Gene therapy

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Gene therapy using an adenovirus vector. In some cases, the adenovirus will insert the new gene into a cell. If the treatment is successful, the new gene will make a functional protein to treat a disease.

In the medicine field, gene therapy (also called human gene transfer) is the therapeutic delivery of nucleic acid into a patient's cells as a drug to treat disease. The first attempt at modifying human DNA was performed in 1980 by Martin Cline, but the first successful nuclear gene transfer in humans, approved by the National Institutes of Health, was performed in May 1989. The first therapeutic use of gene transfer as well as the first direct insertion of human DNA into the nuclear genome was performed by French Anderson in a trial starting in September 1990.

Between 1989 and February 2016, over 2,300 clinical trials had been conducted, more than half of them in phase I.

Not all medical procedures that introduce alterations to a patient's genetic makeup can be considered gene therapy. Bone marrow transplantation and organ transplants in general have been found to introduce foreign DNA into patients.^[5] Gene therapy is defined by the precision of the procedure and the intention of direct therapeutic effects.

Background

Gene therapy was conceptualized in 1972, by authors who urged caution before commencing human gene therapy studies.

The first attempt, an unsuccessful one, at gene therapy (as well as the first case of medical transfer of foreign genes into humans not counting organ transplantation) was performed by Martin Cline on 10 July 1980.^[6][7] Cline claimed that one of the genes in his patients was active six months later, though he never published this data or had it verified^[8] and even if he is correct, it's unlikely it produced any significant beneficial effects treating beta-thalassemia.

After extensive research on animals throughout the 1980s and a 1989 bacterial gene tagging trial on humans, the first gene therapy widely accepted as a success was demonstrated in a trial that started on 14 September 1990, when Ashi DeSilva was treated for ADA-SCID.^[9]

The first somatic treatment that produced a permanent genetic change was performed in 1993.^{[citation needed]}

Gene therapy is a way to fix a genetic problem at its source. The polymers are either translated into proteins, interfere with target gene expression, or possibly correct genetic mutations.

The most common form uses DNA that encodes a functional, therapeutic gene to replace a mutated gene. The polymer molecule is packaged within a "vector", which carries the molecule inside cells.

Early clinical failures led to dismissals of gene therapy. Clinical successes since 2006 regained researchers' attention, although as of 2014, it was still largely an experimental technique.^[10] These include treatment of retinal diseases Leber's congenital amaurosis^{[11][12][13][14]} and choroideremia,^[15] X-linked SCID,^[16] ADA-SCID,^[17][18] adrenoleukodystrophy,^[19] chronic lymphocytic leukemia (CLL),^[20] acute lymphocytic leukemia (ALL),^[21] multiple myeloma,^[22] haemophilia,^[18] and Parkinson's disease.^[23] Between 2013 and April 2014, US companies invested over $600 million in the field.^[24]

The first commercial gene therapy, Gendicine, was approved in China in 2003 for the treatment of certain cancers.^[25] In 2011 Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia.^[26] In 2012 Glybera, a treatment for a rare inherited disorder, became the first treatment to be approved for clinical use in either Europe or the United States after its endorsement by the European Commission.^[10][27]

Approaches

Following early advances in genetic engineering of bacteria, cells, and small animals, scientists started considering how to apply it to medicine. Two main approaches were considered – replacing or disrupting defective genes.^[28] Scientists focused on diseases caused by single-gene defects, such as cystic fibrosis, haemophilia, muscular dystrophy, thalassemia, and sickle cell anemia. Glybera treats one such disease, caused by a defect in lipoprotein lipase.^[27]

DNA must be administered, reach the damaged cells, enter the cell and either express or disrupt a protein.^[29] Multiple delivery techniques have been explored. The initial approach incorporated DNA into an engineered virus to deliver the DNA into a chromosome.^[30][31] Naked DNA approaches have also been explored, especially in the context of vaccine development.^[32]

Generally, efforts focused on administering a gene that causes a needed protein to be expressed. More recently, increased understanding of nuclease function has led to more direct DNA editing, using techniques such as zinc finger nucleases and CRISPR. The vector incorporates genes into chromosomes. The expressed nucleases then knock out and replace genes in the chromosome. As of 2014 these approaches involve removing cells from patients, editing a chromosome and returning the transformed cells to patients.^[33]

Gene editing is a potential approach to alter the human genome to treat genetic diseases,^[34] viral diseases,^[35] and cancer.^[36] As of 2016 these approaches were still years from being medicine.^[37][38]
 

A duplex of crRNA and tracrRNA acts as guide RNA to

introduce a specifically located gene modification based on

the RNA 5’ upstream of the crRNA. Cas9 binds the tracrRNA

and needs a DNA binding sequence (5’NGG3’), which is

called protospacer adjacent motif (PAM). After binding, Cas9

introduces a DNA double strand break, which is then followed

by gene modification via homologous recombination (HDR) or

non-homologous end joining (NHEJ).

Cell types

Gene therapy may be classified into two types:

Somatic

In somatic cell gene therapy (SCGT), the therapeutic genes are transferred into any cell other than a gamete, germ cell, gametocyte, or undifferentiated stem cell. Any such modifications affect the individual patient only, and are not inherited by offspring. Somatic gene therapy represents mainstream basic and clinical research, in which therapeutic DNA (either integrated in the genome or as an external episome or plasmid) is used to treat disease.

Over 600 clinical trials utilizing SCGT are underway in the US. Most focus on severe genetic disorders, including immunodeficiencies, haemophilia, thalassaemia, and cystic fibrosis. Such single gene disorders are good candidates for somatic cell therapy. The complete correction of a genetic disorder or the replacement of multiple genes is not yet possible. Only a few of the trials are in the advanced stages.^[39]

Germline

In germline gene therapy (GGT), germ cells (sperm or egg cells) are modified by the introduction of functional genes into their genomes. Modifying a germ cell causes all the organism's cells to contain the modified gene. The change is therefore heritable and passed on to later generations. Australia, Canada, Germany, Israel, Switzerland, and the Netherlands^[40] prohibit GGT for application in human beings, for technical and ethical reasons, including insufficient knowledge about possible risks to future generations^[40] and higher risks versus SCGT.^[41] The US has no federal controls specifically addressing human genetic modification (beyond FDA regulations for therapies in general).^{[40][42][43][44]}

Vectors

The delivery of DNA into cells can be accomplished by multiple methods. The two major classes are recombinant viruses (sometimes called biological nanoparticles or viral vectors) and naked DNA or DNA complexes (non-viral methods).

