Interviewers: Lydia Morrison, Marketing Communications Writer & Podcast Host, New England Biolabs, Inc.
Interviewees: Professor Jim Haseloff, Ph.D., Department of Plant Science, University of Cambridge
Lydia Morrison:
Welcome to The Lessons from Lab and Life Podcast from New England Biolabs. I'm your host, Lydia Morrison and I hope this episode offers you some new perspective. Today we interview professor Jim Haseloff of the University of Cambridge. His work is primarily focused on using synthetic biology to engineer plant growth, but during the pandemic, he has focused his efforts on increasing global accessibility of low cost instrumentation and access to diagnostics.
Lydia Morrison:
Hi Jim, thanks so much for being here with us today.
Jim Haseloff:
Thanks Lydia. A pleasure.
Lydia Morrison:
I was wondering if you could tell us what you were doing before the pandemic. What was your work focused on?
Jim Haseloff:
My work is mainly focusing on engineering approaches in plant biology. We're very interested in using plants as a re program or platforms for re-probing growth and metabolism in that kind of context. And we've been recently developed a systems using very simple plants, which have advantages of speed and simplicity at many different levels and using them as a test bed for these kinds of engineering approaches. So a lot of our work is all focused on this interface between biology and engineering.
Lydia Morrison:
Where did the idea for that work come from?
Jim Haseloff:
Well, I mean, it's a long, long history here, gestation period with me. I've always been interested in plants and plant biology and also engineering. And I think the recent move towards these simple systems is partly dictated by the growth of tools that started around 15, almost 20 years ago now. And people really framing ideas around the ideas that are pioneered by Tom Knight of using formal engineering principles in biology. And once you start on that train of thought, you end up being increasingly interested in direct manipulation of plant systems and the use of tools that are both modular and reusable and form platforms that're taking them forward. And as part of that move towards developing standardized platforms, we've been very interested in capacity building and sharing technologies as well– Not just in an academic context here at the University of Cambridge, but also more internationally and trying to develop tools that will allow people to work in low resource contexts in Latin America and Africa. I have to try and redress the imbalance that we see at the moment between access to technologies in different countries.
Lydia Morrison:
Yeah, I think that work is really important in terms of equalizing the playing field of scientific advancement around the world. What sort of applications are there for the plant biology work that you do?
Jim Haseloff:
Well at the moment we're particularly interested in using them as platforms for buyer production. And if you think about existing forms of plant biotechnology in agriculture, plants have already proven themselves as the cheapest, lowest cost and highest producing platforms for making bio materials. I guess human societies across the planet use plant-based agriculture for creating all kinds of materials, food, pharmaceuticals, et cetera. And the domestication of plants and the use of them in this way goes back in many cases, 10 or 12,000 years ago where you saw the first domestication of these plants, and we've been using conventional breeding techniques to modify plants for our own use, for this length of time. But now there's all these new tools, tools which allow you not just select variants and mutations, but to generate by rational means directed changes in plant genomes and to effectively mold and create in a way that was really unparalleled in terms of history and interacting with plants.
Jim Haseloff:
So there's this huge opportunity to start doing effectively the things that we've been doing for 10,000 years as a human culture, but to do things in a way that's much more directed towards creating modified plants that are better suited, especially for sustainable practices, better suited for environments, less damaging, at replacing a lot of the chemical and energy inputs that we take for granted in modern agriculture and to create a more natural sustainable systems by direct engineering.
Lydia Morrison:
Yeah, it seems a lot more precise than traditional methods. Could you tell me about the OpenPlant Synthetic Biology Research Center and how that's working to support sustainable agriculture?
Jim Haseloff:
Well, agriculture at the moment is dominated by the last 100 years of technology, where modern agriculture is a quite intensive set of practices. It's dominated by inputs of chemicals, fertilizers, pesticides, and herbicides, and intensive farming practices. And a lot of that technology is where the innovation and regulation and availability of those resources is dictated by relatively few companies. And you have this quite concentrated ownership of a lot of the main agricultural technologies, which dominate modern agriculture. And we think that with these new synthetic biology approaches, the ability to modify crops and to develop new, more sustainable agricultural systems is becoming democratized, being driven by disruptive technologies. And one can draw analogies with the micro computing industry or with mobile devices, with the development of app and the handheld devices et cetera, where you see this disruptive proliferation of lower and lower costs, more available local solutions.
