No Patents on Genes
The Supreme Court ruled unanimously yesterday in Association of Molecular Pathology v. Myriad Genetics that a gene, such as BRCA1 or BRCA2, does not qualify for a patent. The fact that Myriad isolated the DNA is not enough to distinguish it from its in situ counterpart as the information it contains is the same. However, cDNA, a version of the gene that has been stripped of non-coding sequences is subject to patent.
With this ruling the price of most of Myriad’s tests will fall as competition enters the market (the BRACAnalysis tests are actually a number of different tests, as I read the technical specifications, only some of these depend on cDNA. The markets appeared to have been initially confused about this.). Even more importantly, the Myriad patents were broad and they prevented researchers from freely studying the BRCA1 and BRCA2 genes, from improving the tests or from developing additional applications. The giants demanded payment (video) from those who would stand on their shoulders. I think the restrictions retarded progress–as have similar restrictions–to an extent that made the patents difficult to justify.
Although I am broadly in agreement with the ruling, it’s also clear that the limited flexibility of patent law–you get a 20-year patent or nothing–and the fact that patent law is not based on patent theory (pdf) greatly hampers the ability to tailor patent law optimally. The ruling, for example, says that a firm can’t patent a gene that it discovers but it can patent the cDNA that it develops. It’s the discovery, however, that’s expensive. The development of cDNA is today a trivial step. Thus, you can patent the trivial step but not the giant leap.
You might think that the law draws a bright line between discoveries which cannot be patented and inventions which can but that’s not correct. Discoveries can be patented and the ruling goes out of its way to push back against the view that they can’t. The ruling correctly notes that a “considerable danger” is that patents on basic ideas and tools would “inhibit future innovation”. Yet the law makes no mention of these considerations and the court provides no guidance on implementation.
Coherent or not, the recent patent cases do indicate that the SC is no longer acceding to the United States Court of Appeals for the Federal Circuit–they are reestablishing control and pushing back in the right direction on the Tabarrok curve.
A New FDA for the Age of Personalized, Molecular Medicine
In a brilliant new paper (pdf) (html) Peter Huber draws upon molecular biology, network analysis and Bayesian statistics to make some very important recommendations about FDA policy. Consider the following drugs (my list):
Drug A helps half of those to whom it is prescribed but it causes very serious liver damage in the other half. Drug B works well at some times but when administered at other times it accelerates the disease. Drug C fails to show any effect when tested against a placebo but it does seem to work in practice when administered as part of a treatment regime.
Which of these drugs should be approved and which rejected? The answer is that all of them should be approved; that is, all of them should be approved if we can target each drug to the right patient at the right time and with the right combination of other drugs. Huber argues that Bayesian adaptive testing, with molecular biology and network analysis providing priors, can determine which patients should get which drugs when and in what combinations. But we can only develop the data to target drugs if the drugs are actually approved and available in the field. The current FDA testing regime, however, is not built for adaptive testing in the field.
The current regime was built during a time of pervasive ignorance when the best we could do was throw a drug and a placebo against a randomized population and then count noses. Randomized controlled trials are critical, of course, but in a world of limited resources they fail when confronted by the curse of dimensionality. Patients are heterogeneous and so are diseases. Each patient is a unique, dynamic system and at the molecular level diseases are heterogeneous even when symptoms are not. In just the last few years we have expanded breast cancer into first four and now ten different types of cancer and the subdivision is likely to continue as knowledge expands. Match heterogeneous patients against heterogeneous diseases and the result is a high dimension system that cannot be well navigated with expensive, randomized controlled trials. As a result, the FDA ends up throwing out many drugs that could do good:
Given what we now know about the biochemical complexity and diversity of the environments in which drugs operate, the unresolved question at the end of many failed clinical trials is whether it was the drug that failed or the FDA-approved script. It’s all too easy for a bad script to make a good drug look awful. The disease, as clinically defined, is, in fact, a cluster of many distinct diseases: a coalition of nine biochemical minorities, each with a slightly different form of the disease, vetoes the drug that would help the tenth. Or a biochemical majority vetoes the drug that would help a minority. Or the good drug or cocktail fails because the disease’s biochemistry changes quickly but at different rates in different patients, and to remain effective, treatments have to be changed in tandem; but the clinical trial is set to continue for some fixed period that doesn’t align with the dynamics of the disease in enough patients
Or side effects in a biochemical minority veto a drug or cocktail that works well for the majority. Some cocktail cures that we need may well be composed of drugs that can’t deliver any useful clinical effects until combined in complex ways. Getting that kind of medicine through today’s FDA would be, for all practical purposes, impossible.