Viruses

In order to replicate, viruses introduce their genetic material into the host cell, tricking the host's cellular machinery into using it as blueprints for viral proteins. Retroviruses go a stage further by having their genetic material copied into the genome of the host cell. Scientists exploit this by substituting a virus's genetic material with therapeutic DNA. (The term 'DNA' may be an oversimplification, as some viruses contain RNA, and gene therapy could take this form as well.) A number of viruses have been used for human gene therapy, including retroviruses, adenoviruses, herpes simplex, vaccinia, and adeno-associated virus.^[4] Like the genetic material (DNA or RNA) in viruses, therapeutic DNA can be designed to simply serve as a temporary blueprint that is degraded naturally or (at least theoretically) to enter the host's genome, becoming a permanent part of the host's DNA in infected cells.

Non-viral

Non-viral methods present certain advantages over viral methods, such as large scale production and low host immunogenicity. However, non-viral methods initially produced lower levels of transfection and gene expression, and thus lower therapeutic efficacy. Later technology remedied this deficiency.

Methods for non-viral gene therapy include the injection of naked DNA, electroporation, the gene gun, sonoporation, magnetofection, the use of oligonucleotides, lipoplexes, dendrimers, and inorganic nanoparticles.

Hurdles

Some of the unsolved problems include:

• Short-lived nature – Before gene therapy can become a permanent cure for a condition, the therapeutic DNA introduced into target cells must remain functional and the cells containing the therapeutic DNA must be stable. Problems with integrating therapeutic DNA into the genome and the rapidly dividing nature of many cells prevent it from achieving long-term benefits. Patients require multiple treatments.
• Immune response – Any time a foreign object is introduced into human tissues, the immune system is stimulated to attack the invader. Stimulating the immune system in a way that reduces gene therapy effectiveness is possible. The immune system's enhanced response to viruses that it has seen before reduces the effectiveness to repeated treatments.
• Problems with viral vectors – Viral vectors carry the risks of toxicity, inflammatory responses, and gene control and targeting issues.
• Multigene disorders – Some commonly occurring disorders, such as heart disease, high blood pressure, Alzheimer's disease, arthritis, and diabetes, are affected by variations in multiple genes, which complicate gene therapy.
• Some therapies may breach the Weismann barrier (between soma and germ-line) protecting the testes, potentially modifying the germline, falling afoul of regulations in countries that prohibit the latter practice.^[45]
• Insertional mutagenesis – If the DNA is integrated in a sensitive spot in the genome, for example in a tumor suppressor gene, the therapy could induce a tumor. This has occurred in clinical trials for X-linked severe combined immunodeficiency (X-SCID) patients, in which hematopoietic stem cells were transduced with a corrective transgene using a retrovirus, and this led to the development of T cell leukemia in 3 of 20 patients.^[46][47] One possible solution is to add a functional tumor suppressor gene to the DNA to be integrated. This may be problematic since the longer the DNA is, the harder it is to integrate into cell genomes. CRISPR technology allows researchers to make much more precise genome changes at exact locations.^[48]
• Cost – Alipogene tiparvovec or Glybera, for example, at a cost of $1.6 million per patient, was reported in 2013 to be the world's most expensive drug.^[49][50]

Deaths

Three patients' deaths have been reported in gene therapy trials, putting the field under close scrutiny. The first was that of Jesse Gelsinger in 1999. Jesse Gelsinger died because of immune rejection response.^[51] One X-SCID patient died of leukemia in 2003.^[9] In 2007, a rheumatoid arthritis patient died from an infection; the subsequent investigation concluded that the death was not related to gene therapy.^[52]

History

1970s and earlier

In 1972 Friedmann and Roblin authored a paper in Science titled "Gene therapy for human genetic disease?"^[53] Rogers (1970) was cited for proposing that exogenous good DNA be used to replace the defective DNA in those who suffer from genetic defects.^[54]

1980s

In 1984 a retrovirus vector system was designed that could efficiently insert foreign genes into mammalian chromosomes.^[55]

1990s

The first approved gene therapy clinical research in the US took place on 14 September 1990, at the National Institutes of Health (NIH), under the direction of William French Anderson.^[56] Four-year-old Ashanti DeSilva received treatment for a genetic defect that left her with ADA-SCID, a severe immune system deficiency. The defective gene of the patient's blood cells was replaced by the functional variant. Ashanti’s immune system was partially restored by the therapy. Production of the missing enzyme was temporarily stimulated, but the new cells with functional genes were not generated. She led a normal life only with the regular injections performed every two months. The effects were successful, but temporary.^[57]

Cancer gene therapy was introduced in 1992/93 (Trojan et al. 1993).^[58] The treatment of glioblastoma multiforme, the malignant brain tumor whose outcome is always fatal, was done using a vector expressing antisense IGF-I RNA (clinical trial approved by NIH protocolno.1602 November 24, 1993,^[59] and by the FDA in 1994). This therapy also represents the beginning of cancer immunogene therapy, a treatment which proves to be effective due to the anti-tumor mechanism of IGF-I antisense, which is related to strong immune and apoptotic phenomena.

