Michael Kauffman: Cancer, Drug Development, and Market Capitalism (Manifold Podcast #48)

Note: the part of the conversation I found most interesting -- venture and capital markets aspects of drug discovery, complexity and scale of biotech ecosystems, role of IP and US healthcare spending to incentivize discovery -- begins at ~35m.

Steve and Corey speak with Dr. Michael Kauffman, co-founder and CEO of Karyopharm Therapeutics, about cancer and biotech innovation. Michael explains how he and Dr. Sharon Schacham tested her idea regarding cellular nuclear-transport using simulation software on a home laptop, and went on to beat 1000:1 odds to create a billion dollar company. They discuss the relationship between high proprietary drug costs and economic incentives for drug discovery. They also discuss the unique US biotech ecosystem, and why innovation is easier in small (vs. large) companies. Michael explains how Karyopharm is targeting its drug at COVID-induced inflammation to treat people with severe forms of the disease.

Transcript

Michael Kauffman (Bio)

Karyopharm's Publications and Presentations

The Great American Drug Deal: A New Prescription for Innovative and Affordable Medicines by Peter Kolchinsky


man·i·fold /ˈmanəˌfōld/ many and various.

In mathematics, a manifold is a topological space that locally resembles Euclidean space near each point.

Steve Hsu and Corey Washington have been friends for almost 30 years, and between them hold PhDs in Neuroscience, Philosophy, and Theoretical Physics. Join them for wide ranging and unfiltered conversations with leading writers, scientists, technologists, academics, entrepreneurs, investors, and more.

Steve Hsu is VP for Research and Professor of Theoretical Physics at Michigan State University. He is also a researcher in computational genomics and founder of several Silicon Valley startups, ranging from information security to biotech. Educated at Caltech and Berkeley, he was a Harvard Junior Fellow and held faculty positions at Yale and the University of Oregon before joining MSU.

Corey Washington is Director of Analytics in the Office of Research and Innovation at Michigan State University. He was educated at Amherst College and MIT before receiving a PhD in Philosophy from Stanford and a PhD in a Neuroscience from Columbia. He held faculty positions at the University Washington and the University of Maryland. Prior to MSU, Corey worked as a biotech consultant and is founder of a medical diagnostics startup.

Robert Atkinson on US-China Competition and Industrial Policy - Manifold Episode #45

Steve and Corey talk with Robert Atkinson, President of the Information Technology and Innovation Foundation about his philosophy of National Developmentalism. They discuss the history of industrial policy and mercantilism in the US and China. Why did the US lose 1/3 of its manufacturing jobs in the 2000s? How much was due to automation and how much to Chinese competition? Atkinson discusses US R&D and recommends policies that will help the US compete with China.

Other topics: Forced technology transfer, IP theft, semiconductors and Micron technologies (DRAM), why the WTO cannot handle misbehavior by China.

Transcript

Robert Atkinson (Bio)

Information Technology and Innovation Foundation (ITIF)

Big is Beautiful: Debunking the Mythology of Small Business (MIT Press, 2018)

Innovation Economics: The Race for Global Advantage (Yale, 2012)


man·i·fold /ˈmanəˌfōld/ many and various.

In mathematics, a manifold is a topological space that locally resembles Euclidean space near each point.

Steve Hsu and Corey Washington have been friends for almost 30 years, and between them hold PhDs in Neuroscience, Philosophy, and Theoretical Physics. Join them for wide ranging and unfiltered conversations with leading writers, scientists, technologists, academics, entrepreneurs, investors, and more.

Steve Hsu is VP for Research and Professor of Theoretical Physics at Michigan State University. He is also a researcher in computational genomics and founder of several Silicon Valley startups, ranging from information security to biotech. Educated at Caltech and Berkeley, he was a Harvard Junior Fellow and held faculty positions at Yale and the University of Oregon before joining MSU.

Corey Washington is Director of Analytics in the Office of Research and Innovation at Michigan State University. He was educated at Amherst College and MIT before receiving a PhD in Philosophy from Stanford and a PhD in a Neuroscience from Columbia. He held faculty positions at the University Washington and the University of Maryland. Prior to MSU, Corey worked as a biotech consultant and is founder of a medical diagnostics startup.

