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Michael Hunter, MD
1 year ago
5 Drugs That May Increase Your Risk of Dementia
While our genes can't be changed easily, you can avoid some dementia risk factors. Today we discuss dementia and five drugs that may increase risk.
Memory loss appears to come with age, but we're not talking about forgetfulness. Sometimes losing your car keys isn't an indication of dementia. Dementia impairs the capacity to think, remember, or make judgments. Dementia hinders daily tasks.
Alzheimers is the most common dementia. Dementia is not normal aging, unlike forgetfulness. Aging increases the risk of Alzheimer's and other dementias. A family history of the illness increases your risk, according to the Mayo Clinic (USA).
Given that our genes are difficult to change (I won't get into epigenetics), what are some avoidable dementia risk factors? Certain drugs may cause cognitive deterioration.
Today we look at four drugs that may cause cognitive decline.
Dementia and benzodiazepines
Benzodiazepine sedatives increase brain GABA levels. Example benzodiazepines:
Diazepam (Valium) (Valium)
Alprazolam (Xanax) (Xanax)
Clonazepam (Klonopin) (Klonopin)
Addiction and overdose are benzodiazepine risks. Yes! These medications don't raise dementia risk.
USC study: Benzodiazepines don't increase dementia risk in older adults.
Benzodiazepines can produce short- and long-term amnesia. This memory loss hinders memory formation. Extreme cases can permanently impair learning and memory. Anterograde amnesia is uncommon.
2. Statins and dementia
Statins reduce cholesterol. They prevent a cholesterol-making chemical. Examples:
Atorvastatin (Lipitor) (Lipitor)
Fluvastatin (Lescol XL) (Lescol XL)
Lovastatin (Altoprev) (Altoprev)
Pitavastatin (Livalo, Zypitamag) (Livalo, Zypitamag)
Pravastatin (Pravachol) (Pravachol)
Rosuvastatin (Crestor, Ezallor) (Crestor, Ezallor)
Simvastatin (Zocor) (Zocor)
This finding is contentious. Harvard's Brigham and Womens Hospital's Dr. Joann Manson says:
“I think that the relationship between statins and cognitive function remains controversial. There’s still not a clear conclusion whether they help to prevent dementia or Alzheimer’s disease, have neutral effects, or increase risk.”
This one's off the dementia list.
3. Dementia and anticholinergic drugs
Anticholinergic drugs treat many conditions, including urine incontinence. Drugs inhibit acetylcholine (a brain chemical that helps send messages between cells). Acetylcholine blockers cause drowsiness, disorientation, and memory loss.
First-generation antihistamines, tricyclic antidepressants, and overactive bladder antimuscarinics are common anticholinergics among the elderly.
Anticholinergic drugs may cause dementia. One study found that taking anticholinergics for three years or more increased the risk of dementia by 1.54 times compared to three months or less. After stopping the medicine, the danger may continue.
4. Drugs for Parkinson's disease and dementia
Cleveland Clinic (USA) on Parkinson's:
Parkinson's disease causes age-related brain degeneration. It causes delayed movements, tremors, and balance issues. Some are inherited, but most are unknown. There are various treatment options, but no cure.
Parkinson's medications can cause memory loss, confusion, delusions, and obsessive behaviors. The drug's effects on dopamine cause these issues.
A 2019 JAMA Internal Medicine study found powerful anticholinergic medications enhance dementia risk.
Those who took anticholinergics had a 1.5 times higher chance of dementia. Individuals taking antidepressants, antipsychotic drugs, anti-Parkinson’s drugs, overactive bladder drugs, and anti-epileptic drugs had the greatest risk of dementia.
Anticholinergic medicines can lessen Parkinson's-related tremors, but they slow cognitive ability. Anticholinergics can cause disorientation and hallucinations in those over 70.
5. Antiepileptic drugs and dementia
The risk of dementia from anti-seizure drugs varies with drugs. Levetiracetam (Keppra) improves Alzheimer's cognition.
One study linked different anti-seizure medications to dementia. Anti-epileptic medicines increased the risk of Alzheimer's disease by 1.15 times in the Finnish sample and 1.3 times in the German population. Depakote, Topamax are drugs.