In 1992 Claudio Bordignon, working at the Vita-Salute San Raffaele University, performed the first gene therapy procedure using hematopoietic stem cells as vectors to deliver genes intended to correct hereditary diseases.^[60] In 2002 this work led to the publication of the first successful gene therapy treatment for adenosine deaminase deficiency (ADA-SCID). The success of a multi-center trial for treating children with SCID (severe combined immune deficiency or "bubble boy" disease) from 2000 and 2002, was questioned when two of the ten children treated at the trial's Paris center developed a leukemia-like condition. Clinical trials were halted temporarily in 2002, but resumed after regulatory review of the protocol in the US, the United Kingdom, France, Italy, and Germany.^[61]

In 1993 Andrew Gobea was born with SCID following prenatal genetic screening. Blood was removed from his mother's placenta and umbilical cord immediately after birth, to acquire stem cells. The allele that codes for adenosine deaminase (ADA) was obtained and inserted into a retrovirus. Retroviruses and stem cells were mixed, after which the viruses inserted the gene into the stem cell chromosomes. Stem cells containing the working ADA gene were injected into Andrew's blood. Injections of the ADA enzyme were also given weekly. For four years T cells (white blood cells), produced by stem cells, made ADA enzymes using the ADA gene. After four years more treatment was needed.^[62]

Jesse Gelsinger's death in 1999 impeded gene therapy research in the US.^[63][64] As a result, the FDA suspended several clinical trials pending the reevaluation of ethical and procedural practices.^[65]

2000s

The modified cancer gene therapy strategy of antisense IGF-I RNA (NIH n˚ 1602)^[59] using antisense / triple helix anti-IGF-I approach was registered in 2002 by Wiley gene therapy clinical trial - n˚ 635 and 636. The approach has shown promising results in the treatment of six different malignant tumors: glioblastoma, cancers of liver, colon, prostate, uterus, and ovary (Collaborative NATO Science Programme on Gene Therapy USA, France, Poland n˚ LST 980517 conducted by J. Trojan) (Trojan et al., 2012). This anti-gene antisense/triple helix therapy has proven to be efficient, due to the mechanism stopping simultaneously IGF-I expression on translation and transcription levels, strengthening anti-tumor immune and apoptotic phenomena.

2002

Sickle-cell disease can be treated in mice.^[66] The mice – which have essentially the same defect that causes human cases – used a viral vector to induce production of fetal hemoglobin (HbF), which normally ceases to be produced shortly after birth. In humans, the use of hydroxyurea to stimulate the production of HbF temporarily alleviates sickle cell symptoms. The researchers demonstrated this treatment to be a more permanent means to increase therapeutic HbF production.^[67]

A new gene therapy approach repaired errors in messenger RNA derived from defective genes. This technique has the potential to treat thalassaemia, cystic fibrosis and some cancers.^[68]

Researchers created liposomes 25 nanometers across that can carry therapeutic DNA through pores in the nuclear membrane.^[69]

2003

In 2003 a research team inserted genes into the brain for the first time. They used liposomes coated in a polymer called polyethylene glycol, which unlike viral vectors, are small enough to cross the blood–brain barrier.^[70]

Short pieces of double-stranded RNA (short, interfering RNAs or siRNAs) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copied from a faulty gene, then the abnormal protein product of that gene will not be produced.^[71]

Gendicine is a cancer gene therapy that delivers the tumor suppressor gene p53 using an engineered adenovirus. In 2003, it was approved in China for the treatment of head and neck squamous cell carcinoma.^[25]

2006

In March researchers announced the successful use of gene therapy to treat two adult patients for X-linked chronic granulomatous disease, a disease which affects myeloid cells and damages the immune system. The study is the first to show that gene therapy can treat the myeloid system.^[72]

In May a team reported a way to prevent the immune system from rejecting a newly delivered gene.^[73] Similar to organ transplantation, gene therapy has been plagued by this problem. The immune system normally recognizes the new gene as foreign and rejects the cells carrying it. The research utilized a newly uncovered network of genes regulated by molecules known as microRNAs. This natural function selectively obscured their therapeutic gene in immune system cells and protected it from discovery. Mice infected with the gene containing an immune-cell microRNA target sequence did not reject the gene.

In August scientists successfully treated metastatic melanoma in two patients using killer T cells genetically retargeted to attack the cancer cells.^[74]

In November researchers reported on the use of VRX496, a gene-based immunotherapy for the treatment of HIV that uses a lentiviral vector to deliver an antisense gene against the HIV envelope. In a phase I clinical trial, five subjects with chronic HIV infection who had failed to respond to at least two antiretroviral regimens were treated. A single intravenous infusion of autologous CD4 T cells genetically modified with VRX496 was well tolerated. All patients had stable or decreased viral load; four of the five patients had stable or increased CD4 T cell counts. All five patients had stable or increased immune response to HIV antigens and other pathogens. This was the first evaluation of a lentiviral vector administered in a US human clinical trial.^[75][76]

2007

In May researchers announced the first gene therapy trial for inherited retinal disease. The first operation was carried out on a 23-year-old British male, Robert Johnson, in early 2007.^[77]

2008

Leber's congenital amaurosis is an inherited blinding disease caused by mutations in the RPE65 gene. The results of a small clinical trial in children were published in April.^[11] Delivery of recombinant adeno-associated virus (AAV) carrying RPE65 yielded positive results. In May two more groups reported positive results in independent clinical trials using gene therapy to treat the condition. In all three clinical trials, patients recovered functional vision without apparent side-effects.^{[11][12][13][14]}

2009

In September researchers were able to give trichromatic vision to squirrel monkeys.^[78] In November 2009, researchers halted a fatal genetic disorder called adrenoleukodystrophy in two children using a lentivirus vector to deliver a functioning version of ABCD1, the gene that is mutated in the disorder.^[79]

2010s

2010

An April paper reported that gene therapy addressed achromatopsia (color blindness) in dogs by targeting cone photoreceptors. Cone function and day vision were restored for at least 33 months in two young specimens. The therapy was less efficient for older dogs.^[80]

In September it was announced that an 18-year-old male patient in France with beta-thalassemia major had been successfully treated.^[81] Beta-thalassemia major is an inherited blood disease in which beta haemoglobin is missing and patients are dependent on regular lifelong blood transfusions.^[82] The technique used a lentiviral vector to transduce the human ß-globin gene into purified blood and marrow cells obtained from the patient in June 2007.^[83] The patient's haemoglobin levels were stable at 9 to 10 g/dL. About a third of the hemoglobin contained the form introduced by the viral vector and blood transfusions were not needed.^[83][84] Further clinical trials were planned.^[85] Bone marrow transplants are the only cure for thalassemia, but 75% of patients do not find a matching donor.^[84]

Cancer immunogene therapy using modified antigene, antisense/triple helix approach was introduced in South America in 2010/11 in La Sabana University, Bogota (Ethical Committee 14 December 2010, no P-004-10). Considering the ethical aspect of gene diagnostic and gene therapy targeting IGF-I, the IGF-I expressing tumors i.e. lung and epidermis cancers were treated (Trojan et al. 2016).

