Entrepreneurship 101: How to dream big—with your feet on the ground
Hertz Foundation Fellow Dr. Christopher Loose sold his first startup for $80 million. His advice is probably the kind you want to hear.
Christopher Loose, PhD, serves as executive director of Yale University’s Center for Biomedical and Interventional Technology (CBIT). He holds an appointment as assistant professor adjunct of urology in the Yale School of Medicine. He is also a lecturer in entrepreneurship in the School of Management and lecturer in Biomedical Engineering. Additionally, Dr. Loose is an accelerator executive at the Center for Integration of Medicine and Innovative Technology (CIMIT).
Previously, Dr. Loose co-founded Semprus BioSciences with Massachusetts Institute of Technology (MIT) Professors Robert Langer and David Lucchino, and served as chief technology officer until the company was acquired by Teleflex Incorporated in 2012 (TFX: $80M). Semprus Technology was published in Science Translational Medicine and received a Frost and Sullivan Breakthrough Technology Award in 2010. Semprus’s first product, a vascular catheter with a surface modification designed to have reduced thrombus (clot) formation, was FDA-cleared in 2012.
Dr. Loose received the prestigious Hertz Foundation Fellowship and was selected by MIT’s Technology Review as a member of the “TR35,” naming the world’s top 35 innovators under the age of 35. He was awarded the inaugural Peter Strauss Entrepreneurial Award from the Hertz Foundation in 2011 and was also named to Boston Business Journal’s 40 emerging business leaders under 40.
While earning his PhD in chemical engineering at MIT, with his Hertz Fellowship, Dr. Loose co-authored the Semprus Biosciences business plan, which won entrepreneurial competitions at MIT, Harvard University and Oxford University. Prior to his graduate work, Dr. Loose was a chemical engineer at Merck Research Labs after graduating, summa cum laude, with a BSE in chemical engineering from Princeton University.
Chris Loose: As an entrepreneur, focus is critical, especially with a platform technology.
One often knows that you can go after many different product applications, but you ultimately get valued most importantly on the first application you bring forward, and as an entrepreneur you have limited time and limited resources, so you need to choose well and drive deep into clinical and regulatory validation for that first product.
Now, in order to make that often really painful decision about what to invest in and what to leave on the side—at least for a while—there are many aspects of a certain product you need to think through. Obviously market size plays a role. Technical fit to need plays a role.
As I’m looking at new ideas, I often try to follow some of the advice I once got from Bob Langer, who has been very prolific—he has started roughly 50 companies out of his lab, I think, at this point, and I have had the honor of starting two companies with him. Among the other kind of rules of the road he shares, is first: look for a platform company. If you're going to build a company make sure that if you’re successful in one area it can create value in a number of adjacent areas, because that really justifies bringing in the investment, building the whole infrastructure not just for one product but potentially for many.
But within that it's crucially important, and perhaps most important, to select an opportunity that has a very clearly defined first product opportunity that you have the ability to drive to a major value creation event, like a regulatory or a clinical approval.
As you’re building a business you ultimately get valued on that lead asset you’re carrying forward, so it’s important to have a platform but not to lose focus within that platform and make one crucial bet that ultimately can drive the early success of your company.
What really gets me excited is developing new therapies that can help patients. In order to do that you need to think through: who exactly is the patient you’re trying to help? What disease do they have, and what kind of clinical trial could you design that really proves that you’re giving a benefit to that class of patient?
When you do that you have to think through: What type of therapy is practical? How is it given? How frequently and by whom? And understanding that whole pathway from basic discovery to delivering an actual therapeutic requires a great variety of different skills you must bring together.
And early in our startups what we’ve done is first focused on some of the fundamental biology, but then defined: who are the experts along the way that we’re going to need to engage in order to advance all the way through the development, regulatory, and clinical process? And I can’t encourage young innovators enough to think about engaging project development experts and clinical experts early in the discovery process, because that really shapes what you’re trying to discover, and what you’re trying to create that can ultimately help the patient.
