{"id":221919,"date":"2017-03-09T12:00:25","date_gmt":"2017-03-09T17:00:25","guid":{"rendered":"https:\/\/news.harvard.edu\/gazette\/?p=221919"},"modified":"2017-03-10T15:45:59","modified_gmt":"2017-03-10T20:45:59","slug":"how-a-child-made-scientists-think-of-cytokines-as-knobs-instead-of-switches","status":"publish","type":"post","link":"https:\/\/news.harvard.edu\/gazette\/story\/2017\/03\/how-a-child-made-scientists-think-of-cytokines-as-knobs-instead-of-switches\/","title":{"rendered":"How a child made scientists think of cytokines as knobs instead of switches"},"content":{"rendered":"\n\t\n\t
\n\t\t\t\n\t\t\tHealth\t\t<\/a>\n\t\t\n\t\t

\n\t\tHow a child made scientists think of cytokines as knobs instead of switches\t<\/h1>\n\n\t\n\t\n\t
\n\t\t
\n\t\t\t
\n\t\t\t\t\t

\n\t\tTom Ulrich\t<\/p>\n\t\t\t

\n\t\t\tBroad Institute Communications\t\t<\/p>\n\t\t\t\t\t<\/address>\n\t\t<\/div>\n\n\t\t

\n\t\t\tDevelopment could help those suffering forms of cancer, kidney disease, blood disorders\t\t<\/h2>\n\t\t\n<\/header>\n\n\n\n
\n\n\n\t\t

An unusual case of a rare anemia is opening scientists up to a new way of thinking about how to adapt and employ cytokines, messenger molecules of the blood and immune system, as tools for treatment \u2014 tools that are more analog than digital \u2014 and to illustrate the promise of precision medicine.<\/p>\n

Cytokines are workhorses of a vast messaging network used by the blood and immune systems. These proteins influence all manner of activity in these systems, from inflammation to resolution, cell production to cell death.<\/p>\n

Conventional wisdom has held that cytokines are \u201cdigital,\u201d in that they either bind to a cellular receptor \u2014 triggering a cascade of signals within the cell \u2014 or they don\u2019t. If a mutation prevents perfect binding, no cascade. There is no middle ground.<\/p>\n

But maybe there is. A rare case of a rare disease has led an international research team headed by Broad Institute of Harvard and MIT<\/a> associate member Vijay Sankaran of Dana-Farber\/Boston Children\u2019s Cancer and Blood Disorders Center, postdoctoral fellow Ah Ram Kim, and Yale University\u2019s Daryl Klein to propose an \u201canalog\u201d view of cytokine function. It may be, as they show in Cell<\/a>, that cytokine mutations that affect not whether a protein and receptor interact, but the quality of that interaction, can tune a cell\u2019s biochemical response, triggering some signals and not others.<\/p>\n

This insight could give researchers an opening to develop cytokine-based therapeutics tailored to elicit particular activities \u2014 potentially a boon for people suffering forms of cancer, kidney disease, blood disorders, and more.<\/p>\n

The story of how the team came to this understanding begins with a child.<\/p>\n

An unusual case<\/strong><\/p>\n

A few years ago, Sankaran\u2019s colleagues at Dana-Farber\/Boston Children\u2019s (where he is a pediatric hematologist\/oncologist) cared for a young boy diagnosed with Diamond-Blackfan anemia (DBA), a rare blood disorder in which the bone marrow cannot produce red blood cells (RBCs). Transfusions kept the disorder more or less at bay, but when the boy was 6, his family and physicians agreed it was time for a bone marrow transplant.<\/p>\n

\u201cA transplant cures most cases of DBA,\u201d said Sankaran. \u201cBut the child still required transfusions [after the procedure], which is very unusual for this disorder.\u201d (Ultimately, the child passed away from a transplant-related complication.)<\/p>\n

Also unusual was the fact that neither of the boy\u2019s parents, who are first cousins, showed signs of the disorder.<\/p>\n

\u201cMost of the mutations that cause DBA are transmitted from parent to child in a dominant fashion,\u201d said Sankaran. \u201cBut because neither parent was affected, we wondered whether in this case there might be another, recessive cause.\u201d<\/p>\n

Whole exome sequencing of the boy\u2019s DNA did not uncover any of the known DBA-related gene mutations. It did, however, reveal a mutation in the gene for erythropoietin (EPO), a cytokine that controls RBC production.<\/p>\n

When messages fail<\/strong><\/p>\n

As Sankaran and his collaborators probed more deeply into the boy\u2019s case, a picture of a devastating cellular miscommunication began to emerge.<\/p>\n

First, the boy\u2019s medical records revealed that his blood EPO levels \u2014 monitored during his transfusion treatments \u2014 were consistently 100 times higher than normal.<\/p>\n

Second, the mutation itself (a change in a single base pair) is not recorded in the Exome Aggregation Consortium<\/a> (ExAC) database, suggesting it is exceedingly rare.<\/p>\n

Third, when the team studied the mutated gene\u2019s altered protein product, they found the mutation did not change whether the protein could<\/em> bind to its receptor, EPOR, on blood precursor cells. Rather, it changed the cytokine\u2019s binding kinetics \u2014 the rates at which EPO and EPOR bound (associated) and unbound (dissociated). The mutant protein\u2019s association rate was 12 times higher than a normal EPO\u2019s; its dissociation rate, 233 times higher.<\/p>\n

Normally, when tripped by EPO, EPOR alerts three transcription factors \u2014 STAT1, STAT3, and STAT5 \u2014 to kick-start the gene program for RBC production. However, Sankaran and Klein\u2019s team found, the mutant EPO\u2019s quick hit did not provide EPOR a strong enough nudge to alert STAT1 and 3. Without them, the blood precursors could not start making RBCs.<\/p>\n

So the boy\u2019s body, sensing the lack of RBCs, kept churning out EPO, pleading with the bone marrow to make the cells it needed. But because of the mutation, EPOR could not hear the message well enough to do its job.<\/p>\n

