This post from Patrick Wyman is interesting. Key quote:
Rather than casting Columbus as either the hero or the villain in an epic story about the emergence of a recognizably modern world, we should understand him as a replacement-level historical figure: not among the elite, a Clayton Kershaw or prime Carmelo Anthony; not in the mid-to-upper tier of his profession, like Nelson Cruz, Joe Flacco, or CJ McCollum. He was a notable step below that.
It is better and more accurate to think of Columbus as Bronson Arroyo or Nick Young or Trent Dilfer—an innings-eater, a bench player averaging 9 points in 25 minutes of action, the guy handing off the ball to Jamal Lewis. . . .
Outside of his flamboyance and his tendency to bray loudly about what he perceived to be his own personal brilliance and destiny—the 15th-century equivalent of Bronson Arroyo’s Stone Temple Pilots covers or Nick Young’s iconic GIFs—Columbus’s skill sets and attitudes were almost completely typical of the community of Mediterranean and Atlantic sailors to which he belonged. Columbus was remarkable, if he was remarkable at all, for how deeply unremarkable he was.
he types of experience and skills that sent Columbus out into the Atlantic and then safely home were widespread in his world. That, rather than any personal characteristic of Columbus himself, is the extraordinary and impactful thing we should strive to understand. There were dozens, hundreds, even thousands of potential Columbuses running around the bustling port cities of Europe in the 1480s and 1490s. And beyond the sailors themselves, there were shipbuilders who constructed sophisticated vessels capable of long-distance travel at sea, metallurgists who forged cannon, and the financiers whose command of complex mechanisms of credit and repayment paid for all of it. . . .
Columbus was just a person, a representative of a broader Type of Guy who was common along the sea-lanes of the western Mediterranean and Atlantic in the closing decades of the 15th century. . . . His ideas about commercial profits, the use of violence in acquiring those profits, and the potential of enslavement to meet that goal were likewise pretty standard.
It wasn’t just Columbus. Vasco da Gama was a true psychopath who burned alive Muslim passengers on a captured ship in the Indian Ocean. Cortes and Pizarro slaughtered staggering numbers of people in their conquests of the New World empires. Amerigo Vespucci was probably a pimp and definitely a ruthless slaver. Those are just the headline-grabbers, the other people whose names you might know; they’re the tip of the iceberg. The conquest of the Canary Islands in the 1480s, financed by the same group of people who funded Columbus’s voyage in 1492, had been exceedingly brutal. This was the context that produced Columbus, the tradition to which he belonged and to which he contributed. . . .
Major League Baseball is awash in pitchers who can throw 5 innings of three-run baseball every five days. The pitches they throw might look different, but it doesn’t really matter whether you’re starting Bronson Arroyo or Jason Vargas or Mike Leake or Chase Anderson 30 times in a season. There are plenty of lanky wings in the NBA who can shoot 33 percent from three and play a little defense; Kent Bazemore, Mo Harkless, Al-Farouq Aminu, and Reggie Bullock are all variations on the same theme. Mike Shanahan figured out a long time ago that he could find a competent running back to carry the ball 300 times a season in the draft’s late rounds, and NFL coaches have been following that example for two decades now. In the admittedly rarefied context of the incredible baseline levels of skill and athleticism required to play at that level, these people all basically interchangeable. The same is true of Columbus in the 1480s and 1490s. . . .
Interesting. This all makes sense, but I’d never really thought of it that way before.
By this standard, why should we bother to listen to Patrick Wyman since there are hundreds if not thousands of more capable writers?
Ehhh. I’m struggling to think of a figure historically significant for exploration who was a true outlier, as opposed to a capable person who made a unique choice and survived it.
Can you suggest some?
“Can you suggest some?”
Perhaps Ernest Shackleton.
Shackleton had a legendary ability to assess and affect the mood and motivation of his men — witness the quote by explorer Raymond Priestley: “For scientific discovery give me Scott; for speed and efficiency of travel give me Amundsen; but when disaster strikes and all hope is gone, get down on your knees and pray for Shackleton.”
But for other aspects of exploration — such as overall organizational competence, and clear-eyed evaluation of the tasks he set for himself — he was not so great.
So maybe Shackleton is like Derek Jeter: at the very top when it comes to team leadership, but roughly average in other aspects of his profession (among professionals at his position) .
How about Eric the Red and Leif Erikson? At least these guys had decent uncertainty estimates, where Columbus was way overconfident (as well as very wrong!) about the distance to Asia.
Patrick Wyman does the Tides of History podcast. Though it is quite good and I heartily recommend, he is rather dismissive of the Great Man theory of history. The podcast spends a lot of time putting people into the context of their historical environment. But sometimes, you really just have an Alexander or a Augustus or a Napoleon or a Churchill who does something really exceptional. In Columbus’ case, there were certainly other Europeans who came to the New World first. But before Columbus, none of those other players that Wyman mentions were making an effort to go to the New World. After Columbus they were. Columbus is important because he was responsible for the discontinuity. Could one of his peers have done so instead? Sure. But they didn’t. That doesn’t make him “Great” or a “Hero”, but it makes him historically important.
This seems mistaken.
First, it seems obviously wrong to claim that Columbus’ maritime skill set was a “middle relief” level skill set. Maritime navigation was hardly routine even on the Mediterranean much less on the open Atlantic coast. It was a highly hazardous occupation well into the early 20th century. Ships were surely routinely lost, especially on the Atlantic coast. (see “Skeletons on the Zahara” for a great story about a shipwreck on the north African coast in the early 19th century. There is also a recent book about the emergence and history of Venice and its maritime empire). To claim that any 14th century sea captain who survived into his old age after many voyages just on the Mediterranean was “average” seems off, but one who pioneered navigation on the Atlantic and then survived multiple trips? Not to mention that his skill set was regarded well enough that the Spanish crown funded his expedition! It seems unlikely they’d fund such a costly expedition if it was led by a “middle reliever”.
