Jurgen got a project funded in the ZonMw Open Competition

Jurgen Haanstra received a 750k€ grant in the ZonMw Open Competition together with Ruud Brakenhoff from Amsterdam UMC-Cancer Center Amsterdam (A-UMC-CCA). The ZonMw open competition funds research proposals for non-programmed, fundamental research. Through this, ZonMw wants to bring together researchers from two or more disciplines to facilitate excellent team science that results in groundbreaking research of exceptional quality in the field of healthcare.

The project of Jurgen and Ruud will focus on metabolism in head-and neck cancer. Head and neck cancer arises in the mucosal linings of the upper-aerodigestive tract and is generally preceded by precancerous changes that may be visible as lesions.  In total 50% of patients die of the disease despite invasive treatments. We recently discovered that these tumors rewire their metabolic program atypically.  In this project they will use computer models and laboratory experiments to study this atypical metabolic program. They will investigate why these tumor cell reprogram metabolism in this remarkable way, and how this can be exploited to improve diagnosis and treatment of these tumors and their preceding precancerous mucosal changes.

Lab retreat 2018

In the beginning of May we had our yearly lab retreat. This year it was in Blesdijke, all the way up north of the Netherlands, in Friesland.

We enjoyed three days of inspiring scientific discussions, great food, swimming in our own pool, live music and exciting games.

Lab day out in Arnhem

A few weeks ago we had our lab day out and went to Arnhem.

We started at Bas’ house for a delicious lunch and enjoyed the beautiful weather in his garden. Then we walked, biked, bussed or drove to the Openluchtmuseum where we spent the afternoon sunbathing, on a tour through the museum, archery and beugelen (you should google it ;-)). The day ended again near the Rhine for pizzas

It was a great day!

Two new papers are out

Recently two new papers were published:

 

  1. Low affinity uniporter carrier proteins can increase net substrate uptake rate by reducing efflux by Evert Bosdriesz, Meike T Wortel, Jurgen R Haanstra, Marijke J Wagner, Pilar Torre Cortés and Bas Teusink
  2. Metabolite Depletion Affects Flux Profiling of Cell Lines by Avlant Nilsson, Jurgen R.  Haanstra, Bas Teusink and Jens Nielsen

 

In the first paper we compare and test different hypotheses for the existence of low affinity uniporters, in addition to high-affinity ones. Our new model-driven hypothesis shows that a low affinity glucose transporter would experience less inhibition by intracellular glucose and this would give a higher nett uptake rate. However, due to the intimate link between glucose perception and metabolism, direct experimental proof for this hypothesis remained inconclusive. Still, our theoretical results provide a novel reason for the presence of low-affinity transport system.

In the second paper (a commentary) we show that care should be taken with calculating fluxes from long incubation experiments. Over time, some metabolites deplete and this will affect (calculation of)  fluxes

 

Bas on national TV: ‘de 5 smaken van Joël’

Bas Teusink featured in the first episode of ‘de 5 smaken van Joël’.

In this series Joël Broekaert investigates the 5 basic tastes and this episode had the theme ‘sweet‘. Bas explains why people are so fond of sweet food. The episode first aired on Jan 2, 2018 and can be seen here (in Dutch, there are two parts where Bas appears)

 

Jurgen obtained his University Teaching Qualification (BKO)

Jurgen is now certified to teach at university level (University Teaching Qualification or Basiskwalificatie Onderwijs).

Yesterday he received his certificate, flowers and a digital presenting device after completing the individualised track for this course. His course teacher described his teaching as:  ‘Jurgen’s enthusiasm is contagious’

 

Jurgen published a new paper on Network-based drug design in Scientific Reports

Screenshot_paper_Haanstra

Jurgen published a paper from his postdoc in the labs of Prof. Barbara Bakker (UMCG) and Hans Westerhoff (Molecular Cell Physiology, AIMMS, VU)

What it is about:

To avoid side-effects of drug treatment to healthy cells, drug target selection studies often focus on protein targets that are only found a disease-causing cell. However, many disease-causing cells, like parasites and cancer cells, are biochemically very similar to their host and therefore the number of proteins unique to such cells are scarce.

