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Biotech Science

'Kiss of Death' Discoverers Get Nobel Prize 134

Posted by timothy from the ask-your-doctor-if-ubiquitin-is-right-for-you dept.
baldinux writes "Science Daily has written an article describing the cellular process of regulated protein degredation, which has landed three people the Nobel Prize in Chemistry. According to the article, this finding could greatly help researchers understand ubiquitin-mediated protein degradation, making it possible to develop drugs to treat cervical cancer, for example."
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'Kiss of Death' Discoverers Get Nobel Prize More

'Kiss of Death' Discoverers Get Nobel Prize

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  • regulated protein degredation (Score:3, Funny)

    by OverlordQ ( 264228 ) * on Wednesday October 06, 2004 @03:26PM (#10453306) Journal
    Hey . . didn't they try that on Jurrasic Park . . look where *that* got them.

  • Cervical kiss of death? (Score:5, Funny)

    by Anonymous Coward on Wednesday October 06, 2004 @03:28PM (#10453329)
    Whoa! What a loaded statement! Nothing else need be said.

  • That's great, but (Score:5, Funny)

    by blankman ( 94269 ) <blankman42.gmail@com> on Wednesday October 06, 2004 @03:30PM (#10453343) Homepage
    how long until they patent "A process for breaking down and degrading proteins" and send cease-and-desist letters telling everyone to stop digesting ny meat they eat this instant.
    • This is modded funny, but its not all that unlikely. Well at least the patent getting pushed through. Who knows what will happen then.

    • Damn (Score:1, Funny)

      by Anonymous Coward
      We'll finally be rid of that damned Atkins diet!
    • I'll be ready! ;)

      (Score: -1, Vegan Troll)
    • stop digesting ny meat

      Simple. Stop buying meat raised in New York.

    • Well, that's kind of amusing...but you're missing the point. This is not 'digestion' breakdown of proteins. The "Kiss of Death" is a regulated process by which a Ubiquitin molecule is attached specifically to proteins that need to be degraded. This Ubiquitin label is recognized by the Proteasome, a big enzyme that just degrades proteins, and good bye protein.

      This has nothing to do with eating meat.

  • What does that have to do with kissing? (Score:1, Funny)

    by Anonymous Coward
    The article talked a lot about protein, but no kissing!

  • Potentially Broad Application (Score:5, Insightful)

    by Mark of THE CITY ( 97325 ) on Wednesday October 06, 2004 @03:32PM (#10453361) Journal
    Biochemists could, I presume, tailor ubiquitin to grab up undesirable proteins and still have the degradation function work.

    Imagine all the diseases that come from bad proteins! This could unleash a new class of therapies.

    • This is very interesting. Prions, supposedly the cause of CFJDv (The human version of Mad Cow disease) could be targeted. Cancer cells could be neutralized. It's really very broad, the possibilities.

      Now they just need more funding!
    • I recall reading somewhere that proteins and their production / destruction getting messed up was one of the causes of general aging. Sounds kind of brave-new-world-ish but cool nonetheless.

      Queue the morality questions along the lines of genetic engineering.
      • I recall reading somewhere that proteins and their production / destruction getting messed up was one of the causes of general aging. Sounds kind of brave-new-world-ish but cool nonetheless.

        There is a problem with proteins getting cross-linked with carbohydrates that contributes to aging, IIRC. It's not a specific protein, so you'd have trouble tagging it.

        There was a SciAm article a few years back on it - this [antiaging-systems.com] is the only thing I can find at the moment.

    • Re:Potentially Broad Application (Score:5, Informative)

      by Hatta ( 162192 ) on Wednesday October 06, 2004 @04:12PM (#10453745) Journal
      Biochemists could, I presume, tailor ubiquitin to grab up undesirable proteins and still have the degradation function work.