Second, whatever his maritime skill set, he had the vision to sail the Atlantic and the drive – and connections – to sell his vision to the Spanish crown. This alone makes him an extraordinary individual. It’s tempting to compare him to a modern tech entrepreneur – Bezos, Jobs etc – but this dramatically undersells Columbus. Today there are thousands upon thousands of people who can provide hundreds of millions of dollars for ventures. In Columbus’ day, there were very very few people who had the capital to fund such expeditions and getting to them was difficult. Furthermore, the idea of a personal computer or an online bookseller was a relatively small step from the existing commercial infrastructure compared to sailing into the unknown in the hopes of landing in the orient.
Anon:
Middling skills, excellent salesmanship . . . Tim Tebow?
Tim Tebow had extraordinarily high skills. I quote from Wikipedia:
After the 2007 season, Tebow was recognized as a first-team All-SEC selection and a consensus first-team All-American.[43] He won the Heisman Trophy, given to the most outstanding college football player of the year. Tebow also received the Davey O’Brien Award, annually given to the best quarterback in the nation, on February 18 in Fort Worth, Texas.
…
At the end of his college career, Tebow held 5 National Collegiate Athletic Association (NCAA), 14 Southeastern Conference (SEC), and 28 University of Florida statistical records.[71] He was the SEC’s all-time leader in career passing efficiency (170.8), completion percentage (67.1%), passing touchdown to interception ratio (5.5 to 1), rushing yards by a quarterback (2,947), rushing touchdowns (any position) (57), and total touchdowns responsible for (145).[4][72] Among many mentions in the NCAA Division-I record book, Tebow is ranked second in career passing efficiency, third in career yards per attempt (9.33), 8th in career rushing touchdowns, and also owns the record for most consecutive games in which he both threw at least one touchdown pass and scored at least one rushing touchdown (14).[73][74]
https://en.wikipedia.org/wiki/Tim_Tebow
Know very little about football (or, as its called at UC Berkeley: “American football”). But, here is what I found googling his stats for his NFL career. He played three seasons (’10-’12) and threw 12 touchdowns:
https://www.nfl.com/players/tim-tebow/stats/career
A guess: this doesn’t have a p-value of less than .01.
Roger:
Sure, I agree that Tebow is an amazing athlete with some great accomplishments. In calling his skills “middling,” I’m only comparing him to other professional football and baseball players. His salesmanship was excellent, which is why we’re still talking about him rather than about dozens of other players with comparable skills at the pro level.
“Middling skills, excellent salesmanship . . . Tim Tebow?”
Columbus isn’t analogous to a player, a coach or even a GM. He captained an expedition of multiple ships with individual captains and individual crews on an expedition where the rules were unknown. If there is a sports analogy, he’s analogous to an entrepreneur launching a new league. He laid out the rules and managed the league through four seasons.
Reading over Wyman again, he strikes me as just plain wrong. There were not “thousands” of ocean-going captains plying the ports of the Mediterranean. Yes, Cortez slaughtered lots of people and by today’s standards that’s a horrible thing, but in the world of Cortez it was normal. While Columbus was bothering around in the Caribbean the Aztecs were practicing ritual human sacrifice.
Wyman’s point is that the institutions should be condemned for barbarism, not Columbus (a middling player with common views, for his time). Assuming you’re correct, does this change the nature of the problem? That is, Columbus is celebrated when he shouldn’t be? This isn’t about Columbus’ skillz but about the institutions and points of view that have significantly changed over the past 50 years.
I agree with Anonymous. Saying Columbus had a middling skill-set is like saying that of Bezos or Jobs. It misunderstands their skills. Wozniak was considered the genius behind the Apple II, and Jobs just a replaceable salesman. Until they found that he was not so easy to replace.
The essay is wrong for another reason. What Columbus did was arguably the single most important accomplishment in all of human history. It changed the world like nothing else ever. Honoring Columbia is largely a way of recognizing that fact, and not just to credit his sailing skills.
https://www.sd308.org/site/handlers/filedownload.ashx?moduleinstanceid=22685&dataid=23638&FileName=Intro%20to%20Ag%20Notesheet.docx
Basque fishermen were reliably catching cod somewhere away from the European coast, whether it was the Grand Banks or somewhere else, so Columbus’s navigating skills don’t look that special to me. (For spectacular navigating skills, look to the Pacific islanders, but they aren’t relevant for Wyman’s agurement.) Generally, I agree with Wyman about the Great Men Theory of History.
According to Wikipedia:
“Viking documents mention the presence of Basque whalers operating approx. 500 miles east of Greenland in 1412 near Grundarfjörður…” but “The first Basque expedition recorded in Newfoundland took place in 1517”
https://en.wikipedia.org/wiki/Basque_colonization_of_the_Americas
The fact that Basques were operating in the Atlantic doesn’t lessen Columbus’ accomplishments. How many Basque ships were lost in the process of reaching Newfoundland? The Basques were a great seafaring culture. To be mentioned in the same breath with them is a great accomplishment. At the time, the “average” or “journeyman” seafarer never left sight of the coast.
“Not to mention that his skill set was regarded well enough that the Spanish crown funded his expedition! It seems unlikely they’d fund such a costly expedition if it was led by a “middle reliever”.”
Well, that unknown continent in what by all rights should’ve been the middle of the ocean (based on his incorrect estimate of the circumference of the earth) was a great relief to the man. Saved his life. If it hadn’t been there, there is no way he would’ve made ti all the way to Asia.
Though he ever knew why, since until he died he insisted he’d landed on part of Asia.
I can’t access the full text because paywall, but I’m not really buying it. I do like to think in systematic terms, and the general level of talent and technology is of course of primary importance, but there were reasons it was Columbus and not somebody else.