The alternative to the FDA process is large collections of data on patient biomarkers, diseases and symptoms all evaluated on the fly by Bayesian engines that improve over time as more data is gathered. The problem is that the FDA is still locked in an old mindset when it refuses to permit any drugs that are not “safe and effective” despite the fact that these terms can only be defined for a large population by doing violence to heterogeneity. Safe and effective, moreover, makes sense only when physicians are assumed to be following simple, A to B, drug to disease, prescribing rules and not when they are targeting treatments based on deep, contextual knowledge that is continually evolving:
In a world with molecular medicine and mass heterogeneity the FDA’s role will change from the yes-no single rule that fits no one to being a certifier of biochemical pathways:
By allowing broader use of the drug by unblinded doctors, accelerated approval based on molecular or modest—and perhaps only temporary—clinical benefits launches the process that allows more doctors to work out the rest of the biomarker science and spurs the development of additional drugs. The FDA’s focus shifts from licensing drugs, one by one, to regulating a process that develops the integrated drug-patient science to arrive at complex, often multidrug, prescription protocols that can beat biochemically complex diseases.
…As others take charge of judging when it is in a patient’s best interest to start tinkering with his own molecular chemistry, the FDA will be left with a narrower task—one much more firmly grounded in solid science. So far as efficacy is concerned, the FDA will verify the drug’s ability to perform a specific biochemical task in various precisely defined molecular environments. It will evaluate drugs not as cures but as potential tools to be picked off the shelf and used carefully but flexibly, down at the molecular level, where the surgeon’s scalpels and sutures can’t reach.
In an important section, Huber notes that some of the biggest successes of the drug system in recent years occurred precisely because the standard FDA system was implicitly bypassed by orphan drug approval, accelerated approval and off-label prescribing (see also The Anomaly of Off-Label Prescribing).
But for these three major licensing loopholes, millions of people alive today would have died in the 1990s. Almost all the early HIV- and AIDS-related drugs—thalidomide among them—were designated as orphans. Most were rushed through the FDA under the accelerated-approval rule. Many were widely prescribed off-label. Oncology is the other field in which the orphanage, accelerated approval, and off-label prescription have already played a large role. Between 1992 and 2010, the rule accelerated patient access to 35 cancer drugs used in 47 new treatments. For the 26 that had completed conventional followup trials by the end of that period, the median acceleration time was almost four years.
Together, HIV and some cancers have also gone on to demonstrate what must replace the binary, yes/ no licensing calls and the preposterously out-of-date Washington-approved label in the realm of complex molecular medicine.
Huber’s paper has a foreword by Andrew C. von Eschenbach, former commissioner of the FDA, who concludes:
For precision medicine to flourish, Congress must explicitly empower the agency to embrace new tools, delegate other authorities to the NIH and/or patient-led organizations, and create a legal framework that protects companies from lawsuits to encourage the intensive data mining that will be required to evaluate medicines effectively in the postmarket setting. Last but not least, Congress will also have to create a mechanism for holding the agency accountable for producing the desired outcomes.
Big Data, Big Government, Big Brother
In addition to monitoring who you call and when, your email, and your internet searches the government also has access to all of your credit card purchases. We usually don’t think about purchases as communication but what people buy says more about most people than does their email. Buying behavior can be used to predict all manner of information about your political views, affiliations, sexual activity, marriage quality and much more.
James M. Buchanan: A Celebration of Scholarship
I am pleased to announce that a conference and memorial program will be held to celebrate the work of Jim Buchanan. The conference will be on Saturday Sept. 28 and the memorial program to which all of Jim’s students, colleagues and friends are invited will be on Sunday Sept. 29. More information and rsvp here.
Airport Security Signals
Lars Christensen has a theory of airport security:
…my theory is that if you meet an unfriendly bureaucrat at the security check in the airport then it is also very likely it will be hard to start a business in that country. Therefore, I tend to think of airport security as an indicator of the level of government regulation of the country’s economy. This is something that makes me terribly bearish on the US’ long-term growth perspectives every time I encounter a TSA official in an US airport – and makes me terribly depressed about the prospects for Ukraine and it gives me an understanding of why the Scandinavian countries ‘works’ well despite excessively large public sectors.