CRISPR patent fight

Earlier CRISPR posts. MSU symposium with video. Patrick Hsu, one of the speakers (no relation), is from the Zhang lab.

Technology Review: Discovery of the Century?

There’s a bitter fight over the patents for CRISPR, a breakthrough new form of DNA editing.

... In April of this year, Zhang and the Broad won the first of several sweeping patents that cover using CRISPR in eukaryotes—or any species whose cells contain a nucleus (see “Broad Institute Gets Patent on Revolutionary Gene-Editing Method”). That meant that they’d won the rights to use CRISPR in mice, pigs, cattle, humans—in essence, in every creature other than bacteria.

The patent came as a shock to some. That was because Broad had paid extra to get it reviewed very quickly, in less than six months, and few knew it was coming. Along with the patent came more than 1,000 pages of documents. According to Zhang, Doudna’s predictions in her own earlier patent application that her discovery would work in humans was “mere conjecture” and that, instead, he was the first to show it, in a separate and “surprising” act of invention.

The patent documents have caused consternation. The scientific literature shows that several scientists managed to get CRISPR to work in human cells. In fact, its easy reproducibility in different organisms is the technology’s most exciting hallmark. That would suggest that, in patent terms, it was “obvious” that CRISPR would work in human cells, and that Zhang’s invention might not be worthy of its own patent.

What’s more, there’s scientific credit at stake. In order to show he was “first to invent” the use of CRISPR-Cas in human cells, Zhang supplied snapshots of lab notebooks that he says show he had the system up and running in early 2012, even before Doudna and Charpentier published their results or filed their own patent application. That timeline would mean he hit on the CRISPR-Cas editing system independently. In an interview, Zhang affirmed he’d made the discoveries on his own. Asked what he’d learned from Doudna and Charpentier’s paper, he said “not much.”

Not everyone is convinced. “All I can say is that we did it in my lab with Jennifer Doudna,” says Charpentier, now a professor at the Helmholtz Centre for Infection Research and Hannover Medical School in Germany. “Everything here is very exaggerated because this is one of those unique cases of a technology that people can really pick up easily, and it’s changing researchers’ lives. Things are happening fast, maybe a bit too fast.”

Among the patent trolls

This American Life makes the case that Intellectual Ventures are patent trolls cum extortionists. Thanks to a reader for sending me the link. See also this earlier post which examines Malcolm Gladwell's New Yorker article on Nathan Myhrvold and IV. (Gladwell, as usual, gets it all wrong.)

Transcript: ... Alex: We told Intellectual Ventures that Chris Sacca compared their business to a mafia shakedown and in an e-mail, Peter Detkin called that ridiculous and offensive. He then reiterated some of the arguments you’ve heard about how IV protects inventors and went on to say, “We’re a disruptive company that’s providing a way for patent-holders to recognize value.” (By “recognize value,” he means “make money.”) “That wasn’t available before we came on the scene, and we are making a big impact on the market. That obviously makes people uncomfortable. But no amount of name-calling changes the fact that ideas have value.”

Laura: True enough, but lately it seems like a lot of butcher shops have been burning. As we were reporting this story, more and more Intellectual Ventures patents started showing up in the hands of companies like Oasis, companies without employees or operations, who were formed for the purpose of filing lawsuits. They’re known as nonpracticing entities or NPE’s.


... that’s based just on the math of IV’s business model. In order to purchase its 35,000 patents, Intellectual Ventures got money from investors. A lot of money. More than $5 billion dollars.

Laura: And a lot of these investors are venture capitalists who expect very high returns. These are people who are looking for the next Google, the next Apple. People who want to get back many times what they put in. Since its founding in 2000, Intellectual Ventures has generated $2 billion dollars in revenue. But to keep its investors happy, over the next 10 years, says Tom Ewing, they’re going to have to do a lot better than that.

Ewing: So if you calculate this out, that means that over say a 10-year period they’re going to need to collect about $35 billion dollars in licensing revenue, in order for them to be successful among the people who they’re trying to compare themselves with. IV seems to have signed a number of deals. If the stream of deals they’re signing doesn’t increase significantly, then I would imagine they will be forced to file more litigations in order to achieve their revenue targets.

Laura: Tom’s prediction already seems to be coming true. Earlier this month, Intellectual Ventures itself filed a patent infringement suit in federal court against several companies it claimed were infringing some patents it owns.