Tuning in to a new idea<\/strong><\/p>\n

In addition to explaining the child\u2019s grave disease, the findings suggest something new: a different way to think about adapting cytokines therapeutically.<\/p>\n

\u201cIn hematology and immunology, people tend to think about cytokines as working like on and off switches,\u201d Sankaran said. Doctors commonly use or manipulate EPO and other cytokines to treat cancer, autoimmunity, immunodeficiencies, and other conditions, he said. \u201cBut what we\u2019re learning is that maybe they can be tuned.\u201d<\/p>\n

Sankaran points to G protein-coupled receptors (GPCRs) \u2014 a family of multifunctional receptors and popular drug development targets \u2014 as a framework for thinking about the tunable cytokine activity he and his teammates propose. By modifying a cytokine and altering how it interacts with its receptor, it may be possible to nudge that receptor toward a therapeutic response and away from a deleterious one.<\/p>\n

\u201cMaybe we could do better and design agents that act to stimulate some cell types or signaling pathways better than others,\u201d Sankaran mused. \u201cThere are other cytokines that we know can stimulate blood production, but that we haven\u2019t used because they have a lot of side effects. Those are the kinds of problems that we\u2019d like to tackle now that we have this knowledge.\u201d<\/p>\n

Putting precision pediatrics into practice<\/strong><\/p>\n

As this story started with a child, so too does it end with one.<\/p>\n

As Sankaran and Klein were revising their work for publication, the boy\u2019s parents had another baby, a little girl. She too was profoundly anemic, had sky-high blood levels of EPO, and had the same EPO mutation.<\/p>\n

Leveraging what they learned from her brother\u2019s case, Sankaran asked his clinical partners to start treating the infant with recombinant EPO. So far, it seems to be turning the tide.<\/p>\n

\u201cWe always say as geneticists that our goal is to be able to understand a mutation, translate that, and develop a therapy,\u201d Sankaran said. \u201cSo we were really frustrated when we finally understood her older brother\u2019s diagnosis because we have recombinant EPO and use it regularly. We could have saved his life, but just didn\u2019t have that opportunity.<\/p>\n

\u201cHere we had a chance to take a precision medicine approach, and it\u2019s working remarkably well,\u201d he continued. \u201cIt\u2019s incredibly satisfying to be able to take what we\u2019ve learned, put it into practice, and help a child and family.\u201d<\/p>\n\n\n<\/div>\n\n\t\t","protected":false},"excerpt":{"rendered":"