As I interact with a lot of young entrepreneurs who are thinking of starting companies, the most important piece of advice I like to give them, particularly on the technical side, is: find someone who has totally different skills from you, that you can trust and will challenge you. It can help you think through the many aspects it takes to build a business or create a new therapy.
For me this was when Bob Langer introduced me to David Lucchino, who in 2005 became my cofounder of my first startup.
And he took me out of the lab, dragged me into the hospital and really started meeting nurses and purchasers and doctors—who are people I never really interacted with at a deep level—so I could start to understand that if we’re to develop a new product, who are all the stakeholders this product would need to satisfy, and how can I understand all of their incentives, all of their constraints?
Because ultimately to get a new product to patients you need to understand the whole delivery system it must go through in order to bring that forward, and who must become champions. And the only way that was going to happen is by that early interaction and introduction to David, who brought a business and marketing and totally different background, but we challenge each other, we have mutual respect, and it has let us build now two businesses that have brought a number of exciting things into the clinic.
In order to enter this industry, particularly as an entrepreneur, as a first-timer, and I was straight out of grad school when I went into my first startup and I really had no experience developing products. The advice I would give is really to engage people who have gone through that product development experience very early on. They’ll have a lot of rules of the road, a lot of mistakes to avoid, and can really help make you successful even if you don’t have the deep domain experience yet. And it’s amazing how much young entrepreneurs who have a passion and enthusiasm and some really big ideas can engage and draw on people who have deep experience even before potentially they could afford them as consultants or employees.
I think, as entrepreneurs are dreaming big, you can share that energy, share that vision, get people involved and really bring in fantastic folks at a very early stage.
One lesson that was imparted to me early in my previous startup was to think very critically about all the testing and all the features that a medical device must go through to be successful. We were essentially creating a new technology to try to make medical devices safer: reducing clots or infection was ultimately our goal for devices that went into the body.
Now, we thought initially as technologists about the new feature we were creating and how powerful it was and how helpful it could be, but as we started to work with experienced product developers they made us realize that these devices were designed with a certain application in mind; they needed to perform certain functions first and foremost, and as we’re adding our new technology, as we’re making our advance, we couldn’t do any harm to the current standard of care as we’re adding new features onto an existing product.
And that even applies in therapeutics, thinking about not in any way falling short of the standard of care in some aspects as you’re trying to improve another aspect is very important, and experienced product developers can really help you understand that process.
In order to drive new innovative medicines to the clinic, a critical aspect of this is developing a strong intellectual property position because of the great resources required to advanced a medicine. It can be hundreds of millions of dollars to advance from concept through trials, and even billions of dollars before ultimate launch of a product. In order to justify those kinds of investments one needs to be able to have a product that one can protect for a period of time on the market.
The benefits of the patent system are—essentially it’s a trade. For a period of time you’re granted that right to be able to have exclusive access to sell a certain medicine, but in trade for that essentially you have to disclose to the world, “Here is exactly how we did it,” and it can let the world start thinking pretty quickly about: how can they do better? And at the end of the day whole fields of science advance, new medicines move forward, and as things become generic, medicines continue to reach a broader and broader patient population.
Hertz Foundation Fellow Dr. Christopher Loose sold his first startup for $80 million in 2012, and co-founded his second startup, Frequency Therapeutics Inc., in 2015, which is developing methods to restore hearing loss, with greater applications in human regenerative medicine. Even if you aren't in the field of medicine, innovators of any kind looking to found their first startup will benefit from his experience and advice on mentorship, building a balanced team, consulting experts, and how to develop the right first product—one that the rest of your career might be valued on. The Hertz Foundation mission is to provide unique financial and fellowship support to the nation's most remarkable PhD students in the hard sciences. Hertz Fellowships are among the most prestigious in the world, and the foundation has invested over $200 million in Hertz Fellows since 1963 (present value) and supported over 1,100 brilliant and creative young scientists, who have gone on to become Nobel laureates, high-ranking military personnel, astronauts, inventors, Silicon Valley leaders, and tenured university professors. For more information, visit hertzfoundation.org.
