From 57987ddc3ed11ceecdb1694ae034045b76e91d8e Mon Sep 17 00:00:00 2001
From: Liliana Sanfilippo <liliana.sanfilippo@uni-bielefeld.de>
Date: Mon, 30 Sep 2024 10:48:13 +0200
Subject: [PATCH] hp links

---
 src/data/hptimelinedata.tsx | 28 ++++++++++++++++++----------
 1 file changed, 18 insertions(+), 10 deletions(-)

diff --git a/src/data/hptimelinedata.tsx b/src/data/hptimelinedata.tsx
index e82d5ded..cba70868 100644
--- a/src/data/hptimelinedata.tsx
+++ b/src/data/hptimelinedata.tsx
@@ -5,8 +5,14 @@ import JoshuaInterviewSources from "../sources/joshua-inv-sources";
 import MattijsInterviewSources from "../sources/mattij-inv-sources";
 import RnhaleSources from "../sources/rnhale-sources";
 import WischmeyerSources from "../sources/wimscheyer-sources";
+import { useNavigation } from "../utils";
 
-
+function HPLinktoOtherHPTab({tab, text}:{tab: string, text: string}){
+  const {goToPagesAndOpenTab} = useNavigation(); 
+  return(
+    <a onClick={() => goToPagesAndOpenTab(tab, "")}> {text} </a>
+  )
+}
 
 export interface TimelineDatenpunkt {
   title?: string; /* Prof. , Dr., ... */
@@ -485,7 +491,9 @@ export const timelinedata: Array<TimelineDatenpunkt>  = [
     language: "en",
     quote: "[…] Prime Editing system is more complex than the canonical CRISPR systems, with more variables that can influence success or failure.",
     aimofcontact: [<p>Shortly after we decided to use prime editing as the gene editing method for our cystic fibrosis therapy, Mattijs Bulcaen from the Laboratory of Molecular Virology and Gene Therapy at KU Leuven and his colleagues published a paper directly related to our research <TabScrollLink tab="mattijsinv" scrollId="desc-1" num="1" />. In contrast to our approach, Bulcaen et al. 2024 targeted other, less common but drug-refractory CFTR-specific mutations (L227R- and N1303K).  </p>],
-    insights: "The interview with Mattijs was valuable for us in a lot of ways. At that point in the project we were starting to design the components of our prime editor, but we were lacking a broader overview over the state of the field. Mattijs gave us this insight, mentioning techniques like PE3b systems, dsgRNAs and a talk given by David Liu,[Link] the principal investigator behind prime editing that helped us to consider further novel advancements in in Prime Editing and include them into our project. He discussed with us the difficulties that might await us when targeting the CFTR F508del deletion and mentioned that insertions of all the edits possible with prime editing are the hardest to make, the recognition of edits in the region might attract mismatch repair systems and the chromatin organization might negatively impact prime editing efficiency. Also, we learned a lot about how to design our pegRNAs, with important inputs being the 3’ stem loop motif trevopreQ1 used by Mattijs in his publication and the suggestion to use prediction tools to evaluate sgRNA spacer cutting efficiency. We reviewed our approach of testing pegRNAs using the PEAR reporter system and Mattjis recommended to use HEK cell lines for screening because of their easy handling and naturally impaired mismatch repair system. ",
+    insights: [<a>The interview with Mattijs was valuable for us in a lot of ways. At that point in the project we were starting to design the components of our prime editor, but we were lacking a broader overview over the state of the field. Mattijs gave us this insight, mentioning techniques like PE3b systems, dsgRNAs and a talk given by <HPLinktoOtherHPTab tab="liu" text="David Liu" />, the principal 
+      investigator behind prime editing that helped us to consider further novel advancements in in Prime Editing and include them into our project. He discussed with us the difficulties that might await us when targeting the CFTR F508del deletion and mentioned that insertions of all the edits possible with prime editing are the hardest to make, the recognition of edits in the region might attract mismatch repair systems and the chromatin organization might negatively impact prime editing efficiency. Also, we learned a 
+    lot about how to design our pegRNAs, with important inputs being the 3’ stem loop motif trevopreQ1 used by Mattijs in his publication and the suggestion to use prediction tools to evaluate sgRNA spacer cutting efficiency. We reviewed our approach of testing pegRNAs using the PEAR reporter system and Mattjis recommended to use HEK cell lines for screening because of their easy handling and naturally impaired mismatch repair system. </a>],