Nevertheless, due to subtle, quantitative differences between the biochemical reaction networks of disease-causing cell and healthy host cells, a drug can affect the same essential process in one cell-type more than in another. This papers shows a proof-of-principle how quantitative differences in cellular networks can be exploited to selectively hit the disease-causing cells.

In this paper, the authors combined computational and experimental approaches to compare energy metabolism in the causative agent of deadly sleeping sickness, Trypanosoma brucei, with that of human erythrocytes. The computational analysis revealed that inhibitors of the uptake of glucose would affect energy metabolism in T. brucei stronger than in erythrocytes. Computational predictions were validated experimentally in a novel parasite-erythrocytes co-culture system. They  furthermore showed that glucose-transport inhibitors killed trypanosomes without killing neurons or liver cells.

This study shows that very promising and selective drug targets can exist outside the realm of the unique proteins and thereby extends the pool of putative, selective drug targets. The important next step is to translate this knowledge to actual drugs: to design and synthesise drug-like molecules that inhibit the glucose transporter of T. brucei and stay active inside the human body. Furthermore, this network-based approach to drug target selection can also be applied to other diseases like cancer and diabetes.

Waar het over gaat:

Diverse ziekten worden veroorzaakt door snel delende ziekteverwekkers in ons lichaam. Voorbeelden zijn infecties met bacteriën en parasieten, maar bijvoorbeeld ook kanker. Bij de zoektocht naar nieuwe medicijnen moeten we er voor zorgen dat de gezonde cellen van de mens niet geraakt worden. Dit is erg lastig naar mate de ziekteverwekker veel overeenkomsten vertoont met de mens.

Er is met een nieuwe methode gezocht naar verschillen tussen een dodelijke parasiet (Trypanosoma brucei die slaapziekte veroorzaakt) en zijn menselijke gastheer en die ook gevonden. Zowel de parasiet als cellen de mens moeten allebei suiker afbreken in een aantal opeenvolgende stappen om er energie uit te halen om in leven te blijven. Hiervoor gebruiken beiden een vrijwel identiek ’machinepark’. Vanwege deze gelijkenis zal een medicijn die een van de machines minder hard laat werken niet alleen deze machines van de parasiet raken maar ook die in de cellen van de mens. Echter, de beide machineparken hebben dan misschien wel dezelfde machines, maar elk van de twee heeft net een andere hoeveelheid machines die nodig zijn voor specifieke onderdelen van de suikerafbraak en ze misschien wel iets aangepast om ze harder te laten werken. Hierdoor zijn er mogelijk andere zwakke plekken in het machinepark van de parasiet dan in dat van de mens

Met bovenstaande in gedachten, is de suikerafbraak in parasiet en bloedcellen van de mens met elkaar vergeleken met behulp van computermodellen die de werking van beide ‘machineparken’ goed kunnen simuleren. Hieruit bleek dat er inderdaad belangrijke verschillen zijn: als men in de computer de machine die de opname van suiker regelt minder hard laat werken bleek dat de parasiet ineens veel langzamer energie ging maken, terwijl dit nauwelijks effect had voor de snelheid van de energieproductie in de menselijke bloedcellen. Een medicijn die de suikeropname verlaagt zou dus alleen de parasiet zonder energie laten zitten en dus weinig bijeffecten geven. Inderdaad, als parasieten en menselijke bloedcellen in het lab bij elkaar worden gestopt en een chemische stof geven die de suikeropname remt lukt het om alleen de parasieten te doden.

Dit werk laat zien dat we op deze manier goedwerkende en veilige doelwitten voor medicijnen tegen ziekteverwekkers kunnen vinden. De volgende stap is om nu echte medicijnen te maken die parasieten op deze manier in het menselijk lichaam kunnen doden. Deze methode is ook toepasbaar op andere ziektes, zoals kanker.