Sam Warain
2 years ago
Sam Altman, CEO of Open AI, foresees the next trillion-dollar AI company
“I think if I had time to do something else, I would be so excited to go after this company right now.”
Sam Altman, CEO of Open AI, recently discussed AI's present and future.
Open AI is important. They're creating the cyberpunk and sci-fi worlds.
They use the most advanced algorithms and data sets.
GPT-3...sound familiar? Open AI built most copyrighting software. Peppertype, Jasper AI, Rytr. If you've used any, you'll be shocked by the quality.
Open AI isn't only GPT-3. They created DallE-2 and Whisper (a speech recognition software released last week).
What will they do next? What's the next great chance?
Sam Altman, CEO of Open AI, recently gave a lecture about the next trillion-dollar AI opportunity.
Who is the organization behind Open AI?
Open AI first. If you know, skip it.
Open AI is one of the earliest private AI startups. Elon Musk, Greg Brockman, and Rebekah Mercer established OpenAI in December 2015.
OpenAI has helped its citizens and AI since its birth.
They have scary-good algorithms.
Their GPT-3 natural language processing program is excellent.
The algorithm's exponential growth is astounding. GPT-2 came out in November 2019. May 2020 brought GPT-3.
Massive computation and datasets improved the technique in just a year. New York Times said GPT-3 could write like a human.
Same for Dall-E. Dall-E 2 was announced in April 2022. Dall-E 2 won a Colorado art contest.
Open AI's algorithms challenge jobs we thought required human innovation.
So what does Sam Altman think?
The Present Situation and AI's Limitations
During the interview, Sam states that we are still at the tip of the iceberg.
So I think so far, we’ve been in the realm where you can do an incredible copywriting business or you can do an education service or whatever. But I don’t think we’ve yet seen the people go after the trillion dollar take on Google.
He's right that AI can't generate net new human knowledge. It can train and synthesize vast amounts of knowledge, but it simply reproduces human work.
“It’s not going to cure cancer. It’s not going to add to the sum total of human scientific knowledge.”
But the key word is yet.
And that is what I think will turn out to be wrong that most surprises the current experts in the field.
Reinforcing his point that massive innovations are yet to come.
But where?
The Next $1 Trillion AI Company
Sam predicts a bio or genomic breakthrough.
There’s been some promising work in genomics, but stuff on a bench top hasn’t really impacted it. I think that’s going to change. And I think this is one of these areas where there will be these new $100 billion to $1 trillion companies started, and those areas are rare.
Avoid human trials since they take time. Bio-materials or simulators are suitable beginning points.
AI may have a breakthrough. DeepMind, an OpenAI competitor, has developed AlphaFold to predict protein 3D structures.
It could change how we see proteins and their function. AlphaFold could provide fresh understanding into how proteins work and diseases originate by revealing their structure. This could lead to Alzheimer's and cancer treatments. AlphaFold could speed up medication development by revealing how proteins interact with medicines.
Deep Mind offered 200 million protein structures for scientists to download (including sustainability, food insecurity, and neglected diseases).
Being in AI for 4+ years, I'm amazed at the progress. We're past the hype cycle, as evidenced by the collapse of AI startups like C3 AI, and have entered a productive phase.
We'll see innovative enterprises that could replace Google and other trillion-dollar companies.
What happens after AI adoption is scary and unpredictable. How will AGI (Artificial General Intelligence) affect us? Highly autonomous systems that exceed humans at valuable work (Open AI)
My guess is that the things that we’ll have to figure out are how we think about fairly distributing wealth, access to AGI systems, which will be the commodity of the realm, and governance, how we collectively decide what they can do, what they don’t do, things like that. And I think figuring out the answer to those questions is going to just be huge. — Sam Altman CEO
Laura Sanders
2 years ago
Xenobots, tiny living machines, can duplicate themselves.
Strange and complex behavior of frog cell blobs
A xenobot “parent,” shaped like a hungry Pac-Man (shown in red false color), created an “offspring” xenobot (green sphere) by gathering loose frog cells in its opening.
Tiny “living machines” made of frog cells can make copies of themselves. This newly discovered renewal mechanism may help create self-renewing biological machines.
According to Kirstin Petersen, an electrical and computer engineer at Cornell University who studies groups of robots, “this is an extremely exciting breakthrough.” She says self-replicating robots are a big step toward human-free systems.
