What is the story of the industrial revolution? How has petroleum been important for the development of humanity? Brad produces the podcast Context, and How it Began. https://www.bradharris.com/ Transcript here.
I got to talk with Sam Arbesman about The Overedge Catalog, Scientific Discovery, and Complexity. You can check out Sam’s blog at: https://arbesman.net/
Josiah runs the ODIN, check it out here! https://www.the-odin.com/
OIn this episode, I got to sit down with Adam Marblestone to talk about how to accelerate science, what most people don’t understand about Neuroscience, and how to have an outsize impact.
What if tech stagnation, declining growth rates, and the near-inevitable seeming collapse of the West are all because we got worried a few scientists would run off with our tax dollars?
That’s the broad thesis behind Scientific Freedom: The Elixir of Civilization. Published originally in 2008, Scientific Freedom chronicles the journey of physicist Don Braben, as he designs and builds a Venture Research arm at British Petroleum in the 1980s. Braben was successful in funding a transformative research initiative at BP (transformative meaning it fundamentally changes humanity thinks about a subject). In his estimation, 14 out of the 26 groups funded made a transformative discovery, at the cost of only 30 million pounds over 10 years! A few examples of transformative discoveries made by groups funded by Braben in his time at BP are:
- Mike Bennett and Pat Heslop – Harrison discovered a new pathway for evolution and genetic control
- Terry Clark pioneered the study of macroscopic quantum objects
- Stan Clough and Tony Horsewill solved the quantum – classical transition problem by developing new relativity and quantum theories
- Steve Davies developed small artificial enzymes for efficient chiral selection
- Nigel Franks, Jean Louis Deneubourg, Simon Goss, and Chris Tofts quantified the rules describing distributed intelligence in animals
- Herbert Huppert and Steve Sparks pioneered the new field of geologic fluid mechanics
- Jeff Kimble pioneered squeezed states of light
- Graham Parkhouse derived a novel theory of engineering design relating performance to shapes and materials
- Alan Paton, Eunice Allen, and Anne Glover discovered a new symbiosis between plants and bacteria
- Martyn Poliakoff transformed green chemistry
- Colin Self demonstrated that antibodies in vivo can be activated by light
- Gene Stanley and Jos é Teixeira discovered a new liquid – liquid phase transition in water that accounts for many of water’s anomalous properties
- Harry Swinney, Werner Horsthemke, Patrick DeKepper, Jean – Claude Roux, and Jacques Boissonade developed the first laboratory chemical reactors to yield sustained spatial patterns — an essential precursor for the study of multidimensional chemistry
So how did Braben fund proposals, if he didn’t use peer review or grant proposals?
Don quite literally tried to “eliminate every selection rule imposed since about 1970 that appeared to stand in the way of freedom.” Don valued building a relationship, talking with the researchers, to determine whether or not they were of sufficient caliber to make a transformative discovery. Don and his small team were the end all be all. If Don got to know you, was impressed by your work, and thought you were working on something that was challenging and transformative, you got funded. Braben’s conviction was what mattered, and he got results. He understood how difficult it would be for some of these folks to get funding (because of peer review). Don minimized overhead and administration by having minimal staff. For advertising, he would travel from university to university giving talks. He aimed to get to know the researchers at a personal level so that trust and rapport could be built in a way you can’t do with a large funding agency. There was very little structure-no deadlines really to speak of, no reports to generate, just science.
In Don’s approach, he never told anyone “no”. If he thought someone was a quack (for instance, if I claimed that I had disproven super-string theory with only knowledge of calculus), he would kindly probe deeper. ”Will, you say you’ve disproven super-string theory, can you tell me how.” Don wouldn’t tell me to buzz off. For a bumbling or nonsensical answer, he’d just tell me to come back when I had more. This practice let Don filter out fakers, without filtering too aggressively for ideas that might be true, but not accepted by the wider scientific community.
On a practical level, Venture Researchers would be funded for 3 years at a time. Support could be renewed and often was. On renewal, the director of the research program simply asked themselves whether what they were wanting to do was still challenging. If it was, the program got renewed. In this paradigm, trust between funder and scientists was paramount.