Jim Haseloff:
And we think that in agriculture, the same thing's happening as we moved towards simpler ways and faster ways of being able to modify crop systems. So OpenPlant is really designed to try and promote the standardization of these basic tools that are driving these changes, these disruptive changes and also to focus on making them more accessible. In other words, developing lower cost technologies, distributing materials, developing methods for legal frameworks for sharing material, like the open materials transfer agreement that we were in a collaborative effort of being developing. I think it's these kind of facilitating sharing and developing tools for capacity building outside the traditional areas of strength in agriculture.
Lydia Morrison:
Are there specific countries that you're working with to help bring new technologies to their scientists?
Jim Haseloff:
Yeah. There's quite a number of different sets of interactions in our countries across Africa and Latin America, very good colleagues in these countries. There's quite a wide variety of different activities. They range from things like simple sharing of DNA elements and standards for building DNAs as assembly techniques, through to training and teaching activities where we're producing and sharing materials that will be useful for educational purposes. Through to joint grants, looking at low cost technologies for diagnosis and the likes. So it's quite a wide range of activities. So OpenPlant covers itself about 20 different laboratories across Cambridge and Norwich in the UK and quite a wide variety of interactions across the planet with other partners.
Lydia Morrison:
Well, that's wonderful to hear. I'm glad that there's such a large acceptance of the program within the UK and that you're finding so many global partners, because I think it's really important work that you're doing to help democratize sustainable agriculture and really help feed the world.
Jim Haseloff:
Yeah, I'm not sure we're feeding the world yet, but we have aims and hopes.
Lydia Morrison:
Sometime in the near future, though.
Jim Haseloff:
Yeah. I think we are certainly working at more of the high technology end of it. And where you're seeing the arrival of new technologies like gene editing and also basic understanding of, I should say system-wide understanding, of plants systems. And there's this quite interesting dynamic between tools that allow you to make precise changes. Particularly with the new CRISPR Cas9 type technologies. That is exploding as a set of tools. But then that also relies on more traditional areas of basic knowledge. Not just about the components that build up plants, but the systems that underpin the activity in plants, the activities of growth and metabolism, et cetera. So the combination of those two, having an understanding of the genetic principles, that in a system-wide fashion make plants what they are, together with these new tools that allow you to get in and intervene at the DNA level are a very powerful combination potentially. And I think that's our particular interest in trying to make those tools more accessible.
Lydia Morrison:
Absolutely. Yeah. I think it's really interesting. Scientific areas of study used to be so siloed and we've really seen amazing technological advances when we can apply different sciences and different ways of thinking to old scientific problems.
Jim Haseloff:
I think I certainly agree with that. And I think in Cambridge, for example, there's always been a long tradition of innovation in Cambridge. And part of that is due to the very distributed and non-hierarchical nature of the way the university is structured, which really facilitates interdisciplinary interactions and a lot of the... You might say the cool stuff, comes out of that boundaries between disciplines and the way you can establish unusual connections between new technologies. And that's certainly in this position of trying to build links or explore the interface between biology and engineering and computer science. That's kind of where we are. And it's certainly fun, but there's a lot of quite interesting innovation and novelty that lives in that interface.
Lydia Morrison:
Yeah, absolutely. And so much yet to be explored, too.
Jim Haseloff:
Yeah.
Lydia Morrison:
So we've all undergone a lot of changes in our daily habits over the past year. And many scientists were out of the lab for months or maybe longer. How has your work changed during the pandemic?
Jim Haseloff:
Well, I think it's actually been an opportunity in some ways. The move from the lab, initially the lockdown was quite fierce. Everyone was thrown out of the labs, apart from key workers. And then we had a Return to Work, which was still episodic and reduced capacity. And those setbacks, I guess, to normal work were actually an opportunity to take slightly different approaches to the problems that we were interested in. So there was certainly more time to think, to read and to do. And personally I found it a great opportunity to get into the things that one always wanted to do, but never had time to do. And in my case, that's been things like learning more advanced 3D printing, having a chance to more practically apply electronics and other aspects. And given that that was a particular interest of ours, before the pandemic struck, the idea that one could use commodity tools, electronics, optics, 3D printing, et cetera, to build low cost instrumentation.