Researchers described the behavior of xenobots earlier this year (SN: 3/31/21). Small clumps of skin stem cells from frog embryos knitted themselves into small spheres and started moving. Cilia, or cellular extensions, powered the xenobots around their lab dishes.
The findings are published in the Proceedings of the National Academy of Sciences on Dec. 7. The xenobots can gather loose frog cells into spheres, which then form xenobots.
The researchers call this type of movement-induced reproduction kinematic self-replication. The study's coauthor, Douglas Blackiston of Tufts University in Medford, Massachusetts, and Harvard University, says this is typical. For example, sexual reproduction requires parental sperm and egg cells. Sometimes cells split or budded off from a parent.
“This is unique,” Blackiston says. These xenobots “find loose parts in the environment and cobble them together.” This second generation of xenobots can move like their parents, Blackiston says.
The researchers discovered that spheroid xenobots could only produce one more generation before dying out. The original xenobots' shape was predicted by an artificial intelligence program, allowing for four generations of replication.
A C shape, like an openmouthed Pac-Man, was predicted to be a more efficient progenitor. When improved xenobots were let loose in a dish, they began scooping up loose cells into their gaping “mouths,” forming more sphere-shaped bots (see image below). As many as 50 cells clumped together in the opening of a parent to form a mobile offspring. A xenobot is made up of 4,000–6,000 frog cells.
Petersen likes the Xenobots' small size. “The fact that they were able to do this at such a small scale just makes it even better,” she says. Miniature xenobots could sculpt tissues for implantation or deliver therapeutics inside the body.
Beyond the xenobots' potential jobs, the research advances an important science, says study coauthor and Tufts developmental biologist Michael Levin. The science of anticipating and controlling the outcomes of complex systems, he says.
“No one could have predicted this,” Levin says. “They regularly surprise us.” Researchers can use xenobots to test the unexpected. “This is about advancing the science of being less surprised,” Levin says.
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Vitalik
2 years ago
An approximate introduction to how zk-SNARKs are possible (part 1)
You can make a proof for the statement "I know a secret number such that if you take the word ‘cow', add the number to the end, and SHA256 hash it 100 million times, the output starts with 0x57d00485aa". The verifier can verify the proof far more quickly than it would take for them to run 100 million hashes themselves, and the proof would also not reveal what the secret number is.
In the context of blockchains, this has 2 very powerful applications: Perhaps the most powerful cryptographic technology to come out of the last decade is general-purpose succinct zero knowledge proofs, usually called zk-SNARKs ("zero knowledge succinct arguments of knowledge"). A zk-SNARK allows you to generate a proof that some computation has some particular output, in such a way that the proof can be verified extremely quickly even if the underlying computation takes a very long time to run. The "ZK" part adds an additional feature: the proof can keep some of the inputs to the computation hidden.
You can make a proof for the statement "I know a secret number such that if you take the word ‘cow', add the number to the end, and SHA256 hash it 100 million times, the output starts with 0x57d00485aa". The verifier can verify the proof far more quickly than it would take for them to run 100 million hashes themselves, and the proof would also not reveal what the secret number is.
In the context of blockchains, this has two very powerful applications:
- Scalability: if a block takes a long time to verify, one person can verify it and generate a proof, and everyone else can just quickly verify the proof instead
- Privacy: you can prove that you have the right to transfer some asset (you received it, and you didn't already transfer it) without revealing the link to which asset you received. This ensures security without unduly leaking information about who is transacting with whom to the public.
But zk-SNARKs are quite complex; indeed, as recently as in 2014-17 they were still frequently called "moon math". The good news is that since then, the protocols have become simpler and our understanding of them has become much better. This post will try to explain how ZK-SNARKs work, in a way that should be understandable to someone with a medium level of understanding of mathematics.
Why ZK-SNARKs "should" be hard
Let us take the example that we started with: we have a number (we can encode "cow" followed by the secret input as an integer), we take the SHA256 hash of that number, then we do that again another 99,999,999 times, we get the output, and we check what its starting digits are. This is a huge computation.