It was therefore a pleasure today to meet friendly and efficient people at the security check in Chopin airport (Poland). And if my theory has any value this is an indication that Poland has “matured” and the level of regulation is luckily getting lighter. That is good news. So now I am thinking of raising my long-run growth forecasts for Poland…
I recently asked my young son whether he thought he could travel by himself to visit his grandmother in Victoria, Canada. He said that he could navigate the airports fine and getting into Canada was no problem but he was afraid of the security people coming back into the United States. Bear in mind that my son is American.
Partisan Bias Diminishes When Partisans Pay
In November of last year I wrote:
Overall, I am for betting because I am against bullshit. Bullshit is polluting our discourse and drowning the facts. A bet costs the bullshitter more than the non-bullshitter so the willingness to bet signals honest belief. A bet is a tax on bullshit; and it is a just tax, tribute paid by the bullshitters to those with genuine knowledge.
A recent paper provides evidence. It’s well known that Democrats and Republicans give different answers to even basic factual questions when those questions are politically loaded (Did inflation fall under Reagan? Were WMDs found in Iraq? and so forth). But do the respondents really believe their answers or are they simply signalling their affiliations? In other words, are respondents bullshitting? In a new paper, Bullock, Gerber, Huber and Hill provide evidence that the respondents don’t actually believe what they say and the authors do so by making partisans pay for their beliefs. Dylan Matthews at Wonkblog has a good writeup:
They ran two experiments. In the first, they split respondents into two groups: Those in the control group were asked basic factual questions about politics; those in the treatment group were asked the same questions but were entered into a raffle for an Amazon gift card wherein their chances depended on how many questions they got right.
In the control group, the authors find what Bartels, Nyhan and Reifler found: There are big partisan gaps in the accuracy of responses.
…But when there was money on the line, the size of the gaps shrank by 55 percent. The researchers ran another experiment, in which they increased the odds of winning for those who answered the questions correctly but also offered a smaller reward to those who answered “don’t know” rather than answering falsely. The partisan gaps narrowed by 80 percent.
The paper also has implications for democracy. Voting is just another survey without individual consequence so voting encourages expressions of rational irrationality and it’s no surprise why democracies choose bad policies.
Hat tip: @jneeley78.
Astro Teller
Dennis is not more likely to be a dentist. Nevertheless, are you surprised that the head of Google[x] lab–the lab bringing you electronically chauffeured vehicles and googles–is called Astro Teller? I kid you not. Named Eric Teller at birth, he has been called Astro since high school. Would you also be surprised to learn that Astro’s grandfathers both made notable contributions? The first grandfather you have probably already guessed, physicist Edward Teller. The second? Gerard Debreu.
Markets in Everything: AER Publication
From EJMR:
I have a new paper that I consider my best work. For a variety of reasons, the marginal return professionally for this paper is very small for me. But I think it has an excellent shot a top
journal, I would estimate 1/3 at the AER (I have published there before). So I am offering it for sale. Here are the details:1. This paper is not yet posted on my website. It has not been circulated and I have not yet presented it.
2. The paper is applied micro although I will sell it to anyone.
3. Email bids to [email protected]. Use a fake account and make sure to send no revealing information.
4. Your bid is for an AER or QJE. If it ends in Restud, you pay 65%. If it ends in the Journal of Labor Economics, Journal of Public Economics, or EJ, you pay 35%. Other journals are negotiable. You can choose the submission path as long as it starts with one of the top journals.
5. I will contact the winning bid (or highest real bid) to arrange an in person meeting in Philly at the meetings. We will never leave a paper trail.
6. Half of payment is due with a revise and resubmit. I will also make the needed changes. The final half is due with final acceptance.
7. Spare me any discussion of the ethics here. I am dead serious and I will not be commenting further on this thread.
The whole thing could be a troll or an experiment but let’s assume it’s real. An AER could easily be worth 50k, especially for someone early in their career but that’s for one you wrote yourself. An AER written by someone else has a significantly lower expected value since, if revealed, it may end your career. Moreover, suppose the buyer, as unlikely as it seems, takes advantage of the big push and makes it big on their own. Is the buyer not then vulnerable to blackmail from the seller who already has signaled their ethics? I can see this appealing, however, to the scion of some dictator who could afford to pay well over 50k and also afford to make the seller pay if the secret is revealed. Caveat emptor and also caveat venditor. True, there are not many econ PhDs among the dictator set but there are a few and sadly this kind of thing does have precedents.