First, he believed the earth was pear shaped rather than round, with a nipple on top, and on that basis estimated a equatorial circumference much shorter than everyone else did. He was willing to bet his life on that belief, even in the face of all the learned men disagreeing with him. He was thus clearly an outlier in the relevant aspect of self confidence. Of course, the learned men were much closer to correct than he was, and so his was a misplaced self confidence. I’m not moralizing here, it’s a kind of dumb luck that he didn’t die, but nonetheless the reason his voyage to the Americas happened when it did and how it did is because he was uniquely who he was.
I’m also skeptical that he wasn’t an outlier in his cruelty by contemporaneous standards. Again, I can’t read the full text so maybe this is addressed, but weren’t there complaints from his subordinates and associates about his unusual cruelty towards both the indigenous peoples and the Spanish settlers under his jurisdiction?
So Columbus represents overconfidence, willingness to risk bankruptcy and death, and dumb luck. (I am skeptical he was an extreme outlier on the cruelty scale, conditioned on his position. “Crueller than average” maybe.)
Celebrating Columbus that is celebrating the role that combination has played in human history. And, honestly, there is something to that, whether we like it or not.
“I’m also skeptical that he wasn’t an outlier in his cruelty by contemporaneous standards.”
Columbus eventually convinced Isabella that slavery of the indigenous natives of what he still felt was part of Asia should be banned, and that became Spanish law. The Spanish settlers who had been granted land by the Crown were furious and blamed Columbus to a great degree.
Those who had followed Columbus to the New World then simply converted the system from slavery to land-bound serfdom which was, in practice, the same thing. He protested against this, as well.
I’d be a bit wary of claims of extraordinary cruelty against the Spanish settlers, in particular, which was being made by those who wanted him out of the picture so they could continue their virtual enslavement of the natives without him running to the crown to complain.
On the other hand, Columbus was responsible for cruel measures against the indigenous people himself, no doubt of that at all. But as usual, the early history of the Spanish colonization of the New World is more complex than just “Columbus bad”.
And FWIW I support current moves to stop treating Columbus as some kind of hero.
The point is well taken that contemporaneous accounts and judgements from interested parties are unreliable; however, I’ve never heard of him being an unpopular opponent of slavery, only that he was removed for his cruelty. Do you have a source for that?
Isn’t this a little silly? History is history and there are myriad examples of individuals that were the first to do things – it’s a fact of life that they’re the one’s that get the credit and historical kudos. As a couple of posters have indicated above Colombus had some outstanding qualities that rendered him a lucky first. Likewise Edmund Hillary (and Tenzig) – nowaday anyone can with a moderate fitness can be led to the top of Everest. If Watson and Crick (and Franklin) hadn’t worked out the structure of DNA another of their contemporaries would surely have done so soonish. Science provides many examples.
One example that is more pertinent to Columbus is Rod Mackinnon who worked out how to determine crystal structures of ion channel proteins (Nobel prize 2003). Until he got it to work no-one really thought it was possible to crystallize ion channel proteins and determine their structures and now it’s rather commonplace. So it’s not just that he did it first but that he broke through the common convention that it was not possible.
It’s very easy to look at these things with a contemporary hindsight and consider them actually rather unremarkable when in fact they were pretty remarkable indeed.
Rod McKuen too.
You are right, of course, for every possible invention there is always a single individual who “did it first”.
But I think we tend to fetishise “first doers” just because of their priority.
We do that to motivate more people to think outside the box?
Well, maybe there is an utilitarian design behind that…
Buy turning the History into some kind of “Guinness World Records”, collection of stories about people who did it first, buy deemphasizing the systems and institutions that operates in our society, we motivate people to think outside the box and discover new lands… but we also demotivate them to build better institutions and systems.
Like, I think the question who “discovered” America is interesting… but not that important. Why Columbus’ voyage lead to violent colonization of America, while Leifur Eiríksson’s did not.. now this is interesting.
Here’s a review and explanation of Wyman theory that explains how the barbarism and technological progress of western European nations helped it to become dominant, why Columbus was a middling barbarian (and representative of his times), and, generally, how the common people of western Europe, at the time of Columbus, are as important as the warehouses workers of Amazon:
https://www.rollingstone.com/culture/culture-features/the-verge-patrick-wyman-jeff-bezos-european-history-1202656/
Europeans were probably getting to the Americas long before Columbus.
https://www.nytimes.com/1982/10/10/world/rio-artifacts-may-indicate-roman-visit.html
https://www.nytimes.com/1985/06/25/science/underwater-exploring-is-banned-in-brazil.html
I think it was Plato who also wrote that the Phoenicians knew of a large island across the Atlantic and had colonies there, but they tried to keep it classified as a military secret. I can’t find the quote at the moment though.
But who knows? History is filled with propaganda, fraud, coverups, etc.
Maybe it was Diodoros, but I think I’ve read similar from an earlier author:
https://archive.org/details/DiodorosOfSicily034.598/Diodoros%20of%20Sicily%2003%20%284.59-8%29/page/n153/mode/2up
Most good discoveries made by people of average intelligence and skill who are willing to persevere.
I have heard of Columbus, but who in the world are these others so lovingly mentioned? For nostalgia about baseball players of my era, try
https://www.youtube.com/watch?v=TOvvJTv_E_w
which is entitled, Van Lingle Mungo. Frishberg just died at the age of 87 and his tribute to baseball players of his youth is something to bring tears to the eyes of his age group. See how many you can recognize.
The Columbus essay says: “On top of that, João (and practically everyone else who came into contact with him) found Columbus abrasive and ignorant, wholly unaware of what he didn’t know, a walking late medieval example of the Dunning-Kruger effect.”
There ought to be a term for people who cite the Dunning-Kruger effect while being wholly unaware of what it really is.
The essay on great men estimates: “There’s the occasional digression into everyone else: women, low-wage workers, the enslaved, Native Americans and other first nations, and immigrants from all over the world. But these people — also known as 99.999999999999999999999 percent of all humans who’ve ever lived — are treated as a sideshow to the main event: powerful men leading wars against other powerful men.”