Who Don Was Looking for: “The Planck Club”
Don is not egalitarian in his approach. Transformative Research not a program for everyone. He aims to fund researchers who can make the kinds of discoveries that are paradigm shifting for humanity. Perhaps only 100 or scientists in a generation can make the kinds of paradigm shifting impacts Don is interested in finding. These scientists are what Braben refers to as the “Planck Club,” or the group of elite scientists who make the most notable discoveries of a given century. Here Don describes the early 20th century Plank Club:
The twentieth century was strongly influenced by the work of a relatively small number of scientists. A short list might include Planck, Einstein, Rutherford, Dirac, Pauli, Schrödinger, Heisenberg, Fleming, Avery, Fermi, Perutz, Crick and Watson, Bardeen, Brattain and Shockley, Gabor, Townes, McClintock, Black, and Brenner (see Table 1). However, I give this list only to indicate something of the richness of twentieth-century science. I wrote it in a few minutes, and it obviously has many important omissions. Other scientists would doubtless have their own. If the criteria for inclusion were based on success in creating radically new sciences, or of stimulating new and generic technologies, a fuller list could easily run to a couple of hundred.
The biggest breakthroughs often take a long time, and come from people with interests in all kinds of weird areas. Planck, perhaps Don’s favorite example, took 20 years working on Thermodynamics, and would never have made it if his research had been put under the pressure modern researchers are put under. Scientific Freedom, letting people work on their ideas without constraint, is essential to producing the kinds of discoveries the Plank Club made. In essence, Braben is allergic to bureaucracy.
The Cost of Venture Research
One of the frustrating things for Braben, is the relative cheapness of Venture Research. In fact, if you believe Braben, the world is leaving trillion-dollar coins on the sidewalk:
The likely costs can be estimated using back-of-the-envelope figures. Let us assume that there were about 300 transformative researchers — the extended membership of the Planck Club — during the twentieth century. Let us adopt a rule of two by which we increase or decrease cost estimates by a factor of two whichever is the most pessimistic. Allowing for inefficiencies, therefore, let us increase the target number of transformative researchers we must find to 600 — that is, six a year on average over the century. This is a global estimate, but for a TR initiative in a large country such as the United States, then, according to our rule of two, we assume that all the new members might have to be found in that country since it is home to about half of all R & D. If we also assume that the searches will be about 50% efficient, which Venture Research experience indicates would be about right, it would mean that a US TR initiative should find some 12 transformative researchers a year. (For comparison, a maximum of nine scientists can win the Nobel Prizes each year). TR is the cheapest research there is, as it is heavy on intellectual requirements but relatively light on resources. For Venture Research in the late 1980s – early 1990s operating in Europe and the United States, the average cost per project was less than £100,000 a year, including all academic and industrial overheads. Costs have gone up since then, so for our present purposes, we might double them to, say, £200,000 or $400,000 a year per project on average.
Transformative researchers should be supported initially for 3 years. Our experience indicates that about half of them would require a second 3 year term; and half of those, a third term of support. Very few projects should run for more than, say, 9 years. Those leaving the TR scheme either would have succeeded and been transferred to other programs created for them — that is, their research would actually have been transformative — or, the scientists agree that they had probably failed in their Herculean quests. However, these average figures are quoted for guidance; there should in fact be no hard-and- fast rules on the length of support. Remember Planck!
This sum should also be the steady total thereafter. As we have chosen x to be 12, after 9 years, therefore, a TR research budget (i.e., excluding overheads such as the initiative’s administrative costs) would be some $25 million a year. If it turns out to be significantly more than that, the initiative would be tackling
a different problem than TR. After the first 9 years, the TR initiative would have backed some 108 projects, of which according to our experience about 54 should eventually turn out to be transformative in some way.
A TR budget for a smaller country — say, the United Kingdom — should be about half that of the United States, or $ 12.5 million per annum. The Venture
Research budget in our final year of operation (1990) was some $ 5 million, two-thirds of which we spent in Britain. As we had been operating for 10 years, it is possible that we had identified most of the researchers in Britain looking for potentially transformative research support at that time.
That’s only $25 million a year in inflation-adjusted cost for a small country like the UK. They probably spend more on staplers!
Pre-1970’s, research was much smaller than it is now, and it was the norm that scientists could work on their problem of choice, without too much bother or oversight from their overlords. No moloch could touch these angels of knowledge, their tendrils of curiosity reaching out over nature, unencumbered by peer review.
