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Synthetic Cells: Building Life to Understand It

Part 1: Synthetic Cells: Building Life to Understand It

00:00:12:26 You all can see the
00:00:14:06 incredible diversity of life around us.
00:00:17:11 And we all know that there's so many different forms
00:00:19:20 of living organisms.
00:00:22:20 Looking at it, it's hard to believe that
00:00:25:02 from the scientific point of view,
00:00:27:02 there is really only one life form on earth.
00:00:31:16 One life form, which means one type of biology.
00:00:35:22 So the biochemistry of living processes
00:00:38:04 is the same in all known life.
00:00:41:00 The blueprint for all cells is the same.
00:00:45:01 And looking at the molecular level,
00:00:46:28 all cells of every organism we ever know living on earth,
00:00:50:21 will have the same strategy
00:00:52:07 for storing genetic information,
00:00:54:21 and for growing and for making proteins and metabolism.
00:00:58:25 We don't fully understand how
00:01:00:10 even that one type of cells really works,
00:01:02:25 because cells are so complex.
00:01:05:02 They're crowded with proteins, with nucleic acids
00:01:08:00 and with small molecules.
00:01:10:02 And millions of people years have been spent
00:01:12:26 studying biochemistry.
00:01:14:25 Yet we still don't have a complete map
00:01:17:10 of even a single type of live cell.
00:01:20:26 So if you had something so complex,
00:01:23:17 how would you go about understanding it?
00:01:26:11 Well one way of doing it is to make it simpler.
00:01:30:20 And that's the whole point of the field
00:01:32:01 of synthetic cell engineering.
00:01:34:29 We want to build a simplest living cell from scratch.
00:01:38:19 The guiding principle of our field,
00:01:40:11 is a quote from a brilliant physicist.
00:01:43:02 A guy who understood the importance of a hands-on approach
00:01:46:02 to solving problems and paraphrasing him,
00:01:48:17 "Make it yourself so you know how it's made."
00:01:52:27 Synthetic cells are
00:01:54:26 bringing the principles of engineering into biology.
00:01:58:09 We can make cells with full control of
00:02:00:07 all of its parts,
00:02:01:19 just like engineering mechanical devices.
00:02:04:26 And so in many ways we can think of a synthetic cell
00:02:08:02 as a biological breadboard or prototyping board,
00:02:13:01 which is a platform to test different designs,
00:02:15:21 and to engineer biological systems
00:02:17:28 as if they're mechanical or electrical.
00:02:22:11 How do we build a synthetic cell?
00:02:26:22 The anatomy of most synthetic cells is fundamentally
00:02:29:20 not that different from all non-living cells.
00:02:33:16 They're lipid containers, expressing genes into proteins.
00:02:38:16 The cell is surrounded by a lipid membrane,
00:02:42:13 and most of the time that membrane is made
00:02:44:14 of some kind of a lipid known from natural cells.
00:02:48:00 The phospholipids and cholesterol.
00:02:51:04 Lipids have a polar hydrophilic head group,
00:02:54:26 and non-polar hydrophobic tails.
00:02:58:20 And despite its bad reputation, cholesterol is actually
00:03:02:03 good for membranes because it makes them flexible.
00:03:07:03 The membrane often has channels,
00:03:09:27 which are proteins that allow
00:03:11:14 transport of nutrients and signals from the outside,
00:03:15:05 and the removal of waste products
00:03:17:07 from the inside of the cell.
00:03:20:22 In synthetic cells we usually use simple channels
00:03:23:12 that create rather non-specific holes in the membrane.
00:03:27:26 One of the most common channels is called alpha-hemolysin,
00:03:31:22 which is originally a bacterial toxin.
00:03:36:02 Since the main point of having a membrane
00:03:38:01 is to separate self from the environment,
00:03:41:06 the inside of the synthetic cell from the outside,
00:03:44:28 a synthetic cell can also be made in a droplet.
00:03:48:01 A drop of water, surrounded by oil phase.
00:03:52:11 And millions of droplets can be made at the same time
00:03:55:03 in a so-called droplet microfluidic system.
00:03:59:04 In a droplet, you can't use membrane channels,
00:04:01:21 since there's no membrane.
00:04:03:22 But for other applications the microfluidic systems are
00:04:07:08 widely used to make a lot of,
00:04:09:08 lots of different types of synthetic cells.
00:04:13:04 And regardless of how it's done,
00:04:14:21 the compartment is a relatively simple problem.
00:04:17:28 The really interesting stuff is what's going on
00:04:19:29 inside the synthetic cell.
00:04:21:25 The genes, the protein expression and the metabolism.
00:04:26:25 Just like natural life,
00:04:29:03 synthetic cells express proteins from DNA genomes.
00:04:32:18 Those genomes are usually relatively simple,
