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19 Jan

Nikolai’s advice for Entrepreneurs

Nikolais advice for entrepreneurs

I was asked for 7 points of advice for entrepreneurs by Startup Basecamp for their blog. In my time as an entrepreneur, I have read a lot of other startup advice that is very specific, or for advanced stages of business and glosses over the fundamentals. Fundamentals are everything. You win based on fundamentals, not on flea flickers and fumblerooskis.

Keira and I started up our consumer biotechnology company RevBio in 2013, and each of us has had a lot to learn in our transition from science/military/academia/normal life to being business people. But we have done it, and when reflecting on the key points to remember for success, it’s basically that list.

The 8th point that didn’t make the cut is to always make time for grapefruit cocktails.

That’s pretty important too.

Cheers!

-Nikolai

14 Jan

How to make a dragon – a step by step bioengineering guide

Revolution Bio is at the top of the search results for the terms ‘crazy bioengineering dragon idea.’ While we are making color-changing flowers, not dragons, I’m pretty excited that people looking for incredible advances in biotechnology find us on the front page. So I’m going to take a cue from XKCD’s “What If” blag and answer the question “What would it take to engineer a dragon?”

Trogdor the Burninator - Homestar Runner“Feel free to follow along with my simple step-by-step instruction.” – Strongbad, Homestar Runner

Part 1 – Should we bioengineer a dragon?

Before starting in on our dragon, we should carefully consider whether or not this project has a function beyond “Well that’s cool.” Modifying a living creature in any way, shape, or form has ethical implications – conventional breeding included. Animals have been domesticated and bred for millenia, and now broiler chickens have such disproportionate amounts of white meat that they can’t stand up . Soldiers and police rely on German Shepherds, but these dogs often have terrible hip problems as a result of their pedigree. There needs to be a compelling and comprehensive answer as to why we should engineer an organism.

Our reason for engineering a dragon doesn’t have to be as direct as “I need to regain the Iron Throne”, though — maybe there are significant technical advances that could be made by starting this project, like better understanding the developmental processes that result in wings and scales and fire-breathing. Maybe this is an engaging way to get the public intrigued in science, technology and the way the two are rapidly evolving. Maybe there are a LOT of consumers that want a pet dragon, or lap giraffes, or housecats that look like lions and cheetahs, and we just didn’t know it until someone asked the question. (Is this you? Support consumer biotechnology and sign up for our mailing list here).

A lap giraffe - luxury consumer biotechnology
Admit it, you signed up for the waiting list.

Let’s take a close look at why we need a dragon, and then determine whether bioengineering is the best possible solution to those needs.

In some cases, there may be an existing solution that could take the place of bioengineering a dragon. Are you looking for an animal companion that will keep down your goat population? Why not a golden eagle instead? Maybe you want a trusty steed that you can rely on in dangerous situations. Horses might be a little tame for your taste, but a war zebra or an elephant might do just as well.

blog post trogdor part 1 dragon v 747
Left: Airplane, Right: Dragon

It’s also unlikely that bioengineering will be the quick and inexpensive way to accomplish your goal. If your primary goal is personal flight transportation, we have some incredible aeronautical engineering marvels out there in the shape of airplanes and helicopters, and human powered gliders also exist. At today’s level of technology, there is no possible way that making this dragon will be in any way cheaper or faster than mechanical flight. An animal that a human can ride through the air is a tall order.

Right now “because they’re cool” is probably still at the top of your list of reasons to bioengineer a dragon. The cool factor drives a lot of product development in everything from fashion to electronics. Dragons, the imaginary ones that don’t exist, are pretty amazing — but to get from zero to dragon, you are going to have to do a lot of basic research and testing. And when we’re talking about engineering a living creature and all its complexities, this can yield ugly, not-quite-dragon, results.

So, is it worth it? Should we bioengineer a dragon? Share your thoughts below!

Part II – Design

07 Jan

Plant Blindness – Can’t see the forest

Do you suffer from planta ablepsia? Common symptoms include not spending enough time in wild places, being unable to identify what part of which plant generates the french fry, and thinking of plants as “biological wallpaper”

blog post plant blindness banana leaf A banana leaf – trillions of cells turning sunlight and carbon dioxide into a beautifully geometric wallpaper for your computer screen.