That means 1 in every 100,000 billion billion is a great man, if I counted the nines correctly.
Feels like you can apply a pseudo-probabilistic rule of thumb – if someone does a thing at the first moment it is technologically or politically or economically possible, then they are probably replaceable. If they didn’t exist, given the haste at which the thing is done, someone else would have done the same soon enough. If however it’s something they did that was entirely possible to do for hundreds of years, and they just happen to be the one who did it, then they are more special, since you have hundreds of years of people failing to demonstrate their unique genius. If they didn’t exist, it could have taken another few hundred years…
On that metric, I think Columbus isn’t very special. The carrack, the proposal to sail west to asia, all of that came pretty fast before Columbus.
I always think of static electricity. For millennia it was some odd, even annoying, phenomenon.
Then the Leyden jar, allowing accumulation of charge, was discovered on accident: https://en.wikipedia.org/wiki/Leyden_jar
Any average person could have discovered it in the meantime, but they didn’t. Or if they did, they didn’t have the motivation or means to figure it out.
I agree more with this line of thinking. I went to a talk a few years ago by Kathy Fields, co-founder of Proactiv.
She told of how some colleagues complained to her that the product was nothing particularly special or unique, a sort of, anyone could have done this – if you were in dermatology, anyway.
Her reply to them was, “Then why didn’t you?”
Doing a thing is often easy, it’s convincing the elite with the money to make it happen that’s hard. One of the biggest problems with the concentration of wealth these days is that it prevents a lot of good ideas from happening.
You really have to be somewhat independently wealthy to do good science. Multiple times I asked people about their obvious p-hacking and the answer was always they did what was needed to survive.
Woah, really?! We’re not in the 18th and 19th centuries any more. Massive amounts (most) of good science is done by individuals managing fine with academic (and industrial) salaries. It’s unfortunate that you inhabit circles with substantial p-hacking and that’s by definition, I suppose, not good science (tho it might be productive science in the Fayerabend sense – the proof is in the pudding).
But all those advances in vaccine development, protein structure prediction, detection of gravitational waves, cryoelectron microscopic determination of protein structure, development of anti-Covid drugs, massive genome sequencing and ID of human genomic variants, the human contribution to global warming …the list or recent advances is massive… was done by people on pretty normal salaries – like Columbus, perhaps, they have the advantage of some goal-oriented personality traits – but independent wealth certainly isn’t a prerequisite for good science nowadays.
I partially am sympathetic to Anoneuoids point. I think it’s not so much that you personally need a crapload of cash, but just that the “need to get grants” means the need to pander to whatever gets you the grants and since that is much more heavily driven by bad methodology it takes a lot of effort to maintain scientific integrity and funding. I certainly see this with my wife and others in her field, and have heard from multiple people in related fields how difficult it is to do “good work” while providing enough glitz to attract funding.
How do you determine what constitutes an “advance” though?
For 1000+ years the most educated people were “advancing” theological arguments. Today we consider all of that pretty much relevant because the premise it was based on is considered incorrect.
Same with the system of NHST, peer review, etc today.
Not sure what NHST, peer review etc. has got to do with it. But an “advance” is very easy to define and recognise at least in the physical, biological, biomedical sciences. An advance occurs when something that wasn’t known, understood or able to be done becomes known, understood or doable. Usually it has positive consequences/applications beyond the primary goal behind the advance.
So from my top of the head list in post above, work over a couple decades (many scientists, mostly academic, on modest salaries!) has made some progress in computational prediction of protein structures. A major advance (AlphaFold) showing astonishing power in structure prediction was published last year – it seems the problem may be considered more or less solved. An unintended consequence is that a whole bunch of problematic X-ray crystallography structure determination efforts have been brought to completion since the calculated structures are good enough to provide target density for calculating phases for solving the X-ray structures.
A similar backstory could be made for many other examples. High resolution structures from electron microscopy were unobtainable only 10 years ago but recent advances (made by numerous scientists on modest academic salaries mostly) in computation, detector design, sample preparation and so on have made this commonplace with some rather revolutionary consequences. There were no Covid-specific drugs available until recently but a couple (following on from very successful advances in anti-HIV drugs using similar approaches and similar-to-HIV viral targets) are looking promising in clinical trial (this one remans to be determined!)..
At the risk of appearing Pollyanna-ish there are loads of recent scientific advances though it does depend on the field one inhabits probably. These are very recent advances – built on numerous previous advances that one can trace back even 50 years or more (the whole of the biomedical/molecular genetics academic and corporate research effort can be traced back to the 1950s discovery of the structure of DNA – I’m sure you would consider that an advance in understanding).
Daniel – I do agree that obtaining funding is tough but that needn’t equate to a difficulty in maintaining scientific integrity which is a separate issue. There isn’t a god-given right to funding for one’s research – and research is very costly nowadays. Your point highlights for me that there are simply too many people trying to do science now. It makes sense to recognise if you’re not making much progress, and (at least in the UK) academic departments will usually support a spell of teaching/admin focus if you go through a lean spell research-wise. It can also be constructive to foster collaborations as a way to maintain a research effort or to refocus into a more well-funded field. Think we have to recognise (at the personal level) that the way we do things may have to change.
Once again, this typically amounts to a bunch of people stringing together a series of significance tests. The very foundation is flawed.
I haven’t checked it, but if there is indeed an increase in predictive skill then that is an advance.
It looks like you are referring to this: https://www.nature.com/articles/s41586-021-03819-2
I skimmed through it a couple times and can’t tell something. Perhaps I missed it.
Was predictive skill on the “Test set of recent PDB sequences” used at all to tune hyperparameters?
Once again, this typically amounts to a bunch of people stringing together a series of significance tests. The very foundation is flawed.