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Gazette\",\"logo\":\"https:\\\/\\\/news.harvard.edu\\\/gazette\\\/wp-content\\\/uploads\\\/2023\\\/12\\\/Harvard_Gazette_logo.svg\"},\"keywords\":[\"broad institute\",\"cytokines\",\"dana-farber\\\/boston children\\u2019s cancer and blood disorders center\",\"diamond-blackfan anemia\"],\"dateCreated\":\"2017-03-09T17:00:25Z\",\"datePublished\":\"2017-03-09T17:00:25Z\",\"dateModified\":\"2017-03-10T20:45:59Z\"}<\/script>","tracker_url":"https:\/\/cdn.parsely.com\/keys\/news.harvard.edu\/p.js"},"jetpack_featured_media_url":"https:\/\/news.harvard.edu\/wp-content\/uploads\/2017\/03\/analogcytokinesignals-v3.jpg","has_blocks":true,"block_data":{"0":{"blockName":"harvard-gazette\/article-header","attrs":{"blockColorPalette":"","coloredHeading":"","creditText":"","displayDetails":"","displayTitle":"","categoryId":39644,"mediaAlt":"","mediaCaption":"","mediaId":"","mediaSize":"","mediaType":"","mediaUrl":"","poster":"","title":"How a child made scientists think of cytokines as knobs instead of switches","subheading":"Development could help those suffering forms of cancer, kidney disease, blood disorders","className":"is-style-square","backgroundFixed":false,"backgroundTone":"light","centeredImage":false,"coloredBackground":false,"displayOverlay":true,"fadeInText":false,"isAmbient":false,"mediaHeight":0,"mediaLength":"","mediaPosition":"","mediaWidth":0,"posterText":"","titleAbove":false,"useUncroppedImage":false,"lock":[],"metadata":[]},"innerBlocks":[],"innerHTML":"","innerContent":[],"rendered":"<header\n\tclass=\"wp-block-harvard-gazette-article-header alignfull article-header is-style-square has-light-background has-colored-heading\"\n\tstyle=\" \"\n>\n\t\n\t<div class=\"article-header__content\">\n\t\t\t<a\n\t\t\tclass=\"article-header__category\"\n\t\t\thref=\"https:\/\/news.harvard.edu\/gazette\/section\/health\/\"\n\t\t>\n\t\t\tHealth\t\t<\/a>\n\t\t\n\t\t<h1 class=\"article-header__title wp-block-heading \">\n\t\tHow a child made scientists think of cytokines as knobs instead of switches\t<\/h1>\n\n\t\n\t\n\t<div class=\"article-header__meta\">\n\t\t<div class=\"wp-block-post-author\">\n\t\t\t<address class=\"wp-block-post-author__content\">\n\t\t\t\t\t<p class=\"author wp-block-post-author__name\">\n\t\tTom Ulrich\t<\/p>\n\t\t\t<p class=\"wp-block-post-author__byline\">\n\t\t\tBroad Institute Communications\t\t<\/p>\n\t\t\t\t\t<\/address>\n\t\t<\/div>\n\n\t\t<time class=\"article-header__date\" datetime=\"2017-03-09\">\n\t\t\tMarch 9, 2017\t\t<\/time>\n\n\t\t<span class=\"article-header__reading-time\">\n\t\t\t6 min read\t\t<\/span>\n\t<\/div>\n\n\t\t\t<\/div>\n\t\t\n\t\t\t<h2 class=\"article-header__subheading wp-block-heading\">\n\t\t\tDevelopment could help those suffering forms of cancer, kidney disease, blood disorders\t\t<\/h2>\n\t\t\n<\/header>\n"},"2":{"blockName":"core\/group","attrs":{"templateLock":false,"metadata":{"name":"Article content"},"align":"wide","layout":{"type":"constrained","justifyContent":"center"},"tagName":"div","lock":[],"className":"","style":[],"backgroundColor":"","textColor":"","gradient":"","fontSize":"","fontFamily":"","borderColor":"","ariaLabel":"","anchor":""},"innerBlocks":[{"blockName":"core\/freeform","attrs":{"content":"","lock":[],"metadata":[]},"innerBlocks":[],"innerHTML":"\n\t\t<p>An unusual case of a rare anemia is opening scientists up to a new way of thinking about how to adapt and employ cytokines, messenger molecules of the blood and immune system, as tools for treatment \u2014 tools that are more analog than digital \u2014 and to illustrate the promise of precision medicine.<\/p>\n<p>Cytokines are workhorses of a vast messaging network used by the blood and immune systems. These proteins influence all manner of activity in these systems, from inflammation to resolution, cell production to cell death.<\/p>\n<p>Conventional wisdom has held that cytokines are \u201cdigital,\u201d in that they either bind to a cellular receptor \u2014 triggering a cascade of signals within the cell \u2014 or they don\u2019t. If a mutation prevents perfect binding, no cascade. There is no middle ground.<\/p>\n<p>But maybe there is. A rare case of a rare disease has led an international research team headed by <a href=\"https:\/\/www.broadinstitute.org\/\">Broad Institute of Harvard and MIT<\/a> associate member Vijay Sankaran of Dana-Farber\/Boston Children\u2019s Cancer and Blood Disorders Center, postdoctoral fellow Ah Ram Kim, and Yale University\u2019s Daryl Klein to propose an \u201canalog\u201d view of cytokine function. It may be, as they show in <a href=\"http:\/\/www.cell.com\/cell\/home\">Cell<\/a>, that cytokine mutations that affect not whether a protein and receptor interact, but the quality of that interaction, can tune a cell\u2019s biochemical response, triggering some signals and not others.<\/p>\n<p>This insight could give researchers an opening to develop cytokine-based therapeutics tailored to elicit particular activities \u2014 potentially a boon for people suffering forms of cancer, kidney disease, blood disorders, and more.<\/p>\n<p>The story of how the team came to this understanding begins with a child.<\/p>\n<p><strong>An unusual case<\/strong><\/p>\n<p>A few years ago, Sankaran\u2019s colleagues at Dana-Farber\/Boston Children\u2019s (where he is a pediatric hematologist\/oncologist) cared for a young boy diagnosed with Diamond-Blackfan anemia (DBA), a rare blood disorder in which the bone marrow cannot produce red blood cells (RBCs). Transfusions kept the disorder more or less at bay, but when the boy was 6, his family and physicians agreed it was time for a bone marrow transplant.<\/p>\n<p>\u201cA transplant cures most cases of DBA,\u201d said Sankaran. \u201cBut the child still required transfusions [after the procedure], which is very unusual for this disorder.\u201d (Ultimately, the child passed away from a transplant-related complication.)<\/p>\n<p>Also unusual was the fact that neither of the boy\u2019s parents, who are first cousins, showed signs of the disorder.<\/p>\n<p>\u201cMost of the mutations that cause DBA are transmitted from parent to child in a dominant fashion,\u201d said Sankaran. \u201cBut because neither parent was affected, we wondered whether in this case there might be another, recessive cause.\u201d<\/p>\n<p>Whole exome sequencing of the boy\u2019s DNA did not uncover any of the known DBA-related gene mutations. It did, however, reveal a mutation in the gene for erythropoietin (EPO), a cytokine that controls RBC production.