Plants are everywhere, but people tend to ignore them. As time spent in the woods becomes time spent in front of a screen, it’s easy to go through life without having to look closely at the green things around us. This has become known as plant blindness and it’s something that botanists, educators, and gardeners across the world are working to end.

blog post plant blindness allOne plant, many uses. A) Banana; B) Banana C) Banana D) Banana

We depend on plants not only for the food we eat, what we feed our animals, and the fibers we wear, but for their role in maintaining a living planet. Plants breathe with us, consuming carbon dioxide and releasing oxygen. They purify water and release it into the atmosphere, influencing the water cycle. They provide habitat for animals and insects, and tie soil to the landscape, maintaining a healthy ecosystem capable of sustaining life.

“…people don’t understand that plants are absolutely integral to our survival and the survival of every other living thing on the planet. We could not live without them.” – Thomas A Block, Director Morris Hill Arboretum

Our understanding of these processes is not complete, neither within a plant nor on a global scale. Forests pull up to 30% of the carbon dioxide humans produce out of the air and into their timber – but we don’t know the best way to manage them to mitigate climate change. Botanical research and seed preservation face devastating budget cuts, weakening our ability to study biodiversity and improve conservation efforts. Even with growing interest in local farming and protecting the environment, there is a long way to go before plants are appreciated the way they need to be.

blog post plant blindness tree
A society grows great when old men plant trees whose shade they know they shall never sit in. Plant, study and preserve for the next generation.

Plants are more than just background scenery – they have a critical role to play in our future. We hope our color-changing flower will ignite a new fascination with plants, inspiring people to take a second look at the tree in their backyard and the flowers in their garden.

References:
Botanists battle ‘plant blindness’ with seeds of knowledge in the Philadelphia Post by V.A. Smith
29 Dec

Consumer Biotechnology

We love answering questions! Joshua E. asks What fields do you think consumer biotech can enter and what tools can be used to achieve these goals?

Hi Joshua,

Consumer biotechnology is just that – biotechnology made for you to use in your everyday life.

When people hear the word ‘biotechnology’ they think of scientists in white lab coats working for years on complex scientific problems.
blog post consumer biotechnology scientists
This is what Google thinks a scientist looks like. We suggest you visit Looks Like Science for some more diversity.

This means that unless you are interested in becoming one of those people in white lab coats, you often don’t have the opportunity to have hands on experience with ‘biotech’. It can seem like a mysterious process.

Computers started out a bit like this too – they weren’t available to the general public at first, and people reacted to them with skepticism. What could they possibly be good for?

“There is a world market for maybe 5 computers”
Thomas Watson, IBM Chairman, 1943

Today everyone owns multiple computers—tablets, laptops, cell phones, entertainment systems, etc. They have made a whole new world of connection and technology possible.

The interesting thing is that the turning point in computer innovation wasn’t just better/cheaper technology or the demonstrated benefit of a time-saving spreadsheet. Games played an important role. The accessibility and availability of the technology to add some fun and interest to the everyday person’s life is what made the computer exciting. And, it got people thinking about what else computers could do.

blog post consumer biotechnology Pong

This entertained a generation.

blog post consumer biotechnology pacman
Then this did.

blog post consumer biotechnology dragons

Then suddenly, dragons.

Today, fields like genetic engineering and synthetic biology share the fundamental goal of allowing us to engineer biological systems. Tools like CRISPR genome editing and mathematical models of biological systems allow us to develop new biotechnology with greater precision.

We’ve already done some great things with this – insulin, for example, comes from genetically engineered bacteria and improves the quality of life for millions of diabetics. Artemesinin (a powerful malaria drug) is now produced on an industrial scale in microbial bioreactors. These are important life-saving uses of biotechnology.

But this is not what will spur the same sort of creative innovation that has taken computer technology from four ton machines to the iPhone. To do that, we need people to have biotechnology in their hands. At Revolution Bio, we’re making Pong for the biotech world: Color-changing flowers. They’re beautiful, accessible, and something that everyone can appreciate.

That’s what consumer biotechnology is all about, making advanced biological science personal and fun. Like Pong, this is just the start. We think consumer biotechnology could have an impact in everything from the gardens we plant, the materials we use for building, the fabrics we wear, even the way you recycle.

It’s safe to say that we can’t predict the most amazing advances to come out of this movement. Who would have imagined Skyrim while playing PONG? We’re excited to be a part of this incredible new field and we’re looking forward to making consumer biotechnology a part of your life.

We love answering questions! Ask your question here

13 Dec

Wonder where that poinsettia came from?

