THE SE­CRET CHEM­ISTRY OF PRO­TEINS For years, scientists have been try­ing to get a han­dle on dark mat­ter, the mys­te­ri­ous sub­stance hold­ing our uni­verse to­gether. Now new re­search has led to a stun­ning dis­cov­ery: our bod­ies may also be de­pen­dent on their pow

World of Knowledge (Australia) - - Human Body -

Everyone knows that a cater­pil­lar changes com­pletely when it be­comes a but­ter­fly. How­ever, para­dox­i­cally, it also stays the same. The process is prob­a­bly the most dra­matic trans­for­ma­tion in the an­i­mal king­dom: limbs ap­pear where there were none, while or­gans move through­out the body, mu­tat­ing, dis­in­te­grat­ing and being put back to­gether again. They’re two crea­tures that couldn’t be more dif­fer­ent, but the but­ter­fly and cater­pil­lar have an iden­ti­cal genome. How? What caused the cater­pil­lar’s me­ta­mor­pho­sis, if not its ge­netic blue­print?

The an­swer has as­ton­ished even ex­pe­ri­enced bi­ol­o­gists. The change from cater­pil­lar to but­ter­fly is ac­tu­ally con­trolled by pro­teins. Pro­teins are poly­mer chains formed from amino acids and

are based on a blue­print in the DNA. All the body’s pro­teins link to­gether to form the “pro­teome”.

In mod­ern medicine, this is con­sid­ered a dull area of study and is of­ten over­looked. Pro­teins were re­searched a long time ago, their role in the body re­duced to being a source of en­ergy and build­ing block for mus­cles, or­gans and the blood. But that was a big mis­take be­cause, in ac­tual fact, pro­teins are the most ac­tive de­sign­ers of life and im­ple­ment our ge­netic makeup. Fur­ther­more, there are 400,000 dif­fer­ent pro­teins that af­fect ev­ery process in the body, mak­ing up 15% of our over­all mass. They in­flu­ence heal­ing, com­mu­ni­ca­tion be­tween cells and the im­mune sys­tem. “Many peo­ple think that we’re con­trolled by our genes,” ex­plains Pro­fes­sor Matthias Mann from the Max Planck In­sti­tute of Bio­chem­istry. “But, in re­al­ity, it’s the pro­teins that do some­thing in us and to us.”

The strange thing is that around 50% of these pro­teins are still com­pletely un­known. They are a kind of dark mat­ter in our bod­ies – and we’re only just be­gin­ning to un­der­stand the power they have over us.


The role pro­teins play in the body is cru­cial, but it was long thought im­pos­si­ble to de­code their pow­er­ful net­work. Af­ter all, a sin­gle cell can be con­trolled by up to 10,000 pro­teins. “Our pro­teome is prob­a­bly a lot more com­plex than our genome,” ex­plains Pro­fes­sor Mann. How­ever, with the com­put­ing power now avail­able, it’s fi­nally pos­si­ble to unscramble the com­pli­cated pro­tein codes in the body and put them in a data­base. It’s a job for Dr Sean O’donoghue, data vi­su­al­i­sa­tion scientist at the Com­mon­wealth Sci­en­tific and In­dus­trial Re­search Or­gan­i­sa­tion (CSIRO) in Syd­ney. For years, he and his team have been putting to­gether gene maps to de­pict the cos­mos of pro­teins in our body – and has stum­bled across thou­sands of pre­vi­ously un­known chains. For the re­searchers, it’s like dis­cov­er­ing hu­man dark mat­ter with­out hav­ing a clue what it ac­tu­ally does. “It may sound ab­surd, but we had to do two things,” ex­plains Dr An­drea Schafferhans from the Tech­ni­cal Univer­sity of Mu­nich. “First we had to dis­cover pro­teins we didn’t know were there, and then we had to find out why we didn’t know about them.” How­ever, all that’s about to change.


For medicine, the dis­cov­ery of dark mat­ter in the body is both a bless­ing and a curse. On one hand, it could pro­vide in­sights into pro­tein-based ill­nesses like can­cer and type 2 di­a­betes, neu­rode­gen­er­a­tive dis­eases such as Parkin­son’s and Alzheimer’s, and it might also be a way of managing the age­ing process. In other words it

“Dark pro­teins def­i­nitely have an im­por­tant role, but we don’t know what it is yet.” AN­DREA SCHAFFERHANS, DE­PART­MENT OF BIO­CHEM­ISTRY AT THE TECH­NI­CAL UNIVER­SITY OF MU­NICH “Just as you can’t see dark mat­ter in the uni­verse us­ing a tele­scope, you can’t rep­re­sent dark pro­teins us­ing con­ven­tional meth­ods.” DR PETER WRIGHT, THE SCRIPPS RE­SEARCH IN­STI­TUTE IN CAL­I­FOR­NIA

could al­low doc­tors to reach ar­eas that were pre­vi­ously closed off, de­spite re­cent med­i­cal ad­vance­ments. On the other hand, re­searchers have con­fided to O’donoghue that the dis­cov­ery of dark mat­ter feels like an ad­mis­sion of fail­ure for medicine – a blank area on a map that was meant to have been fully ex­plored a long time ago.