Surely not. That’s a million miles away from the true nature of our knowledge. If someone determines the gene sequence of a strain of the Covid RNA virus no meaningful test of significance is required (since the “signal” at every step of the procedure is way above the “noise”). If the sequence is used to express the Covid protease in a bacterium, purify this and determine its atomic resolution structure no meaningful tests of significance are required although there will be some measures of quality control in the structure determination. Drug molecules designed to inhibit the protease based on the protease structure do inhibit the protease and in the case of HIV (a better example since we’re only in the very early stages of drug design for covid protease) are part of a very effective antiHIV therapy. It’s difficult to escape the conclusion that our knowledge in many areas is robust and at the very least operational.
Much of this knowledge is rather binary rather in the way that if I want to investigate whether I closed the door after leaving the house I don’t need to do significance tests – I just look and see that it’s closed (or not). The structure of DNA and the nature of genetic inheritance at the molecular level was not known 80 years ago. 60 years ago it was. That was an advance. We didn’t know and understand something fundamental – as a result of scientific advances (produced by individuals on modest academic salaries or stipends!) we then did.
I always think its funny when people think we have this amazing understanding of biology but its all about essentially invisible things.
Then they have no idea when it comes to stuff like:
“How common it is for someone who has regular periods to have an unusual period one month?”
In your example everything gets connected to reality via the protease inhibitor, which was determined effective via NHST.
I’ve worked in a molecular bio lab and known many. They would argue similar to you that statistics are unneccesary for their work. Then you see that any time the expected result fails to appear a technical issue is to blame and they throw out the blot (or whatever) without ever telling anyone.
This is how you get 10%, or even lower, replication rates anywhere you look (eg, cancer and spinal cord research).
Who said “we have this amazing understanding of biology”? I’m saying that there are things that we know to a high level of certainty as a result of scientific advances (mostly, during the last 100 years anyway, by individuals on rather modest salaries/stipends – to stick to your original point!).
Are you suggesting that we don’t know the structure of DNA and the mechanism of DNA replication, transcription etc.? If not how do you explain the fact that the Polymerase Chain Reaction works? Do you consider that we don’t know the sequence of the coronavirus genome or at least the strains that have been identified so far? Do we not know the structure of the HIV and covid proteases?? etc.
It’s silly to link my points where knowledge is robust with some statement about regular/unusual periods! It’s obvious that we can understand some things and not others (tho someone more qualified than me might be able to address the unusual periods). Or do you think that we have to accept biology as an entire package and that if we don’t understand everything (unusual periods and all) we can’t have confidence about anything??
Actually, I wouldn’t be surprised if eventually most cellular DNA is decided to exist as DNA and RNA-DNA triple helixes. The double helix structure everyone gets taught would then turn out to be a minor form or experimental artifact.
@ Chris
Here is a good review on the different possible structures of DNA. There are dozens of them (you can search and find a pdf of this paper):
https://www.jstor.org/stable/24110017
And now its estimated ~66% of the human genome consists of repetitive elements:
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1002384
When your DNA consists of long chains of primarily repetitive elements, a double helix is not expected to be the most common structure.
In addition to that, more and more evidence is coming out that DNA-RNA triple helices cover a substantial part of the genome: https://www.sciencedirect.com/science/article/pii/S2451945616303464
It is like anything in biology. When you look at the actual evidence rather than read the textbook explanation, things become far less clear.
I’m not sure if you are still reading this, but I’ll move on:
How do you explain it works despite that its unlikely we know the structure of DNA?
Ah…I thought we’d more or less done. I was addressing your points that scientists need independent wealth to do good science (not true) and that the concept of advance (in your eyes) is dubious.
Both not true I think – of course we know the structure of DNA – that’s not negated by the fact that new structural forms of DNA have been identified including DNA-RNA triple helices and so on which may be more prevelant in vivo than we might have thought (remains to be determined; most likely involved in gene regulation).
Determination of the structure of DNA was a massive advance which underlies our understanding of transcription, replication, DNA repair, the action of the majority of classes of restriction enzymes (each of which largely requires that DNA is in/can form an antiparallel base-paired structure), homologous recombination etc. The whole of the molecular genetics/molecular medicine revolution is based on that (cloning, PCR, gene sequencing, human genome sequencing and uncovering the molecular basis of genetic disorders, deeper understanding of evolution and so on).
How do you explain it (PCR) works despite that its unlikely we know the structure of DNA?
PCR works by the mechanism proposed by Mullins – it’s based on complementary base pairing of RNA primers to specified regions of double stranded DNA, the use of heat-tolerant DNA polymerases within heating-cooling cycles to seperate and reanneal parent then daughter double helical strands and so on. it works because we know the structure of DNA (antiparallel strands; commplementary base pairing etc.)
The idea that we don’t know something because we don’t know everything is not that helpful nor interesting. In any case one can take an entirely operational view of many scientific methods and advances. We know PCR works because we can see it working before our very eyes! We know it works because we’ve determined the sequence of the Covid virus genome and variants. We know that we know the structure of the Covid and HIV viral proteases since we can use rational structure-based design to invent inhibitors that fit into the active site and show (for HIV anyway- it’s early days for Covid) that they form part of successful therapies (so long as you’re in a wealthy country or wealthy enough in a poor country).
To do PCR you need to take a template and add some extract that catalyzes polymerization (something containing the polymerase), the raw materials (nucleotide triphosphates), and some oligionucleotide primers.
The structure of DNA is not required at all. You really only need complementary base pairing to explain it.
To do PCR you need to take a template and add some extract that catalyzes polymerization (something containing the polymerase), the raw materials (nucleotide triphosphates), and some oligionucleotide primers.
The structure of DNA is not required at all. You really only need complementary base pairing to explain it.
you need two templates and they need to be complementary (aka antiparallel base-paired DNA) – i.e. one for each RNA primer. We know this since we’ve designed the primers such that they anneal and instigate DNA synthesis in the correct direction (5′ – 3′ on each strand).
We know that the DNA we’re amplifying is anitparallel and base paired since we have to use heating and cooling to seperate and reanneal the strands. We can design restriction sites into the primers so that after amplification the DNA can be inserted into a plasmid and we’re likely to use restriction enzymes that require palindromic base sequences within double stranded antiparallel DNA.