Before 1970 or so, tenured academics with an individual turn of mind could usually dig out modest sources of funding to tackle any problem that interested them without first having to commit themselves in writing. Afterward, unconditional sources of funds would become increasingly difficult to find. Today, they are virtually nonexistent.
For Don, this change precipitated a decline in our ability to create breakthrough research. Peer review snuffed out all the weird people following their interesting passions. Instead of cool wacky scientists, we got salesman-scientists in suits. As people who can’t get funding say, “That dog won’t hunt.” There is a possibility that this change has precipitated our relative stagnation. Bureaucracy, and a lack of scientific freedom, the ability to get a small amount of unconditional money to follow your research interests, means that we don’t get a Planck Club for the later half of the 20th century. Technology is the child of science, and if science is sick, maybe it makes us worse at creating the kinds of technology that keeps our world progressing towards a brighter future. Braben believes that although we have gotten many advancements in recent memory (the book was originally published in 2008), most of these are technologies leftover from the harvest of the early 20th century of research. This is important (and I think scores points for Don) because this gives him the title of being one of the earlier “alarm bells” of secular stagnation/decadence/tech stagnation in our society. Here, Don talks about the gift of the discoveries of the Planck Club:
“This prodigious progress came from our growing ability to harvest the fruits of humanity’s intellectual prowess — scientific endeavour, as it is usually called. Material wealth continued to accelerate through most of the last century despite financial crashes and global wars. But then gradually, around about 1970, signs of major change began to emerge. Science’s very success had unsurprisingly led to a steady expansion in scientists’ numbers. That could not continue indefinitely, of course, and the inevitable crunch came when there were more than could adequately be funded. This was not only a numbers problem — the unit costs of research were also increasing. The funding agencies should have seen this coming, but they did not. Indeed, as I shall explain, many today do not accept this version of events and are thereby contributing to one of the greatest tragedies of modernity. This perhaps surprising statement arises because the agencies’ virtually universal response to the crisis was to restrict the types of research they would fund. Thus, to use a truly horrible word, they would prioritize, and focus funding on the most attractive objectives — that is, objectives the agencies perceived to be the most attractive. Thus, for the first time since the Renaissance, the limits of thinking began to be systematically curtailed.”
Thanks to that precious gift, and despite the havoc of world wars, financial crashes, and a threefold rise in population, per capita economic growth soared in the twentieth century, reaching a peak, coincidentally perhaps, around about 1970. It then began a steady decline.
Why hasn’t Venture Research caught on? I can only speculate, but I think letting folks run wild is not something that scales. Don might respond that it’s perfectly okay that it doesn’t scale-venture research is not for everyone, it’s just for the select members of folks who have the capability to make transformative discoveries like the ones that belong in “The Planck Club.” It is important however, that someone is doing this kind of science funding.
We’ve many more researchers now than in the past, and there are simple bureaucratic reasons why oversight has become more important than research results. It’s like building a vaccine-if you are a regulator, you don’t get points for the hundred of thousands of lives you save, you only get punished if 365 folks get guillain-barré from your vaccine. The first researcher who gets public money, and spends “a little too much time down in Aruba” makes the front page of the Times, and the whole funding program is toast. On the bright side, it truly doesn’t take much money to set up a venture research unit, and it’s something that a rich tech founder could easily fund (Patrick Collison, are you still with me here?).
Scientific Freedom, for Braben, is something akin to the air we breathe. It’s essential, but less obvious that water, health and security. It’s tough to notice how important it is when you have it, but you sure as hell start to notice when it’s gone. With it, society prospers, and we continue to find our own century’s “Plank Club,” without it, we stagnate.
I really enjoyed the opportunity to talk to Alexey about New Science, and the future of research. Transcript and show notes here.
I got to talk to Geoff Shullenberger about Girard, the premodern/modern/postmodern distinction, academia, Christianity and a whole lot more. Transcript here.
Link to the transcript and show notes here.
Schizophrenia is a terrible disease. Its symptoms can include delusions, hallucinations, and amnesia. Schizophrenia affects 1.1% of the population, and 10% of persons with schizophrenia will take their own life.