2011

In 2007 and 2008, a man (Timothy Ray Brown) was cured of HIV by repeated hematopoietic stem cell transplantation (see also allogeneic stem cell transplantation, allogeneic bone marrow transplantation, allotransplantation) with double-delta-32 mutation which disables the CCR5 receptor. This cure was accepted by the medical community in 2011.^[88] It required complete ablation of existing bone marrow, which is very debilitating.

In August two of three subjects of a pilot study were confirmed to have been cured from chronic lymphocytic leukemia (CLL). The therapy used genetically modified T cells to attack cells that expressed the CD19 protein to fight the disease.^[20] In 2013, the researchers announced that 26 of 59 patients had achieved complete remission and the original patient had remained tumor-free.^[89]

Human HGF plasmid DNA therapy of cardiomyocytes is being examined as a potential treatment for coronary artery disease as well as treatment for the damage that occurs to the heart after myocardial infarction.^[90][91]

In 2011 Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia; it delivers the gene encoding for VEGF.^[92][26] Neovasculogen is a plasmid encoding the CMV promoter and the 165 amino acid form of VEGF.^[93][94]

2012

The FDA approved Phase 1 clinical trials on thalassemia major patients in the US for 10 participants in July.^[95] The study was expected to continue until 2015.^[85]

In July 2012, the European Medicines Agency recommended approval of a gene therapy treatment for the first time in either Europe or the United States. The treatment used Alipogene tiparvovec (Glybera) to compensate for lipoprotein lipase deficiency, which can cause severe pancreatitis.^[96] The recommendation was endorsed by the European Commission in November 2012^{[10][27][97][98]} and commercial rollout began in late 2014.^[99] Alipogene tiparvovec was expected to cost around $1.6 million per treatment in 2012,^[100] revised to $1 million in 2015,^[101] making it the most expensive medicine in the world at the time.^[102] As of 2016, only one person had been treated with drug.^[103]

In December 2012, it was reported that 10 of 13 patients with multiple myeloma were in remission "or very close to it" three months after being injected with a treatment involving genetically engineered T cells to target proteins NY-ESO-1 and LAGE-1, which exist only on cancerous myeloma cells.^[22]

2013

In March researchers reported that three of five adult subjects who had acute lymphocytic leukemia (ALL) had been in remission for five months to two years after being treated with genetically modified T cells which attacked cells with CD19 genes on their surface, i.e. all B-cells, cancerous or not. The researchers believed that the patients' immune systems would make normal T-cells and B-cells after a couple of months. They were also given bone marrow. One patient relapsed and died and one died of a blood clot unrelated to the disease.^[21]

Following encouraging Phase 1 trials, in April, researchers announced they were starting Phase 2 clinical trials (called CUPID2 and SERCA-LVAD) on 250 patients^[104] at several hospitals to combat heart disease. The therapy was designed to increase the levels of SERCA2, a protein in heart muscles, improving muscle function.^[105] The FDA granted this a Breakthrough Therapy Designation to accelerate the trial and approval process.^[106] In 2016 it was reported that no improvement was found from the CUPID 2 trial.^[107]

In July researchers reported promising results for six children with two severe hereditary diseases had been treated with a partially deactivated lentivirus to replace a faulty gene and after 7–32 months. Three of the children had metachromatic leukodystrophy, which causes children to lose cognitive and motor skills.^[108] The other children had Wiskott-Aldrich syndrome, which leaves them to open to infection, autoimmune diseases, and cancer.^[109] Follow up trials with gene therapy on another six children with Wiskott-Aldrich syndrome were also reported as promising.^[110][111]

In October researchers reported that two children born with adenosine deaminase severe combined immunodeficiency disease (ADA-SCID) had been treated with genetically engineered stem cells 18 months previously and that their immune systems were showing signs of full recovery. Another three children were making progress.^[18] In 2014 a further 18 children with ADA-SCID were cured by gene therapy.^[112] ADA-SCID children have no functioning immune system and are sometimes known as "bubble children."^[18]

Also in October researchers reported that they had treated six hemophilia sufferers in early 2011 using an adeno-associated virus. Over two years later all six were producing clotting factor.^[18][113]

2014

In January researchers reported that six choroideremia patients had been treated with adeno-associated virus with a copy of REP1. Over a six-month to two-year period all had improved their sight.^[114][115] By 2016, 32 patients had been treated with positive results and researchers were hopeful the treatment would be long-lasting.^[15] Choroideremia is an inherited genetic eye disease with no approved treatment, leading to loss of sight.

In March researchers reported that 12 HIV patients had been treated since 2009 in a trial with a genetically engineered virus with a rare mutation (CCR5 deficiency) known to protect against HIV with promising results.^[116][117]

Clinical trials of gene therapy for sickle cell disease were started in 2014.^[118][119] There is a need for high quality randomised controlled trials assessing the risks and benefits involved with gene therapy for people with sickle cell disease.^[120]

2015

In February LentiGlobin BB305, a gene therapy treatment undergoing clinical trials for treatment of beta thalassemia gained FDA "breakthrough" status after several patients were able to forgo the frequent blood transfusions usually required to treat the disease.^[121]

In March researchers delivered a recombinant gene encoding a broadly neutralizing antibody into monkeys infected with simian HIV; the monkeys' cells produced the antibody, which cleared them of HIV. The technique is named immunoprophylaxis by gene transfer (IGT). Animal tests for antibodies to ebola, malaria, influenza, and hepatitis were underway.^[122][123]

In March, scientists, including an inventor of CRISPR, Jennifer Doudna, urged a worldwide moratorium on germline gene therapy, writing "scientists should avoid even attempting, in lax jurisdictions, germline genome modification for clinical application in humans" until the full implications "are discussed among scientific and governmental organizations".^{[124][125][126][127]}

