed. This leads to the second conclusion of thepresent thesis:

Human diseases, especially cancers, may begin as aperturbation of otherwise symbiotic micro-organisms.Humans surviving exposure to atomic fall-outs, or

cancer patients heavily treated with chemotherapy and/or radiation, are at particularly high risk of developingbone marrow diseases. The prototype of a malignantdisease caused by chemical exposure is the preleukemic

disorder called myelodysplastic syndromes or MDS.The incidence of myelodysplastic syndromes is surpris-ingly on the rise, probably reflecting, among otherfactors, an increasingly toxic environment. We havepreviously hypothesized that MDS may have a viraletiology. The virus however, may not necessarily be anacquired pathogen, but one existing in a latent, symbi-otic state in the bone marrow, which is awakened fromdormancy by a poorly understood set of co-factors. Nosingle organism has yet been incriminated in its etiol-ogy, and none may ever be. We hypothesize that thedisease may arise as a result of a reshuffling of thenormal ‘bone marrow flora’ rather than a single patho-gen. In addition to the circumstantial evidence suggest-ing that MDS represent a chronic inflammatory processrather than a true malignant disease, direct proofdemonstrating the reactivation of several pathogens,which normally exist in a latent, quiescent state in thebone marrow has been mounting in MDS patients.Besides chemical exposure, a compromised immunestatus of the host (for example as a result of aging), orthe acquisition of an exogenous pathogen would be twolikely candidates for the role of co-factors responsiblefor disrupting the normal symbiotic state of the bonemarrow flora. In other words, an unfortunate coordina-tion of factors acts in concert to perturb the existinghomeostasis in the marrow, providing selective growthadvantage to otherwise dormant pathogens, resulting inthe heterogeneous group of marrow disorders groupedunder the banner of MDS. Because the most consistentassociation of MDS is with toxic exposure, we proposethat myelodysplasia is to the human body, what globalwarming is to the earth. This leads us to our thirdconclusion:

If disease states result from perturbations in thenormal flora of an organ, then sequencing the humangenome alone will be inadequate both to explain theetiology or design curative therapies.Clearly, defining the genetic abnormalities in a trans-

formed myelodysplastic cell may be sufficient to illus-trate how the abnormal cell is different from a normalcell, but not why. And if the major contribution to thewhy comes from the activities of other life-forms withinand around the transformed cell, then an understandingof their role in maintaining the normal states is equallyimportant. This leads us to our fourth and finalconclusion:

There is an urgent need to define the ‘normal flora’ ofeach organ.An important lesson of infectious disease is that a

single organism is capable of causing a variety ofdiseases, only one of which may be contagious, andmost of which may bear no resemblance to each other.For example, the retrovirus HTLV-1 can cause a hu-man T-cell leukemia (HTL) in the lymphoid cells, aswell as a neurological disorder called tropical spastic

A. Raza / Leukemia Research 25 (2001) 179–181 181

paraparesis. Or the bacterium helicobactor pylori,which has been implicated in both gastric ulcers andgastric cancers, as well as mucosa associated lymphoidtissue (MALT) lymphoma. Pathogens provide only oneof several necessary steps that convert a normal cellinto a frankly malignant one. Thankfully, a congrega-tion of the required co-factors remains a rare event,making cancers an infrequent anomaly rather than therelentless rule. If we are to understand the preciseetiology and design curative therapies for these excep-tionally complicated diseases, then every variable in theequation must be defined with equal vigor. Sequencingthe genes that control critical cell functions, is only onestep towards this goal. An intense and detailed charac-terization of the intra- and extra-cellular micro-organ-isms which directly impact upon the cell must beundertaken with similar commitment. The ‘DNA mi-cro-array technology’ needs to be developed in tandemwith the ‘micro-organism array technology’, or we willonce again face the disappointments and dashed hopesso familiar to cancer researchers. This can only besuccessfully accomplished by simultaneously definingthe normal flora of each organ, and understanding its

contribution towards the maintenance of homeostasiswithin the organ via cellular interactions, as well as thechanges seen in this flora during evolution of diseasedstates. Our health depends on the finely tuned orches-tration of key in vivo functions performed by thesemicroscopic creatures. Disease states generally appearnot because these organisms change character via ge-netic mutations, but because we change the conditionsnecessary for their survival and optimum activity. It istime to grant them the respect they deserve by accept-ing their profound role not only in disease, but moreimportantly, in maintaining our health.

Further Reading

Margulis L, Sagan D. Microcosmos. California: University of Cali-fornia Press, 1997.

Margulis L, Sagan D. Slanted Truths. Essays on Gaia, symbiosis andevolution. New York: Copernicus/Springer–Verlag, 1997.

Barlow C. From Gaia to Selfish Genes. Selected writings in the LifeSciences. MA: MIT Press, 1994.

Raza A. Initial transforming event in myelodysplastic syndromes maybe viral: case for cytomegalovirus. Med Oncol 1998;15:165–173

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