P.S. I did like the discounting by journal, a nice, accurate touch.
Burned by the FDA
If you lived in Great Britain or Germany and your physician prescribed a pharmaceutical, would you ask them, “has this pharmaceutical been approved by the U.S. FDA?” Probably not. At FDAReview.org Dan Klein and I argue that international reciprocity is a no-brainer:
If the United States and, say, Great Britain had drug-approval reciprocity, then drugs approved in Britain would gain immediate approval in the United States, and drugs approved in the United States would gain immediate approval in Great Britain. Some countries such as Australia and New Zealand already take into account U.S. approvals when making their own approval decisions. The U.S. government should establish reciprocity with countries that have a proven record of approving safe drugs—including most west European countries, Canada, Japan, and Australia. Such an arrangement would reduce delay and eliminate duplication and wasted resources. By relieving itself of having to review drugs already approved in partner countries, the FDA could review and investigate NDAs more quickly and thoroughly.
Unfortunately, even when they can, the US FDA does not take advantage of international knowledge as the WSJ notes in European Sunscreen Roadblock on U.S. Beaches:
Eight sunscreen ingredient applications have been pending before the U.S. Food and Drug Administration for years—some for up to a decade—for products available in many overseas countries. The applications were filed through the federal TEA process (time and extent application), which allows the FDA to approve the ingredients if they have been used for at least five years abroad and have proved effective and safe.
…Henry Lim, chairman of dermatology at Henry Ford Hospital in Detroit and a member of the American Academy of Dermatology, says multiple UVA filters still awaiting clearance in the U.S. have been used effectively outside the country for years.
“The U.S. is an island by itself on this one,” he said. “They’re available in Canada, available in Europe, available in Asia, available in Mexico, and available in South America.”
The sunscreens available in the U.S. are not without risk and in some ways, as the WSJ discusses, the European standards are stricter than the US standards so there really is no reason why sunscreens available in Europe and Canada should not also be available in the United States.
Hat tip: Kurt Busboom.
Addendum: 27 states have driver’s license reciprocity with Germany. Why not pharmaceutical reciprocity? With hat tip to whatsthat in the comments.
Kidney Conscription in Iran
Al Roth points us to this story in Farsi about Iran’s plan to exempt kidney donors from military service. Google Translate reports:
Donate one of your kidneys to be exempted from military service
Acting Human Resources department Stadkl Armed Forces exemptions from military service the soldiers announced the donor organ. According to ISNA, General Moussa Kamali on donor exemption from military service, said the donor organ to make it happen efficiency, We’ll exempt him from military service. According to him, for example, people who donate one of his kidneys has been the inclusion of medical waivers are exempt from military service. Stadkl Armed Forces Acting Human Resources department stating Srfdashtn donation card member, was not the reason for exemption from military service, said those who donate their organ, even during military service are exempt from military service.
No doubt some people will find this unjust. Indeed it is but certainly less unjust than conscription without such an option.
Titling of Property
The NYTimes has an excellent piece on Greece’s broken property system:
In this age of satellite imagery, digital records and the instantaneous exchange of information, most of Greece’s land transaction records are still handwritten in ledgers, logged in by last names. No lot numbers. No clarity on boundaries or zoning. No obvious way to tell whether two people, or 10, have registered ownership of the same property.
As Greece tries to claw its way out of an economic crisis of historic proportions, one that has left 60 percent of young people without jobs, many experts cite the lack of a proper land registry as one of the biggest impediments to progress. It scares off foreign investors; makes it hard for the state to privatize its assets, as it has promised to do in exchange for bailout money; and makes it virtually impossible to collect property taxes.
… less than 7 percent of the country has been properly mapped, officials say. Experts say that even the Balkan states, recovering from years of Communism and civil war, are far ahead of Greece when it comes to land registries attached to zoning maps — an approach developed by the Romans and in wide use in much of the developed world since the 1800s.