      Well, you'd want to play with the enzyme that attaches the ubiquitin tag to the target protein, the "ubiquitin ligase." It's hard to say how exactly you'd do that until gene therapy pans out. You could potentially activate or deactivate existing ligases, but you'd have to know which one targets the protein of interest, and hope that it doesn't destroy too much else.

      It's also interesting to note that ubiquitin is not only a "kiss of death" Substrates destined for the proteasome are polyubiquitinated(in series). Monoubiquitin can serve as an intracellular trafficking signal, or a molecular switch turning an enzyme on or off in much the same way as phosphorylation does. There's still a lot of work to do to find out the fine details of who gets how many ubiquitins and what exactly it does.

      Biochemists could, I presume, tailor ubiquitin to grab up undesirable proteins and still have the degradation function work.

      Interestingly there are diseases caused by malfunctioning ubiquitin ligase. The mental retardation disorder Angelmans disease is caused by a knockout of the ubiquitin ligase E6-AP on the maternal chromasome. Due to genetic imprinting, the maternal form is only used in the brain, so this is like a brain specific knockout of this ligase.

      It's not known exactly what targets of E6-AP are responsible for the disease, but in a mouse model the protein CaMKII was hyperphosphorylated and deactivated. CaMKII is one of the major proteins in the brain (approx 10% of brain protein by mass), and it is essential for Long Term Potentiation, a major mode of synaptic plasticity. This is exciting because it's the first time that CaMKII and LTP deficiancies have been linked to learning in humans. Protein phosphatase activity was also reduced in these brains, suggesting a phosphatase deactivation as the proximal cause of CaMKII hyperphosphorylation. Elucidating how E6-AP knockout leads to phosphatase dysregulation will be a large part of my thesis research, if I can ever get some phospho-CaMKII antibodies that work...
      • Is this the same Angelman's linked to Prader-Willi Syndrome? IIRC, if the defective gene is on a maternal chromosome, it causes one of those two conditions, if it's on a paternal chromosome it causes the other.
      • Ligase, right. I'm an ex-laser jock, not a biochemist!
    • "This could unleash a new class of terror."

  • I think I should clarify what all this means... (Score:5, Informative)

    by mtrisk ( 770081 ) on Wednesday October 06, 2004 @03:33PM (#10453368) Journal
    From the first couple of comments, it seems people don't know what the heck this is talking about. Let me explain:

    The human body has a natural mechanism for recycling proteins. What nobody understood, however, was how it knew what proteins to recycle - after all, if proteins were just recycled randomly we'd all be globs of jelly.

    So then these guys came along and figured it out: when the body wants to recycle a protein, it attaches another protein as a label, called ubiquitin.

    The science isn't exactly new - 1980s - but it was significant, and best of all, pure research. (So you can stop with the whining about drugs)

    Congrats to these guys. It really is an honor for a University to have a Nobel Laureate in their staff, and UC Irvine just got one. =]

  • Like programming? (Score:4, Insightful)

    by powerpuffgirls ( 758362 ) on Wednesday October 06, 2004 @03:33PM (#10453371)
    The degradation is not indiscriminate but takes place through a process that is controlled in detail so that the proteins to be broken down at any given moment are given a molecular label, a 'kiss of death', to be dramatic. The labelled proteins are then fed into the cells' "waste disposers", the so called proteasomes, where they are chopped into small pieces and destroyed.

    Isn't this similar to the way OO languages are doing, create an object, use it and dispose it.

    Actuall, isn't this the way we are doing things on a daily basis? It's interesting to find out that even our body is unknowingly doing almost the same process.
    • "Isn't this similar to the way OO languages are doing, create an object, use it and dispose it." If that's the case, I'd hate to see the biological equivalent of dependency hell.