A "succinct" proof is one where both the size of the proof and the time required to verify it grow much more slowly than the computation to be verified. If we want a "succinct" proof, we cannot require the verifier to do some work per round of hashing (because then the verification time would be proportional to the computation). Instead, the verifier must somehow check the whole computation without peeking into each individual piece of the computation.
One natural technique is random sampling: how about we just have the verifier peek into the computation in 500 different places, check that those parts are correct, and if all 500 checks pass then assume that the rest of the computation must with high probability be fine, too?
Such a procedure could even be turned into a non-interactive proof using the Fiat-Shamir heuristic: the prover computes a Merkle root of the computation, uses the Merkle root to pseudorandomly choose 500 indices, and provides the 500 corresponding Merkle branches of the data. The key idea is that the prover does not know which branches they will need to reveal until they have already "committed to" the data. If a malicious prover tries to fudge the data after learning which indices are going to be checked, that would change the Merkle root, which would result in a new set of random indices, which would require fudging the data again... trapping the malicious prover in an endless cycle.
But unfortunately there is a fatal flaw in naively applying random sampling to spot-check a computation in this way: computation is inherently fragile. If a malicious prover flips one bit somewhere in the middle of a computation, they can make it give a completely different result, and a random sampling verifier would almost never find out.
It only takes one deliberately inserted error, that a random check would almost never catch, to make a computation give a completely incorrect result.
If tasked with the problem of coming up with a zk-SNARK protocol, many people would make their way to this point and then get stuck and give up. How can a verifier possibly check every single piece of the computation, without looking at each piece of the computation individually? There is a clever solution.
see part 2
Sanjay Priyadarshi
1 year ago
Using Ruby code, a programmer created a $48,000,000,000 product that Elon Musk admired.
Unexpected Success
Shopify CEO and co-founder Tobias Lutke. Shopify is worth $48 billion.
World-renowned entrepreneur Tobi
Tobi never expected his first online snowboard business to become a multimillion-dollar software corporation.
Tobi founded Shopify to establish a 20-person company.
The publicly traded corporation employs over 10,000 people.
Here's Tobi Lutke's incredible story.
Elon Musk tweeted his admiration for the Shopify creator.
30-October-2019.
Musk praised Shopify founder Tobi Lutke on Twitter.
Happened:
Explore this programmer's journey.
What difficulties did Tobi experience as a young child?
Germany raised Tobi.
Tobi's parents realized he was smart but had trouble learning as a toddler.
Tobi was learning disabled.
Tobi struggled with school tests.
Tobi's learning impairments were undiagnosed.
Tobi struggled to read as a dyslexic.
Tobi also found school boring.
Germany's curriculum didn't inspire Tobi's curiosity.
“The curriculum in Germany was taught like here are all the solutions you might find useful later in life, spending very little time talking about the problem…If I don’t understand the problem I’m trying to solve, it’s very hard for me to learn about a solution to a problem.”
Studying computer programming
After tenth grade, Tobi decided school wasn't for him and joined a German apprenticeship program.
This curriculum taught Tobi software engineering.
He was an apprentice in a small Siemens subsidiary team.
Tobi worked with rebellious Siemens employees.
Team members impressed Tobi.
Tobi joined the team for this reason.
Tobi was pleased to get paid to write programming all day.
His life could not have been better.
Devoted to snowboarding
Tobi loved snowboarding.
He drove 5 hours to ski at his folks' house.
His friends traveled to the US to snowboard when he was older.
However, the cheap dollar conversion rate led them to Canada.
2000.
Tobi originally decided to snowboard instead than ski.
Snowboarding captivated him in Canada.
On the trip to Canada, Tobi encounters his wife.
Tobi meets his wife Fiona McKean on his first Canadian ski trip.
They maintained in touch after the trip.
Fiona moved to Germany after graduating.
Tobi was a startup coder.
Fiona found work in Germany.
Her work included editing, writing, and academics.
“We lived together for 10 months and then she told me that she need to go back for the master's program.”
With Fiona, Tobi immigrated to Canada.
Fiona invites Tobi.
Tobi agreed to move to Canada.
Programming helped Tobi move in with his girlfriend.
Tobi was an excellent programmer, therefore what he did in Germany could be done anywhere.
He worked remotely for his German employer in Canada.
Tobi struggled with remote work.
Due to poor communication.
No slack, so he used email.
Programmers had trouble emailing.