     implementation: "The inputs given by Mattijs directly impacted our design choices for multiple parts of the project. For the pegRNA design, we decided to use the same 3’ motif as Mattijs had used and also, like he suggested, checked our spacer candidates for predicted cleavage efficiency. Also we used HEK cells for screening our pegRNAs. We looked further into PE systems that influence cellular mismatch repair (such as PE4) and tried to include these into our design. ",
     interview: <>
       <QaBox q="You mentioned that it was quite challenging to target the F508del mutation. Could you provide more detailed reasons for why this is the case or explain why this mutation is particularly difficult to target compared to others?" a="Yes, that's the million-dollar question. First of all, let me clarify: our group has never directly worked on that mutation because we immediately focused on the drug-refractory mutations, such as nonsense mutations where the protein is not formed, indel mutations, or severe missense mutations that do not respond to modulator therapies. Of course, we know several groups in the field who either work on gene editing or focus on cystic fibrosis (CF). We've heard from some of them who attempted to target the F508del mutation. For example, some collaborators really tried to design different guides but were unable to find anything above the detection limit. F508del is probably one of the most logical mutations to try to correct, not just for CF but for the entire gene-editing field. If you look at the frequencies of mutations that cause genetic diseases, the F508del mutation is by far the most common deletion mutation causing a severe disease. This is because CF, along with sickle cell disease, is one of the most common deadly inherited diseases, and it's overrepresented within CF. So, it makes sense that they would have been trying to target it from the beginning. Interestingly, if you read the Prime Editing paper by Anzalone, F508del is mentioned in the introduction in connection with cystic fibrosis. So, it's somewhat surprising that after all this time—it's been almost five years now—they haven't published or released anything on F508del. However, last weekend, there was an online seminar where David Liu gave a talk, and he showed some unpublished data indicating that they managed to achieve quite good Prime Editing efficiency on F508del. It's worth noting that David Liu rarely presents unpublished data unless the publication is either accepted or very close to acceptance. So, we all kind of expect that the paper will be published soon, perhaps within the next week or at least within a month. From what I saw, it appears they leveraged many of the approaches available today to enhance Prime Editing. Now, regarding your question about why this mutation is so difficult to target with Prime Editing, I can't provide an exact answer. However, I can list some potential difficulties associated with the mutation, and it’s likely that F508del is challenging for several of these reasons. For instance, it could be related to the genomic region itself. Writing insertions can be more difficult; the easiest edits are single-point mutations, followed by deletions, and the most challenging are insertions. This difficulty arises because it involves writing a third strand and then relying on DNA damage repair mechanisms to fix it. It could also be that the region around the F508del mutation is challenging due to flap equilibration or that it attracts pathways such as mismatch repair that negatively impact Prime Editing. Additionally, the chromatin organization around that region could play a role. Over the past year, we’ve gathered clues that chromatin organization significantly affects Prime Editing capability, while this is much less of an issue for Cas9 and base editors. Studying this is not straightforward; you would need to conduct experiments like ATAC-seq to determine the chromatin organization around the mutation and how it might interfere. I also noticed on a slide that dsgRNAs were mentioned, though David Liu didn't discuss them in his talk. After looking them up online, I found that this technique, published a few years ago by other researchers, is specifically designed to open up chromatin. It seems they use different guides, without the three-prime extension, to open up the chromatin, which could be one way to overcome the limitations in Prime Editing efficiency. There could be other factors as well, and it’s often difficult to predict what will work and what won't. We have prediction tools for Prime Editing guides that work to some extent, but they are not as effective as the prediction tools available for regular CRISPR guide RNAs. This suggests that the Prime Editing system is more complex than the canonical CRISPR systems, with more variables that can influence success or failure. I hope this answers your question somewhat." />