<\/p>\n<p><strong>When messages fail<\/strong><\/p>\n<p>As Sankaran and his collaborators probed more deeply into the boy\u2019s case, a picture of a devastating cellular miscommunication began to emerge.<\/p>\n<p>First, the boy\u2019s medical records revealed that his blood EPO levels \u2014 monitored during his transfusion treatments \u2014 were consistently 100 times higher than normal.<\/p>\n<p>Second, the mutation itself (a change in a single base pair) is not recorded in the <a href=\"http:\/\/exac.broadinstitute.org\/\">Exome Aggregation Consortium<\/a> (ExAC) database, suggesting it is exceedingly rare.<\/p>\n<p>Third, when the team studied the mutated gene\u2019s altered protein product, they found the mutation did not change whether the protein <em>could<\/em> bind to its receptor, EPOR, on blood precursor cells. Rather, it changed the cytokine\u2019s binding kinetics \u2014 the rates at which EPO and EPOR bound (associated) and unbound (dissociated). The mutant protein\u2019s association rate was 12 times higher than a normal EPO\u2019s; its dissociation rate, 233 times higher.<\/p>\n<p>Normally, when tripped by EPO, EPOR alerts three transcription factors \u2014 STAT1, STAT3, and STAT5 \u2014 to kick-start the gene program for RBC production. However, Sankaran and Klein\u2019s team found, the mutant EPO\u2019s quick hit did not provide EPOR a strong enough nudge to alert STAT1 and 3. Without them, the blood precursors could not start making RBCs.<\/p>\n<p>So the boy\u2019s body, sensing the lack of RBCs, kept churning out EPO, pleading with the bone marrow to make the cells it needed. But because of the mutation, EPOR could not hear the message well enough to do its job.<\/p>\n<p><strong>Tuning in to a new idea<\/strong><\/p>\n<p>In addition to explaining the child\u2019s grave disease, the findings suggest something new: a different way to think about adapting cytokines therapeutically.<\/p>\n<p>\u201cIn hematology and immunology, people tend to think about cytokines as working like on and off switches,\u201d Sankaran said. Doctors commonly use or manipulate EPO and other cytokines to treat cancer, autoimmunity, immunodeficiencies, and other conditions, he said. \u201cBut what we\u2019re learning is that maybe they can be tuned.\u201d<\/p>\n<p>Sankaran points to G protein-coupled receptors (GPCRs) \u2014 a family of multifunctional receptors and popular drug development targets \u2014 as a framework for thinking about the tunable cytokine activity he and his teammates propose. By modifying a cytokine and altering how it interacts with its receptor, it may be possible to nudge that receptor toward a therapeutic response and away from a deleterious one.<\/p>\n<p>\u201cMaybe we could do better and design agents that act to stimulate some cell types or signaling pathways better than others,\u201d Sankaran mused. \u201cThere are other cytokines that we know can stimulate blood production, but that we haven\u2019t used because they have a lot of side effects. Those are the kinds of problems that we\u2019d like to tackle now that we have this knowledge.\u201d<\/p>\n<p><strong>Putting precision pediatrics into practice<\/strong><\/p>\n<p>As this story started with a child, so too does it end with one.<\/p>\n<p>As Sankaran and Klein were revising their work for publication, the boy\u2019s parents had another baby, a little girl. She too was profoundly anemic, had sky-high blood levels of EPO, and had the same EPO mutation.<\/p>\n<p>Leveraging what they learned from her brother\u2019s case, Sankaran asked his clinical partners to start treating the infant with recombinant EPO. So far, it seems to be turning the tide.<\/p>\n<p>\u201cWe always say as geneticists that our goal is to be able to understand a mutation, translate that, and develop a therapy,\u201d Sankaran said. \u201cSo we were really frustrated when we finally understood her older brother\u2019s diagnosis because we have recombinant EPO and use it regularly. We could have saved his life, but just didn\u2019t have that opportunity.<\/p>\n<p>\u201cHere we had a chance to take a precision medicine approach, and it\u2019s working remarkably well,\u201d he continued. \u201cIt\u2019s incredibly satisfying to be able to take what we\u2019ve learned, put it into practice, and help a child and family.\u201d<\/p>\n","innerContent":["\n\t\t<p>An unusual case of a rare anemia is opening scientists up to a new way of thinking about how to adapt and employ cytokines, messenger molecules of the blood and immune system, as tools for treatment \u2014 tools that are more analog than digital \u2014 and to illustrate the promise of precision medicine.<\/p>\n<p>Cytokines are workhorses of a vast messaging network used by the blood and immune systems. These proteins influence all manner of activity in these systems, from inflammation to resolution, cell production to cell death.<\/p>\n<p>Conventional wisdom has held that cytokines are \u201cdigital,\u201d in that they either bind to a cellular receptor \u2014 triggering a cascade of signals within the cell \u2014 or they don\u2019t. If a mutation prevents perfect binding, no cascade. There is no middle ground.<\/p>\n<p>But maybe there is. A rare case of a rare disease has led an international research team headed by <a href=\"https:\/\/www.broadinstitute.org\/\">Broad Institute of Harvard and MIT<\/a> associate member Vijay Sankaran of Dana-Farber\/Boston Children\u2019s Cancer and Blood Disorders Center, postdoctoral fellow Ah Ram Kim, and Yale University\u2019s Daryl Klein to propose an \u201canalog\u201d view of cytokine function. It may be, as they show in <a href=\"http:\/\/www.cell.com\/cell\/home\">Cell<\/a>, that cytokine mutations that affect not whether a protein and receptor interact, but the quality of that interaction, can tune a cell\u2019s biochemical response, triggering some signals and not others.<\/p>\n<p>This insight could give researchers an opening to develop cytokine-based therapeutics tailored to elicit particular activities \u2014 potentially a boon for people suffering forms of cancer, kidney disease, blood disorders, and more.<\/p>\n<p>The story of how the team came to this understanding begins with a child.<\/p>\n<p><strong>An unusual case<\/strong><\/p>\n<p>A few years ago, Sankaran\u2019s colleagues at Dana-Farber\/Boston Children\u2019s (where he is a pediatric hematologist\/oncologist) cared for a young boy diagnosed with Diamond-Blackfan anemia (DBA), a rare blood disorder in which the bone marrow cannot produce red blood cells (RBCs). Transfusions kept the disorder more or less at bay, but when the boy was 6, his family and physicians agreed it was time for a bone marrow transplant.