“We’re amazed at how much we still don’t un­der­stand,” ad­mits Schafferhans. From a sci­en­tific per­spec­tive, the dis­cov­ery of dark pro­teins is com­pa­ra­ble to “the search for dark mat­ter in the uni­verse,” ac­cord­ing to Dr Peter Wright of the Scripps Re­search In­sti­tute in Cal­i­for­nia. Even the world’s most re­spected scientists feel as if they’ve been thrown back to square one: the search for an­swers is like grop­ing around a pitch-black room for objects that a hu­man has never seen be­fore.

What O’donoghue and his team have man­aged to find out about the body’s dark mat­ter shows that, de­spite its shad­owy na­ture, it plays an im­por­tant role. The be­hav­iour of dark pro­teins marks them out as dif­fer­ent from reg­u­lar va­ri­eties and con­trasts with ev­ery known bod­ily

“Mil­lions of dif­fer­ent pro­tein mol­e­cules are mov­ing around our bod­ies – and most of them are ‘dark mat­ter’” BERN­HARD KUESTER, PRO­TEOME RE­SEARCHER AT THE TECH­NI­CAL UNIVER­SITY OF MU­NICH

struc­ture. They keep to them­selves and hardly ever in­ter­act with other pro­teins, but they still have a far-reach­ing in­flu­ence on the body. This in­de­pen­dent be­hav­iour would ex­plain why they pre­fer to float out­side cells and glan­du­lar tis­sue.

From ex­am­in­ing nor­mal pro­teins, ex­perts know that these wan­der­ers have highly specialised jobs re­lat­ing to cel­lu­lar com­mu­ni­ca­tion and the im­mune sys­tem. Pro­fes­sor O’donoghue pre­dicts that the dis­cov­ery of dark pro­teins will there­fore have a wide­spread im­pact on the future of medicine. Just like the study of dark mat­ter in physics, dark pro­teins will usher in a new era of re­search. And the de­vel­op­ment has al­ready be­gun: in China, for in­stance, scientists -have dis­cov­ered a link be­tween pro­teins and the pro­duc­tion of an­ti­bod­ies to com­bat harm­ful germs. Re­searchers from the Chi­nese Academy of Sci­ence in Yun­nan man­aged to iso­late 700 pep­tides (short chain pro­teins) from the dark mat­ter of pre­vi­ously undis­cov­ered pro­teins. They were so ef­fec­tive at fight­ing bac­te­ria with­out side-ef­fects that they could help kick­start a new gen­er­a­tion of an­tibi­otics.

But that’s not all. For many re­searchers, the dis­cov­ery of dark pro­teins sheds new light on dis­eases we still don’t un­der­stand. It’s as if a door that was pre­vi­ously locked shut has sud­denly opened. Ex­am­ples in­clude Alzheimer’s and Parkin­son’s – both of which are caused by pro­tein ag­gre­ga­tion, or clump­ing. For years, it was clear that a treat­ment was hid­ing in the pro­teome – but it couldn’t be found. Now, af­ter the dis­cov­ery of dark pro­teins, a break­through is fi­nally within reach.


But be­fore we gain com­plete ac­cess to our bod­ily func­tions us­ing the dark pro­teins, there’s an­other puz­zle to solve. Although other re­search teams have be­gun mapping the dark mat­ter, more blind spots are ap­pear­ing in our knowl­edge of the genome. For ex­am­ple, Pro­fes­sor Akhilesh Pandey, a bio­chemist at Johns Hop­kins Univer­sity in Baltimore, has iden­ti­fied 193 dark pro­teins, which, de­spite being formed from amino acids in the body, don’t have a blue­print in the genome. “The fact that 193 of the pro­teins came from DNA se­quences pre­dicted to be non-cod­ing means that we don’t fully un­der­stand how cells read DNA,” ex­plains Pro­fes­sor Pandey. Just as star­tling is the dis­cov­ery that 2,000 of the pro­teins in our bod­ies might not ex­ist, de­spite ap­pear­ing on the gene maps. So what’s the ex­pla­na­tion for these phan­tom pro­teins? Well, we sim­ply don’t know. The changes that ex­plor­ing the dark pro­teins in our body will make to peo­ple’s lives is un­known – it could even be as dra­matic as the me­ta­mor­pho­sis of a cater­pil­lar. But one thing is now cer­tain: whether it’s in the fight against hith­erto in­cur­able dis­eases, boost­ing life ex­pectancy or tap­ping into new re­serves of power, “dark pro­teins def­i­nitely have an im­por­tant role,” ex­plains Schafferhans. “But we don’t know what it is yet.”

“Many peo­ple think that we’re con­trolled by our genes. But, in re­al­ity, it’s the pro­teins that do some­thing in us and to us.” PRO­FES­SOR MATTHIAS MANN, PRO­TEOME RE­SEARCHER AT THE MAX PLANCK IN­STI­TUTE OF BIO­CHEM­ISTRY

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