Since being founded in 2013, the number of employees at HUB (Hubrecht Organoid Technology) has almost doubled every year and has risen to more than 40 today.
Image Credit: PHC Europe B.V.
CEO Robert Vries believes that HUB will continue to experience rapid growth for a while: ‘We are currently receiving more project requests for primarily diagnostics and screening than we can take on. And with the major steps currently being taken in the field of personalized medicine, this number will certainly increase.’
Over ten years after the cultivation of the first organoid – which happened at the Hubrecht Institute by Toshiro Sato in the group headed by Hans Clevers – the route to commercial applications is open, says Robert Vries. After joining in 2013, Vries has been striving to make HUB the world’s leading organoid center.
Central to this ambitious aim is the exclusive license for the patents which are for producing organoids out of adult stem cells – often referred to as ASC organoids. The patents stem from the research conducted at the Hubrecht Institute – a KNAW (Royal Dutch Academy of Sciences) institute – and are the property of the KNAW.
With this license, for which we pay the KNAW an annual fee, we can commercially exploit the technology in the form of licenses and/ or research and development work for primarily pharmaceutical companies. The benefit of this expanded patent portfolio, which includes over 50 patents in 14 patent classes and encompasses all aspects of (making) the ASC organoids, is that companies that want to work with such organoids cannot circumvent us."
Robert Vries, CEO, HUB
Almost all organs
One of the many advantages of organoid technology is that the human cells can be allowed to grow in the mini-organs without them changing; the cultures continue to be extremely stable, both from the phenotype and genotype aspects.
ASC Organoid Technology uses epithelial cells, making this methodology suitable for making 3D mini-structures that contain epithelial cells, for example, the intestine, liver, thyroid, lung, kidney and stomach.
This method, however, is not appropriate for tissues that lack epithelial cells, for example, neurons, blood vessels, and muscle tissue (including the heart).
To make such structures, more suitable methods are available that use pluripotent stem cells (IPS). However, this approach is not comparable to the ASC method for structures with epithelial cells and is only appropriate for cultivating healthy cells.
The emphasis of organoid research was initially on cultivating healthy cells, with the long-term aim of being applied to cell therapy and regenerative medicine. Meanwhile, the attention has moved to preclinical drug diagnostics and screening and, as a result, personalized medicine too.
‘In any case, the road to cell therapy is very long, even longer (and also more uncertain) than the road to launching medicines on the market based on small molecules. However, we noticed that we could grow not only healthy cells but diseased cells as well, such as cancer cells. That opened the door to applications that can be developed a lot faster, for example, disease modeling by growing organoids directly from diseased patient tissue. Furthermore, direct cloning of multiple individual cells from primary tumors enabled molecular and functional analysis of tumor heterogeneity. And we can also work with CRISP-mediated genome modification. Human organoids appear to be very receptive to this, which offers an enormous range of possibilities in the area of modeling of malignant transformation and mutagenesis after defect DNA repair.’
HUB was founded in 2013 to apply organoid technology for testing as a diagnostic tool or when developing new medicines. The decision was also taken to set the organization up as a non-profit company in the form of a foundation.
Research technician Josje Heuvelmans in a section of HUB’s treasure chamber, a biobank that currently has almost a thousand organoids stored at -80 °C in freezers provided by PHC Europe. Image Credit: PHC Europe B.V.
We saw an enormous amount of different applications. This is not so easy to accommodate in one for-profit company: investors often want focus, so either regenerative medicines or diagnostics, and often for a specific disease. And that’s exactly what we didn’t want. We also wanted to properly set up the platform and entrench it in the Netherlands through the structure with the KNAW patents. This meant that we had to be profitable from the beginning; first earn money and then spend it. That was a challenge because – certainly in 2013 – we had to earn that money with a very early version of the technology."
Robert Vries, CEO, HUB
Founded by the Hubrecht Institute and the UMC Utrecht, HUB began with two former post-docs at the Hubrecht: the current Scientific Director Sylvia Boj, who oversaw the lab activities, and Robert Vries, who focused on developing the business.
When HUB started, numerous technicians at the Hubrecht Institute were employed on specific projects.
In addition to the ~25 people working across numerous laboratories, HUB is also expanding its workforce. HUB now also employs regulatory specialists, lawyers, and business developers who keep the 40+ licensing agreements we hold with companies globally on the right track.