Today is Poinsettia day!

This time of year, you probably have a poinsettia on your table, and maybe there’s more than one at work. In Mexico, they’d get to be 15 feet tall, but after the Christmas season in North America they’ll be lucky to be saved by that one person in the office with that green viney thing growing all the way around their cubicle (If you know the name of that plant, that’s you. You’re the one that saves the poinsettias).

Row after row of poinsettia flowers grown in Florida for the holiday season

Row after row of poinsettia flowers grown in Florida for the holiday season

We buy over 34 million of the plants each year – that’s nearly 150 million dollars! And these days they come in red, cream, hot pink, salmon, burgundy and combinations of the two! We got the chance to see these beautiful plants in person during our last visit to an enormous indoor plant grower in Florida. You can see the (almost mile long) shade house and the beautiful poinsettias within.

We put together a little infographic in honor of these flowers with the big holiday spirit. Enjoy!

05 Dec

Inspired by Biofabricate!

I couldn’t snag a ticket to Biofabricate 2014, but enjoyed following along with the conversation on Twitter throughout the day! The excitement was palpable & I was inspired to make the infographic below – I hope it helps you share the adventure of #growingthefuture. I’m looking forward to 2015 and a year full of beautiful biology (including color-changing flowers!) – K

What did you think of the conference?

01 Jul

Lessons learned from a business accelerator: contracts

spine

A business accelerator is a fun and competitive (and crazy) experience.  You will definitely learn a lot over the course of one.  But remember, the accelerator itself is a business for the VC firm, exactly like your fledgling business.  It’s not a charity.  It’s not community service the VC firm does for the benefit of the community.  It only exists to make money.
So if you are lucky enough to have you and your business selected to participate in an accellerator– What does that mean?

It means you need to start fighting.

JDoyleBox

The VC firm thinks that your business has a decent chance to become a profitable company.  They think that their investment of $20,000 will yield returns of millions in a few years.  They think that their business accelerator program will give you the training and the opportunities to achieve that business success.  You might be surprised and flattered at this – we were.  We liked our cool little idea, we thought it was nice that someone else was willing to give us a chance.  We didn’t really take to heart that this was a business transaction where each side commits to making this a successful venture.

Our advice to you?  Make them put their commitment in writing.

When we were first selected for the program, we signed a letter of intent, a brief 1.5 page document about our responsibilities to the accelerator. The responsibilities of the accelerator to us were not documented here, and we expected to see them in the detailed contract which was forthcoming. This 7 page contract was more detailed—but only about the nature and type of shares that we would give them in exchange for their financial and material support. Very practical, and, from our limited experience, reasonable. After all, it makes sense that these guys would want to protect their investment.

However, we also needed to think about protecting our own investment. We were leaving jobs, moving overseas, and committing fully to a program we would be dependent on for the next three months.  Aside from the words ‘material support’, there was not another or further defined responsibility for the accelerator in the contract.  No mention of the mentors or training that would be provided, no description of the facilities, no outline of the opportunities they would provide. Under our current agreement, there are many ways that we can be in violation of the contract, but it is impossible to hold the accelerator accountable. We are entirely dependent on their sense of fairness and goodwill – a dangerous place to be as a new start up.

So, when you receive the contract, start asking questions.  Question yourself, your business partners, and question the accelerator. Identify your framework for success and express it confidently. If you require specific materials, facilities, mentoring, or consulting to be successful, verify that they can provide it and make them commit to providing it in writing before you sign.  If you feel the terms are unfavorable say so, and have the research at hand to back it up. Reading the contract start to finish isn’t enough.  You can read the whole thing, understand everything in it, and still not know what it means.  Instead, try reading a section, then restating that section out loud to your business partners and advisors in your own words.  You might see some obvious and trivially easy adjustments you can make to protect yourselves and your company.

Another note – absolutely everything is negotiable.

ReaganGorbachevtreaty

We negotiated. We agonized about it and spent hours drafting emails and worried that we’d be rejected from the program outright, but we shared our concerns.  And as a result, we reduced the equity exchanged for their investment by 30%.

Remember your position at the negotiating table if you get a contract like this.  They chose you.  They think your idea, your business, your team has a chance of hitting it big.  Their business depends on finding ideas and teams and businesses like yours, and they depend on you being a success.  You need to address items that are important to you and work out contract wording that makes you confident in this partnership. A good business partner will respond to your concerns, a bad one will dismiss them with “that’s not important.”