<\/p>\n<p>\u201cA transplant cures most cases of DBA,\u201d said Sankaran. \u201cBut the child still required transfusions [after the procedure], which is very unusual for this disorder.\u201d (Ultimately, the child passed away from a transplant-related complication.)<\/p>\n<p>Also unusual was the fact that neither of the boy\u2019s parents, who are first cousins, showed signs of the disorder.<\/p>\n<p>\u201cMost of the mutations that cause DBA are transmitted from parent to child in a dominant fashion,\u201d said Sankaran. \u201cBut because neither parent was affected, we wondered whether in this case there might be another, recessive cause.\u201d<\/p>\n<p>Whole exome sequencing of the boy\u2019s DNA did not uncover any of the known DBA-related gene mutations. It did, however, reveal a mutation in the gene for erythropoietin (EPO), a cytokine that controls RBC production.<\/p>\n<p><strong>When messages fail<\/strong><\/p>\n<p>As Sankaran and his collaborators probed more deeply into the boy\u2019s case, a picture of a devastating cellular miscommunication began to emerge.<\/p>\n<p>First, the boy\u2019s medical records revealed that his blood EPO levels \u2014 monitored during his transfusion treatments \u2014 were consistently 100 times higher than normal.<\/p>\n<p>Second, the mutation itself (a change in a single base pair) is not recorded in the <a href=\"http:\/\/exac.broadinstitute.org\/\">Exome Aggregation Consortium<\/a> (ExAC) database, suggesting it is exceedingly rare.<\/p>\n<p>Third, when the team studied the mutated gene\u2019s altered protein product, they found the mutation did not change whether the protein <em>could<\/em> bind to its receptor, EPOR, on blood precursor cells. Rather, it changed the cytokine\u2019s binding kinetics \u2014 the rates at which EPO and EPOR bound (associated) and unbound (dissociated). The mutant protein\u2019s association rate was 12 times higher than a normal EPO\u2019s; its dissociation rate, 233 times higher.<\/p>\n<p>Normally, when tripped by EPO, EPOR alerts three transcription factors \u2014 STAT1, STAT3, and STAT5 \u2014 to kick-start the gene program for RBC production. However, Sankaran and Klein\u2019s team found, the mutant EPO\u2019s quick hit did not provide EPOR a strong enough nudge to alert STAT1 and 3. Without them, the blood precursors could not start making RBCs.<\/p>\n<p>So the boy\u2019s body, sensing the lack of RBCs, kept churning out EPO, pleading with the bone marrow to make the cells it needed. But because of the mutation, EPOR could not hear the message well enough to do its job.<\/p>\n<p><strong>Tuning in to a new idea<\/strong><\/p>\n<p>In addition to explaining the child\u2019s grave disease, the findings suggest something new: a different way to think about adapting cytokines therapeutically.<\/p>\n<p>\u201cIn hematology and immunology, people tend to think about cytokines as working like on and off switches,\u201d Sankaran said. Doctors commonly use or manipulate EPO and other cytokines to treat cancer, autoimmunity, immunodeficiencies, and other conditions, he said. \u201cBut what we\u2019re learning is that maybe they can be tuned.\u201d<\/p>\n<p>Sankaran points to G protein-coupled receptors (GPCRs) \u2014 a family of multifunctional receptors and popular drug development targets \u2014 as a framework for thinking about the tunable cytokine activity he and his teammates propose. By modifying a cytokine and altering how it interacts with its receptor, it may be possible to nudge that receptor toward a therapeutic response and away from a deleterious one.<\/p>\n<p>\u201cMaybe we could do better and design agents that act to stimulate some cell types or signaling pathways better than others,\u201d Sankaran mused. \u201cThere are other cytokines that we know can stimulate blood production, but that we haven\u2019t used because they have a lot of side effects. Those are the kinds of problems that we\u2019d like to tackle now that we have this knowledge.\u201d<\/p>\n<p><strong>Putting precision pediatrics into practice<\/strong><\/p>\n<p>As this story started with a child, so too does it end with one.<\/p>\n<p>As Sankaran and Klein were revising their work for publication, the boy\u2019s parents had another baby, a little girl. She too was profoundly anemic, had sky-high blood levels of EPO, and had the same EPO mutation.<\/p>\n<p>Leveraging what they learned from her brother\u2019s case, Sankaran asked his clinical partners to start treating the infant with recombinant EPO. So far, it seems to be turning the tide.<\/p>\n<p>\u201cWe always say as geneticists that our goal is to be able to understand a mutation, translate that, and develop a therapy,\u201d Sankaran said. \u201cSo we were really frustrated when we finally understood her older brother\u2019s diagnosis because we have recombinant EPO and use it regularly. We could have saved his life, but just didn\u2019t have that opportunity.<\/p>\n<p>\u201cHere we had a chance to take a precision medicine approach, and it\u2019s working remarkably well,\u201d he continued. \u201cIt\u2019s incredibly satisfying to be able to take what we\u2019ve learned, put it into practice, and help a child and family.\u201d<\/p>\n"],"rendered":"\n\t\t<p>An unusual case of a rare anemia is opening scientists up to a new way of thinking about how to adapt and employ cytokines, messenger molecules of the blood and immune system, as tools for treatment \u2014 tools that are more analog than digital \u2014 and to illustrate the promise of precision medicine.<\/p>\n<p>Cytokines are workhorses of a vast messaging network used by the blood and immune systems. These proteins influence all manner of activity in these systems, from inflammation to resolution, cell production to cell death.<\/p>\n<p>Conventional wisdom has held that cytokines are \u201cdigital,\u201d in that they either bind to a cellular receptor \u2014 triggering a cascade of signals within the cell \u2014 or they don\u2019t. If a mutation prevents perfect binding, no cascade. There is no middle ground.<\/p>\n<p>But maybe there is. A rare case of a rare disease has led an international research team headed by <a href=\"https:\/\/www.broadinstitute.org\/\">Broad Institute of Harvard and MIT<\/a> associate member Vijay Sankaran of Dana-Farber\/Boston Children\u2019s Cancer and Blood Disorders Center, postdoctoral fellow Ah Ram Kim, and Yale University\u2019s Daryl Klein to propose an \u201canalog\u201d view of cytokine function. It may be, as they show in <a href=\"http:\/\/www.cell.com\/cell\/home\">Cell<\/a>, that cytokine mutations that affect not whether a protein and receptor interact, but the quality of that interaction, can tune a cell\u2019s biochemical response, triggering some signals and not others.