HUB (Hubrecht Organoid Technology) uses CO2 incubators by PHC Europe for cultivating organoids. Pictured is lab assistant Ramazan Senlice next to one of the currently seventeen incubators. Image Credit: PHC Europe B.V.
Organoids can be used across a myriad of applications, from patient-specific optimization of drug therapies (personalized medicine) to in-vitro preclinical models for screening the effectiveness of potential medicines.
All of these applications first require the development of good models. Just like animal models in preclinical research, the behavior of an organoid in a test also has to have a certain clinical relevance.
Cystic fibrosis (CF) is one of the first illnesses for which this has been comprehensively tackled. CF is a hereditary disease that results in serious damage, for example, to the digestive system and lungs. CF is the result of a defect in the CFTR gene in 70,000 to 100,000 CF patients worldwide.
This gene defect results in the excess production of organ secretions which become thick and sticky, meaning affected organs no longer function correctly.
‘A challenge in the treatment of CF lies in the diversity of the genetic defect. More than 2,000 different mutations have been identified in CF patients, with twelve mutations occurring in half of the population and the rest being distributed over the other half. Therefore, a medicine can be less effective for one patient than for another. While in the past you could only determine this experimentally, we can now predict the effectiveness. For this, we use a test developed at the UMCU/WKZ (Utrecht University Medical Centre / Wilhelmina Children’s Hospital) by Jeffrey Beekman, the in vitro FIS assay, with FIS standing for forskoloin-induced-swelling. An important investment we made for this is the design of a CF biobank with more than 400 organoid cultures of CF patients that represent more than 100 mutations. With this biobank, companies can predict the effectiveness of new substances on the entire population or specific mutations within this population. Various studies on other diseases show that this is an especially effective method. These studies show a correlation of over 80% between what happens in the patient and what happens in the organoid. If you create a new medicine based on these samples, the chance that you already know you’re heading in the right direction is a lot bigger than if you rely on classic preclinical testing. One of the reasons medicines are so expensive is because the majority doesn’t make it to the finish line: more than 90% fail. If you already know what is going to happen before you start with clinical trials, you can go through the process a lot more efficiently,’ explains Robert Vries.
The laboratories responsible for tissue cultivation are organizationally divided into three departments: screening, CF and other illnesses, and oncology.
A major obstacle in treating CF lies in the diversity of the genetic defect. Over 2,000 mutations have been identified in CF patients, with only twelve mutations occurring in half of the population whilst the rest are distributed over the other half.
The laboratories for tissue cultivation are organisationally divided across three departments: oncology, CF and other illnesses, and screening. Image Credit: PHC Europe B.V.
EUR 15,000 for an organoid
It requires around five months and EUR 15,000 to produce an adequate amount of organoid material for a biobank. Not only does this apply to organoids that can be used to conduct further experiments (and whereby you cultivate new cells from an original organoid in the ‘master cell’ bank for the ‘working cell’ banks that act as the source for experiments), but also to those organoids that are cultivated for patient studies.
The latter now represent the bulk of the biobank’s growth, with almost 1,000 different organoids. The expense associated with creating such organoids is relatively low when compared to the costs of the, in part, still experimental CF medicines.
When the advance in treatment efficacy is also taken into account (and therefore only prescribed medicines that work), then in addition to increasing in-patient benefit, these patient-specific organoids will even result in savings.
For the original organoid, things are not as bad as they appear. After all, that €15,000 is being invested in an organoid that can be utilized for years and can be applied to all sorts of research. As a result, there is potential to reduce costs to just a few euros per experiment.
Robert Vries is certain that these costs will reduce: ‘If we can scale up the production of organoids to the numbers we see in oncology, this technology will also become a lot more inexpensive.’
Robert Vries, CEO of HUB (Hubrecht Organoid Technology), predicts that his company will become increasingly busy with the ultimate breakthrough of
personalised medicine. Image Credit: PHC Europe B.V.
The next step in development is to predict which medicines work (best) when aided by an organoid cultivated from stem cells that are from the diseased tissue of a CF patient.
‘You might think that it’s just a small step from drug screening to organoid cultures, but in practice, there’s a lot more to it. When it comes to diagnostics for predicting what types of medicines patients need, there’s an entire protocol in place along with the associated technology. Academically speaking, there is a kind of proof-of-concept for this, but you do need to prove that the approach is actually suitable for clinical application. We therefore also need to conduct clinical trials for the organoids themselves, which is what we’re currently doing. We haven’t had any negative tests to date, so we’ve had a successful run!’
