Of Mice and Medicine Men

Dr. Se-Jin Lee, MD., PhD. has in­creased muscling on mice in re­search lab­o­ra­tory tri­als show­ing promis­ing po­ten­tial The work of an unas­sum­ing and some­what hum­ble Johns Hop­kins re­searcher holds the po­ten­tial to rev­o­lu­tion­ize the treat­ment of dis­eases sap­pin

The Suit - - Contents - re­ported by amy arm­strong

The work of an unas­sum­ing and some­what hum­ble Johns Hop­kins re­searcher holds the po­ten­tial to rev­o­lu­tion­ize the treat­ment of dis­eases sap­ping away mus­cle strength, as well as to mit­i­gate some of the mus­cle-drain­ing ef­fects of ag­ing.

Dr. Se-Jin Lee, M.D., Ph.D., who is the Michael and Ann Hankin and Part­ners of Brown Ad­vi­sory Pro­fes­sor in Sci­en­tific In­no­va­tion and Pro­fes­sor of Molec­u­lar Bi­ol­ogy and Ge­net­ics at Johns Hop­kins Univer­sity School of Medicine in Bal­ti­more. Lee was in­ter­viewed re­gard­ing the cur­rent sta­tus of his re­search into the ef­fects of a pro­tein he dis­cov­ered in 1995 and named myo­statin. Nat­u­rally oc­cur­ring in mam­mals, this pro­tein plays a cru­cial role in reg­u­lat­ing mus­cle growth by pre­vent­ing mus­cles from grow­ing too large for the skele­tal frame upon which they func­tion.

Lee’s re­search demon­strated that the myo­statin pro­tein sig­nals other dor­mant or non-ac­tive mus­cle-build­ing cells to ac­ti­vate when mus­cle build­ing or re­pair be­comes nec­es­sary. This dis­cov­ery led to a num­ber of ques­tions, the most im­por­tant of which re­volved around what ef­fects the re­moval of myo­statin would have on mus­cu­lar de­vel­op­ment. The phar­ma­ceu­ti­cal in­dus­try re­sponded with in­ter­est in how peo­ple suf­fer­ing from mus­cle de­ple­tion could be helped, and the sports in­dus­try was also in­ter­ested, hop­ing that mas­tery

of myo­statin could lead to en­hanced per­for­mance, pos­si­bly prov­ing to be an al­ter­na­tive to con­tro­ver­sial steroids.

In­ter­est­ingly enough, Lee – an avid sports fan him­self, to say the least – is much more in­ter­ested in the po­ten­tial that med­i­cal reg­u­la­tion of the myo­statin pro­tein presents for an ag­ing Amer­ica los­ing its mus­cle strength and for pa­tients whose ill­nesses leave them fight­ing mus­cle de­te­ri­o­ra­tion, than he is in myo­statin’s ap­pli­ca­tion to sports fig­ures, in­clud­ing any ac­com­pa­ny­ing fi­nan­cial wind­falls that might re­sult.

In 2008, he told David Ep­stein from Sports Il­lus­trated that he would do an in­ter­view on the con­di­tion that Ep­stein make it em­i­nently clear to read­ers that Lee’s work was not now – and would not be – di­rected to­ward en­hanc­ing ath­letic per­for­mance. Ep­stein com­plied, and the sports world learned first-hand from Lee about the med­i­cal ap­pli­ca­tions of his re­search at a time when na­tional at­ten­tion fo­cused on an­abolic steroid abuse as the Roger Cle­mens scan­dal un­folded in pro­fes­sional base­ball.

Fast-for­ward to 2014, and Lee’s in­sis­tence that his mus­cle-reg­u­lat­ing pro­tein dis­cov­ery be limited to med­i­cal uses ap­pears to be hold­ing firm. The list of cur­rent re­search tri­als he pro­vided to The Suit Mag­a­zine ad­dresses med­i­cal is­sues such as mus­cle wast­ing after hip frac­ture surgery, mus­cle at­ro­phy post hip re­place­ment, mus­cle weak­ness after a fall and myo­statin’s role in treat­ing var­i­ous types of can­cer. Each of th­ese tri­als rep­re­sents common geri­atric health is­sues that Lee has reg­u­larly in­sisted his re­search needs to ad­dress.