@@ -595,7 +603,7 @@ export const timelinedata: Array<TimelineDatenpunkt>  = [
     cardtext: "",
     language: "de",
     quote: "Children are the world's best “mucus hiders”.",
-    aimofcontact: "In the interview with Katrin Westhoff [Link], she invited us to join a few physiotherapy sessions – not just as spectators but as participants. We gladly accepted and visited her in her practice. Over a few hours, we took part in four sessions with different children – not all of them CF patients.  ",
+    aimofcontact: [<a>In the interview with <HPLinktoOtherHPTab tab="westhoffinv" text="Katrin Westhoff" />, she invited us to join a few physiotherapy sessions – not just as spectators but as participants. We gladly accepted and visited her in her practice. Over a few hours, we took part in four sessions with different children – not all of them CF patients.  </a>],
     insights: "During the sessions, we could ask Katrin as well as the respective parents and children questions. We learned that breathing therapy is also useful for other illnesses and that you can easily do some of the exercises yourself. Despite having cystic fibrosis, the children were better at the breathing exercises than we and Katrin were! The sessions take 30 to 60 minutes and include both manual therapy and playful elements to help engage the children. Most older children range from mildly unhappy to enthusiastic, but babies often cry during the treatments as it feels uncomfortable. This is often hard on the parents even though the treatment brings good results. A lot of children tend to hide that they have mucus sitting in their lungs by suppressing coughs. Especially with young children, it is important to stay on top of it and do regular breathing therapy even if it seems like it is currently not necessary. We also learned about the various informational material aimed at children to help explain therapies and symptoms to them and what accessories for breathing therapy there are. For example, a flutter is to train breathing out forcefully by breathing against a small weight and a binder can be worn at night to promote deep breathing. ",
     implementation: "The most important thing was that both Katrin and the parents agreed that the children were able to inhale at an early age and that there were generally no physical problems with inhalation in general. This reinforced our decision to work towards delivery by inhalation. It was very interesting to see the different ways children deal with their exercises and hear about the progress they made.  ",
     text: [<ol>
@@ -631,8 +639,8 @@ export const timelinedata: Array<TimelineDatenpunkt>  = [
     cardtext: "",
     language: "de",
     quote: "At first, our world fell apart. I still remember the conversation with the doctor. ",
-    aimofcontact: [<p>We learned from our discussion with Max [Link Max] that cystic fibrosis (CF) has a profound impact on the whole family – not just the patient. In order to gain further insight into this subject, we sought to engage with the next of kin of CF patients.
-      We were able to make contact with Julia through the self-help group of Mukviszidose e.V. [Link https://www.muko.info/ ], of which Max is a member. She subsequently reached out to us following Max's request for potential candidates for an interview with a patient group.
+    aimofcontact: [<p>We learned from our discussion with <HPLinktoOtherHPTab tab="maxfirst" text="Max" /> that cystic fibrosis (CF) has a profound impact on the whole family – not just the patient. In order to gain further insight into this subject, we sought to engage with the next of kin of CF patients.
+      We were able to make contact with Julia through the self-help group of <a href="https://www.muko.info/ " >Mukviszidose e.V. </a> of which Max is a member. She subsequently reached out to us following Max's request for potential candidates for an interview with a patient group.
       She and her husband have a six-year-old daughter carrying the F508del mutation in the CFTR gene and a toddler without CF.  </p>],
     insights: [<p> The interview with Julia shifted our focus to a new group of stakeholders: The patient’s support systems. Most people do not get genetically tested before having children and due to that, many people could get in the position of having a loved one with CF.