    • Re:Like programming? (Score:5, Informative)

      by pgolik ( 526039 ) on Wednesday October 06, 2004 @03:46PM (#10453483) Homepage
      Not exactly like in programming. As far as I know (I'm not a programmer) the OO languages use object disposal to free up resources. Degradadtion of macromolecules like proteins (through ubiquitine pathway discovered by the Nobel laureates) or RNAs is, however, primarily a way to control different cellular processes. The cell adjusts to different needs by altering the set of proteins that it contains (called the proteome). If proteins were infinitely stable there would be no way of up- or downregulating their levels - once made they would stay there forever. So proteins (and mRNAs that encode them) have a built-in end-of-life mechanism that, together with varying the synthesis rate, makes regulation possible. There is more to it - protein degradation is also used to remove damaged or incorrectly made proteins. So, to sum it up: protein degradation is essential for both regulation and quality control of cell's proteins. Even though there are no direct practical applications so far, the significance of the discovery is great - we do know that if something goes wrong with the cell's regulatory mechanisms we get cancer, understanding ubiqutination brings us closer to understanding how cancer happens.

    • Re:Like programming? (Score:3, Interesting)

      by Have Blue ( 616 )
      This isn't *quite* like mark-and-sweep garbage collection. The additional ubiquitin just makes the protein "vulnerable" to the protein destroyers which are distributed throughout the body. The equivalent of the Java GC would be if the body marked proteins for a long period, then entered a relatively brief phase of rapid protein recycling, which AFAIK doesn't happen.
      • It's the exact opposite of mark-and-sweep, it's mark-and-destroy. This is possible because there are no long-distance "references" - all "referenced" objects are adjacent.

        I suppose, in programming, this is much closer to refcounting, where each object's utility can be fully determined by looking at just that one object.

  • Hmmm... (Score:3, Interesting)

    by static0verdrive ( 776495 ) on Wednesday October 06, 2004 @03:35PM (#10453386) Homepage Journal
    Is cervical cancer different from other cancer? I'm not trolling here, I'm genuinely confused. Why mention that over other forms of cancer - is there something about this research that limits the types of cancer that can be fought with the resulting drugs?

    • Nope (Score:3, Informative)

      by mtrisk ( 770081 )
      The cancer part is interesting - I hadn't thought about that in my previous post. The idea is to engineer ubiquitin to attach itself to cancer cells, therefore causing the body to kill the proteins inside, effectively killing the cells. (Well, cells are proteins.)

      It's a very interesting concept, not limited to any type of cancer as far as I know, but again, this is 1980s research, not brand new as the article suggests, but still exciting.

    • Re:Hmmm... (Score:5, Informative)

      by Hatta ( 162192 ) on Wednesday October 06, 2004 @03:40PM (#10453436) Journal
      There are many, many different types of cancer. At least one for every tissue in the body. Cancers retain many of the properties of the parent tissue. Many breast cancers for instance, are estrogen dependant. So an estrogen antagonist can help shrink many breast cancers. This wouldn't work at all for skin/lung/colon/whatever cancer. I'm not sure about the specifics of cervical cancer, but it's likely there are proteins specifically expressed in cervical tissue that could be targetd for degradation by an engineered ubiquitin ligase.

    • Re:Hmmm... (Score:3, Interesting)

      by pgolik ( 526039 )
      Most cases of cervical cancer are related to HPV infections. HPV uses a very clever mechanism to overcome cellular defenses. One of the main proteins that protect cells and keep them from becoming cancerous is the p53 protein. In most cancers something must happen to p53 for the cancerogenesis to proceed. HPV makes a protein (called E6) that binds p53 and by doing that marks it for degradation by the ubiquitn pathway. Understanding how that pathway works is therefore essential for treating HPV dependent can

    • Re:Hmmm... (Score:2, Informative)

      by Threni ( 635302 )
      > Is cervical cancer different from other cancer?

      One difference is that there is now a vaccine for cervical cancer which is apparantly 100% effective, so it's one of the less important cancers in terms of saving human life in the long run.

      http://news.bbc.co.uk/1/hi/health/2495029.stm

    • Is cervical cancer different from other cancer?