Current treatments for schizophrenia are less than ideal. There is no cure, and the best we can do is treat symptoms. Current treatments, like modern anti-psychotics blunt experience, and come with a host of terrible side effects. Medication adherence is poor, and antipsychotics slowly destroy your brain.
Efforts to find a “cure” for schizophrenia have been unsuccessful, but a potential avenue has opened up which I believe is very important. I have come across two cases of people suffering from schizophrenia experiencing a very significant reduction in symptoms-enough that both patients could lead a normal life. Both of these patients underwent bone marrow transplants (BMT) for blood cancer.
Another patient, who was 70 years old, developed schizophrenia after receiving a bone marrow transplant from a relative with schizophrenia. This is very odd, considering that it is very uncommon to develop Schizophrenia so late in life. This suggests some causative mechanism-that perhaps in some cases of schizophrenia, getting a bone marrow transplant can in some sense provide relief for your symptoms, or it’s or the opposite, have you get the disease.
It is important to note, that so far, N=3, but the effect size is massive, suggesting that this needs to be studied further.
I have put together a review of the current literature available, and summarized the key points. Included are some concluding remarks, next steps, and important patterns I have noticed as well.
Case Study #1: Remission of Psychosis in Treatment-Resistant Schizophrenia following Bone Marrow Transplantation: A Case Report
The first case study I found was the case of a 24 year old man in Japan. He led a fairly normal life, had normal social skills, graduated from college, and worked at a corporation for a living. At 23 years old, he began to experience insomnia, irritability and anxiety. He also began to experience persecutory delusions, paranoid ideation, and spoke incoherently. He was diagnosed as suffering from “paranoid schizophrenia.” He was treated with the antipsychotic Quetiapine (300 mg/day) a common antipsychotic, but it seemed to have no effect, and his auditory hallucinations, social avoidance, persecutory delusions, and suspiciousness continued to progress. He was subsequently given Risperidone (12mg/day) and Olanzapine (20 mg/day). His condition did not improve at all, and his social function continued to deteriorate. He was diagnosed with “treatment-resistant schizophrenia.”
When the man was 24 years old, he was diagnosed with acute myeloid leukemia. He experienced tiredness, his gums bled, and he suffered from pain in his joints. They determined he was a good candidate for BMT. The man underwent an allogenic (from another person) Bone Marrow Transplant, and 30 days later, his psychotic symptoms had almost disappeared, without the administration of any neuroleptic treatment. 8 years after his BMT, there are no residual psychiatric symptoms, and his social functioning has gotten drastically better.
Graph showing tha patients drastic reduction in PANSS. PANSS stands for positive and negative syndrome scale. It is used to note the severity of the symptoms of schizophrenia.
Case Study #2: Serendipitous Improvement of Schizophrenia After Triple Bone Marrow Stem Cell Transplant
The second case study I found was a 21-year-old male in Mexico. He was diagnosed at age 15 with schizophrenia. He was suspicious, socially withdrawn, and suffered from auditory hallucinations. His symptoms were so severe, he was forced to drop out of high school, and only left the house for therapy. He was prescribed Risperidone (4mg/day) and Olanzapine (10mg/day) without success.
One year after his diagnosis of schizophrenia, he was diagnosed with Hodgkin’s Lymphoma. He received a series of three bone marrow transplants. The patient underwent an autologous BMT, but three months later relapsed. He received another autologous (from himself) BMT, and relapsed a second time. He finally received an allogenic (from another person) BMT, and the treatment for Hodgkins Lymphoma was successful. After his first BMT, his PANSS dropped from 147, to 89.
Graph showing tha patients drastic reduction in PANSS. PANSS stands for positive and negative syndrome scale. It is used to note the severity of the symptoms of schizophrenia.
Case Study 5: Severe chronic psychosis after allogeneic SCT from a schizophrenic sibling.
(IE Sommer 2015) found a third case study that is of particular interest. It comes from a 67 year old retired man. He was married, had two adult children, and had a blank psychiatric history. He was diagnosed with lymphocytic leukemia, and bone marrow aplasia. He received chemotherapy, and an allogeneic BMT from one of his brothers. His brother had schizophrenia since early adulthood, and required treatment with multiple antipsychotics. Approximately five months after his BMT, he began to develop frequent hallucinations, delusions, and he was angry with a flat affect. He developed homicidal and suicidal ideation, and was admitted to a psychiatric clinic. He was given an MRI, a neurological evaluation and electroencephalography-it all revealed no abnormalities. He suffered from no metabolic disorders, or underlying infections. He was treated with risperidone 3mg/day, and Citalopram 20mg/day, but it did not work. He was given haloperidol 1mg, which did not help either.