Patients have also learned about the potential of utilizing organoids. In their enthusiasm, however, patients tend to oversimplify things – something that Robert Vries can envisage, particularly in the case of serious illnesses which there are currently no medicines available for, such as CF.
‘Patients themselves call us to ask us to create an organoid of their bodily material and send it to a pharmaceutical company that is developing medicines for their illness so that the company can make these specifically for him or her. That’s not possible, of course, but it may happen in the future. And, in fact, it’s already happening for groups of patients with specific genetic defects. Eloxx Pharmaceuticals, for example, is developing a medicine against a stop codon – in part thanks to the use of organoids – which seems that it will also be effective for a certain form of CF. In this case, patients have literally said: I have that mutation, do something!’
Busy at the lab
The preliminary positive results for CF have meant interest in other disease profiles has quickly gathered – particularly in oncology.
‘While CF is a “clear” illness, with low incidence, things are a lot more complex and comprehensive for cancer. But, the medical need is also high in this field, which provides a great deal of motivation in our work. However, we are too small to tackle all illnesses. What’s more, we dedicate one-third of our time to the technological development of new scientific methods, which we optimize and scale-up for application in the pharmaceutical industry.’
The vigorous growth of HUB – which happened in parallel to the growth of the global market for 3D constructs (almost zero in 2013; now €700 million) – is also reflected in the laboratories. The laboratories are now spread over two adjacent buildings because of the lack of space.
The current plan is to relocate at the beginning of 2022 to a new building. However, until this occurs, the company will have to rent additional space. Organizationally, the laboratory work is currently split across three departments: screening, CF and other illnesses, and oncology.
Physically, these departments are well connected. For example, histology and molecular biology are both in one building, where an ML2 lab for virology and a quarantine lab can also be found.
Tissue cultivation is undertaken in the ‘main building,’ where the offices are also housed. In the ‘main building,’ there is a clear distinction between the various diseases in the current 17 CO2 incubators: (patient) cells that are associated with a specific illness are cultivated in each incubator.
The caution required when dividing equipment between each disease and/or department is also reflected in the selection process of the incubator supplier: PHC Europe, which also supplies numerous -80 °C freezers.
We simply need to have the right equipment. This certainly applies to the incubators, which are essential to our work. In addition to specific conditions regarding stability and notification (alarms), if an incubator experienced a failure or its temperature deviated slightly, it’s important for us to be able to find this information in the logged data. After all, these are valuable materials, often stemming from seriously ill patients. There’s no compromising in this regard."
Robert Vries, CEO, HUB
Regarding sample safety: “After all, these are valuable materials, often stemming from seriously ill patients. There’s no compromising in this regard”
Offering reliable capacity in incubation and ULT freezing Incubators are critical pieces of equipment at the HUB. The Unit has 17 CO2 Incubators.
The following models are used
- MCO-170AICUVH-PE – With a 165-liter capacity and weighing 80 kg, the MCO-170AICUVH-PE occupies 620 mm x 750 mm x 905 mm.
- MDF-DU700VH – The -80 °C ULT Freezer from PHC is a VIP ECO ULT Freezer (model name MDF-DU700VH-PE). This range of VIP ECO Freezers reduces cost and environmental impact by utilizing natural refrigerants and is designed for minimal energy consumption and has an optimal footprint.
Image Credit: PHC Europe B.V.
About PHC Europe B.V.
Founded in 1990 as subsidiary of the PHC Holdings Corporation, it is our mission to become a leading, trusted brand for sustainable healthcare and biomedical product solutions, which support the work of our customers to improve the health and well-being of people around the world.
For more than 25 years now, we respond to the needs of our pharmaceutical, biotechnology, hospital/clinical and industrial customers, offering an unique perspective on scientific research in general. As a result we play a critical role in product development for worldwide applications and have established a reputation as a manufacturer of high-quality and innovative medical and laboratory equipment.
Long lasting relationships have been built with leading pharmaceutical, healthcare and biotechnology companies as well as with major academic and research institutes in Europe. PHC Europe B.V. has set the standard in many aspects. V.I.P. panels, Cool Safe compressors, Active Background Contamination Control and the world’s first -152 °C ULT freezer. Where PHC Europe B.V. took the initiative, the others followed. This made us a very important player in both the ultra-low temperature and the CO2 market.
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