There are loads of high resolution X-ray and NMR structures of DNA and DNA bound to proteins (transcription factors, DNA polymerase, all sorts). Note that thse proteins that act on DNA make interaction specifically involving minor and major groove topologies and there wouldn’t be minor and major grooves if the DNA wasn’t in an antiparallel double stranded base-paired helical configuration. The very nature of the interactions of the proteins that carry out the fundamental cellular functions involving DNA requires to a large extent that the DNA is in/can adopt a double helical antiparallel base paired structure. There are some fantastic structures in the Protein Data Bank of double stranded antiparallel DNA with bound restriction enzymes, transcription factors, histone proteins, transcriptional repressors etc.. These require very specific interactions with double stranded antiparallel base paired DNA topologies and this fact indicates that they are very likely to require this fundamental DNA structural topology to perform their functions in living cells.
PCR works just fine on ssDNA. There is no antiparallel template required because it is created in the artificial conditions of the test tube.
https://www.quora.com/Can-PCR-work-with-a-single-stranded-DNA-template
You gotta start thinking about what we are actually doing and observing rather than the explanation you read in a book. Then you will “know” much less.
Yes you’re quite right – I’d forgotten you can start PCR off with single stranded DNA though you need a forward and reverse primer else it doesn’t work (you just make extremely long copies that amplify linearly rather than exponentially presumably). So the first replication round produces the template for the reverse primer and then the reaction occurs on double stranded DNA (which is why you need the heating part of the heat-cool cycle).
Not sure where you’re going with this since you’re not going to convince me that DNA isn’t predominantly a double stranded antiparallel helical structure since the enzymes/proteins that act on/interact with DNA to a large extent require that the DNA is double stranded with a topology involving major/minor grooves – pretty much as was modeled from very limited information way back in 1953.
But thanks for the reminder that you can start a PCR reaction with single stranded DNA.
The point is that PCR can work even if DNA is not a double helix, or even if it does not consist of anti-parallel strands. So your argument that we know these things with high confidence because PCR works does not hold water.
It seems DNA *can* form a double helix, but this structure is likely to be a minor one. Ie, found outside repetitive elements during G1 phase in areas not being actively transcribed. It is, however, very overrepresented in the short non-repetitive sequences used for many in vitro experiments.
Here we go again… I’ve gotta assume your evidence for this is that you read it in a book, or else you would have mentioned the actual observations that lead you to this conclusion.
Actually this conversation got me thinking about restriction enzymes. Restriction sites are primarily palindromes. I’d bet they have some “special” structure (not the canonical B-DNA) as well.
When the new strands are synthesised in PCR reactions they use the template strands and they’re obviously synthesised in the opposite drection of the template – i.e. antiparallel. These new template-daughter strands need to be heated to separate them – so they must be in a base-paired anti-parallel configuration etc…
It’s common to design restriction sites into the ends of the antiparallel double stranded DNA product. If you cut these with the appropriate restriction enzymes you can generate sticky ends (an overhang on the 5′ or 3′ strand of the antiparallel base-paired DNA) allowing the PCR product to be neatly ligated into a plasmid. Difficult to understand how this could work if the DNA wasn’t antiparallel base paired.
Of course if it pains you to accept something that we actually know quite well, you can take an operational approach (I suggested this earlier) and simply recognise that this fundamental reaction works (proof-in-pudding-wise). So we can for example determine the sequence of coronavirus variants while being blissfully unaware of how these techniques work – I find it much more interesting to know what’s going on at a molecular level and it makes troubleshooting much more profitable when things don’t go as planned!
Just had a quick look in the protein data bank for some structures you can look at. There are many hundreds of DNA-protein complexes:
For example these directly show the double helical nature of DNA in nucleosome particles which is the form of a much of eukaryotic DNA (try PDB entries: 1EQZ; 7EA5; 6ESF). Most repressor proteins and restriction enzymes rely on specific interactions with double-helical DNA often involving interactions within the major groove (e.g. PDB: 6CRO; 1DDN; 2BJC; 1YFI).
You can find 100’s more examples (Google Protein Data Bank).
Actually this conversation got me thinking about restriction enzymes. Restriction sites are primarily palindromes. I’d bet they have some “special” structure (not the canonical B-DNA) as well.
What makes you think so?
Lets say 100k examples, all for human protein/dna, that are 100 bp long. That would be 10 million bp, about 0.3% of the 3 billion bp human genome.
So even accepting the in vitro structure is also true in vivo, that is a small minority of the genome.
As cited above, ~66% of the genome is now supposed to be repetitive elements (so-called junk DNA) where we expect “alternative” structures to appear.
I checked the first one and quickly looked at the paper:
https://www.rcsb.org/structure/1EQZ
They had to cherry-pick a DNA sequence, remove all the “bad” structures, add an ideal amount of some organic solvent, and grow crystals in microgravity to get this result. I knew the conditions would be artificial but this just made me laugh.
I have no doubt you *can* get a double helix structure, but that does not mean that is how it works in vivo.
So even accepting the in vitro structure is also true in vivo, that is a small minority of the genome.
Well yes yes one could argue that the structures we’ve got are not representative even if we’ve got hundreds if not thousands of these. However these structures exist within a vast context of independent biochemical, mechanistic and structural prior knowledge. There have been lowish resolution electron microscopic structures for decades that have defined the basic dimensions of the nucleosome and it seems that much of chromosomal DNA is organized as double stranded DNA within these structures (recent research has identified that nucleosome structure is quite dynamic and subject to remodelling). The high resolution X-ray/EM structures effectively allow a more detailed look at something that was known already.
