Venom-producing snake organoids developed in the lab

News article 22 Jan 2020
SnakeOrganoids: Credit Ravian Van Ineveld Copyright- Princess Maxima Center For Pediatric Oncology

Professor Nick Casewell from LSTM’s Centre for Snakebite Research and Interventions (CSRI) has been involved in a ground-breaking project that has developed a method to grow snake venom glands as organoids, or mini organs derived from stem cells. These lab-grown mini glands produce and secrete active toxins found in snake venom and hold much promise for improving our understanding of venom toxins and for use in helping to mitigate the devastating impact of snakebite.

The research was led by three PhD students working in the group of Professor Hans Clevers at the Hubrecht Institute, Utrecht, the Netherlands, and the results of their research have been published in the journal Cell.

Working with a team of international collaborators they found an effective method to develop and maintain venom gland organoids in order to study the impact and potential benefit of proteins contained within venom, and the findings could have far-reaching consequences for antivenom production as well as for the targeted development of new venom-based drugs.

Professor Casewell, an expert in the evolution of venom, said: “The model developed here is very exciting. It will enable us to better understand how venom is produced and regulated, while at the same time proving us with a unique resource for the study of toxins involved in causing life-threatening pathologies following snakebite.”

Jens Puschhof, Joep Beumer and Yorick Post were inspired by their colleagues’ success of growing mini mammal organs in the lab and wondered whether a similar process would work for reptilians too and began exploring this with venom glands. They set up a collaboration with snake experts in Leiden, Amsterdam and LSTM to collect venom glands from nine different snakes and attempted to grow miniature versions of these glands in a dish. Surprisingly, similar conditions to those used for human tissues worked, although the team had to tweak the temperature by lowering it to 32˚C, to support the indefinite growth of the glands.

Through a high-resolution microscope they observed that the cells of the organoids are filled with dense structures that resemble the venom containing vesicles of venom glands. Indeed, various analyses showed that the organoids produce the vast majority of venom components, or toxins, made by the snakes.

For the first time, Professor Casewell (with LSTM's Dr Stuart Ainsworth and Taline Kazandjian) and the team from the Hubrecht Institute were able to study the toxin production of individual cells in the venom gland and found that different groups of cells appear responsible for producing different venom toxins.

In addition, the researchers found that changing the factors in the growth medium of the organoids could change the composition of the venom, giving them control over the kind of venom that is produced. In a collaborative effort, they also showed that neurotoxins produced by the organoids are active and can block nerve firing in various cell systems, similar to the neurotoxins produced by the snakes themselves.

The success of growing reptilian organoids for the first time suggests that tissues from other vertebrate animals such as lizards or fish could also be grown in this way. Consequently, the Hubrecht team are currently setting up a large collection of 50 venom gland organoids, including from more snakes and other venomous animals, together with collaborators elsewhere in the Netherlands and Professor Casewell and the team at LSTM.

Yorick Post said: “It was amazing to see that what started with our curiosity about potential snake venom gland organoids transformed into a technology with many potential applications affecting human healthcare.”   

Snake Venom Gland Organoids

Yorick Post Jens Puschhof  Joep Beumer Harald M.Kerkkamp Merijn Bakker Julien Slagboom Buysde Barbanson Nienke R.Wevers Xandor M.Spijkers Thomas Olivier Taline D.Kazandjian Stuart Ainsworth Carmen Lopez Iglesias Willine J.van de Wetering  Maria C.Heinz Ravian L.van Ineveld Regina G.D.M.van Kleef Harry Begthel Jeroen Korving Yotam E.Bar-Ephraim Walter Getreuer Anne C.Rios  Remco H.S.Westerink Hugo J.G.Snippert Alexander van Oudenaarden Peter J.Peters Freek J.Vonk Jeroen Kool  Michael K.Richardson Nicholas R.Casewell Hans Clevers 

Cell Volume 180, Issue 2, 23 January 2020, Pages 233-247.e21