Laura: In early July, the bankrupt tech company Nortel put its 6,000 patents up for auction as part of a liquidation. A bidding war broke out between the Silicon Valley powerhouses. Google said in press accounts that it wanted the patents purely to defend itself against lawsuits and it was willing to spend over $3 billion dollars to get them. But that wasn’t enough. The portfolio eventually sold to Apple and a strange consortium of other tech companies, including Apple competitor Microsoft.* The price tag? 4.5 billion dollars. Five times the opening bid. More than double what most people were expecting. The largest patent auction in history.

Alex: Think of that — 4.5 billion dollars on patents that these companies almost certainly don’t want for their technical secrets. That 4.5 billion dollars won’t build anything new, won’t bring new products to the shelves, won’t open up new factories that can hire people who need jobs. That’s 4.5 billion dollars that adds to the price of every product these companies sell you — 4.5 billion dollars essentially wasted, buying arms for an ongoing patent war. The big companies, Google, Apple, Microsoft, will probably survive this war. The likely casualties, the companies out there now that no one’s ever heard of that could one day take their place.

The education of Nathan Myhrvold

I came across this long 1998 interview with Nathan Myhrvold, which covers his childhood, education as a physicist, brief postdoc with Hawking, software startup and its acquisition by Microsoft, subsequent role there including the creation of Microsoft Research.

NM: Initially I wanted to go on in math. I talked to a professor at UCLA and they said the two best schools for mathematics were Princeton and Berkeley. I have been bad about procrastinating. So I put off applying, and I applied only to those two schools, which, if my kids do that, I’ll kill them. Of course they should apply to many, many schools, and they should keep their options open. I only applied to those two, and I got into both of them. I decided to go Princeton and I decided applied math was more interesting than pure math. So I went into this applied math program that could let you do whole variety of different things.

So the next degree I got was a master’s degree in mathematical economics. Then I finally got a Ph.D. in theoretical physics. A friend of mine said that I was trying to have more degrees than a thermometer. And they’re all on different topics, which in a way was a mistake because I could have been out much sooner if I had concentrated and focused on just one area.

DA: You were still in your young, early twenties.

NM: I was 23 so it wasn’t like I wasted that much time. And I’m glad I did because it was great to see all of these other fields and learn something about them.

DA: Were you considering spending your career as an academic?

NM: Oh absolutely, that was the only thing. I’m sure if you had interviewed me when I was in graduate school at Princeton, I would have been very full of myself about that. And I would explain in an enormous, articulate way about what else would one do? You know, what greater thing could one aspire to? But of course I’m not there.

...

NM: ... People have a lot of metaphors for entrepreneurship. I like two of those metaphors. One is white water rafting, and I say white water rafting because you have a skill in rafting that counts for something. I know a number of people that are great rafters. But you’re also going on this wild river, and the current is going, and you’re going to get splashed, and wet and thrown, and even the best rafters have been thrown out of the raft and capsized and everything else. It’s partially under your control, and it’s partially not under your control. And a lot of people don’t realize that.

I talked to a lot of people when I first started this company. There was a venture capitalist who had been an entrepreneur, and he was full of sage advice. I remember I was in his office, which was in the Bank America Tower in San Francisco. It was on the 50th floor with this stunning view. And he says, “You know, having a company is like having a baby.”

I said, “Okay.” He says, “No, no, no, it’s not like what you’re thinking. You’re thinking it’s like the man’s role in having a baby, a half hour of fun, and nine months later you pass out cigars and you’re a proud father.” He said, “No, it’s like the woman’s role in having a baby. It’s nine months of incredible discomfort and pain and all this; and then the hard work starts.” And I have to say he was right. You know at the time I listened to him. I heard him out. I didn’t realize how true that was.

...

DA: Did the whole company go to Microsoft?