After at­tend­ing Johns Hop­kins, Lee grad­u­ated from the

Med­i­cal Sci­en­tist Train­ing Pro­gram, a fed­er­ally-funded MD/PhD pro­gram, spend­ing time as a staff as­so­ciate at the Carnegie In­sti­tu­tion of Wash­ing­ton’s Depart­ment of Em­bry­ol­ogy in Bal­ti­more. Then Lee re­ceived an of­fer from the Johns Hop­kins Molec­u­lar Bi­ol­ogy and Ge­net­ics Depart­ment – one of the best de­part­ments in biological sciences any­where in the world. “The depart­ment has had three sit­ting mem­bers re­ceive the Nobel Prize in Medicine or Phys­i­ol­ogy, in­clud­ing our cur­rent chair, Carol Grei­der, who re­ceived the prize for her work on telom­erase,” Lee said.

Be­liev­ing that he was in an ex­cel­lent po­si­tion to make a dif­fer­ence sci­en­tif­i­cally, lit­tle did he know that the dis­cov­ery by his team would trig­ger such a firestorm of in­ter­est in slow-paced, repet­i­tive sci­en­tific re­search.

Lee spent a num­ber of years fo­cus­ing on ge­net­i­cally en­gi­neered mice, ei­ther to delete in­di­vid­ual genes or to pro­duce too much of an in­di­vid­ual pro­tein. It was in 1995, while work­ing with lab­o­ra­tory mice in an at­tempt to un­der­stand the role sig­nal­ing mole- cules played in reg­u­lat­ing em­bry­onic de­vel­op­ment and adult tis­sue home­osta­sis, that Lee and his team dis­cov­ered the myo­statin pro­tein.

Lee and his re­search staff ge­net­i­cally al­tered some of the mice by lim­it­ing the amount of myo­statin in their sys­tems. “We found that delet­ing the myo­statin gene in mice led to mice with about twice the nor­mal mus­cle mass through­out the body, demon­strat­ing that myo­statin nor­mally acts to limit mus­cle mass,” Lee said. This lack of myo­statin pro­duced mice with sig­nif­i­cantly larger mus­cle mass, quickly earn­ing them the name “knock­out mice” within the sci­en­tific com­mu­nity.

The pub­li­ca­tion of his ini­tial re­search re­sults in a stan­dard re­search pa­per out­lin­ing their find­ings opened a flood­gate of ques­tions from within the med­i­cal phar­ma­ceu­ti­cal in­dus­try re­gard­ing prac­ti­cal ap­pli­ca­tions. In rel­a­tively short or­der, the some­what un­wanted me­dia spot­light ze­roed in on Lee.

His ef­forts cur­rently fo­cus on two gen­eral ar­eas. The first is in con­tin­u­ing to un­der­stand how myo­statin works at the molec­u­lar and cel­lu­lar level. There are still many unan­swered key ques­tions re­gard­ing the pro­tein, and Lee be­lieves that a greater un­der­stand­ing of the mech­a­nisms by which it acts will have im­por­tant im­pli­ca­tions for the de­vel­op­ment of ther­a­peu­tics tar­get­ing this path­way. The sec­ond area his re­search im­pacts is a po­ten­tial un­der­stand­ing re­gard­ing the role of myo­statin in dis­eases hav­ing mus- cle-wast­ing symp­toms, along with the con­se­quences of ma­nip­u­lat­ing this path­way in var­i­ous dis­ease states.

Although Lee’s cur­rent work fo­cuses almost en­tirely on mice, his re­search has shown that nat­u­rally oc­cur­ring mu­ta­tions in the myo­statin gene also lead to in­creased mus­cle mass in other species, in­clud­ing cat­tle, dogs and sheep. In ad­di­tion, there are some in­ter­est­ing stud­ies show­ing that vari­ants of myo­statin can in­crease rac­ing per­for­mance in horses, ac­cord­ing to Lee.