Tobi's startup was developing a browser.
After the dot-com crash, individuals left that startup.
It ended.
Tobi didn't intend to work for any major corporations.
Tobi left his startup.
He believed he had important skills for any huge corporation.
He refused to join a huge corporation.
Because of Siemens.
Tobi learned to write professional code and about himself while working at Siemens in Germany.
Siemens culture was odd.
Employees were distrustful.
Siemens' rigorous dress code implies that the corporation doesn't trust employees' attire.
It wasn't Tobi's place.
“There was so much bad with it that it just felt wrong…20-year-old Tobi would not have a career there.”
Focused only on snowboarding
Tobi lived in Ottawa with his girlfriend.
Canada is frigid in winter.
Ottawa's winters last.
Almost half a year.
Tobi wanted to do something worthwhile now.
So he snowboarded.
Tobi began snowboarding seriously.
He sought every snowboarding knowledge.
He researched the greatest snowboarding gear first.
He created big spreadsheets for snowboard-making technologies.
Tobi grew interested in selling snowboards while researching.
He intended to sell snowboards online.
He had no choice but to start his own company.
A small local company offered Tobi a job.
Interested.
He must sign papers to join the local company.
He needed a work permit when he signed the documents.
Tobi had no work permit.
He was allowed to stay in Canada while applying for permanent residency.
“I wasn’t illegal in the country, but my state didn’t give me a work permit. I talked to a lawyer and he told me it’s going to take a while until I get a permanent residency.”
Tobi's lawyer told him he cannot get a work visa without permanent residence.
His lawyer said something else intriguing.
Tobis lawyer advised him to start a business.
Tobi declined this local company's job offer because of this.
Tobi considered opening an internet store with his technical skills.
He sold snowboards online.
“I was thinking of setting up an online store software because I figured that would exist and use it as a way to sell snowboards…make money while snowboarding and hopefully have a good life.”
What brought Tobi and his co-founder together, and how did he support Tobi?
Tobi lived with his girlfriend's parents.
In Ottawa, Tobi encounters Scott Lake.
Scott was Tobis girlfriend's family friend and worked for Tobi's future employer.
Scott and Tobi snowboarded.
Tobi pitched Scott his snowboard sales software idea.
Scott liked the idea.
They planned a business together.
“I was looking after the technology and Scott was dealing with the business side…It was Scott who ended up developing relationships with vendors and doing all the business set-up.”
Issues they ran into when attempting to launch their business online
Neither could afford a long-term lease.
That prompted their online business idea.
They would open a store.
Tobi anticipated opening an internet store in a week.
Tobi seeks open-source software.
Most existing software was pricey.
Tobi and Scott couldn't afford pricey software.
“In 2004, I was sitting in front of my computer absolutely stunned realising that we hadn’t figured out how to create software for online stores.”
They required software to:
to upload snowboard images to the website.
people to look up the types of snowboards that were offered on the website. There must be a search feature in the software.
Online users transmit payments, and the merchant must receive them.
notifying vendors of the recently received order.
No online selling software existed at the time.
Online credit card payments were difficult.
How did they advance the software while keeping expenses down?
Tobi and Scott needed money to start selling snowboards.
Tobi and Scott funded their firm with savings.
“We both put money into the company…I think the capital we had was around CAD 20,000(Canadian Dollars).”
Despite investing their savings.
They minimized costs.
They tried to conserve.
No office rental.
They worked in several coffee shops.
Tobi lived rent-free at his girlfriend's parents.
He installed software in coffee cafes.
How were the software issues handled?
Tobi found no online snowboard sales software.
Two choices remained:
Change your mind and try something else.
Use his programming expertise to produce something that will aid in the expansion of this company.
Tobi knew he was the sole programmer working on such a project from the start.
“I had this realisation that I’m going to be the only programmer who has ever worked on this, so I don’t have to choose something that lots of people know. I can choose just the best tool for the job…There is been this programming language called Ruby which I just absolutely loved ”
Ruby was open-source and only had Japanese documentation.
Latin is the source code.
Tobi used Ruby twice.
He assumed he could pick the tool this time.
Why not build with Ruby?
How did they find their first time operating a business?
Tobi writes applications in Ruby.
He wrote the initial software version in 2.5 months.