00:04:35:04 up to a dozen genes at a time.
00:04:38:27 To look at the scale of engineering we're talking about,
00:04:41:28 we can compare genome sizes of natural and artificial cells.
00:04:45:27 So humans have about 20,000 genes.
00:04:48:23 Bacteria about an order of magnitude less.
00:04:52:10 First live organism
00:04:54:00 with a completely synthetic genome has 474 genes.
00:04:58:18 And our non-living synthetic minimal cell,
00:05:01:18 it usually has about a dozen genes.
00:05:04:04 So as you can see, there's a lot of room for engineering,
00:05:07:15 larger synthetic cell genomes,
00:05:09:14 and also a lot of technical progress
00:05:11:17 we need to make to get there.
00:05:14:27 To make a complete cell, complete live cell,
00:05:18:22 the genes need to be expressed into proteins.
00:05:22:09 In synthetic cells, protein expression is done by
00:05:24:29 in vitro translation system.
00:05:27:22 Actually most of proteins and small molecules
00:05:30:00 in a synthetic cell are employed in translation processes,
00:05:33:18 not unlike what happens in live cells.
00:05:36:28 The in vitro translation system contains
00:05:39:18 ribosomes, tRNA, RNA polymerases to make mRNA,
00:05:44:06 enzymes to load amino acids into tRNA,
00:05:47:09 and small molecules needed for translation.
00:05:50:10 All of those components are purified,
00:05:52:09 and then recombined to encapsulate inside a synthetic cell,
00:05:56:01 creating a synthetic cytoplasm.
00:05:59:20 The most commonly used in vitro translation system,
00:06:02:16 is made from component purified from bacteria.
00:06:05:22 It's possible to use many different source organisms though,
00:06:09:10 all the way up to a human cell,
00:06:11:08 derived protein expression systems.
00:06:14:05 The bacterial system is used because
00:06:16:09 it's the fastest and cheapest one to work with.
00:06:19:05 Other organisms are used when we need
00:06:21:04 to express more complex genes,
00:06:23:13 or do some post-translational modifications to proteins.
00:06:27:05 And this is one of the main reasons
00:06:28:16 why synthetic cells can be thought of as jigsaw puzzles,
00:06:31:27 because the protein expression and metabolism
00:06:34:10 can come from any number of different organisms.
00:06:37:04 It builds a hybrid cell that combines properties
00:06:40:16 of different kinds of metabolism.
00:06:44:09 The complete synthetic cell,
00:06:46:04 a membrane surrounding protein expression system
00:06:48:25 is not alive.
00:06:50:21 It performs some but not all functions of live cells.
00:06:54:23 It's currently a very fast growing area of research.
00:06:58:18 Although we don't yet have a hard definition
00:07:00:18 of what makes a cell alive,
00:07:02:21 by working with synthetic cells we can begin to learn
00:07:05:10 what confers the properties of live cells,
00:07:07:26 such as the ability to replicate or grow.
00:07:12:05 How can we use synthetic cells?
00:07:16:10 Synthetic cells can have many applications in research,
00:07:19:25 and many practical applications relevant to everyday life.
00:07:24:05 For one, understanding natural cells is necessary
00:07:27:19 for building synthetic cells,
00:07:29:20 and it works the other way around too.
00:07:32:10 If we build an understandable synthetic live cell,
00:07:35:22 we'll learn a ton about natural life.
00:07:38:26 Similarly making cells from scratch requires
00:07:41:27 a lot of progress in research technologies.
00:07:44:21 Building new bio engineering tools,
00:07:46:27 while having synthetic living systems,
00:07:49:09 will be a tool in and of itself for biology.
00:07:54:01 Some other specific applications of synthetic cells
00:07:57:13 are making new bio-materials not found in nature,
00:08:01:16 building bio computers that run on
00:08:03:11 artificial genetic circuits.
00:08:05:24 Using synthetic cells to reconstitute primordial cells
00:08:09:05 and studying the origin of life.
00:08:11:24 Synthetic cells are basics for astropharmacy applications,
00:08:15:18 and help with search for life elsewhere in the solar system.
00:08:19:08 And synthetic cells are excellent bio factories,
00:08:21:29 for making small molecules and protein products,
00:08:24:11 and for developing new metabolic engineering circuits.
00:08:28:05 Also the ability to engineer cells and cell-like systems,
00:08:32:05 is very valuable for studying diseases,
00:08:34:22 and for making small amounts of drugs,
00:08:37:00 which will be foundation of future personalized medicine.
00:08:42:00 In the second part of this talk,
00:08:43:18 I'll cover different ways to make synthetic cells,
00:08:46:26 applications of this technology,
00:08:49:00 and the international community
00:08:50:21 working on synthetic cell engineering.
00:08:53:17 (upbeat music)