Jim Haseloff:
And as part of our activities, we've been looking at how you can develop these tools which are much more accessible for biologists. Biologists tend not to be programmers. And they think in a much more concrete, graphical way. So trying to find tools that are more suited and easier for biologists to grapple with, rather than take a whole course required to learn text-based computing to develop No Code approaches so people can build and focus on that side of the process, the creation side of it. And that's been a really useful thing. So we've, at the same time, developed a lot of resources for remote learning. Before the pandemic we were doing in-person workshops, across Latin America and Africa.
Jim Haseloff:
And the opportunity to stop has meant that we've been able to focus or forced to focus on remote learning tools. So tutorial systems, manuals for learning, video tutorials, et cetera. And resources that are to go with those. And so it's actually been quite productive and challenging in that way.
Lydia Morrison:
Absolutely. And certainly those remote learning tools aren't going to go out of style anytime soon. I think with the new interconnectivity of everybody over the internet, that has really been forced upon us in the last couple of months, there's no going back from here. So I'm sure that those efforts will be appreciated far into the future.
Jim Haseloff:
Yeah. I guess we've all been converted into what we thought the future would be with telepresence and everything.
Lydia Morrison:
Right. The future has been forced upon us.
Jim Haseloff:
Yeah. We're still waiting for the hover cars though.
Lydia Morrison:
So what sort of instruments have you developed?
Jim Haseloff:
Well, we run a project or a program of projects, where we fund interested students and postdocs to propose projects and then for them to do them. And that's gone ahead. We have this Biomaker program, which includes some local funding for small scale projects. Which gives people experience in project management and also allows them to pursue particular interests that they might have. And these are all documented on the biomaker.org site. And you'll see that there's quite a wide variety of crazy ideas and interesting ideas. I think they often go together. Personally, more focused around the lab, we've been really interested in diagnostics, which has a double-edged sword really. Some of the requirements for diagnostics are things like constant temperature reactors, ways of measuring either gene expression or some kind of visual assay, quantification of materials. All those things are extremely useful in the plant DNA assembly and plant monitoring side of things as well.
Jim Haseloff:
So there's this common interest in developing new instruments. Using these really low threshold tools like No Code programming and the like. And there's an open source programming environment that we love and we've adopted called XOD, X-O-D which is an open source project, which embraces the data flow principles for programming. And it means that you can string together graphical nodes, which encompass the properties of particular pieces of hardware and essentially just wire them up. So you can have teams of people who are, you say proper programmers, who can create these nodes, or there's a very large pool of these publicly accessible nodes.
Jim Haseloff:
And you string them together on your laptop in a graphical fashion, simply wiring them together. And they work with low cost commodity electronics, like Arduino based systems. So the debugging and the feedback is really very simple. So you construct your graphical program, press the go button and it downloads into the hardware and it either works or it doesn't work and you get some feedback on screen and then you can very easily modify and prototype.
Jim Haseloff:
For those who are either afraid of, or don't have the requisite text-based programming skills, it's extremely easy to pick up. And in fact, there's many analogies with the way biologists would put together a DNA circuit. Which tends to be less about texts and more about graphics and representing interactions in a graphical way. So it's actually sits extremely well with the way many biologists already think. And it provides a set of learning tools that are quite widely applicable.
Jim Haseloff:
So we seem to have something of a snowballing community of people who are picking up these new tools and finding their work and then extending or expanding their experience with them. And we have these various project-based systems to explore that. And the types of instruments that are being made, a very wide variety, really just limited by the kind of sensors and devices that are available commercially and they're extremely broad. So that's quite a wide variety of things.
Lydia Morrison:
Yeah, that's really interesting. And I love that you're putting the designing capability in the hands of young students and graduate students to be able to devise these new instruments themselves. What sort of diagnostics are you designing these instruments to read?
Jim Haseloff:
Well, there's a number of different assay systems, LAMP reactions, that is that... They are extremely important as low-cost indicators. There are a number of CRISPR based tools as well, rolling circle type amplification system, isothermal amplification systems, that are all of interest. And the common theme between them all is that they usually require some kind of either isothermal or cycling temperature control, which needs to be accurate and that they usually require, or would benefit from, some kind of monitoring of the progress and the reaction. And so each of those are quite well suited to this kind of low cost hardware instrumentation.
Jim Haseloff:
And I think in particular where there are simple, low cost diagnostics, like the LAMP reaction, where NEB has played a really prominent role in popularizing and debugging those reactions. One of the bottlenecks to match the low cost of the reactions would be the availability of some kind of isothermal devices that would be useful for running those reactions.