Tobi and Scott founded Snowdevil to sell snowboards.
Tobi coded for 16 hours a day.
His lifestyle was unhealthy.
He enjoyed pizza and coke.
“I would never recommend this to anyone, but at the time there was nothing more interesting to me in the world.”
Their initial purchase and encounter with it
Tobi worked in cafes then.
“I was working in a coffee shop at this time and I remember everything about that day…At some time, while I was writing the software, I had to type the email that the software would send to tell me about the order.”
Tobi recalls everything.
He checked the order on his laptop at the coffee shop.
Pennsylvanian ordered snowboard.
Tobi walked home and called Scott. Tobi told Scott their first order.
They loved the order.
How were people made aware about Snowdevil?
2004 was very different.
Tobi and Scott attempted simple website advertising.
Google AdWords was new.
Ad clicks cost 20 cents.
Online snowboard stores were scarce at the time.
Google ads propelled the snowdevil brand.
Snowdevil prospered.
They swiftly recouped their original investment in the snowboard business because to its high profit margin.
Tobi and Scott struggled with inventories.
“Snowboards had really good profit margins…Our biggest problem was keeping inventory and getting it back…We were out of stock all the time.”
Selling snowboards returned their investment and saved them money.
They did not appoint a business manager.
They accomplished everything alone.
Sales dipped in the spring, but something magical happened.
Spring sales plummeted.
They considered stocking different boards.
They naturally wanted to add boards and grow the business.
However, magic occurred.
Tobi coded and improved software while running Snowdevil.
He modified software constantly. He wanted speedier software.
He experimented to make the software more resilient.
Tobi received emails requesting the Snowdevil license.
They intended to create something similar.
“I didn’t stop programming, I was just like Ok now let me try things, let me make it faster and try different approaches…Increasingly I got people sending me emails and asking me If I would like to licence snowdevil to them. People wanted to start something similar.”
Software or skateboards, your choice
Scott and Tobi had to choose a hobby in 2005.
They might sell alternative boards or use software.
The software was a no-brainer from demand.
Daniel Weinand is invited to join Tobi's business.
Tobis German best friend is Daniel.
Tobi and Scott chose to use the software.
Tobi and Scott kept the software service.
Tobi called Daniel to invite him to Canada to collaborate.
Scott and Tobi had quit snowboarding until then.
How was Shopify launched, and whence did the name come from?
The three chose Shopify.
Named from two words.
First:
Shop
Final part:
Simplify
Shopify
Shopify's crew has always had one goal:
creating software that would make it simple and easy for people to launch online storefronts.
Launched Shopify after raising money for the first time.
Shopify began fundraising in 2005.
First, they borrowed from family and friends.
They needed roughly $200k to run the company efficiently.
$200k was a lot then.
When questioned why they require so much money. Tobi told them to trust him with their goals. The team raised seed money from family and friends.
Shopify.com has a landing page. A demo of their goal was on the landing page.
In 2006, Shopify had about 4,000 emails.
Shopify rented an Ottawa office.
“We sent a blast of emails…Some people signed up just to try it out, which was exciting.”
How things developed after Scott left the company
Shopify co-founder Scott Lake left in 2008.
Scott was CEO.
“He(Scott) realized at some point that where the software industry was going, most of the people who were the CEOs were actually the highly technical person on the founding team.”
Scott leaving the company worried Tobi.
Tobis worried about finding a new CEO.
To Tobi:
A great VC will have the network to identify the perfect CEO for your firm.
Tobi started visiting Silicon Valley to meet with venture capitalists to recruit a CEO.
Initially visiting Silicon Valley
Tobi came to Silicon Valley to start a 20-person company.
This company creates eCommerce store software.
Tobi never wanted a big corporation. He desired a fulfilling existence.
“I stayed in a hostel in the Bay Area. I had one roommate who was also a computer programmer. I bought a bicycle on Craiglist. I was there for a week, but ended up staying two and a half weeks.”
Tobi arrived unprepared.
When venture capitalists asked him business questions.
He answered few queries.
Tobi didn't comprehend VC meetings' terminology.
He wrote the terms down and looked them up.
Some were fascinated after he couldn't answer all these queries.
“I ended up getting the kind of term sheets people dream about…All the offers were conditional on moving our company to Silicon Valley.”