A fundamental element of all cellular life is that DNA must be continually monitored for damage and all cells have rather sophisticated repair mechanisms – this works because cellular DNA is largely in the form of double stranded anti-parallel base paired helices – you can’t repair a damaged DNA strand site if there wasn’t the complementary strand to use as a template. Proteins that interact with DNA in cells generally have structures that conform with the major/minor groove architecture of helical DNA.
and so on…
Of course if one isn’t that interested in how things work then you can take the operational viewpoint that things do work (PCR, cloning, covid variant genome sequencing, vaccine preparation, etc) without worrying too much about how.
They had to cherry-pick a DNA sequence, remove all the “bad” structures, add an ideal amount of some organic solvent, and grow crystals in microgravity to get this result. I knew the conditions would be artificial but this just made me laugh.
I have no doubt you *can* get a double helix structure, but that does not mean that is how it works in vivo.
Yes that is quite amusing. That structure was around the first high resolution nucleosome structure determined and it obviously wasn’t easy. Many more structures have been determined in the intervening years using completely different methods (e.g. high res electron microscopy) and the structures are very similar (double stranded DNA around a core histone complex). So the essential nucleosome structure is rather reproducible and matches pretty well with earlier low resolution EM structures obtained from cells.
If would be an astonishing improbability to find that all the structures of DNA we find under different conditions, in cells or out of cells, in complex with DNA-binding proteins/enzymes, the biochemical and mechanistic information that all indicate that DNA is predominantly a helical antiparallel base paired structure is an artefact of some sort or another.
But of course you’re welcome to choose to think that. I’ve said a couple of times that we can pretend we don’t know what we know and take an operational approach and recognise that things work (PCR, clonong, covid viral genome sequencing, vaccine development etc.).
I’ve learned quite a little bit (about nucleosome structure actually) so thanks for this conversation. I’m going to draw a line under it from my side but if you fancy having the last word go ahead..
Also known as stringing together a bunch of NHST results filtered by publication and peer review bias. That is all I’m saying.
And no one is going to publish an unexpected structure that isn’t easily seen via their methods, they will send it up on a space shuttle before thinking the “highly variable” results indicate the structure is indeed highly dynamic.
“the concentration of wealth these days is that it prevents a lot of good ideas from happening.”
I really doubt that. Most of what people think are great business ideas just don’t work – which is why two out of three businesses fail. Ever been to a “Big Lots” store? I’ve never bought anything from that store because everything I pick up in there has something weird about it. The “big lots” are auction lots of failed retail products. It’s a what’s what of retail failure. And speaking of retail failure, next time you’re in Canada, head on over to The Real Canadian Superstore – Loblaw’s Corp’s answer to Wal Mart. Canadian retailers always fail in the US and this store exemplifies that in some strange way that I can’t quite put my finger on. There’s something just wrong about that store, and wherever it’s positioned next to Wal Mart you’ll find the Wal Mart much busier.
If 320 Million people all try various business ideas and 2/3 of them fail vs 320 Thousand elite frothy venture capital funded people try business ideas and 1/2 fail, which gets us the bigger diversity of successful projects?
“If 320 Million people all try various business…”
Sure, I agree, as you’ve seen I’m a big advocate of ground up. But outside of having a business worth pursuing, capital isn’t the problem for most business. It’s regulation: employer regulation, land use regulation, tax regulation, tenant regulation, product regulation, vax regulation….even fifty years ago much of that didn’t exist.
Of course, in the end that comes back to capital because more regulation favors greater scale. That’s why the big tech companies don’t mind some regulation. It’s a protective moat for them.
I took my elderly mother for a perm today. The salon has six chairs but only two workers. Why? Probably because it’s a family operation and the regulatory cost of hiring outside the family is too high.
To the extent that wealth is concentrated, regulation is a big reason why: it protects established wealth. We keep hearing about the price of off-patent meds going through the roof. Why? No competition because the regulatory cost is too high for multiple producers.
jim, could you please name such an off-patent drug that has this problem?
epipens
Not sure that’s quite right re Epipens. Epipens is both a drug (epinephrine) and a device (injector) and although the former is obviously completely generic the Epipens injector is still under patent protection and it’s the latter that has limited generic versions – there are some of these tho but are considered inferior.
The high pricing of Mylens Epipens seems due to rather commonplace opportunistic price-hiking under patent-protection.
An account of the current situation here:
https://www.nyulawreview.org/wp-content/uploads/2021/08/SherkowZettler-fin-1.pdf
Yes, and whatever Shkreli was selling too. But you’re just making my point I think.
Regulations favor enormous conglomorates, then capital is only really available to them. And a guy who wants to open an HVAC installer with 3 employees is stuck with high cost of capital (it’s much riskier to loan to him than a “too big to fail” GM or ATT) and no personal savings to use to fund the business also because profit has concentrated into a tiny minority.
Capital is VERY MUCH a big big problem that prevents people from opening hair salons, painting services, plumbing services, delivery businesses, tree trimmers, computer network installers etc. Not that they don’t exist, but the regulatory burden on them plus the concentration of capital is choking our economy.
Chris: I’d count patent protection as a big old “regulatory burden”. I’m anti patent and I think there are good reasons to believe that the “fairy tale” about patents promoting innovation is bullshit. There have been a steady stream of history and economics papers coming out saying similar things. It’s not the mainstream view, but can’t be dismissed out of hand either.
You’re pushing on an open door on that one Daniel. I think some patent protection is warranted but this has got out of hand largely due to lobbying by powerful corporations (many of them pharma).
There is an interesting contrast in the open source nature of publicly-funded scientific information that provides an example on the value to innovation of lack of patent (or patent-like) protection. All of the data on genome and protein sequences, natural human gene variants and their phenotypes, scientific papers (increasingly), scientific software and so on is freely available despite attempts to monetize this (e.g. human genome; and corporate publishing is still pretty successful in monetizing reseach done with public funds). There are many people able to make innovations in bioinformatics, for example, who wouldn’t be able to do so if all of these resources were owned and access sold.