Part 2: Synthetic Cells: Approach and Applications

00:00:06:07 (light electronic music)
00:00:13:22 In the first part of the series,
00:00:16:00 I introduced synthetic minimal cells,
00:00:18:17 which are non-living biochemical|reactors that have some,
00:00:22:13 but not all functions of life cells.
00:00:26:06 Another type of synthetic|cells was also built,
00:00:29:07 and that one actually is alive.
00:00:31:27 The Craig Venter Institute|synthetic bacteria,
00:00:34:14 known as JCVI Syn cells.
00:00:37:07 They're cells derived from a natural,
00:00:39:06 living bacteria: a mycoplasma.
00:00:42:07 The bacteria have one of the smallest
00:00:44:10 possible living genomes.
00:00:46:02 And that genome was minimized|to remove everything
00:00:48:18 that was not absolutely crucial|for survival of the bug.
00:00:53:00 This smallest cell is still living,
00:00:55:22 but we don't know the|entire list of proteins
00:00:57:26 and molecules that make that cell.
00:01:00:12 So while synthetic, the JCVI Syn cells
00:01:03:02 are not yet fully understood.
00:01:07:13 On the other hand,
00:01:08:27 the non-living synthetic minimal cells
00:01:11:03 are made from a list of very|well-defined components.
00:01:14:14 Those still-dead synthetic cells
00:01:17:04 are not yet capable of independent life,
00:01:19:26 but we can understand them like|no other biological system,
00:01:23:21 and we can engineer it as needed.
00:01:27:14 These are the two fundamentally|different approaches
00:01:29:23 to building synthetic cells:
00:01:31:28 the top-down approach|of taking living cells,
00:01:35:08 and making them simpler to the point
00:01:37:04 when we can actually understand the cell,
00:01:39:21 and the bottom-up|approach of taking known,
00:01:42:07 well-defined, non-living components,
00:01:44:21 and putting them together|into a more complex system
00:01:47:26 that will eventually become alive.
00:01:51:29 Neither of those approaches produced
00:01:53:26 a fully controllable living cell yet.
00:01:57:03 Top-down synthetic cell is alive,
00:02:00:00 but not fully understood.
00:02:02:07 And bottom-up synthetic|cell is completely known,
00:02:05:08 but not yet alive.
00:02:07:12 And so the goal of|synthetic cell engineering
00:02:09:16 is to have those two|approaches meet in the middle.
00:02:12:13 Make a living, but fully understood cell.
00:02:19:07 (light music)
00:02:21:10 Some advantages of using synthetic cells
00:02:24:01 are that it's safer and cheaper|to work with that system
00:02:28:19 than with natural cells.
00:02:31:03 Because synthetic cells are made
00:02:32:12 of biochemical components and not alive,
00:02:35:25 you don't need to treat them
00:02:36:26 as genetically modified organisms,
00:02:38:24 so bio-safety rules are much less strict.
00:02:42:08 Experiments also take much less time,
00:02:44:12 because you can iterate the design faster,
00:02:47:07 and those cells are engineered and built
00:02:49:11 so you don't have to wait|for a culture to grow.
00:02:52:16 And experiments are also cheaper,
00:02:54:16 which comes from the|faster turnaround time
00:02:56:24 and the less bio-safety constraints.
00:03:00:29 A lot of biology research
00:03:02:18 suffers from low reproducibility
00:03:04:20 and from difficulty|distinguishing signal from noise.
00:03:08:18 And this is mostly because|no two natural cells
00:03:10:23 are ever alike.
00:03:12:20 Even genetically identical|cells will end up being
00:03:15:18 just a little bit|different from each other,
00:03:17:22 with changes that they|accumulate during lifetime.
00:03:21:03 So when you're measuring any|signal from natural cells,
00:03:24:10 you always get a lot of noise.
00:03:27:11 But all synthetic cells
00:03:29:07 that are created together|will be identical.
00:03:33:03 So any measurement done|on a synthetic cell
00:03:35:19 is much more precise.
00:03:37:23 And that's why when we want to measure
00:03:39:17 a changing in experiment,
00:03:41:19 it's easier to identify|the signal we're looking at
00:03:44:24 in a simpler synthetic-cell system.
00:03:48:10 Another good thing about the|fact that synthetic cells
00:03:50:24 can be made according to a precise recipe
00:03:53:16 is that if you have a|recipe, you can digitize it.
00:03:57:01 And no complex life cell can|be so completely described,
00:04:00:19 because we don't know the composition
00:04:02:11 of any other biological system
00:04:04:04 as well as we know what|goes into a synthetic cell.
00:04:08:00 And digital information can be|sent across large distances.
00:04:11:26 So it's possible to send|information about making
00:04:14:12 a particular synthetic|cell to a remote location,
00:04:17:08 for example, for making|drugs on demand or vaccines.
00:04:21:14 And if you can send something|across a large distance,
00:04:24:26 you can also imagine sending information
00:04:27:08 to really remote locations,
00:04:28:28 like a spaceship or a Mars colony,