Canada received Tobi.
He wanted to consult his team before deciding. Shopify had five employees at the time.
2008.
A global recession greeted Tobi in Canada. The recession hurt the market.
His term sheets were useless.
The economic downturn in the world provided Shopify with a fantastic opportunity.
The global recession caused significant job losses.
Fired employees had several ideas.
They wanted online stores.
Entrepreneurship was desired. They wanted to quit work.
People took risks and tried new things during the global slump.
Shopify subscribers skyrocketed during the recession.
“In 2009, the company reached neutral cash flow for the first time…We were in a position to think about long-term investments, such as infrastructure projects.”
Then, Tobi Lutke became CEO.
How did Tobi perform as the company's CEO?
“I wasn’t good. My team was very patient with me, but I had a lot to learn…It’s a very subtle job.”
2009–2010.
Tobi limited the company's potential.
He deliberately restrained company growth.
Tobi had one costly problem:
Whether Shopify is a venture or a lifestyle business.
The company's annual revenue approached $1 million.
Tobi battled with the firm and himself despite good revenue.
His wife was supportive, but the responsibility was crushing him.
“It’s a crushing responsibility…People had families and kids…I just couldn’t believe what was going on…My father-in-law gave me money to cover the payroll and it was his life-saving.”
Throughout this trip, everyone supported Tobi.
They believed it.
$7 million in donations received
Tobi couldn't decide if this was a lifestyle or a business.
Shopify struggled with marketing then.
Later, Tobi tried 5 marketing methods.
He told himself that if any marketing method greatly increased their growth, he would call it a venture, otherwise a lifestyle.
The Shopify crew brainstormed and voted on marketing concepts.
Tested.
“Every single idea worked…We did Adwords, published a book on the concept, sponsored a podcast and all the ones we tracked worked.”
To Silicon Valley once more
Shopify marketing concepts worked once.
Tobi returned to Silicon Valley to pitch investors.
He raised $7 million, valuing Shopify at $25 million.
All investors had board seats.
“I find it very helpful…I always had a fantastic relationship with everyone who’s invested in my company…I told them straight that I am not going to pretend I know things, I want you to help me.”
Tobi developed skills via running Shopify.
Shopify had 20 employees.
Leaving his wife's parents' home
Tobi left his wife's parents in 2014.
Tobi had a child.
Shopify has 80,000 customers and 300 staff in 2013.
Public offering in 2015
Shopify investors went public in 2015.
Shopify powers 4.1 million e-Commerce sites.
Shopify stores are 65% US-based.
It is currently valued at $48 billion.
Sammy Abdullah
2 years ago
R&D, S&M, and G&A expense ratios for SaaS
SaaS spending is 40/40/20. 40% of operating expenses should be R&D, 40% sales and marketing, and 20% G&A. We wanted to see the statistics behind the rules of thumb. Since October 2017, 73 SaaS startups have gone public. Perhaps the rule of thumb should be 30/50/20. The data is below.
30/50/20. R&D accounts for 26% of opex, sales and marketing 48%, and G&A 22%. We think R&D/S&M/G&A should be 30/50/20.
There are outliers. There are exceptions to rules of thumb. Dropbox spent 45% on R&D whereas Zoom spent 13%. Zoom spent 73% on S&M, Dropbox 37%, and Bill.com 28%. Snowflake spent 130% of revenue on S&M, while their EBITDA margin is -192%.
G&A shouldn't stand out. Minimize G&A spending. Priorities should be product development and sales. Cloudflare, Sendgrid, Snowflake, and Palantir spend 36%, 34%, 37%, and 43% on G&A.
Another myth is that COGS is 20% of revenue. Median and averages are 29%.
Where is the profitability? Data-driven operating income calculations were simplified (Revenue COGS R&D S&M G&A). 20 of 73 IPO businesses reported operational income. Median and average operating income margins are -21% and -27%.
As long as you're growing fast, have outstanding retention, and marquee clients, you can burn cash since recurring income that doesn't churn is a valuable annuity.
The data was compelling overall. 30/50/20 is the new 40/40/20 for more established SaaS enterprises, unprofitability is alright as long as your business is expanding, and COGS can be somewhat more than 20% of revenue.