The “someone would have done it” argument is obviously true, but that other “someone” couldn’t have been just anyone, so I don’t think it’s appropriate to say that “Columbus wasn’t special” or extraordinary. By the standards of his time, at any rate, he clearly was.
Someone would have piloted the first Apollo mission had Neil Armstrong not been selected, but Armstrong was an extraordinary individual by any account. He had distinguished himself on several occasions by making life- and mission-saving snap decisions. While someone else would have obviously taken his place on the first moon mission, we can’t assume the outcome would have been the same.
I think that the button hole was invented 800 years after the button was. Does this fit into your probabilistic rule of thumb?
This is old news, they used to discuss the “mediocrity” of Columbus even during his lifetime (https://en.wikipedia.org/wiki/Egg_of_Columbus)
“Columbus being at a party with many noble Spaniards, where, as was customary, the subject of conversation was the Indies: one of them undertook to say: —”Mr. Christopher, even if you had not found the Indies, we should not have been devoid of a man who would have attempted the same that you did, here in our own country of Spain, as it is full of great men clever in cosmography and literature.” Columbus said nothing in answer to these words, but having desired an egg to be brought to him, he placed it on the table saying: “Gentlemen, I will lay a wager with any of you, that you will not make this egg stand up as I will, naked and without anything at all.” They all tried, and no one succeeded in making it stand up. When the egg came round to the hands of Columbus, by beating it down on the table he fixed it, having thus crushed a little of one end; wherefore all remained confused, understanding what he would have said: that after the deed is done, everybody knows how to do it; that they ought first to have sought for the Indies, and not laugh at him who had sought for it first, while they for some time had been laughing, and wondered at it as an impossibility.”
The article does rather point out the story is probably made up.
Though to me, the moral of the tale is more something about ambiguous objective specifications. The method seems less a leap of creativity, than “oh okay, you’re allowed to break the egg, it’s rather easy if you are allowed to break the egg”.
Isn’t this all about tail behavior, which is easier to assess in broad jumping than football, or seafaring. In Galton’s Natural Inheritance, a book now banned at UCL there is considerable discussion of such matters including some data on the Cambridge Tripos exams where one sees some truly impressive heavy tails. Of course the exam scores weren’t necessarily predictive of future performance. On Columbus, I strongly recommend the recent counterfactual novel by Laurent Binet, “Civilisations” in which the Incas conquer Europe.
R:
Not banned yet, it seems!
My understanding is that Columbus had a superior understanding of the winds in the Atlantic, north of the Equator – which way they tended to blow at a given latitude.
Without this knowledge, he wouldn’t have made it over and back.
I am unaware of evidence that this knowledge was widespread.
I was under the impression Columbus was rehabbed when Protestants looked at Catholics ~100 years ago and went “Our bad. Got any good Catholics we can elevate? What about that Columbus fella?”, and the a Knights of a Columbus went “Yah, bro.”
Toss him on the heap, I really don’t care.
Chris:
Very interesting article. You’re right that I’m not quite right on that. Seems that the high quality of the branded device and the patent protection of that device is the barrier to switching. I suspect that if EpiPen was a brand-new product, no one would think twice about paying $600 for an injection device that could save one’s life. That’s pretty damned cheap. The controversy here is that the price *used to be lower*.
Thanks to regulations, Epipens cost a lot less in Europe.
Which contradicts your point somewhat.
There are generic alternatives in the US: Adrenaclick, Auvi-Q, and a product by Teva. (Or you could simply use a syringe.)
“Thanks to regulations, Epipens cost a lot less in Europe.”
That’s not relevant to my point. The **price** (not cost) of medical things is lower in many countries because of price controls, but that has nothing to do with the cost of creating those things. There are competitors to the EpiPen, but many users of EpiPen are still complaining because EpiPen is apparently a far superior product to most substitute devices, and people prefer to have the superior product at a lower cost. I was incorrect, however, to say that EpiPen is off-patent. As Chris pointed out, it’s not.
“Which contradicts your point somewhat.”
My point was about the cost of regulation from an investment point of view – that is the cost of creating a competitive product – so I don’t think it contradicts my point – it was just an incorrect example. However, in much of Europe, and in Japan and Canada (I’m not sure about the UK and Australia), US-made medical devices generate virtually no profit because of price controls. It’s common for device makers to cut sales in those countries when margins shrink too much. Without the uncontrolled market in the US and the profit it generates, the US medical device industry would probably shrink quite a bit. Price controls are a different type of regulations, but they create the same result: lower supply. Interestingly, it’s the opposite of modern housing market regulation. In housing it’s taboo to regulate rental prices since everyone knows that price controls reduce housing stock. Instead, people outraged at the cost of rental housing implement tenant protection regulations – which still drive up the cost of housing and reduce housing stock, but aren’t taboo. :)
Shifting to a tangential topic: it’s amazing that people think $300 is too much to pay for a device that lasts 18mo and treats an existing condition that could kill them in an instant. (I worked with a guy once who’s allergy to shellfish was so bad he couldn’t be in a building where shellfish were being served.) That’s $17 / mo – 2.5 hrs work per month even in the lowest min wage state in the US. Most people spend more time than that working on their beany baby collections and spend three times that monthly on alcohol. If such devices were available exclusively on a bidding market they’d probably command five to ten times that amount. Eventually the stream of patented improvements that allow the EpiPen branded device to remain on patent will dry up and the device will be widely available at low cost forever more, and all this will be a footnote to history
The price of epipens is related to Joe Manchin’s daughter.
https://www.washingtonpost.com/news/powerpost/wp/2016/08/24/ceo-at-center-of-epipen-price-hike-controversy-is-sen-joe-manchins-daughter/?hpid=hp_hp-top-table-main_manchin-810a%3Ahomepage%2Fstory
For more on her unsavory history see what happened when her father was Governor of West Virginia:
https://www.post-gazette.com/business/businessnews/2007/12/21/MBA-mystery-in-Morgantown/stories/200712210224
Once you read that 2007 article, you will possibly come away with an altered view of the family.