Here from our course on development economics at MRUniversity is our video which covers the theory and empirical research on titling from Peru to Palau:
http://youtu.be/1CFqK_lHngs
Assorted links
1. Economic Rewards to Motivate Blood Donations, important summary of the evidence in Science.
2. Words that cannot be spoken: raw milk.
3. Econometrics by simulation blog.
4. EU to ban olive oil in dishes? Way to upset the Greeks even more.
5. How does copyright law work in space?
The Battle over Junk DNA
Last year the ENCODE Consortium, a big-data project involving 440 scientists from 32 laboratories around the world, announced with great fanfare that 80% of the human genome was functional or as the NYTimes put it less accurately but more memorably “at least 80 percent of this DNA is active and needed.” What the NYTimes didn’t say was that this claim was highly controversial to the point of implausibility. A fascinating, sharply-worded critique, On the immortality of television sets: “function” in the human genome according to the evolution-free gospel of ENCODE has recently been published by Graur et al. Here is some of the flavor:
This absurd conclusion was reached through various means, chiefly (1)
by employing the seldom used “causal role” definition of biological function and
then applying it inconsistently to different biochemical properties, (2) by committing
a logical fallacy known as “affirming the consequent,” (3) by failing to appreciate
the crucial difference between “junk DNA” and “garbage DNA,” (4) by using
analytical methods that yield biased errors and inflate estimates of functionality, (5)
by favoring statistical sensitivity over specificity, and (6) by emphasizing statistical
significance rather than the magnitude of the effect. Here, we detail the many logical
and methodological transgressions involved in assigning functionality to almost
every nucleotide in the human genome. The ENCODE results were predicted by one
of its authors to necessitate the rewriting of textbooks. We agree, many textbooks
dealing with marketing, mass-media hype, and public relations may well have to be
rewritten.
Graur et al. make a number of key points. ENCODE essentially defined “functional” as sometimes involved in a specified set of biochemical reactions (I am simplifying!). But every microbiological system is stochastic and sooner or later everything is involved in some kind of biochemical reaction even if that reaction goes nowhere and does nothing. In contrast, Graur et al. argue that “biological sense can only be derived from evolutionary context” which in this case means that functional is defined as actively protected by selection.
There are a variety of ways of identifying whether a sequence is actively protected by selection. One method, for example, looks for sequences that are highly similar (conserved) across species. Once evolution has hit on the recipe for hemoglobin, for example, it doesn’t want that recipe messed with–thus the chimp and human DNA that blueprints hemoglobin is very similar and not that different from that of dogs. In other areas of the genome, however, even closely related species have different sequences which suggests that that portion of the DNA isn’t being selected for, it’s randomly mutating because there is no value to its conservation. When functional is defined using selection, most human DNA does not look functional.
It’s also interesting to note that the size of the genome varies significantly across species but in ways that appear to have little to do with complexity. The human genome, for example, is about 3GB, quite a bit more than the fruit fly at 170MB, But the onion is 17GB! (One of the reasons that onions are used in a lot of science labs, by the way, is that the onion genome is so big it makes onion nuclei large enough so that you can easily see them with low-powered microscopes.) Now one could argue that this lack of correlation between genome size and complexity is simply a result of an anthropocentric definition of complexity. Maybe an onion really is complex. Two points counter this view, however. First, similar species can have very different genome sizes. Second, we know why the genome of some species is really large. It’s filled with transposons, so-called jumping genes, sometimes analogized to viruses, that cut and paste themselves into the genome. Some of these transposons, like Alu in humans, are short sequences that repeat themselves millions of times. It’s very difficult to believe that these boring repetitions are functional (n.b. this is not to say that they don’t have an effect.) The fact that it’s this kind of repetitious, not-conserved DNA that accounts for a large fraction of the differences in genome size is highly suggestive of non-functionality.
Why discuss such an esoteric (for economists) paper on a (nominally!) economics blog? The Graur et al. paper is highly readable, even for non-experts. It’s even funny, although I laughed somewhat sheepishly since some of the comments are unnecessarily harsh. Many of the critiques, such as the confusion between statistical and substantive significance, arise in economics and many other fields. The Graur paper also makes some points which are going to be important in economics. For example they write:
“High-throughput genomics and the centralization of science funding have enabled Big Science to generate “high-impact false positives” by the truckload…”
Exactly right. Big data is coming to economics but data is not knowledge and big data is not wisdom.