Jim Haseloff:
And so that's the particular sweet spot that we were looking at. If you go back a few years and think about the early PCR machines, a number of those early PCR machines didn't involve metal blocks where you mounted the tubes in and hot beds, et cetera. They're actually a secondary development. Some of the early versions of PCR machines involved heated air and cool air blowing across the tube surface. And there's the first version of Roche lightcycler. And there's also an Australian device, the Rotor-Gene, which I think is owned by QIAGEN now, involved these kinds of air driven processes.
Jim Haseloff:
And they were relatively expensive, sophisticated machines but the principle is still there. So my particular project has been to use the kind of heaters that you find in car vents, they are low cost, 12 volt heaters, but have a reasonable capacity, and they're very cheap because them commodity devices and use those with blower fans, which allow you to direct the heat through a sealed vessel.
Jim Haseloff:
And there are a number of different materials on the 3D printing market that allow you to create custom devices with channels and manifolds for directing the flow of air inside simple closed loops. And you can design air flows in order to heat up tubes very efficiently. And that is quite cheap. So there's effectively a fan, a heater and some electronics to control it with an accurate temperature regulator and the tubes just sit in the manifold in the middle of that. And that's what we've been building and that's working quite well. You can get very tight temperature control, certainly less than half a degree variation, and it's feasible to make these at very low cost.
Lydia Morrison:
That's really interesting. And so what is the readout look like on a device like that? Or are you then reading out the assay in a different manner?
Jim Haseloff:
Well, the moment we're sticking with simplicity. So we're using the colorimetric LAMP assay developed at NEB I think mainly. And using that as a readout for the terminal portion of the reaction. It's a simple color change. But we've also got experiments underway. Looking at fiber optic devices to read out directly from tubes inside these reactors. And that's quite interesting because it also means that you can think about using that for real time PCR. And we have versions of these devices that are already potentially suitable for PCR by simply changing the venting.
Jim Haseloff:
So rather than having a closed loop of heated air, having a vented system and these electronics it makes it quite easy to control a motor like a servo. So you have vents, so you have hot air and cool air alternating. So you can develop the kind of thermal cycling that you need for PCR type devices. And inside these, one can use fiber optics to read out directly from the tubes. So it's sort of a stepwise process and the bottom rungs, if you like, we've climbed. And so we're now looking at how we can take this forward, and once you've got something in place, it makes it much easier of course, to then progress.
Lydia Morrison:
Yeah, of course. And I think that's really interesting that you were able to design a system to support really accurate temperature maintenance for a simple assay, like the loop mediated isothermal assay because that is certainly a great one. Especially with the colorimetric readout, that basically allows a visual detection of positive and negative results. That's wonderful to see. Hopefully, the 3D printing of that and the commodity components that go into it will make this an easy point of care assay for remote doctor's offices or even remote laboratories to continue monitoring both COVID and other viral diseases.
Jim Haseloff:
You know one of the nice things about the lockdown has been the gathering together of similar minded folk. So we were having last year, weekly meetings with a group who're exploring quite radically distinct solutions. And I think the sharing of ideas has been extremely helpful and useful, certainly to me. And I think we'll see lots of different solutions appearing, which in different contexts might have different benefits and pitfalls. But this mixing of ideas, the sharing of ideas. And so there's a number of these projects looking at the integration of circuit board technology, looking at 3D printing of metal holders. A whole range of these different approaches that have been coming together. And it's quite an interesting time. And I think, as you said before, some of the habits that we picked up over the last year, I certainly hope to stick with this level of communication and sharing.
Lydia Morrison:
I hope so too. And I think you really hit on one of the benefits– If there are to be any of the pandemic–it has really made a global community of scientists, I think, and brought the science community closer together and into a space where people feel comfortable more freely sharing ideas and working with collaborators around the world. Thanks so much for joining me today, Jim, it's been a really interesting conversation.
Jim Haseloff:
Thank you, Lydia.
Lydia Morrison:
Thanks for joining us for this episode of The Lessons from Lab and Life Podcast. Join us next time when we interview professor Karmella Haynes of Emory University. Her work focuses on using chromatin based systems to control gene expression and how these methods can be used to improve the accessibility of DNA during CRISPR/cas directed gene editing.
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