      Yes. It's like breast cancer; as it only concerns a females sexual organs, it gets a hell of a lot of research. Which is all good, I mean who cares about male prostate cancer which is more deadly and more common than either of the trendy cancers? Everyone loves titties!!

      <sarcasm>

  • HSV (Score:4, Informative)

    by pete-classic ( 75983 ) <hutnick@gmail.com> on Wednesday October 06, 2004 @03:35PM (#10453391) Homepage Journal
    I recently learned (through an unpleasant personal, but not-quite-that-personal, experience) that HSV, an STD, is the "major cause of cervical cancer" [umm.edu].

    Watch out, guys. Especially watch out ladies.

    -Peter

    • Re:HSV (Score:2, Informative)

      by Anonymous Coward
      RTFA, its HPV not HSV. big difference (warts or herpes). Its a virus too, it doesn't go away it just hopefully gets suppressed by the immune system. It is spread by direct skin contact downstairs, condoms are only 30% effective.

      You can carry HPV for months/years without symptoms, or you can grow warts on your naughty bits! It can be a precursor to cervical cancer!

      According to the CDC http://www.cdc.gov/std/HPV/STDFact-HPV.htm#common [cdc.gov] 80% of women will be infected at some point in their lives (and presumabl

    • Re:HSV (Score:3, Informative)

      by stilwebm ( 129567 )
      I believe you mean Human papilloma virus (HPV). OK checking the link verifies it. I'm glad you brought it up though because so few people are aware of it. There have been studies showing that 75% of sexually active women harbor the virus [indiana.edu], most with no symptoms. Most will never develop symptoms, but the scariest statistic is that 93% of cervical cancer cases are linked to HPV [about.com].

      A vaccine is in research trials, but it only works before being exposed, so it must be given to younger women before they are sex
    • No dude. HSV is Herpies Simplex Virus (same thing as a cold sore but when it's down there they call it herpies). HPV (Human Pappiloma Virus) - genital warts - is the main cause of cervical cancer. Not HSV.
    • HPV (human papillomavirus) is the one that's strongly linked to cervical cancers. There are vaccine trials underway.

      They'll become standard course of treatment in the not too distant future, eradicating a large percentage of cervical cancers. Score one for the good guys.
    • There is a lot of research underway indicating a link between many types of cancer to viral infections, including prostate and lung cancer. I don't have any links, but keep your eyes peeled. Viruses do a lot more subtle and insidious things than we're aware.

  • So, then we just need something to elimiate this ubiquitin and we'll live forever? Sweet!

  • low blow (Score:4, Funny)

    by Doc Ruby ( 173196 ) on Wednesday October 06, 2004 @03:38PM (#10453417) Homepage Journal
    "Kiss of Death" causes "cervical cancer"? Nerds, that's just an excuse not to please your girlfriend.
    • *shrug* Who needs an excuse? :D
    • "Kiss of Death" causes "cervical cancer"? Nerds, that's just an excuse not to please your girlfriend

      Nah, it's more like a cover up attempt to reason out why we don't have girlfriends. I mean... why we would rather not have girlfriends, not because we can't get girlfriends.. nope, not us! We have good legitimage reasons.

      Runs over to the corner and cries

    • Nerds, that's just an excuse not to please your girlfriend.

      Please *whom*?

      Ahh, good thing there is dict.org..
  • I read in another article that these folks worked on this research in the '80-es. It sure is a long way to a nobel prize! The youngest of the three guys is 57 years old. The other two are 67 and 73.

    Well, I should get really busy if I want to get my Nobel prize while I can still enjoy the money and fame.
    • A Nobel prize should be hard to get - there are a lot of people working hard on projects that may or may not turn out with glorious, world-changing results. When someone does make a breakthrough, they should be rewarded and remembered; I think that's the point of such awards.