In October, researchers announced that they had treated a baby girl, Layla Richards, with an experimental treatment using donor T-cells genetically engineered using TALEN to attack cancer cells. One year after the treatment she was still free of her cancer (a highly aggressive form of acute lymphoblastic leukaemia [ALL]).^[128] Children with highly aggressive ALL normally have a very poor prognosis and Layla's disease had been regarded as terminal before the treatment.^[129]

In December, scientists of major world academies called for a moratorium on inheritable human genome edits, including those related to CRISPR-Cas9 technologies^[130] but that basic research including embryo gene editing should continue.^[131]

2016

In April the Committee for Medicinal Products for Human Use of the European Medicines Agency endorsed a gene therapy treatment called Strimvelis^[132][133] and the European Commission approved it in June.^[134] This treats children born with adenosine deaminase deficiency and who have no functioning immune system. This was the second gene therapy treatment to be approved in Europe.^[135]

In October, Chinese scientists reported they had started a trial to genetically modify T-cells from 10 adult patients with lung cancer and reinject the modified T-cells back into their bodies to attack the cancer cells. The T-cells had the PD-1 protein (which stops or slows the immune response) removed using CRISPR-Cas9.^[136][137]

A 2016 Cochrane systematic review looking at data from four trials on topical cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy does not support its clinical use as a mist inhaled into the lungs to treat cystic fibrosis patients with lung infections. One of the four trials did find weak evidence that liposome-based CFTR gene transfer therapy may lead to a small respiratory improvement for people with CF. This weak evidence is not enough to make a clinical recommendation for routine CFTR gene therapy.^[138]

2017

In February Kite Pharma announced results from a clinical trial of CAR-T cells in around a hundred people with advanced Non-Hodgkin lymphoma.^[139]

In March, French scientists reported on clinical research of gene therapy to treat sickle-cell disease.^[140]

In August, the FDA approved tisagenlecleucel for acute lymphoblastic leukemia.^[141] Tisagenlecleucel is an adoptive cell transfer therapy for B-cell acute lymphoblastic leukemia; T cells from a person with cancer are removed, genetically engineered to make a specific T-cell receptor (a chimeric T cell receptor, or "CAR-T") that reacts to the cancer, and are administered back to the person. The T cells are engineered to target a protein called CD19 that is common on B cells. This is the first form of gene therapy to be approved in the United States. In October, a similar therapy called axicabtagene ciloleucel was approved for non-Hodgkin lymphoma.^[142]

In December the results of using an adeno-associated virus with blood clotting factor VIII to treat nine haemophilia A patients were published. Six of the seven patients on the high dose regime increased the level of the blood clotting VIII to normal levels. The low and medium dose regimes had no effect on the patient's blood clotting levels.^[143][144]

In December, the FDA approved Luxturna, the first in vivo gene therapy, for the treatment of blindness due to Leber's congenital amaurosis.^[145] The price of this treatment was 850,000 US dollars for both eyes.^[146][147]

Speculative uses

Speculated uses for gene therapy include:

Fertility

Gene Therapy techniques have the potential to provide alternative treatments for those with infertility. Recently, successful experimentation on mice has proven that fertility can be restored by using the gene therapy method, CRISPR.^[148] Spermatogenical stem cells from another organism were transplanted into the testes of an infertile male mouse. The stem cells re-established spermatogenesis and fertility.^[149]

Gene doping

Athletes might adopt gene therapy technologies to improve their performance.^[150] Gene doping is not known to occur, but multiple gene therapies may have such effects. Kayser et al. argue that gene doping could level the playing field if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports.^[151]

Human genetic engineering

Genetic engineering could be used to cure diseases, but also to change physical appearance, metabolism, and even improve physical capabilities and mental faculties such as memory and intelligence. Ethical claims about germline engineering include beliefs that every fetus has a right to remain genetically unmodified, that parents hold the right to genetically modify their offspring, and that every child has the right to be born free of preventable diseases.^{[152][153][154]} For parents, genetic engineering could be seen as another child enhancement technique to add to diet, exercise, education, training, cosmetics, and plastic surgery.^[155][156] Another theorist claims that moral concerns limit but do not prohibit germline engineering.^[157]
Possible regulatory schemes include a complete ban, provision to everyone, or professional self-regulation. The American Medical Association’s Council on Ethical and Judicial Affairs stated that "genetic interventions to enhance traits should be considered permissible only in severely restricted situations: (1) clear and meaningful benefits to the fetus or child; (2) no trade-off with other characteristics or traits; and (3) equal access to the genetic technology, irrespective of income or other socioeconomic characteristics."^[158]

As early in the history of biotechnology as 1990, there have been scientists opposed to attempts to modify the human germline using these new tools,^[159] and such concerns have continued as technology progressed.^[160][161] With the advent of new techniques like CRISPR, in March 2015 a group of scientists urged a worldwide moratorium on clinical use of gene editing technologies to edit the human genome in a way that can be inherited.^{[124][125][126][127]} In April 2015, researchers sparked controversy when they reported results of basic research to edit the DNA of non-viable human embryos using CRISPR.^[148][162] A committee of the American National Academy of Sciences and National Academy of Medicine gave qualified support to human genome editing in 2017^[163][164] once answers have been found to safety and efficiency problems "but only for serious conditions under stringent oversight."^[165]

Regulations

Regulations covering genetic modification are part of general guidelines about human-involved biomedical research. There are no international treaties which are legally binding in this area, but there are recommendations for national laws from various bodies.

The Helsinki Declaration (Ethical Principles for Medical Research Involving Human Subjects) was amended by the World Medical Association's General Assembly in 2008. This document provides principles physicians and researchers must consider when involving humans as research subjects. The Statement on Gene Therapy Research initiated by the Human Genome Organization (HUGO) in 2001 provides a legal baseline for all countries. HUGO’s document emphasizes human freedom and adherence to human rights, and offers recommendations for somatic gene therapy, including the importance of recognizing public concerns about such research.^[166]

United States

No federal legislation lays out protocols or restrictions about human genetic engineering. This subject is governed by overlapping regulations from local and federal agencies, including the Department of Health and Human Services, the FDA and NIH's Recombinant DNA Advisory Committee. Researchers seeking federal funds for an investigational new drug application, (commonly the case for somatic human genetic engineering,) must obey international and federal guidelines for the protection of human subjects.^[167]

NIH serves as the main gene therapy regulator for federally funded research. Privately funded research is advised to follow these regulations. NIH provides funding for research that develops or enhances genetic engineering techniques and to evaluate the ethics and quality in current research. The NIH maintains a mandatory registry of human genetic engineering research protocols that includes all federally funded projects.