       We considered the societal impacts, such as the rising health care costs, which Nicole Friedlein emphasized during our interview. She explained how the long-term nature of treatment, frequent hospital visits, and the need for specialized medications place a significant
@@ -640,7 +648,7 @@ export const timelinedata: Array<TimelineDatenpunkt>  = [
       stressing the emotional strain that accompanies not only the illness itself but also the financial pressures. She also showed us more perspectives on parenting of children with CF, than we heard before, and told us about the way from the first diagnosis to growing accustomed
       to and living with a child with CF. Julia also confirmed that most children will have no issue using an inhalative therapy like we envision our gene therapy to be and shone light onto the comparatively very good situation for CF patients in Germany. </p>],
     implementation: [<p> This interview helped us confirm the delivery method we planned to use as we were previously concerned how and if children would be able to use the inhalative therapy. Besides that, Julia gave us further insights into the emotional side of
-      dealing with CF and we were able to discuss the situation for patients in Germany in comparison to other countries better in later interviews [Link Joshua]. </p>],
+      dealing with CF and we were able to discuss the situation for patients in Germany in comparison to other countries better in later interviews <HPLinktoOtherHPTab tab="joshua" text="Joshua" />. </p>],
     interview: <>
       <QaBox q="Can you tell us a bit about your family? How old are your children and yourselves?" a="I’m 37, my husband is 44, and our daughter is six, turning seven soon. We also have a son who’s about a year and a half." />
       <QaBox q="Does your son also have cystic fibrosis?" a="No, he doesn’t." />
@@ -684,7 +692,7 @@ export const timelinedata: Array<TimelineDatenpunkt>  = [
       podcast of the Bonnel foundation</a>.</p>],
     insights: [<p> Joshua showed us just how dire the situation is for CF patients is in some regions. It was shocking to hear there is only one doctor
       knowledgeable about CF in Thailand and that many doctors dismiss the possibility of CF due to racial bias and misinformation. Additionally, we confirmed how much the accessibility
-      of care depends on the healthcare system, as we already touched on during the interview with Nicole Friedlein [link]. On the parenting level, Joshua brought in many perspectives contrary to what we previously heard. In the interview with Max [Link], we learned he vehemently avoids ponding water while Joshua’s daughter is allowed to roam around with no such restrictions. Neither have chronic infections.</p>],
+      of care depends on the healthcare system, as we already touched on during the interview with <HPLinktoOtherHPTab tab="nicole" text="Nicole Friedlein" />,. On the parenting level, Joshua brought in many perspectives contrary to what we previously heard. In the interview with <HPLinktoOtherHPTab tab="maxfirst" text="Max" />,, we learned he vehemently avoids ponding water while Joshua’s daughter is allowed to roam around with no such restrictions. Neither have chronic infections.</p>],
     implementation: [<p>The interview with Josh made us realize we too needed to look at the reason why we chose F508del. Did we, too, fall for bias?
       Despite a change of target not being feasible anymore, we looked into it and traced back our steps that led to our decision. We did not find as much
       information about other mutations when first researching cystic fibrosis, especially in the context of prime editing. Mattijs Bulceans's paper on
@@ -752,7 +760,7 @@ export const timelinedata: Array<TimelineDatenpunkt>  = [
     implementation: [<> <p>We decided to use HEK293T cells lines which do overexpress the
       correct CFTR and those which express CFTR with F508del for the Patch-Clamp measurements. To conduct the
       Patch-Clamp experiments, we contacted the Cellular Neurophysiology group to perform the necessary
-      measurements. It was a pleasure to work together with Dr. Oliver Dräger[Link], who is working as a post-doc for
+      measurements. It was a pleasure to work together with <HPLinktoOtherHPTab tab="patchclamp" text="Dr. Oliver Dräger" />, who is working as a post-doc for
       the Cellular Neurophysiology working group at Bielefeld University. He taught us about the Patch-Clamp
       method and spent his valuable time supporting our project by guiding our Patch-Clamp measurements. </p>
       <p>In summary, through the interview with Prof. Dr. Wischmeyer and the collaboration with his employee
@@ -971,7 +979,7 @@ export const timelinedata: Array<TimelineDatenpunkt>  = [
     language: "de",
     quote: "X",
     aimofcontact: [<p>The goal of the discussion with Steffen Bira and Serra Gürcan from Corden Pharma was to gain insight into the design, stability, and practical application of lipid nanoparticles (LNPs) for use in gene therapy. The conversation focused on the possibility of using Corden Pharma’s LNP starter kits, understanding the factors affecting the stability of LNPs, and exploring options for incorporating antibodies into LNPs to target specific cells. </p>],
-    insights: [<p>Steffen Bira and Serra Gürcan of Corden Pharma[Link Corden Pharmahttps://cordenpharma.com/] indicated that our planned spray drying approach of LNPs has not been extensively explored within their operations. The company focuses primarily on the aseptic fill and finish of LNPs, particularly for injectable formulations. However, they acknowledged the potential for spray drying and recommended consulting with specialized companies to assess the feasibility.