Finally, the Graur paper tells us something about disputes in economics. Economists are sometimes chided for disagreeing about the importance of such basic questions as the relative role of aggregate demand and aggregate supply but physicists can’t even find most of the universe and microbiologists don’t agree on whether the human genome is 80% functional or 80% junk. Is disagreement a result of knaves and fools? Sometimes, but more often disagreement is just the way the invisible hand of science works.
Hat tip: Monique van Hoek.
The ABCs of Bitcoin Secrets
You may perhaps have heard of the intriguing mathematician Shinichi Mochizuki who has produced an alleged proof of an important theorem that is so difficult and involves the creation of so much original mathematics and notation that no one is sure whether the proof is valid. Here is one description:
On August 31, 2012, Japanese mathematician Shinichi Mochizuki posted four papers on the Internet.
The titles were inscrutable. The volume was daunting: 512 pages in total. The claim was audacious: he said he had proved the ABC Conjecture, a famed, beguilingly simple number theory problem that had stumped mathematicians for decades.
Then Mochizuki walked away. He did not send his work to the Annals of Mathematics. Nor did he leave a message on any of the online forums frequented by mathematicians around the world. He just posted the papers, and waited.
…The problem, as many mathematicians were discovering when they flocked to Mochizuki’s website, was that the proof was impossible to read. The first paper, entitled “Inter-universal Teichmuller Theory I: Construction of Hodge Theaters,” starts out by stating that the goal is “to establish an arithmetic version of Teichmuller theory for number fields equipped with an elliptic curve…by applying the theory of semi-graphs of anabelioids, Frobenioids, the etale theta function, and log-shells.”
This is not just gibberish to the average layman. It was gibberish to the math community as well.
“Looking at it, you feel a bit like you might be reading a paper from the future, or from outer space,” wrote Ellenberg on his blog.
“It’s very, very weird,” says Columbia University professor Johan de Jong, who works in a related field of mathematics.
Mochizuki had created so many new mathematical tools and brought together so many disparate strands of mathematics that his paper was populated with vocabulary that nobody could understand. It was totally novel, and totally mystifying.
But there may be more secrets, secrets upon secrets because Ted Nelson has recently argued that this same mathematician, Shinichi Mochizuki, is also the elusive Satoshi Nakamoto who unleashed bitcoin on the world and then disappeared. Now this is almost too delicious to be true so take it with more than a grain of salt. Mochizuki, for example, has bona fides as a mathematician but he does not appear to have a record of sophisticated software creation. But if true, this would be awesome.
Hat tip: Barry Klein
The Man of System
One sometimes hears arguments for busing or against private schools that say we need to prevent the best kids from leaving in order to benefit their less advantaged peers. I find such arguments distasteful. People should not be treated as means. I must confess, therefore, that I took some pleasure at the findings of a recent paper by Carrell, Sacerdote, and West:
We take cohorts of entering freshmen at the United States Air Force Academy and assign half
to peer groups designed to maximize the academic performance of the lowest ability students.
Our assignment algorithm uses nonlinear peer eff ects estimates from the historical pre-treatment
data, in which students were randomly assigned to peer groups. We find a negative and signi ficant treatment eff ect for the students we intended to help. We provide evidence that within our
“optimally” designed peer groups, students avoided the peers with whom we intended them to
interact and instead formed more homogeneous sub-groups. These results illustrate how policies
that manipulate peer groups for a desired social outcome can be confounded by changes in the
endogenous patterns of social interactions within the group.
I was reminded of Adam Smith’s discussion of exactly this issue in The Theory of Moral Sentiments:
The man of system, on the contrary, is apt to be very wise in his own conceit; and is often so enamoured with the supposed beauty of his own ideal plan of government, that he cannot suffer the smallest deviation from any part of it. He goes on to establish it completely and in all its parts, without any regard either to the great interests, or to the strong prejudices which may oppose it. He seems to imagine that he can arrange the different members of a great society with as much ease as the hand arranges the different pieces upon a chess-board. He does not consider that the pieces upon the chess-board have no other principle of motion besides that which the hand impresses upon them; but that, in the great chess-board of human society, every single piece has a principle of motion of its own, altogether different from that which the legislature might chuse to impress upon it. If those two principles coincide and act in the same direction, the game of human society will go on easily and harmoniously, and is very likely to be happy and successful. If they are opposite or different, the game will go on miserably, and the society must be at all times in the highest degree of disorder.
Do note that this discussion is not a critique of the paper which is very well done.