NM: Yes, well most of the company came. There were about 15 people who were employees, and a whole bunch of them were part time. The eight full time people all came, and we weren’t sure how long it was going to last. We weren’t sure whether we would like Seattle. We weren’t sure whether Microsoft really would like us once they saw us up close. It turns out this group had an illustrious career at Microsoft. I’m still here. My brother Cameron is a Vice President here at Microsoft. He actually didn’t join when we first came up. He was the only full time guy not to join. He went back to Berkeley and finished up that last quarter, and joined the following year. The guy who’s the technical lead on Windows 3.1, Windows 95, and is now technical lead for natural language in the company, came from my company. The guy who is the technical lead for graphics and Windows NT came from my company. The guy who’s the technical lead for multi-media for a long time at Microsoft, came from my company. These eight guys that came up, all had stellar careers. We sort of spread out throughout Microsoft and wound up in very senior
positions. ...

See here for a NYTimes update on his company Intellectual Ventures, also discussed in this earlier blog post: Gladwell amongst the patent trolls.

Gladwell amongst the patent trolls

Malcolm Gladwell writes about Nathan Myhrvold's company Intellectual Ventures in the recent New Yorker. (Myhrvold is the former cosmologist who left physics and eventually became consigliere to Bill Gates, founding Microsoft Research and charting Microsoft's blue sky research direction. He famously missed the importance of the Internet until the mid 90's.) If you read this blog often, you know my opinion about Gladwell: he has a good nose for interesting topics, but not enough brainpower or common sense for reliable analysis. The same is true here: he produces an interesting profile of Myhrvold (although see here for a much better one from 1997 by Ken Auletta) and friends, but seems to entirely miss a number of important points. Intellectual Ventures is not about real inventions, but about patenting around ideas so that they have a future claim on the ones that turn out the be useful. In other words, they are patent trolls. Gladwell does not seem to realize the difference between rampant speculation and true invention: the hours of painstaking work in the lab required to convert an idea into reality.

Here's an excerpt about how the "invention" process works -- get some smart guys in a room and let them talk (every theory group lounge is a fount of commercializable ideas ;-). Yes! if your inventors are smart enough, they can produce 36 new inventions at dinner! Is this a statement about real innovation, or about what a patent attorney might manage to get the understaffed, overburdened USPTO to approve? It makes a mockery of what real inventors and innovators do. Why start a company and hire engineers to build a prototype? Just get a few lawyers and patent everything in sight...

How useful is it to have a group of really smart people brainstorm for a day? When Myhrvold started out, his expectations were modest. Although he wanted insights like Alexander Graham Bell’s, Bell was clearly one in a million, a genius who went on to have ideas in an extraordinary number of areas—sound recording, flight, lasers, tetrahedral construction, and hydrofoil boats, to name a few. ...

But then, in August of 2003, I.V. held its first invention session, and it was a revelation. “Afterward, Nathan kept saying, ‘There are so many inventions,’ ” Wood recalled. “He thought if we came up with a half-dozen good ideas it would be great, and we came up with somewhere between fifty and a hundred. I said to him, ‘But you had eight people in that room who are seasoned inventors. Weren’t you expecting a multiplier effect?’ And he said, ‘Yeah, but it was more than multiplicity.’ Not even Nathan had any idea of what it was going to be like.”

The original expectation was that I.V. would file a hundred patents a year. Currently, it’s filing five hundred a year. It has a backlog of three thousand ideas. Wood said that he once attended a two-day invention session presided over by Jung, and after the first day the group went out to dinner. “So Edward took his people out, plus me,” Wood said. “And the eight of us sat down at a table and the attorney said, ‘Do you mind if I record the evening?’ And we all said no, of course not. We sat there. It was a long dinner. I thought we were lightly chewing the rag. But the next day the attorney comes up with eight single-spaced pages flagging thirty-six different inventions from dinner. Dinner.”

For the cognoscenti out there, yes, the Wood mentioned in the article is none other than Star Warrior Lowell Wood, former head of the zany (useless?) O Group (NYTimes 1984) at Livermore. Wood is perfect for Myhrvold's purposes -- for decades his group bamboozled the US defense establishment with wild ideas that cost taxpayers billions of dollars. Follow the link to the Times article and tell me how many of the ideas mentioned turned into something useful, now almost a quarter century later.

Rather than leave you with a completely negative impression of the article, I include the following excerpt, which has Wood noticing something about cancer cells in the bloodstream that seems to have eluded biologists and medical researchers for some time. It is true that there are great ideas out there just waiting to be discovered, but lots of people can have the same idea. The hard part is making the idea into a practical, commercially viable reality.