      Now if you happen to be a super-genius with glorious ideas and world-changing abilities, then maybe you could do something faster and easier than other scientists. But you probably wouldn't be invited to all the scientist parties.
    • Scientific Nobel prizes generally take decades to be awarded because it takes that long to sift through all the "hot topic" stuff which might not turn out to be that important from the science which may or may not be important at the time but turns out to revolutionize the way certain things are done or understood. It's like a lifetime achievement award, sure you could give them out when people are young, but then you'd have ended up giving ones to Milli Vanilli and Billy Ray Cyrus, or the Baha Men...
    • 10,000,000.00 SEK = 1,359,599.39 USD Split between 3 people, that is not really THAT much money to enjoy. I'm sure these guys still have time.
    • With few exceptions, the Nobel prize is not awarded posthumously, so it is not at all unusual for it to be awarded to people who made significant contributions decades earlier.

      The down side is that sometimes getting nominated for the Nobel means community recognition that an intended recipient is getting close to the end of their life.
  • You might find the information over at the Nobel website more interresting: http://nobelprize.org/chemistry/laureates/2004/pub lic.html [nobelprize.org].
  • My Bad... [laddertheory.com]

  • Targeted Degradation (Score:5, Informative)

    by 00Sovereign ( 106393 ) on Wednesday October 06, 2004 @03:56PM (#10453567)
    The biggest problem to developing any potential theapies from these groundbreaking discoveries is to figure out how to target particular proteins or classes of proteins. There are numerous E3 ubiquitin ligases in cells that target a varety of proteins for degradation. However, the molecular mechanisms by which this recognition takes place is still rather uncertain. The structure of the molecular interaction must be determined at atomic resolution (A difficult process which commonly uses X-ray crystallography and very, very intensive computing).

    I see two methods which would lead to useful therapies:

    The first is the simplest and will therefore also most likely be the first viable strategy: harnessing natural ubiquitin ligases to target and downregulate harmful proteins. This means that any therapies will be limited to natural ubiquitination processes. Humankind will find ways to make these reactions better, or ways stimulate them in diseased cells.

    The second approach is de novo design. Once the structure of the target is determined, enzymes can be desgined to target it for ubiquitination/degradation. However, this requires an understanding of biochemistry far beyond what currently exists. Not only does the therapeutic enzyme have to recognize the target, but it must also catalyze the ubiquitination reaction. At this time, I do not believe that anyone has designed a functional protein-based enzyme from the ground up. This technique has greater potential, as we could target ANY protein we dislike, but we are not quite able to implement it yet.

    • Re:Targeted Degradation - Third approach (Score:2, Informative)

      by Anonymous Coward
      inhibit proteasome activity. One might argue about how useful it is (it is certainly not a miracle cure) but vecade (bortezomib) is already FDA approved [fda.gov]. It is pretty clearly the best treatment available for replased myeloma.

  • One more thought... (Score:5, Informative)

    by 00Sovereign ( 106393 ) on Wednesday October 06, 2004 @04:11PM (#10453732)
    Targeted protein degradation has applicaitons beyond anti-cancer therapies. Alzheimer's Disease seems to be caused by the build-up of amyoloid beta protein in neurons, which is due to the failure to degrade this protein. One potential therapy is to use other ubiquitin ligases to target amyoloid beta for degradation as a method to break up protein plaques.

    Similarly, antiviral potential exists as well. For example, if we could engineer ubiquitin ligases to target HIV proteases (The target of the protease inhibitor component of anti-HIV "cocktails"), we would have another method to hamper viral replication.

    As with all new developments, however, there exist numerous problems that must to be overcome before we see practical and clinical results.

    • Targeted protein degradation has applicaitons beyond anti-cancer therapies. Alzheimer's Disease seems to be caused by the build-up of amyoloid beta protein in neurons, which is due to the failure to degrade this protein. One potential therapy is to use other ubiquitin ligases to target amyoloid beta for degradation as a method to break up protein plaques.