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How imagining the worst case scenario can help calm anxiety.
- Stoicism is the philosophy that nothing about the world is good or bad in itself, and that we have control over both our judgments and our reactions to things.
- It is hardest to control our reactions to the things that come unexpectedly.
- By meditating every day on the "worst case scenario," we can take the sting out of the worst that life can throw our way.
Are you a worrier? Do you imagine nightmare scenarios and then get worked up and anxious about them? Does your mind get caught in a horrible spiral of catastrophizing over even the smallest of things? Worrying, particularly imagining the worst case scenario, seems to be a natural part of being human and comes easily to a lot of us. It's awful, perhaps even dangerous, when we do it.
But, there might just be an ancient wisdom that can help. It involves reframing this attitude for the better, and it comes from Stoicism. It's called "premeditation," and it could be the most useful trick we can learn.
Broadly speaking, Stoicism is the philosophy of choosing your judgments. Stoics believe that there is nothing about the universe that can be called good or bad, valuable or valueless, in itself. It's we who add these values to things. As Shakespeare's Hamlet says, "There is nothing either good or bad, but thinking makes it so." Our minds color the things we encounter as being "good" or "bad," and given that we control our minds, we therefore have control over all of our negative feelings.
Put another way, Stoicism maintains that there's a gap between our experience of an event and our judgment of it. For instance, if someone calls you a smelly goat, you have an opportunity, however small and hard it might be, to pause and ask yourself, "How will I judge this?" What's more, you can even ask, "How will I respond?" We have power over which thoughts we entertain and the final say on our actions. Today, Stoicism has influenced and finds modern expression in the hugely effective "cognitive behavioral therapy."
Helping you practice StoicismCredit: Robyn Beck via Getty Images
One of the principal fathers of ancient Stoicism was the Roman statesmen, Seneca, who argued that the unexpected and unforeseen blows of life are the hardest to take control over. The shock of a misfortune can strip away the power we have to choose our reaction. For instance, being burglarized feels so horrible because we had felt so safe at home. A stomach ache, out of the blue, is harder than a stitch thirty minutes into a run. A sudden bang makes us jump, but a firework makes us smile. Fell swoops hurt more than known hardships.
What could possibly go wrong?
So, how can we resolve this? Seneca suggests a Stoic technique called "premeditatio malorum" or "premeditation." At the start of every day, we ought to take time to indulge our anxious and catastrophizing mind. We should "rehearse in the mind: exile, torture, war, shipwreck." We should meditate on the worst things that could happen: your partner will leave you, your boss will fire you, your house will burn down. Maybe, even, you'll die.
This might sound depressing, but the important thing is that we do not stop there.
Stoicism has influenced and finds modern expression in the hugely effective "cognitive behavioral therapy."
The Stoic also rehearses how they will react to these things as they come up. For instance, another Stoic (and Roman Emperor) Marcus Aurelius asks us to imagine all the mean, rude, selfish, and boorish people we'll come across today. Then, in our heads, we script how we'll respond when we meet them. We can shrug off their meanness, smile at their rudeness, and refuse to be "implicated in what is degrading." Thus prepared, we take control again of our reactions and behavior.
The Stoics cast themselves into the darkest and most desperate of conditions but then realize that they can and will endure. With premeditation, the Stoic is prepared and has the mental vigor necessary to take the blow on the chin and say, "Yep, l can deal with this."
Catastrophizing as a method of mental inoculation
Seneca wrote: "In times of peace, the soldier carries out maneuvers." This is also true of premeditation, which acts as the war room or training ground. The agonizing cut of the unexpected is blunted by preparedness. We can prepare the mind for whatever trials may come, in just the same way we can prepare the body for some endurance activity. The world can throw nothing as bad as that which our minds have already imagined.
Stoicism teaches us to embrace our worrying mind but to embrace it as a kind of inoculation. With a frown over breakfast, try to spend five minutes of your day deliberately catastrophizing. Get your anti-anxiety battle plan ready and then face the world.