<\/p>\n<p>This insight could give researchers an opening to develop cytokine-based therapeutics tailored to elicit particular activities \u2014 potentially a boon for people suffering forms of cancer, kidney disease, blood disorders, and more.<\/p>\n<p>The story of how the team came to this understanding begins with a child.<\/p>\n<p><strong>An unusual case<\/strong><\/p>\n<p>A few years ago, Sankaran\u2019s colleagues at Dana-Farber\/Boston Children\u2019s (where he is a pediatric hematologist\/oncologist) cared for a young boy diagnosed with Diamond-Blackfan anemia (DBA), a rare blood disorder in which the bone marrow cannot produce red blood cells (RBCs). Transfusions kept the disorder more or less at bay, but when the boy was 6, his family and physicians agreed it was time for a bone marrow transplant.<\/p>\n<p>\u201cA transplant cures most cases of DBA,\u201d said Sankaran. \u201cBut the child still required transfusions [after the procedure], which is very unusual for this disorder.\u201d (Ultimately, the child passed away from a transplant-related complication.)<\/p>\n<p>Also unusual was the fact that neither of the boy\u2019s parents, who are first cousins, showed signs of the disorder.<\/p>\n<p>\u201cMost of the mutations that cause DBA are transmitted from parent to child in a dominant fashion,\u201d said Sankaran. \u201cBut because neither parent was affected, we wondered whether in this case there might be another, recessive cause.\u201d<\/p>\n<p>Whole exome sequencing of the boy\u2019s DNA did not uncover any of the known DBA-related gene mutations. It did, however, reveal a mutation in the gene for erythropoietin (EPO), a cytokine that controls RBC production.<\/p>\n<p><strong>When messages fail<\/strong><\/p>\n<p>As Sankaran and his collaborators probed more deeply into the boy\u2019s case, a picture of a devastating cellular miscommunication began to emerge.<\/p>\n<p>First, the boy\u2019s medical records revealed that his blood EPO levels \u2014 monitored during his transfusion treatments \u2014 were consistently 100 times higher than normal.<\/p>\n<p>Second, the mutation itself (a change in a single base pair) is not recorded in the <a href=\"http:\/\/exac.broadinstitute.org\/\">Exome Aggregation Consortium<\/a> (ExAC) database, suggesting it is exceedingly rare.<\/p>\n<p>Third, when the team studied the mutated gene\u2019s altered protein product, they found the mutation did not change whether the protein <em>could<\/em> bind to its receptor, EPOR, on blood precursor cells. Rather, it changed the cytokine\u2019s binding kinetics \u2014 the rates at which EPO and EPOR bound (associated) and unbound (dissociated). The mutant protein\u2019s association rate was 12 times higher than a normal EPO\u2019s; its dissociation rate, 233 times higher.<\/p>\n<p>Normally, when tripped by EPO, EPOR alerts three transcription factors \u2014 STAT1, STAT3, and STAT5 \u2014 to kick-start the gene program for RBC production. However, Sankaran and Klein\u2019s team found, the mutant EPO\u2019s quick hit did not provide EPOR a strong enough nudge to alert STAT1 and 3. Without them, the blood precursors could not start making RBCs.<\/p>\n<p>So the boy\u2019s body, sensing the lack of RBCs, kept churning out EPO, pleading with the bone marrow to make the cells it needed. But because of the mutation, EPOR could not hear the message well enough to do its job.<\/p>\n<p><strong>Tuning in to a new idea<\/strong><\/p>\n<p>In addition to explaining the child\u2019s grave disease, the findings suggest something new: a different way to think about adapting cytokines therapeutically.<\/p>\n<p>\u201cIn hematology and immunology, people tend to think about cytokines as working like on and off switches,\u201d Sankaran said. Doctors commonly use or manipulate EPO and other cytokines to treat cancer, autoimmunity, immunodeficiencies, and other conditions, he said. \u201cBut what we\u2019re learning is that maybe they can be tuned.\u201d<\/p>\n<p>Sankaran points to G protein-coupled receptors (GPCRs) \u2014 a family of multifunctional receptors and popular drug development targets \u2014 as a framework for thinking about the tunable cytokine activity he and his teammates propose. By modifying a cytokine and altering how it interacts with its receptor, it may be possible to nudge that receptor toward a therapeutic response and away from a deleterious one.<\/p>\n<p>\u201cMaybe we could do better and design agents that act to stimulate some cell types or signaling pathways better than others,\u201d Sankaran mused. \u201cThere are other cytokines that we know can stimulate blood production, but that we haven\u2019t used because they have a lot of side effects. Those are the kinds of problems that we\u2019d like to tackle now that we have this knowledge.\u201d<\/p>\n<p><strong>Putting precision pediatrics into practice<\/strong><\/p>\n<p>As this story started with a child, so too does it end with one.<\/p>\n<p>As Sankaran and Klein were revising their work for publication, the boy\u2019s parents had another baby, a little girl. She too was profoundly anemic, had sky-high blood levels of EPO, and had the same EPO mutation.<\/p>\n<p>Leveraging what they learned from her brother\u2019s case, Sankaran asked his clinical partners to start treating the infant with recombinant EPO. So far, it seems to be turning the tide.<\/p>\n<p>\u201cWe always say as geneticists that our goal is to be able to understand a mutation, translate that, and develop a therapy,\u201d Sankaran said. \u201cSo we were really frustrated when we finally understood her older brother\u2019s diagnosis because we have recombinant EPO and use it regularly. We could have saved his life, but just didn\u2019t have that opportunity.<\/p>\n<p>\u201cHere we had a chance to take a precision medicine approach, and it\u2019s working remarkably well,\u201d he continued. \u201cIt\u2019s incredibly satisfying to be able to take what we\u2019ve learned, put it into practice, and help a child and family.