An NIH advisory committee published a set of guidelines on gene manipulation.^[168] The guidelines discuss lab safety as well as human test subjects and various experimental types that involve genetic changes. Several sections specifically pertain to human genetic engineering, including Section III-C-1. This section describes required review processes and other aspects when seeking approval to begin clinical research involving genetic transfer into a human patient.^[169] The protocol for a gene therapy clinical trial must be approved by the NIH's Recombinant DNA Advisory Committee prior to any clinical trial beginning; this is different from any other kind of clinical trial.^[168]

As with other kinds of drugs, the FDA regulates the quality and safety of gene therapy products and supervises how these products are used clinically. Therapeutic alteration of the human genome falls under the same regulatory requirements as any other medical treatment. Research involving human subjects, such as clinical trials, must be reviewed and approved by the FDA and an Institutional Review Board.^[170][171]

Popular culture

Gene therapy is the basis for the plotline of the film I Am Legend^[172] and the TV show Will Gene Therapy Change the Human Race?.^[173] In 1994, gene therapy was a plot element in The Erlenmeyer Flask, The X-Files' first season finale. It is also used in Stargate as a means of allowing humans to use Ancient technology.

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The circumgalactic medium has been hard to observe, but new tools now make it possible.

By Lisa Grossman 7:00am, July 12, 2018 

Original link:  https://www.sciencenews.org/article/cosmic-cloak-controls-galaxy-future-coming-focus?utm_source=editorspicks071518&utm_medium=email&utm_campaign=Editors_Picks 

 

COSMIC CLOAK  Whirls of cold and hot gas billow in this simulation of a circumgalactic medium surrounding a galaxy. With new tools and simulations, researchers have learned that the CGM helps a galaxy recycle its materials. 

M.S. Peeples et al/FOGGIE Project

There’s more to a galaxy than meets the eye. Galaxies’ bright stars seem to spiral serenely against the dark backdrop of space. But a more careful look reveals a whole lot of mayhem.

“Galaxies are just like you and me,” Jessica Werk, an astronomer at the University of Washington in Seattle, said in January at a meeting of the American Astronomical Society. “They live their lives in a constant state of turmoil.”

Much of that turmoil takes place in a huge, complicated setting called the circumgalactic medium, or CGM. This vast, roiling cloud of dust and gas is a galaxy’s fuel source, waste dump and recycling center all in one. Astronomers think the answers to some of the most pressing galactic mysteries — how galaxies keep forming new stars for billions of years, why star formation abruptly stops — are hidden in a galaxy’s enveloping CGM.

“To understand the galaxies, you have to understand the ecosystem that they’re in,” says astronomer Molly Peeples of the Space Telescope Science Institute in Baltimore.

Yet this galactic atmosphere is so diffuse that it’s invisible — a liter of CGM contains just a single atom. It has taken almost 60 years and an upgrade to the Hubble Space Telescope just to begin probing distant CGMs and figuring out how their constant churning can make or break galaxies.

“Only recently have we been able to really, truly, observationally characterize the relationship between this gaseous cycle and the properties of the galaxy itself,” Werk says.

Armed with the first extragalactic census, astronomers are now piecing together how a CGM controls its galaxy’s life and death. And new theoretical studies hint that galaxies’ stars would be arranged very differently without a medium’s frenetic flows. Plus, new observations show that some CGMs are surprisingly lumpy. A better understanding of CGMs, enabled by new telescopes and computer simulations, could change how scientists think about everything from galaxy collisions to the origins of our own atoms.

“The CGM is the part of the iceberg that’s under the water,” says astrophysicist Kevin Schawinski of ETH Zurich, who studies the more conventional parts of galaxies. “We now have good measurements where we’re sure it’s important.”

Frenetic fog

Researchers use a bright source of background light, like a quasar, to learn about a galaxy’s circumgalactic medium, a diffuse cloud of gas and metals (pink in the illustration) surrounding a galaxy. Gas is recycled between the galaxy and the CGM.

C. Chang

Sources: J. Tumlinson, M.S. Peeples and J.K. Werk/Annual Review of Astronomy and Astrophysics 2017; M.S. Peeples/Nature 2015

Waiting for Hubble

That 2009 Hubble telescope upgrade, which made the CGM census possible, almost didn’t happen.

In a cosmic coincidence, the Hubble telescope’s chief champions were also the first astronomers to figure out how to observe a galaxy’s CGM. Lyman Spitzer of Princeton University and John Bahcall of the Institute for Advanced Study in Princeton, N.J., and other astronomers noticed something strange after the 1963 discovery of quasars (SN Online: 3/21/14), bright beacons now known to be white-hot disks surrounding supermassive black holes in the centers of distant galaxies.

Everywhere astronomers looked, quasars’ spectra — the rainbow created when their light is spread out over all wavelengths — were notched with dark holes. Some wavelengths of light weren’t getting through.

In 1969, Spitzer and Bahcall realized what was going on: The missing light was absorbed by gas at the edges of galaxies, the same stuff that would later be called the CGM. Astronomers had been peering at quasars shining through CGMs like headlights through a fog.

Not much more could be done at the time, though. Earth’s atmosphere also absorbs light in those same wavelengths, making it difficult to tell which light-blocking atoms were in a galaxy’s CGM and which came from closer to home. Knowing that a CGM was there was one thing; taking its measurements would require something extra.

Spitzer and Bahcall knew what they needed: a space telescope that could observe from outside Earth’s atmosphere. The pair were two of the most vocal and consistent champions of the Hubble Space Telescope, which launched in 1990. Spitzer’s colleagues called him Hubble’s “intellectual and political father.”