+    insights: [<p>Steffen Bira and Serra Gürcan of <a href="https://cordenpharma.com/">Corden Pharma</a>indicated that our planned spray drying approach of LNPs has not been extensively explored within their operations. The company focuses primarily on the aseptic fill and finish of LNPs, particularly for injectable formulations. However, they acknowledged the potential for spray drying and recommended consulting with specialized companies to assess the feasibility.
       The stability of the lipids used in LNPs during the spray drying process was also identified as an area requiring further investigation.
       The stability of LNPs, in particular in the context of the shear forces encountered in inhalation therapy, was identified as a critical factor. Corden Pharma highlighted that while the stability of individual lipid components can be evaluated, the stability of a complete LNP formulation containing RNA or other payloads must be empirically tested. The company put forward the suggestion that cryoprotectants and varying temperature conditions might be considered to
       enhance the stability of LNPs during processing. Corden Pharma outlined the process used to select the lipids included in their LNP starter kits, nothing that these combinations are based on established interactions and research findings, particularly in RNA-containing formulations. The kits are designed to facilitate the creation of stable LNPs by providing materials that have been tested for their physical-chemical properties, encapsulation efficiency, and potency. Furthermore, the company highlighted that a single LNP starter kit can be used for multiple batches, offering a practical solution for experimental work.
@@ -1056,7 +1064,7 @@ export const timelinedata: Array<TimelineDatenpunkt>  = [
     quote: "The implementation of the hygiene concept is proving more difficult than expected due to the bureaucracy at the university. Nevertheless, the interview gave us a good insight into this labyrinth of regulations and we got started the prozess of implementation.",
     quoteVorname: "Vera",
     quoteNachname: "Köhler",
-    aimofcontact: [<p>We contacted the university because of the urgent need to address the issue of hygiene for students and staff, particularly those with immunocomprised students and staff. There was a need to develop an effective hygiene concept to ensure the health and safety of these people. We developed this concept in collaboration with Max, our CF friend. [Link] </p>],
+    aimofcontact: [<p>We contacted the university because of the urgent need to address the issue of hygiene for students and staff, particularly those with immunocomprised students and staff. There was a need to develop an effective hygiene concept to ensure the health and safety of these people. We developed this concept in collaboration with <HPLinktoOtherHPTab tab="maxfirst" text="Max" />, our CF friend. </p>],
     insights: [<p>We learnt that our hygiene concept is very well-developed. But although a well-developed hygiene concept is already existing, strategic development and a step-by-step approach are needed. In particular, the step-by-step implementation was emphasized, like starting with equipping the toilets. Bureaucratic hurdles, such as the need to apply to the rectorate, were identified as a major challenge. In addition, it became clear that there is a great need for sanitary facilities and facilities for the disabled, especially due to the needs of students and staff with health problems. Interaction and networking with other universities was also considered valuable. </p>],
     implementation: [<p>The next phase of developing a new hygiene concept is to maintain contact with Mr. Johannfunke in order to continue to advance the hygiene concept in collaboration. The strategic approach entails the incremental implementation of measures, exemplified by the establishment of the inaugural toilet facility within the main building. It is of the utmost importance to ensure the uninterrupted implementation of the hygiene concept. In order to achieve this, it is essential to draw upon the existing plans and measures that have already been implemented in new buildings.  We are working on advancing the plans at a higher level and are in regular dialogue with the Central contact point Barrier-free in order to overcome bureaucratic hurdles and actively promote the topic. Furthermore, it is necessary to intensify lobbying work in order to gain greater support for this issue at both the university and political levels. </p>],
     language: "de",
-- 
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