      The problem here is that in order to tag and then transport the beta amyloid proteins to the proteosome for degradation, you first need to break up the

  • Nice animation of the process (Score:4, Informative)

    by Shipud ( 685171 ) on Wednesday October 06, 2004 @04:15PM (#10453778)
    Here [712designs.com] Ciechanover & Herhsko got the Lasker prize for ubiquitination a few years back. Getting the Lasker prize is a pretty good indicator for receiving the Noble as well.

  • The man who is not happy today is at Caltech. (Score:3, Interesting)

    by Anonymous Coward on Wednesday October 06, 2004 @04:22PM (#10453834)
    His name is Alex Varshavsky. Many thought that when the Nobel prize was awarded for ubiquitin-regulated degradation of proteins ("the kiss of death"), he would be among the winners. He's won a number of big scientific awards, usually with Avram Hershko (one of today's winners). The suprise today was that Varshavsky was left off and Irwin Rose (UCI) was included.

  • So the body attaches a tag on the protein, and says, "You be quittin'!"
    Sounds like a good way to handle corporate restructuring, to me.
  • so... is ubiquitin the antidote to unobtanium? :)
  • Can the research now focus on how to attatch ubiquitin to goatse?
  • Does anyone here reading Slashdot even have a cervix?

    Sorry had to ask.. :-)

    -Hack

  • Nobel Committee Needs Reorganization! (Score:3, Interesting)

    by mulescent ( 682036 ) on Wednesday October 06, 2004 @05:46PM (#10454582)
    As a chemist, I must say its very odd to watch the prize in chemistry being awarded for what is, essentially, biology. This happened last year too - the chemistry prize was awarded to those who figured out how cell membrane-spanning channels worked. The work thats being done in the field of biology needs to be acknowledged, but perhaps the Nobel committee should create a separate biology prize so the chemists can get their due!

    • As a chemist, I must say its very odd to watch the prize in chemistry being awarded for what is, essentially, biology

      Biology really isn't anything more than the summation of a very large number of chemical processes. It's nothing more than applied chemistry.

      And as for chemistry and physics, the two overlap so well that I really consider them different areas of emphasis on the same subject matter.

      I'm not a chemist, physicist, or biologist by title or trade, but I've had at least three years of
      • It would be nice to see a category for biochemistry / molecular biology and one for pure chemistry of nonliving systems. This way, the guy that comes up with a cool way to synthesize hydrocarbons from ambient CO2 and water using only sunlight as the energy source doesn't have to compete with the guy (or lady) who finds a universal cure for cancer.

      • Oh, civils are alright. They actually have to learn structures (statics), and fluid dynamics, and fun engineering stuff like that.

        It's the industrial and operations people who shouldn't get engineering degrees.

      • Biology really isn't anything more than the summation of a very large number of chemical processes. It's nothing more than applied chemistry.

        Maybe molecular biology & biochemistry are. How does your statement apply to:
        * Systematics & Taxonomy
        * Population biology / Pop. genetics
        * Developmental biology
        .
        .
        and it goes on.

        Certain techniques involving chemical tools are used in Biology. But to say that biology is "applied chemistry" is like saying that physics is applied mathematics.
        • Maybe molecular biology & biochemistry are. How does your statement apply to:

          * Systematics & Taxonomy
          * Population biology / Pop. genetics
          * Developmental biology

          I get the distinct impression that you don't really have much of an education in biology. Am I wrong? I'll certainly be willing to eat crow if I am. And if you do have more than a passing education in it, I'll be happy to explain in detail why each of those is nothing more than applied chemistry.

          There are, of course, some aspect
    • It's exactly the same story -- the Medicine & Physiology prize rarely goes to physicians (or even the somewhat dying breed of non-molecular biologists that go by the name of "physiologist") -- instead both the Medicine and Chemistry prize tend to go to molecular biologists/cell biologists/biochemists (no real difference between those names).

      Considering that I'm a genomicist, I should be happy -- my near infinitesimal chances of winning a Nobel are doubled, but still, I can see that actual physicians an

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