A study on charity finds that reminding people how nice it feels to give yields better results than appealing to altruism.
- A study finds asking for donations by appealing to the donor's self-interest may result in more money than appealing to their better nature.
- Those who received an appeal to self-interest were both more likely to give and gave more than those in the control group.
- The effect was most pronounced for those who hadn't given before.
Even the best charities with the longest records of doing great fundraising work have to spend some time making sure that the next donation checks will keep coming in. One way to do this is by showing potential donors all the good things the charity did over the previous year. But there may be a better way.
A new study by researchers in the United States and Australia suggests that appealing to the benefits people will receive themselves after a donation nudges them to donate more money than appealing to the greater good.
How to get people to give away free money
The postcards that were sent to different study subjects. The one on the left highlighted benefits to the self, while the one on the right highlighted benefits to others.List et al. / Nature Human Behaviour
The study, published in Nature Human Behaviour, utilized the Pick.Click.Give program in Alaska. This program allows Alaska residents who qualify for dividends from the Alaska Permanent Fund, a yearly payment ranging from $800 to $2000 in recent years, to donate a portion of it to various in-state non-profit organizations.
The researchers randomly assigned households to either a control group or to receive a postcard in the mail encouraging them to donate a portion of their dividend to charity. That postcard could come in one of two forms, either highlighting the benefits to others or the benefits to themselves.
Those who got the postcard touting self-benefits were 6.6 percent more likely to give than those in the control group and gave 23 percent more on average. Those getting the benefits-to-others postcard were slightly more likely to give than those receiving no postcard, but their donations were no larger.
Additionally, the researchers were able to break the subject list down into a "warm list" of those who had given at least once before in the last two years and a "cold list" of those who had not. Those on the warm list, who were already giving, saw only minor increases in their likelihood to donate after getting a postcard in the mail compared to those on the cold list.
Additionally, the researchers found that warm-list subjects who received the self-interest postcard gave 11 percent more than warm-list subjects in the control group. Amazingly, among cold-list subjects, those who received a self-interest postcard gave 39 percent more.
These are substantial improvements. At the end of the study, the authors point out, "If we had sent the benefits to self message to all households in the state, aggregate contributions would have increased by nearly US$600,000."
To put this into perspective, in 2017 the total donations to the program were roughly $2,700,000.
Is altruism dead?
Are all actions inherently self-interested? Thankfully, no. The study focuses entirely on effective ways to increase charitable donations above levels that currently exist. It doesn't deny that some people are giving out of pure altruism, but rather that an appeal based on self-interest is effective. Plenty of people were giving before this study took place who didn't need a postcard as encouragement. It is also possible that some people donated part of their dividend check to a charity that does not work with Pick.Click.Give and were uncounted here.
It is also important to note that Pick.Click.Give does not provide services but instead gives money to a wide variety of organizations that do. Those organizations operate in fields from animal rescue to job training to public broadcasting. The authors note that it is possible that a more specific appeal to the benefits others will receive from a donation might prove more effective than the generic and all-inclusive "Make Alaska Better For Everyone" appeal that they used.
In an ideal world, charity is its own reward. In ours, it might help to remind somebody how warm and fuzzy they'll feel after donating to your cause.
Inventions with revolutionary potential made by a mysterious aerospace engineer for the U.S. Navy come to light.
- U.S. Navy holds patents for enigmatic inventions by aerospace engineer Dr. Salvatore Pais.
- Pais came up with technology that can "engineer" reality, devising an ultrafast craft, a fusion reactor, and more.
- While mostly theoretical at this point, the inventions could transform energy, space, and military sectors.
The U.S. Navy controls patents for some futuristic and outlandish technologies, some of which, dubbed "the UFO patents," came to life recently. Of particular note are inventions by the somewhat mysterious Dr. Salvatore Cezar Pais, whose tech claims to be able to "engineer reality." His slate of highly-ambitious, borderline sci-fi designs meant for use by the U.S. government range from gravitational wave generators and compact fusion reactors to next-gen hybrid aerospace-underwater crafts with revolutionary propulsion systems, and beyond.