00:04:30:28 to make urgently needed|drugs or a biological test.
00:04:35:21 The so-called astro pharmacy|is not the only area
00:04:38:13 of applications of synthetic|cells for space exploration.
00:04:42:13 And with synthetic cells, we can make
00:04:43:29 simplest possible lifelike models,
00:04:46:19 and we can study the conditions necessary
00:04:48:26 for the origin of life,
00:04:50:21 both on earth and elsewhere|in the solar system.
00:04:54:09 We can also use synthetic cells
00:04:55:25 to explore how else can life look like,
00:04:58:19 and figure out conditions that are needed
00:05:00:13 for life to evolve,
00:05:02:00 and this would help us|finding life on other planets.
00:05:06:21 The ability to make custom synthetic cells
00:05:09:21 producing a specific|small molecule or protein
00:05:12:28 can also be used for making drugs.
00:05:15:19 So right now, to make a|biologically-produced drug
00:05:19:08 like a protein or complex natural product,
00:05:22:02 life cells are set up|in large bioreactors,
00:05:25:03 most often bacteria or|yeast making that drug.
00:05:28:14 It takes a lot of work to engineer
00:05:30:16 a strain of life cells|producing certain molecules.
00:05:33:29 And that's mostly because|life cells are so complex
00:05:37:02 that it makes it hard to|insert a new metabolic pathway
00:05:39:28 into that cell,
00:05:41:02 and then to take the product out
00:05:42:22 of a natural cell and purify it.
00:05:45:03 So, drugs are made in those big batches
00:05:47:20 for large populations of patients.
00:05:51:08 With synthetic cells being so simple,
00:05:53:16 and much easier to engineer
00:05:55:04 for production of specific molecule,
00:05:57:13 it might become possible to|make custom drugs on demand:
00:06:00:17 in small doses for small|populations of patients,
00:06:04:04 or even for one person.
00:06:06:10 This makes it possible to imagine
00:06:07:22 a personalized medicine|approach to treating infections,
00:06:11:11 or cancers, or metabolic syndromes,
00:06:13:29 or for example, for making|personalized vaccines on demand.
00:06:23:25 Building synthetic life cells
00:06:26:05 is definitely a bigger job|than one country can support.
00:06:29:25 And in many ways, our work is not unlike
00:06:32:10 the high-energy particle physics field,
00:06:34:28 with their need for giant|particle accelerators,
00:06:37:22 or the need for international|support of a space station.
00:06:41:23 Making life from scratch is this giant
00:06:44:04 research and engineering challenge,
00:06:46:05 uniting the international community,
00:06:48:14 and we're organized in a|Build-A-Cell initiative.
00:06:51:25 Build-A-Cell supports|a group of researchers,
00:06:54:10 ethicists, and policymakers,
00:06:56:21 exploring the ways to build|and safely use synthetic cells.
00:07:01:20 At the backbone of our community|is in-person interactions.
00:07:05:16 We're meeting twice a year|at Build-A-Cell workshops,
00:07:08:01 and we have weekly|international virtual seminars
00:07:11:11 with recordings available online.
00:07:13:23 We have year-round working groups,
00:07:15:14 preparing policy guidelines|and shared protocols,
00:07:18:13 and we're training students
00:07:20:01 and growing connections with other fields
00:07:22:13 to make some of those|applications I was talking about,
00:07:25:09 distributed to the broader|scientific community.
00:07:28:29 We also talk to the public about|engineering synthetic life.
00:07:33:29 So the ultimate goal of our community
00:07:37:01 is to build a synthetic living organism.
00:07:40:12 And we have to do that collaborating
00:07:42:01 across geographical and|institutional boundaries.
00:07:45:25 We really want people from|different universities
00:07:48:09 in different countries to work together,
00:07:50:19 contributing to solving this|biggest puzzle of biology.
00:07:54:11 And we want building|international distributed network
00:07:57:15 of laboratories engineering|living organisms.
00:08:02:03 The end result will be|a fully understandable
00:08:04:28 synthetic life cell,
00:08:06:19 and the existence of a united|international community.
00:08:09:25 Training researchers in-field,
00:08:12:06 operating across geographical boundaries,
00:08:14:18 will help us build a new model|of scientific collaboration.
00:08:18:22 In the last few centuries,
00:08:20:10 we went from engineering in|steel to engineering electrons,
00:08:24:10 and biological engineering|is just now catching up.
00:08:27:20 Building synthetic cells, we're right now
00:08:30:13 moving on to the next step|of using biological parts
00:08:34:01 to engineer new types of life.
00:08:36:25 Our synthetic cell community|is always open for feedback,
00:08:40:01 and always willing to talk to people.
00:08:42:12 And we can talk to|people from other fields.
00:08:44:08 Anyone really who wants to learn
00:08:45:26 about building life from scratch.
00:08:48:15 (light music)