Cur­rently, Lee and his re­search team con­tinue to fo­cus on a group of pro­teins re­ferred to as the trans­form­ing growth fac­tor-ß su­per­fam­ily. “This group of pro­teins func­tion as sig­nal­ing

mol­e­cules that act to reg­u­late the state of growth and/or dif­fer­en­ti­a­tion of tar­get cells and tis­sues,” Lee ex­plains. “Be­cause th­ese nor­mally act from out­side the cell, ma­nip­u­lat­ing the ac­tiv­i­ties of th­ese mol­e­cules, it is more straight­for­ward than those that act in­tra-cel­lu­larly.”

The body-build­ing in­dus­try is wildly in­ter­ested in the ef­fects it per­ceives the reg­u­la­tion of myo­statin could have on mus­cle en­hance­ment. The 2008 Sports Il­lus­trated ar­ti­cle high­lighted cur­rent spec­u­la­tion that myo­statin reg­u­la­tion could lead to gene ther­apy aimed at al­ter­ing DNA. In the­ory, this type of mus­cle en­hance­ment might be able to cir­cum­vent drug test­ing. The body-build­ing com­mu­nity, by en­vi­sion­ing yet another way to ma­nip­u­late mus­cle mass, has been con­tro­ver­sial, to say the least. Lee re­mains adamant, how­ever, that the goal of his work is not to im­prove the odds of ath­letes, but to help ag­ing Amer­ica trade in their canes and wheel­chairs for more ac­tive golden years. For now, he has been able to limit myo­statin re­search to valid med­i­cal pur­poses only. Yet, he knows that once a myo­statin reg­u­la­tor hits the mar­ket, it’s highly likely that some peo­ple will get their hands on the drug and use it for en­hanc­ing ath­letic per­for­mance in hu­mans and an­i­mals, body­build­ing, bulk­ing up food sources and other, as yet uniden­ti­fied non-med­i­cal uses.

De­spite lament­ing th­ese pos­si­bil­i­ties, Lee be­lieves that the med­i­cal ram­i­fi­ca­tions war­rant con­tin­ued re­search.

“Peo­ple who suf­fer from a dis­ease can de­velop a se­vere wast­ing pro- cess, which is called cachexia,” Lee ex­plains, “Cachexia is also known as a wast­ing syn­drome – mean­ing loss of weight, mus­cle at­ro­phy, fa­tigue, weak­ness and sig­nif­i­cant loss of ap­petite in some­one who is not ac­tively try­ing to lose weight. The for­mal def­i­ni­tion of cachexia is the loss of body mass that can­not be re­versed nu­tri­tion­ally. Even if the af­fected pa­tient eats more calo­ries, lean body mass will be lost, in­di­cat­ing a pri­mary pathol­ogy is in place.”

Ten dif­fer­ent clin­i­cal tri­als are in the sec­ond phase of re­search aimed at de­vel­op­ing myo­statin in­hibitors to treat pa­tients with mus­cle loss. “For now, we are fo­cused on myo­statin – but this type of re­search al­ways ends up mov­ing in di­rec­tions that may be un­ex­pected, so it is dif­fi­cult to pre­dict where we will be in the fu­ture,” said Lee. “My work on myo­statin has cer­tainly been in­ter­est­ing. It is too early to say how im­por­tant this will be one day, but I am anx­iously await­ing the re­sults of the clin­i­cal tri­als to see whether this is go­ing to work.”

This last state­ment came with the kind of know­ing chuckle that only a re­search sci­en­tist could fully ap­pre­ci­ate. Lee cau­tions that any med­i­cal us­age of myo­sta­tion reg­u­la­tion is not years, but most likely decades in the fu­ture. Yet, the pos­si­bil­ity that his work has more than laid the foun­da­tion for ad­vance­ments in mus­cu­lar support to aid com­ing gen­er­a­tions as they age, seems to be an un­usu­ally bank­able one. In our opin­ion, savvy bio­med­i­cal in­vestors might wisely eval­u­ate phar­ma­ceu­ti­cal com­pa­nies cur­rently run­ning clin­i­cal tri­als based on the po­ten­tial changes that mas­tery of this pro­tein rep­re­sents for the med­i­cal com­mu­nity.

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