Of course, the existence of patents does not mean these technologies have actually been created, but there is evidence that some demonstrations of operability have been successfully carried out. As investigated and reported by The War Zone, a possible reason why some of the patents may have been taken on by the Navy is that the Chinese military may also be developing similar advanced gadgets.
Among Dr. Pais's patents are designs, approved in 2018, for an aerospace-underwater craft of incredible speed and maneuverability. This cone-shaped vehicle can potentially fly just as well anywhere it may be, whether air, water or space, without leaving any heat signatures. It can achieve this by creating a quantum vacuum around itself with a very dense polarized energy field. This vacuum would allow it to repel any molecule the craft comes in contact with, no matter the medium. Manipulating "quantum field fluctuations in the local vacuum energy state," would help reduce the craft's inertia. The polarized vacuum would dramatically decrease any elemental resistance and lead to "extreme speeds," claims the paper.
Not only that, if the vacuum-creating technology can be engineered, we'd also be able to "engineer the fabric of our reality at the most fundamental level," states the patent. This would lead to major advancements in aerospace propulsion and generating power. Not to mention other reality-changing outcomes that come to mind.
Among Pais's other patents are inventions that stem from similar thinking, outlining pieces of technology necessary to make his creations come to fruition. His paper presented in 2019, titled "Room Temperature Superconducting System for Use on a Hybrid Aerospace Undersea Craft," proposes a system that can achieve superconductivity at room temperatures. This would become "a highly disruptive technology, capable of a total paradigm change in Science and Technology," conveys Pais.
High frequency gravitational wave generator.
Credit: Dr. Salvatore Pais
Another invention devised by Pais is an electromagnetic field generator that could generate "an impenetrable defensive shield to sea and land as well as space-based military and civilian assets." This shield could protect from threats like anti-ship ballistic missiles, cruise missiles that evade radar, coronal mass ejections, military satellites, and even asteroids.
Dr. Pais's ideas center around the phenomenon he dubbed "The Pais Effect". He referred to it in his writings as the "controlled motion of electrically charged matter (from solid to plasma) via accelerated spin and/or accelerated vibration under rapid (yet smooth) acceleration-deceleration-acceleration transients." In less jargon-heavy terms, Pais claims to have figured out how to spin electromagnetic fields in order to contain a fusion reaction – an accomplishment that would lead to a tremendous change in power consumption and an abundance of energy.
According to his bio in a recently published paper on a new Plasma Compression Fusion Device, which could transform energy production, Dr. Pais is a mechanical and aerospace engineer working at the Naval Air Warfare Center Aircraft Division (NAWCAD), which is headquartered in Patuxent River, Maryland. Holding a Ph.D. from Case Western Reserve University in Cleveland, Ohio, Pais was a NASA Research Fellow and worked with Northrop Grumman Aerospace Systems. His current Department of Defense work involves his "advanced knowledge of theory, analysis, and modern experimental and computational methods in aerodynamics, along with an understanding of air-vehicle and missile design, especially in the domain of hypersonic power plant and vehicle design." He also has expert knowledge of electrooptics, emerging quantum technologies (laser power generation in particular), high-energy electromagnetic field generation, and the "breakthrough field of room temperature superconductivity, as related to advanced field propulsion."
Suffice it to say, with such a list of research credentials that would make Nikola Tesla proud, Dr. Pais seems well-positioned to carry out groundbreaking work.
A craft using an inertial mass reduction device.
Credit: Salvatore Pais
The patents won't necessarily lead to these technologies ever seeing the light of day. The research has its share of detractors and nonbelievers among other scientists, who think the amount of energy required for the fields described by Pais and his ideas on electromagnetic propulsions are well beyond the scope of current tech and are nearly impossible. Yet investigators at The War Zone found comments from Navy officials that indicate the inventions are being looked at seriously enough, and some tests are taking place.
If you'd like to read through Pais's patents yourself, check them out here.