Videos in this Talk
  • Part 1: Synthetic Cells: Building Life to Understand It
    Part 1: Synthetic Cells: Building Life to Understand It
    Audience:
    • General Public
    • Student
    • Researcher
    • Educators
    • Educators of H. School / Intro Undergrad
    • Educators of Adv. Undergrad / Grad
  • Part 2: Synthetic Cells: Approach and Applications
    Part 2: Synthetic Cells: Approach and Applications
    Audience:
    • General Public
    • Student
    • Researcher
    • Educators
    • Educators of H. School / Intro Undergrad
    • Educators of Adv. Undergrad / Grad
Speaker: Kate Adamala
Total Duration: 0:18:15
Recorded: July 2020
All Talks in Bioengineering

Talk Overview

Life on Earth evolved once – this means that all biological systems on our planet are rooted in the same fundamental framework. This framework is extremely complex and we have yet to fully understand the processes inside each living cell. One way of understanding complex systems is to break them down into simpler parts. This is the principle of engineering the synthetic cell: to use our current knowledge of biology for building a living cell with the least amount of parts and complexity. Synthetic cells can be used to teach us about the basic principles of life and evolution, and they hold promise for a range of applications including biomaterials and drug development. Dr. Kate Adamala narrates a 2-part introduction to this exciting field.

Speaker Bio

Kate Adamala

Kate Adamala

Dr. Kate Adamala is a synthetic biologist and a McKnight Land-Grant Assistant Professor in the Department of Genetics, Cell Biology and Development at the University of Minnesota. Her research interests include astrobiology, synthetic cell engineering and biocomputing. Adamala is a co-founder and steering group member of the international Build-a-Cell Initiative, which seeks to broaden the… Continue Reading

Playlist: Famous Discoveries

Related Resources

https://www.buildacell.org/101
https://www.statnews.com/2017/07/28/cell-build-from-scratch/
https://www.nature.com/articles/d41586-018-07289-x
https://www.frontiersin.org/articles/10.3389/fbioe.2020.00927/full

Credits

Brittany Anderton (iBiology): Producer
Eric Kornblum (iBiology): Videographer and Editor
Kate Adamala (UMN): Graphics and Narration

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