The adoptive transfer of schizophrenia is a likely description of what happened, even though the patient was never formally diagnosed due to his advanced age, and its proximity to his BMT.
An analysis using a payer database:
The Impact of Bone Marrow Transplantation In Patients With Psychiatric Diagnoses: Medication Adherence Assessment by Brittany Galop
(Galop 2020) took a novel approach to determine whether or not BMT had an effect on patients suffering from psychiatric diagnoses. Galop measured the utilization of psychiatric medication before, and after a BMT as a proxy to determine whether or not there was a reduction in symptoms. Galop then gathered a database of anonymized patient data, the Truven MarketScan data, which included data on 8,233 patients that had undergone an Allogeneic BMT.
Medication usage, was measured in two ways:
Medication Possession Ratio, or MPR, defined as the sum of the days’ supply for all fills of a given drug in a particular time period, divided by the number of days in the time period.
Proportion of Days Covered, or PDC, defined as the number of days “covered” divided by the number of days in the period.
For antipsychotic medications, the sample size was 70 patients who had been prescribed antipsychotics. MPR Prescriptions dropped from 1195 to 895, a reduction of 25.1%.
MPR prescriptions for Antipsychotics dropped 25.1% post BMT. Thanks to (Gallop 2020) for the chart, emphasis added by me.
PDC Prescriptions also dropped, from 1071, to 829, a reduction of 22.6%.
PDC prescriptions for Antipsychotics dropped 22.6% post BMT. Thanks to (Gallop 2020) for the chart, emphasis added by me.
Some limitations that Galop explicitly acknowledges: if you need a BMT, you are suffering from generally poor health, and you may end up feeling a lot better because your underlying disease has been treated, not your Schizophrenia. Additionally, the study included a range of defined psychiatric conditions, not just schizophrenia. I plan to pull out the patients afflicted with Schizophrenia, and run through the data as well in a more targeted manner.
After having gathered the current evidence, I think it is likely that a certain percentage (perhaps as high as 30-40%) of individuals suffering from schizophrenia could be treated with BMT in order to provide a substantial reduction in symptoms.
Some limitations-this is all observational, it could be that each individual’s underlying schizophrenia condition was actually some weird symptom related to their blood cancer. I think the third case study, of the 67 year old man developing what appears to be schizophrenia after a bone marrow transplant provides some amount of evidence against this thought.
Commonalities of the first two case studies:
- They were both diagnosed with leukemia approximately one year after they were diagnosed with schizophrenia.
- Both case studies were treatment resistant to risperidone.
- Both suffered from acute schizophrenia, and suffered from hallucinations.
- Both young men in their 20s.
- One suffered from myeloid leukemia, the other from Hodgkin’s Lymphoma.
- One recovered after an allogenic (from another person) BMT, the other from an autologous (from themselves) BMT.
Although this is just two case studies, along with the prescription reduction Brittany observed in her data analysis, I think there is enough evidence that this needs to be studied further as a potential treatment for schizophrenia. Currently, BMT mortality rates have dropped to about 10%, and in a fashion similar to Moore’s law for computer chips, seem to be getting better over time at a fast clip. This mortality rate is also in the context of patients suffering from a severe illness (you only get a BMT if you have blood cancer!), suggesting that soon, we will be able to use this treatment more widely. In fact, there have already been people treated with BMT for diseases such as Crohn’s disease. I also have my suspicions that, barring graft vs host disease, cleanliness probably could be improved, and easy gains made in ways similar to this.
It is also important to note, I do not believe that BMT will work for every case of Schizophrenia, I think there is evidence that there are broadly two categories of Schizophrenia-immune disturbance related Schizophrenia, and hormonal/growth factor disturbance schizophrenia, with immune disturbance related Schizophrenia-suggesting that there is a potential diagnostic tool that could be used to verify-this will likely work for you, or it won’t.
More to follow!