Bahcall never stopped advocating for Hubble. In February 2005, six months before his death at age 70 from a rare blood disorder, he cowrote an article in the Los Angeles Times urging Congress to restore funding for a mission to fix some aging Hubble instruments, which NASA had canceled after the 2003 Columbia space shuttle disaster.

“What is at stake is not only a piece of stellar technology but our commitment to the most fundamental human quest: understanding the cosmos,” Bahcall and colleagues wrote. “Hubble’s most important discoveries could be in the future.”

His plea was answered: The space shuttle Atlantis brought astronauts to repair Hubble for the last time in May 2009 (SN Online: 5/19/09). During the repair, the astronauts installed the Cosmic Origins Spectrograph, which could pick up diffuse CGM gas with 30 times the sensitivity of any previous instrument. Although earlier spectrographs on Hubble had picked out CGMs a few quasar-beams at a time, the new device let astronomers search around dozens of galaxies, using the light of even dimmer quasars.

“It blew the field wide open,” Werk says.

Gas flows out from M82, the Cigar galaxy, to its invisiblecircumgalactic medium in this Hubble image.

NASA, ESA, Hubble Heritage Team

The circumgalactic census

A team led by Jason Tumlinson of Baltimore’s Space Telescope Science Institute, Hubble’s academic home, made a catalog of 44 galaxies with a quasar sitting behind them from Hubble’s perspective. In a 2011 paper in Science, the researchers reported that every time they looked within 490,000 light-years of a galaxy, they saw spectra dappled with blank spots from atoms absorbing light. That meant that CGMs weren’t odd cloaks worn by just a few galaxies. They were everywhere.

Tumlinson’s team spent the first few years after Hubble’s upgrade like 19th century naturalists describing new species. The group measured the mass and the chemical makeup of the galaxies’ CGMs and found they were huge cisterns of heavy elements. CGMs contain 10 million times the mass of the sun in oxygen alone. In many cases, the mass of a CGM is comparable to the mass of the entire visible part of its galaxy.

The finding offers an answer to a long-standing cosmic mystery: How do galaxies have enough star-forming fuel to keep going for billions of years? Galaxies build stars from collapsing clouds of cool gas at a constant rate; the Milky Way, for example, makes one to two solar masses’ worth of stars every year. But there isn’t enough cool gas within the visible part of a galaxy, the disk containing its stars, to support observed rates of star formation.

“We think that gas probably comes from the CGM,” Werk says. “But exactly how that gas is getting into galaxies, where it gets in, the timescale on which it gets in, are there things that prevent it from getting in? Those are big questions that keep us all awake at night.”

Werk and Peeples realized that all that mass could help solve two other cosmic bookkeeping problems. All elements heavier than helium (which astronomers lump together as “metals”) are forged by nuclear fusion in the hearts of stars. When stars use up their fuel and explode as supernovas, they scatter those metals around to be folded into the next generation of stars.

But if you add up all the metals in the stars, gas and dust in a given galaxy’s disk, it’s not enough to account for all the metals the galaxy has ever made. The mismatch gets even worse if you include the hydrogen, helium, electrons and protons — basically all the ordinary matter that should have collected in the galaxy since the Big Bang. Astronomers call all those bits baryons. Galaxies seem to be missing 70 to 95 percent of that stuff.

So Peeples and Werk led a comprehensive effort to tally all the ordinary matter in about 40 galaxies observed with Hubble’s new spectrometer. The researchers published the results in two 2014 papers in the Astrophysical Journal.

At the time, Werk reported that at least half of galaxies’ missing ordinary matter can be accounted for in their CGMs. In a 2017 update, Werk and colleagues found that the mass of baryons just in the form of cool gas in a galaxy’s CGM could be nearly 90 billion solar masses. “Obviously, this mass could resolve the galactic missing baryons problem,” the team wrote.

“It’s a classic science story,” Schawinski says. The researchers had a hypothesis about where the missing material should be and made predictions. The group made observations to test those predictions and found what it sought.

In a separate study, Peeples showed that although metals are born in galaxies’ starry disks, those metals don’t stay there. Only 20 to 25 percent of the metals a galaxy has ever produced remains in the stars, gas and dust in the disk, where the metals can be incorporated into new stars and planets. The rest probably ends up in the CGM.

“If you look at all the metals the galaxies ever produced in their whole lifetime, more of them are outside the galaxy than are still inside the galaxy,” Tumlinson says, “which was a huge shock.”

Recycling centers

So how did the metals get into the CGM? Quasars’ spectra couldn’t help with that question. Their light shows only a slice through a single galaxy at a single moment in time. But astronomers can track galaxies’ growth and development with computer simulations based on physical rules for how stars and gas behave.

This strategy revealed the churning, ever-changing nature of gas in galaxies’ CGMs. Simulations such as EAGLE, or Evolution and Assembly of GaLaxies and their Environments, which is run out of Leiden University in the Netherlands, showed that metals can reach CGMs through stars’ violent lives: in powerful winds of radiation blowing away from massive young stars, and in the death throes of supernovas spraying metals far and wide.

This EAGLE simulation shows that, over time, metals (colors)move away from the center of a galaxy to the circumgalactic medium.

J. Tumlinson, M.S. Peeples and J.K. Werk/Annual Review of Astronomy and Astrophysics 2017

Once the metals are in the CGM, though, they don’t always stay put. In simulations, galaxies seem to use the same gas over and over again.

“It’s basically just gravity,” Peeples says. “Throw a baseball up, and it’ll come back to the ground.” The same goes for gas flowing out of galaxies: Unless the gas travels fast enough to escape the galaxy’s gravity altogether, those atoms will eventually fall back into the disk — and form new stars.

Some simulations show discrete gas parcels making the trip from a galaxy’s disk out into the CGM and back again several times. Together, CGMs and their galaxies are giant recycling devices.

That means that the atoms that make up planets, plants and people may have taken several trips to circumgalactic space before becoming part of us. Over hundreds of millions of years, the atoms that eventually became part of you traveled hundreds of thousands of light-years.