It may very well be that this is your only shot and you have to take it regardless of the terms – that’s fine.  Such is life.  But it never hurts to stand up for yourself. You will need that backbone to make it in the business world.

27 Jun

Synthetic biology, indigo is your color.

Indigo-Guizhou

Color is at the heart of our project here at Revolution Bio. Color makes things brighter, more fun, and more engaging. Color can also become a rallying point for people interested in building a common cause.

The field of synthetic biology is fractured at the moment, with competing definitions and widely varied goals. We need a symbol that’s accessible and meaningful, one that welcomes people interested in the field and provides an umbrella for future discussions. A color with a story might be the place to start.

Given that synthetic biology takes inspiration from nature and engineers beyond it, I think indigo might be the right color for this new field. Indigo is a deep blue dye originally derived from Indigofera plants – huge quantities of plants, as it makes up only about 0.5% of the plant leaf. However, you cannot extract indigo directly from plants, only the colorless, water-soluble precursor, indican. Indican must first hydrolyze to indoxyl, and then oxidize to become the molecule indigo. A variant of this molecular reaction is what turns your colonies blue when you do a blue-white screen during cloning.

Being a striking and vibrant dye, indigo is in high demand. In the 19th century, demand drove intensive cultivation of Indigofera plants and contributed to the slave trade in India and the Americas. But even this dehumanizing, industrial production could not satisfy the demand for ‘blue gold.’ And so researchers began to look for ways to make synthetic indigo. Some limited progress was made through the 1800s towards a synthetic indigo, but it wasn’t until 1901 that the first industrially relevant process was put into use. Later that century, affordable synthetic indigo made blue fabric (and blue jeans) ubiquitous.

The investigation into the best way to make synthetic indigo and indigo dyes is ongoing. It is challenging – indigo is not water soluble, and harsh chemical conversions are required to manufacture indoxyl and set the dye. Synthetic indigo manufacturing yields a product ten times cheaper than the natural plant based extractions. However, the natural dyes are still sought after though, for high-end fabric and cosmetic applications.

The indigo arc– from a rare natural ingredient, through massive industrial production, to a renewed search for a better solution– is a common one, and I believe synthetic biology has a role to play in finding a better solution. Using engineering principles in combination with biological components to understand and improve the biochemical pathways in Indigofera we may be able to come full circle on indigo, developing an all-natural production platform that meets the global demand. Inspired by nature, engineered by people? Sounds like synthetic biology to me.

What do you think? Does synthetic biology look good in indigo?

23 Jun

A frustrating week for the Revolution

Lesson Learned

When we were developing our scientific plan for this summer, we came to the logical and obvious conclusion that time was more important to us than money. Three months is a very short time frame to do meaningful science, and we believed that spending money (purchasing competent cells, synthesizing DNA, etc.) to gain time was the prudent choice. Our accelerator provided a few opportunities to save time, so we took advantage of all of them.

First, we ordered our supplies through the university. We were told we would be receiving the university discount on all purchases, that they knew the suppliers for the area, that they had some pricing agreements we could capitalize on, and that we wouldn’t have to pay for shipping. Great! Next, we ordered approximately 10,000 basepairs of DNA through a bulk purchase with special pricing and rapid turnaround, as negotiated by an accelerator partner. That’s exactly what we needed, to save us time and kick start our project. We kept the 1 August deadline in mind when planning our experiments and our budget, and while it may have cost a bit more to order some items, we felt that it was a fair price to pay for the extra time.

Things started to go wrong almost immediately. Irish regulatory approval hadn’t been obtained prior to our arrival, so we were unable to begin work for weeks. The reagents ordered through the university took weeks or months to show up. The price agreement for DNA synthesis wasn’t actually in place when the accelerator started, the accelerator group order took three weeks to put together, and ‘rapid synthesis’ ended up meaning about four weeks or so. While frustrating, we had planned some leeway into our timeline because something like this always happens. Because we had shown up with our own DNA and our own reagents, we could start working once the regulatory approval had come in.

Last week things took a turn for the worse. We received our itemized invoice list for supplies and reagents, and it became apparent that there had been serious problems – our estimated $3000 budget had somehow exploded to $9000. We also learned we would have to extend our stay in Ireland for a month– an additional stress on a budget that was now stretched pretty thin. And worst of all, we found out that DNA sequences central to our scientific proof-of-concept had just been… forgotten. They were dropped from the gene synthesis order and we weren’t informed.