\u201d<\/p>\n"}],"innerHTML":"\n<div class=\"wp-block-group alignwide\">\n\n\n\n<\/div>\n","innerContent":["\n<div class=\"wp-block-group alignwide\">\n\n","\n\n<\/div>\n"],"rendered":"\n<div class=\"wp-block-group alignwide has-global-padding is-content-justification-center is-layout-constrained wp-block-group-is-layout-constrained\">\n\n\n\t\t<p>An unusual case of a rare anemia is opening scientists up to a new way of thinking about how to adapt and employ cytokines, messenger molecules of the blood and immune system, as tools for treatment \u2014 tools that are more analog than digital \u2014 and to illustrate the promise of precision medicine.<\/p>\n<p>Cytokines are workhorses of a vast messaging network used by the blood and immune systems. These proteins influence all manner of activity in these systems, from inflammation to resolution, cell production to cell death.<\/p>\n<p>Conventional wisdom has held that cytokines are \u201cdigital,\u201d in that they either bind to a cellular receptor \u2014 triggering a cascade of signals within the cell \u2014 or they don\u2019t. If a mutation prevents perfect binding, no cascade. There is no middle ground.<\/p>\n<p>But maybe there is. A rare case of a rare disease has led an international research team headed by <a href=\"https:\/\/www.broadinstitute.org\/\">Broad Institute of Harvard and MIT<\/a> associate member Vijay Sankaran of Dana-Farber\/Boston Children\u2019s Cancer and Blood Disorders Center, postdoctoral fellow Ah Ram Kim, and Yale University\u2019s Daryl Klein to propose an \u201canalog\u201d view of cytokine function. It may be, as they show in <a href=\"http:\/\/www.cell.com\/cell\/home\">Cell<\/a>, that cytokine mutations that affect not whether a protein and receptor interact, but the quality of that interaction, can tune a cell\u2019s biochemical response, triggering some signals and not others.<\/p>\n<p>This insight could give researchers an opening to develop cytokine-based therapeutics tailored to elicit particular activities \u2014 potentially a boon for people suffering forms of cancer, kidney disease, blood disorders, and more.<\/p>\n<p>The story of how the team came to this understanding begins with a child.<\/p>\n<p><strong>An unusual case<\/strong><\/p>\n<p>A few years ago, Sankaran\u2019s colleagues at Dana-Farber\/Boston Children\u2019s (where he is a pediatric hematologist\/oncologist) cared for a young boy diagnosed with Diamond-Blackfan anemia (DBA), a rare blood disorder in which the bone marrow cannot produce red blood cells (RBCs). Transfusions kept the disorder more or less at bay, but when the boy was 6, his family and physicians agreed it was time for a bone marrow transplant.<\/p>\n<p>\u201cA transplant cures most cases of DBA,\u201d said Sankaran. \u201cBut the child still required transfusions [after the procedure], which is very unusual for this disorder.\u201d (Ultimately, the child passed away from a transplant-related complication.)<\/p>\n<p>Also unusual was the fact that neither of the boy\u2019s parents, who are first cousins, showed signs of the disorder.<\/p>\n<p>\u201cMost of the mutations that cause DBA are transmitted from parent to child in a dominant fashion,\u201d said Sankaran. \u201cBut because neither parent was affected, we wondered whether in this case there might be another, recessive cause.\u201d<\/p>\n<p>Whole exome sequencing of the boy\u2019s DNA did not uncover any of the known DBA-related gene mutations. It did, however, reveal a mutation in the gene for erythropoietin (EPO), a cytokine that controls RBC production.<\/p>\n<p><strong>When messages fail<\/strong><\/p>\n<p>As Sankaran and his collaborators probed more deeply into the boy\u2019s case, a picture of a devastating cellular miscommunication began to emerge.<\/p>\n<p>First, the boy\u2019s medical records revealed that his blood EPO levels \u2014 monitored during his transfusion treatments \u2014 were consistently 100 times higher than normal.<\/p>\n<p>Second, the mutation itself (a change in a single base pair) is not recorded in the <a href=\"http:\/\/exac.broadinstitute.org\/\">Exome Aggregation Consortium<\/a> (ExAC) database, suggesting it is exceedingly rare.<\/p>\n<p>Third, when the team studied the mutated gene\u2019s altered protein product, they found the mutation did not change whether the protein <em>could<\/em> bind to its receptor, EPOR, on blood precursor cells. Rather, it changed the cytokine\u2019s binding kinetics \u2014 the rates at which EPO and EPOR bound (associated) and unbound (dissociated). The mutant protein\u2019s association rate was 12 times higher than a normal EPO\u2019s; its dissociation rate, 233 times higher.<\/p>\n<p>Normally, when tripped by EPO, EPOR alerts three transcription factors \u2014 STAT1, STAT3, and STAT5 \u2014 to kick-start the gene program for RBC production. However, Sankaran and Klein\u2019s team found, the mutant EPO\u2019s quick hit did not provide EPOR a strong enough nudge to alert STAT1 and 3. Without them, the blood precursors could not start making RBCs.<\/p>\n<p>So the boy\u2019s body, sensing the lack of RBCs, kept churning out EPO, pleading with the bone marrow to make the cells it needed. But because of the mutation, EPOR could not hear the message well enough to do its job.<\/p>\n<p><strong>Tuning in to a new idea<\/strong><\/p>\n<p>In addition to explaining the child\u2019s grave disease, the findings suggest something new: a different way to think about adapting cytokines therapeutically.<\/p>\n<p>\u201cIn hematology and immunology, people tend to think about cytokines as working like on and off switches,\u201d Sankaran said. Doctors commonly use or manipulate EPO and other cytokines to treat cancer, autoimmunity, immunodeficiencies, and other conditions, he said. \u201cBut what we\u2019re learning is that maybe they can be tuned.\u201d<\/p>\n<p>Sankaran points to G protein-coupled receptors (GPCRs) \u2014 a family of multifunctional receptors and popular drug development targets \u2014 as a framework for thinking about the tunable cytokine activity he and his teammates propose. By modifying a cytokine and altering how it interacts with its receptor, it may be possible to nudge that receptor toward a therapeutic response and away from a deleterious one.<\/p>\n<p>\u201cMaybe we could do better and design agents that act to stimulate some cell types or signaling pathways better than others,\u201d Sankaran mused. \u201cThere are other cytokines that we know can stimulate blood production, but that we haven\u2019t used because they have a lot of side effects. Those are the kinds of problems that we\u2019d like to tackle now that we have this knowledge.\u201d<\/p>\n<p><strong>Putting precision pediatrics into practice<\/strong><\/p>\n<p>As this story started with a child, so too does it end with one.