...Last March, Myhrvold decided to do an invention session with Eric Leuthardt and several other physicians in St. Louis. Rod Hyde came, along with a scientist from M.I.T. named Ed Boyden. Wood was there as well.

“Lowell came in looking like the Cheshire Cat,” Myhrvold recalled. “He said, ‘I have a question for everyone. You have a tumor, and the tumor becomes metastatic, and it sheds metastatic cancer cells. How long do those circulate in the bloodstream before they land?’ And we all said, ‘We don’t know. Ten times?’ ‘No,’ he said. ‘As many as a million times.’ Isn’t that amazing? If you had no time, you’d be screwed. But it turns out that these cells are in your blood for as long as a year before they land somewhere. What that says is that you’ve got a chance to intercept them.”

How did Wood come to this conclusion? He had run across a stray fact in a recent issue of The New England Journal of Medicine. “It was an article that talked about, at one point, the number of cancer cells per millilitre of blood,” he said. “And I looked at that figure and said, ‘Something’s wrong here. That can’t possibly be true.’ The number was incredibly high. Too high. It has to be one cell in a hundred litres, not what they were saying—one cell in a millilitre. Yet they spoke of it so confidently. I clicked through to the references. It was a commonplace. There really were that many cancer cells.”

Wood did some arithmetic. He knew that human beings have only about five litres of blood. He knew that the heart pumps close to a hundred millilitres of blood per beat, which means that all of our blood circulates through our bloodstream in a matter of minutes. The New England Journal article was about metastatic breast cancer, and it seemed to Wood that when women die of metastatic breast cancer they don’t die with thousands of tumors. The vast majority of circulating cancer cells don’t do anything.

“It turns out that some small per cent of tumor cells are actually the deadly ones,” he went on. “Tumor stem cells are what really initiate metastases. And isn’t it astonishing that they have to turn over at least ten thousand times before they can find a happy home? You naïvely think it’s once or twice or three times. Maybe five times at most. It isn’t. In other words, metastatic cancer—the brand of cancer that kills us—is an amazingly hard thing to initiate. Which strongly suggests that if you tip things just a little bit you essentially turn off the process.”

That was the idea that Wood presented to the room in St. Louis. From there, the discussion raced ahead. Myhrvold and his inventors had already done a lot of thinking about using tiny optical filters capable of identifying and zapping microscopic particles. They also knew that finding cancer cells in blood is not hard. They’re often the wrong size or the wrong shape. So what if you slid a tiny filter into a blood vessel of a cancer patient? “You don’t have to intercept very much of the blood for it to work,” Wood went on. “Maybe one ten-thousandth of it. The filter could be put in a little tiny vein in the back of the hand, because that’s all you need. Or maybe I intercept all of the blood, but then it doesn’t have to be a particularly efficient filter.”

Wood was a physicist, not a doctor, but that wasn’t necessarily a liability, at this stage. “People in biology and medicine don’t do arithmetic,” he said. He wasn’t being critical of biologists and physicians: this was, after all, a man who read medical journals for fun. He meant that the traditions of medicine encouraged qualitative observation and interpretation. But what physicists do—out of sheer force of habit and training—is measure things and compare measurements, and do the math to put measurements in context. At that moment, while reading The New England Journal, Wood had the advantages of someone looking at a familiar fact with a fresh perspective.

That was also why Myhrvold had wanted to take his crew to St. Louis to meet with the surgeons. He likes to say that the only time a physicist and a brain surgeon meet is when the physicist is about to be cut open—and to his mind that made no sense. Surgeons had all kinds of problems that they didn’t realize had solutions, and physicists had all kinds of solutions to things that they didn’t realize were problems. At one point, Myhrvold asked the surgeons what, in a perfect world, would make their lives easier, and they said that they wanted an X-ray that went only skin deep. They wanted to know, before they made their first incision, what was just below the surface. When the Intellectual Ventures crew heard that, their response was amazement. “That’s your dream? A subcutaneous X-ray? We can do that.”

Let me close with my usual observation (specifically aimed at venture capitalists, research lab directors and university administrators) concerning an asymmetry in cognitive depth: yes, physicists can casually read the New England Journal of Medicine and come up with interesting insights, but, no, biologists and medical doctors cannot read Physical Review.