At the heart of these problems is a lack of communication and a lack of oversight.

With ordering, I failed to convey the importance of the budget to us and our goals for the summer. I made the assumption that reagent costs would be reasonably similar, but I didn’t ask follow up questions about costs, and the purchaser didn’t volunteer the information. Instead, reagents cost about 2.5x as much as they would in the US. Despite providing links and pricing for all reagents, I made the assumption that should there be a serious price discrepancy I would be notified and asked to determine the best course of action. I was not, and we received other items which cost thirty or fifty times their equivalent in the states. Thankfully, the university is now working with us to rectify the situation as much as possible, but much of the damage has already been done.

With the accelerator, I did not fully account for the fact that the program is in its first year. I did not adequately plan for potential scheduling conflicts and bureaucratic hold ups , and I made the assumption that it was important to hold to that 1 August deadline. I didn’t continue to push for information regarding the schedule and as a result, we have been surprised several times by substantive changes to the proposed timeline, all of which have resulted in the commitment of more money than originally budgeted.

And with the DNA synthesis, I made the assumption that this would be a straightforward order, conducted in much the same way that we would have done on our own, but with more favorable pricing terms. However, once again we did not communicate the importance of these items to our project, nor did we request the specifics of the synthesis agreement before committing to it. This particular lack of communication has cost us the time we hoped to buy at the beginning of the program. Without money or time, we now find ourselves working on a scientific Plan D to make something of this summer.

It has been a painful lesson to learn, but at this point it has become abundantly clear that we failed to provide the appropriate oversight for our project. Entrepreneurs, do not be afraid to ask for updates every day. Be as persistent as necessary to identify pricing, timeline, and terms of partnership. Consider what happens if the partnership fails or if the contract is not fulfilled. And if it sounds like someone is offering exactly what you need, treat the offer with skepticism until you have proof that they can deliver exactly what it is you need. Your business, your project, will never be as important to anyone else as it is to you, and while it is necessary to build a good team, that team needs to be selected based on first-hand experience of the competence and ability of your partners.

Revolution has just learned an expensive lesson. But this experience has shaped our team, helping us understand that we already had the expertise to do the best possible job in meeting scientific challenges. And, it has given us a lens to evaluate opportunities with a critical eye. We won’t make the same mistakes twice.

04 Jun

Getting Started

media

Look at those beautiful little tubes of DNA sitting on ice – we’ve gotten our regulatory approval, we have our genetic components, the enzymes to put them together and the cells they’ll go into. We’re all set for some molecular biology!

Here’s a quick run-down of our work today:
A month ago, we synthesized 1000 basepair pieces of DNA out of our list of color-changing flower components. On their own, these strings of A,T,C,and G won’t do anything – we need to arrange them in the proper context.

First, the DNA fragments need to be inserted into a plasmid. This is a circular piece of DNA that, when inserted in a bacteria, will be replicated and maintained with very little error. The plasmid Nikolai is building will contain our synthesized DNA, the replication instructions, and a way to identify bacteria that have taken up the plasmid. To insert the synthesized DNA in the plasmid, we add the two types of DNA to a tube with a buffer that contains ions and molecules needed to carry out the reaction. Then we add some glue – an enzyme, ‘ligase,’ which connects the ends of the DNA together.

Dr. Braun at the bench setting up a DNA ligation

Dr. Braun at the bench setting up a DNA ligation

How does the ligase know whether it’s connecting the plasmid to the synthesized DNA or to itself? It doesn’t! So we need to develop ways to tell whether or not our synthesized DNA is in the right spot. The pJET kit we’re using has a neat way to do this. The plasmid is already cut right in the middle of a gene that generates a toxic product. If you don’t insert a piece of DNA, the ligase will re-connect the two ends of the plasmid, completing the toxic gene sequence. The toxic gene will be expressed, and those bacteria will die. However, if the synthesized DNA was inserted into the plasmid, it will interrupt the toxic gene, preventing it from killing the bacterial cell. The cell will live, replicate the DNA, and now you have a self-maintaining stock of your DNA part.

This is only the first step. Once this process is complete we’ll have to ‘read’ the plasmids to make sure that the DNA we have is what we think it is. Even if they’re correct, these plasmids don’t have all the necessary information yet so we’ll have to do some additional steps to add the rest of the information. There’s a lot of science to share – ask questions in the comments below!