<\/p>\n<p>As Sankaran and Klein were revising their work for publication, the boy\u2019s parents had another baby, a little girl. She too was profoundly anemic, had sky-high blood levels of EPO, and had the same EPO mutation.<\/p>\n<p>Leveraging what they learned from her brother\u2019s case, Sankaran asked his clinical partners to start treating the infant with recombinant EPO. So far, it seems to be turning the tide.<\/p>\n<p>\u201cWe always say as geneticists that our goal is to be able to understand a mutation, translate that, and develop a therapy,\u201d Sankaran said. \u201cSo we were really frustrated when we finally understood her older brother\u2019s diagnosis because we have recombinant EPO and use it regularly. We could have saved his life, but just didn\u2019t have that opportunity.<\/p>\n<p>\u201cHere we had a chance to take a precision medicine approach, and it\u2019s working remarkably well,\u201d he continued. \u201cIt\u2019s incredibly satisfying to be able to take what we\u2019ve learned, put it into practice, and help a child and family.\u201d<\/p>\n\n\n<\/div>\n"}},"jetpack-related-posts":[{"id":332885,"url":"https:\/\/news.harvard.edu\/gazette\/story\/2021\/10\/massage-helps-injured-muscles-heal-faster-and-stronger\/","url_meta":{"origin":221919,"position":0},"title":"Massage helps injured muscles heal faster and stronger","author":"harvardgazette","date":"October 6, 2021","format":false,"excerpt":"Using a controlled massage system, researchers found that treatment led to greater repair and strength recovery in mice.","rel":"","context":"In "Science & Tech"","block_context":{"text":"Science & 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during pregnancy regulate stress differently in the brain 45 years later, results of a long-term study demonstrate.","rel":"","context":"In "Science & Tech"","block_context":{"text":"Science & Tech","link":"https:\/\/news.harvard.edu\/gazette\/section\/science-technology\/"},"img":{"alt_text":"Woman showing signs of stress.","src":"https:\/\/news.harvard.edu\/wp-content\/uploads\/2021\/04\/iStock-stress2500.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/news.harvard.edu\/wp-content\/uploads\/2021\/04\/iStock-stress2500.jpg?resize=350%2C200 1x, https:\/\/news.harvard.edu\/wp-content\/uploads\/2021\/04\/iStock-stress2500.jpg?resize=525%2C300 1.5x, https:\/\/news.harvard.edu\/wp-content\/uploads\/2021\/04\/iStock-stress2500.jpg?resize=700%2C400 2x"},"classes":[]},{"id":184603,"url":"https:\/\/news.harvard.edu\/gazette\/story\/2016\/06\/making-bone-marrow-transplants-safer\/","url_meta":{"origin":221919,"position":2},"title":"Making bone marrow transplants safer","author":"harvardgazette","date":"June 7, 2016","format":false,"excerpt":"Harvard Stem Cell Institute scientists have taken the first steps toward developing a treatment that would make bone marrow-blood stem cell transplantation safer.","rel":"","context":"In "Health"","block_context":{"text":"Health","link":"https:\/\/news.harvard.edu\/gazette\/section\/health\/"},"img":{"alt_text":"","src":"https:\/\/news.harvard.edu\/wp-content\/uploads\/2016\/06\/053016_week-0022scadden_rahul-palchaudhuri_605.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/news.harvard.edu\/wp-content\/uploads\/2016\/06\/053016_week-0022scadden_rahul-palchaudhuri_605.jpg?resize=350%2C200 1x, https:\/\/news.harvard.edu\/wp-content\/uploads\/2016\/06\/053016_week-0022scadden_rahul-palchaudhuri_605.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":149956,"url":"https:\/\/news.harvard.edu\/gazette\/story\/2013\/11\/viral-infections-may-have-met-their-match\/","url_meta":{"origin":221919,"position":3},"title":"Viral infections may have met their match","author":"harvardgazette","date":"November 24, 2013","format":false,"excerpt":"A Massachusetts General Hospital-led research team of Harvard affiliates has identified an immune cell protein that is critical to setting off the body\u2019s initial response against viral infection.","rel":"","context":"In "Health"","block_context":{"text":"Health","link":"https:\/\/news.harvard.edu\/gazette\/section\/health\/"},"img":{"alt_text":"","src":"https:\/\/news.harvard.edu\/wp-content\/uploads\/2013\/11\/reinecker-nature-immun-11-13-web.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/news.harvard.edu\/wp-content\/uploads\/2013\/11\/reinecker-nature-immun-11-13-web.jpg?resize=350%2C200 1x, https:\/\/news.harvard.edu\/wp-content\/uploads\/2013\/11\/reinecker-nature-immun-11-13-web.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":302376,"url":"https:\/\/news.harvard.edu\/gazette\/story\/2020\/04\/covid-19s-consequences-for-the-heart\/","url_meta":{"origin":221919,"position":4},"title":"Coronavirus and the heart","author":"Lian Parsons","date":"April 14, 2020","format":false,"excerpt":"Heart damage has recently emerged as yet another grim outcome in the virus's repertoire of possible complications.","rel":"","context":"In "Health"","block_context":{"text":"Health","link":"https:\/\/news.harvard.edu\/gazette\/section\/health\/"},"img":{"alt_text":"heart model.","src":"https:\/\/news.harvard.edu\/wp-content\/uploads\/2020\/04\/heart-2500.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/news.harvard.edu\/wp-content\/uploads\/2020\/04\/heart-2500.jpg?resize=350%2C200 1x, https:\/\/news.harvard.edu\/wp-content\/uploads\/2020\/04\/heart-2500.jpg?resize=525%2C300 1.5x, https:\/\/news.harvard.edu\/wp-content\/uploads\/2020\/04\/heart-2500.jpg?resize=700%2C400 2x"},"classes":[]},{"id":341558,"url":"https:\/\/news.harvard.edu\/gazette\/story\/2022\/06\/brain-controls-symptoms-of-sickness\/","url_meta":{"origin":221919,"position":5},"title":"How the brain responds to infection","author":"Lian Parsons","date":"June 8, 2022","format":false,"excerpt":"Study illuminates connections to immune system.","rel":"","context":"In "Science & Tech"","block_context":{"text":"Science & Tech","link":"https:\/\/news.harvard.edu\/gazette\/section\/science-technology\/"},"img":{"alt_text":"Catherine Dulac and Jessica Osterhout.","src":"https:\/\/news.harvard.edu\/wp-content\/uploads\/2022\/04\/040722_Dulac_194.jpeg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/news.harvard.edu\/wp-content\/uploads\/2022\/04\/040722_Dulac_194.jpeg?resize=350%2C200 1x, https:\/\/news.harvard.edu\/wp-content\/uploads\/2022\/04\/040722_Dulac_194.jpeg?resize=525%2C300 1.5x, https:\/\/news.harvard.edu\/wp-content\/uploads\/2022\/04\/040722_Dulac_194.jpeg?resize=700%2C400 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