Laser Augmented Turbojet Propulsion System
Credit: Dr. Salvatore Pais
The 'Monkeydactyl' was a flying reptile that evolved highly specialized adaptations in the Mesozoic Era.
- The 'Monkeydactly', or Kunpengopterus antipollicatus, was a species of pterosaur, a group of flying reptiles that were the first vertebrates to evolve the ability of powered flight.
- In a recent study, a team of researchers used microcomputed tomography scanning to analyze the anatomy of the newly discovered species, finding that it was the first known species to develop opposable thumbs.
- As highly specialized dinosaurs, pterosaurs boasted unusual anatomy that gave them special advantages as aerial predators in the Mesozoic Era.
A newly discovered flying dinosaur nicknamed "Monkeydactyl" is the oldest known creature that evolved opposable thumbs, according to new research published in Current Biology.
The 160-million-year-old reptile is officially named Kunpengopterus antipollicatus. Discovered in China, the dinosaur was a darwinopteran pterosaur, a subgroup of pterosaurs, which first appeared 215 million years ago during the Triassic Period. Pterosaurs, like the pterodactyl, were the first vertebrates to evolve the ability of powered flight.
But unlike other pterosaurs, the Monkeydactyl was the only species in its group known to have opposable thumbs. It's a rare adaptation for non-mammals: The only extant examples are chameleons and some species of tree frogs. (Most birds have at least one opposable digit, though that digit is usually classified as a hallux, not a pollex, which means "thumb" in Latin.)
To analyze the anatomy of K. antipollicatus, an international team of researchers used microcomputed tomography scanning, which generates images of the inside of the body.
"The fingers of 'Monkeydactyl' are tiny and partly embedded in the slab," study co-author Fion Waisum Ma said in a press release. "Thanks to micro-CT scanning, we could see through the rocks, create digital models, and tell how the opposed thumb articulates with the other finger bones."
"This is an interesting discovery. It provides the earliest evidence of a true opposed thumb, and it is from a pterosaur — which wasn't known for having an opposed thumb."
As a tree-dwelling reptile, the Monkeydactyl probably evolved opposable thumbs so it could grasp tree branches, which would have helped it hang, avoid falls, and obtain food. This arboreal (tree-dwelling) locomotion would help the Monkeydactyl adapt to its home ecosystem, the subtropical forests of the Tiaojishan Formation in China during the Jurassic Period.
The researchers noted that the forests of the Tiaojishan Formation were likely warm and humid, thriving with "a rich and complex" diversity of tree-dwelling animals. But while the forests were home to multiple pterosaur species, the Monkeydactyl was likely the only one that was arboreal, spending most of its time in the treetops, while other pterosaurs occupied different levels of the forest.
K. antipollicatus and its phylogenetic position. (A and B) Holotype specimen BPMC 0042 (A) and a schematic skeletal drawing (B). Scale bars, 50 mm.Credit: Zhou et al.
This process — in which competing species manage to coexist by using the environment in different ways — is called "niche partitioning."
"Tiaojishan palaeoforest is home to many organisms, including three genera of darwinopteran pterosaurs," study author Xuanyu Zhou said in the press release. "Our results show that K. antipollicatus has occupied a different niche from Darwinopterus and Wukongopterus, which has likely minimized competition among these pterosaurs."
In general, pterosaurs are a prime example of how animals can evolve remarkably specialized adaptations. As pioneers of vertebrate flight, pterosaurs had strong and lightweight skeletons that ranged widely in size, with some boasting wingspans of more than 30 feet. The largest pterosaurs weighed more than 650 pounds and had jaws twice the length of Tyrannosaurus rex.
Unlike birds, which jump into the air using only their hind limbs, pterosaurs used their exceptionally strong hind limbs and forelimbs to push off the ground and gain enough launch power for flight. That these massive dinosaurs managed to fly, and did so successfully for about 80 million years, has long fascinated and puzzled scientists.The recent discovery shows that pterosaurs developed even more remarkable adaptations than previously thought, suggesting there's still more to learn about the "monsters of the Mesozoic skies."