“This is my favorite thing,” Tumlinson says. “At some point, your carbon, your oxygen, your nitrogen, your iron was out in intergalactic space.”

How galaxies die

But not all galaxies get their CGM gas back. Losing the gas could shut off star formation in a galaxy for good. No one knows how star formation shuts off, or quenches. But the answer is probably in the CGM.

Galaxies come in two main forms: young spiral galaxies that are making stars and old blobby galaxies where star formation is quenched (SN Online: 4/23/18).

“How galaxies quench and why they stay that way is one of the most important questions in galaxy formation generally,” Tumlinson says. “It just has to have something to do with the gas supply.”

Reading what's not there

Using light from a quasar (QSO), researchers can “see” CGMs. In this example, spectra from two galaxies, G1 and G2, have certain wavelengths missing (red, in bottom boxes) where the CGM atoms are absorbing light.

J. Tumlinson et al/Science 2011

One possibility, suggested in a paper posted online February 20 at arXiv.org, is that sprays of supernova-heated gas could get stripped from galaxies. Physicist Chad Bustard of the University of Wisconsin–Madison and colleagues simulated the Large Magellanic Cloud, a satellite galaxy of the Milky Way, and found that the small galaxy’s outflowing gas was swept away by the slight pressure of the galaxy’s movement around the Milky Way.

Alternatively, a dead galaxy’s CGM gas could be too hot to sink into the galaxy and form stars. If so, star-forming galaxies should have CGMs full of cold gas, and dead galaxies should be shrouded in hot gas. Hot gas would stay floating above the galactic disk like a hot air balloon, too buoyant to sink in and form stars.

But Hubble saw the opposite. Star-forming galaxies had CGMs chock-full of oxygen-VI — meaning that the gas was so hot (a million degrees Celsius or more) that oxygen atoms lost five of their original electrons. Dead galaxies had surprisingly little oxygen-VI.

“That was puzzling,” Tumlinson says. “If theory told us anything, it should have gone the other way.”

In 2016, Benjamin Oppenheimer, a computational astrophysicist at the University of Colorado Boulder, suggested a solution: The “dead” galaxies didn’t lack oxygen at all. The gas was just too hot for Hubble to observe. “In fact, there is even more oxygen around those passive galaxies,” Oppenheimer says.

All that hot gas could potentially explain why those galaxies died — except that these galaxies were full of star-forming cold gas, too.

“The dead galaxies have plenty of fuel left in the tank,” Tumlinson says. “We don’t know why they’re not using it. Everybody’s chasing that problem.”

Grabbing at the elephant

The chase comes at a good time. Until recently, observers had no way to map a single galaxy’s CGM. Researchers have had to add up dozens of quasar beams to understand the composition of CGMs on average.

“We’ve been like the three blind people grabbing at the elephant,” says John O’Meara, an observational astronomer at Saint Michael’s College in Colchester, Vt.

Teams using two new spectrographs — KCWI, the Keck Cosmic Web Imager on the Keck telescope in Hawaii, and MUSE, the Multi Unit Spectroscopic Explorer on the Very Large Telescope in Chile — are racing to change that. These instruments, called integral field spectrographs, can read spectra across a full galaxy all at once. Given enough background light, astronomers can now examine a single galaxy’s entire CGM. Finally, astronomers have a way to test theories of how gas circulates into and out of a galaxy.

The European Southern Observatory’s Medusa-like MUSEinstrument was installed on the Very Large Telescope in Chilein 2014 to take spectra across a full galaxy.

Eric Le Roux/Service Communication/UCBL/MUSE/ESO

A Chilean team, led by astronomer Sebastian Lopez of the University of Chile in Santiago and colleagues, used MUSE to observe a small dim galaxy that happens to be sandwiched between a bright, distant galaxy and a massive galaxy cluster closer to Earth. The cluster acts as a gravitational lens, distorting the image of the distant galaxy into a long bright arc (SN: 3/10/12, p. 4). The light from that arc filtered through the CGM of the sandwiched galaxy, which the team called G1, at 56 different points.

Surprisingly, G1’s CGM was lumpy, not smooth as expected, the team reported in the Feb. 22 Nature. “The assumption has been that that gas is distributed homogeneously around every system,” Lopez says. “This is not the case.”

MUSE makes a mark

Light from a source galaxy is deflected and magnified by an intervening galaxy cluster to form the bright arc seen in the projected image at far right. Unlike a quasar’s narrow beam of light, the extensive arc lights up a large area of galaxy G1’s CGM, showing it is surprisingly lumpy.

Carlos Polanco, ESO

O’Meara is leading a group that is hot on Lopez’s trail. Last year, while KCWI was being installed, O’Meara got an hour of observing time and was able to see hydrogen — which is associated with cool, star-forming gas — in the CGM of another galaxy backlit by a bright lensed arc. He’s not ready to discuss the results in detail yet, but the team is submitting a paper to Science.

FOGGIE computer simulations improve CGM resolution.In these renderings of the same galaxy, the bottom showsFOGGIE at work. The galaxy’s shape and size change dramatically.

 M. Peeples, G. Snyder et al/FOGGIE project

Meanwhile, Peeples’ team is revisiting how computers render CGMs. “The resolution of the circumgalactic medium in simulations is, um, bad,” she says. Existing simulations are good at matching the visible properties of galaxies — their stars, the gas between the stars, and the overall shapes and sizes. But they “utterly fail at reproducing the properties of the circumgalactic medium,” she says.

So she’s running a new set of simulations called FOGGIE, which focus on CGMs for the first time. “We’re finding that it changes everything,” she says: The shape, star formation history and even the orientation of the galaxy in space look different.

Together, the new observations and simulations suggest that the CGM’s function in the life cycle of a galaxy has been underestimated. Theorists like Peeples and observers like O’Meara are working together to make new predictions about how the CGM should look. Then the researchers will check real galaxies to see if they match.

“Molly will post a really amazing new render of a simulation on Slack, and I’ll go, ‘Holy crap, that looks weird!’ ” O’Meara says. “I’ll go scampering off to find a similar example in the data, and we get into this positive feedback loop of going ‘Holy crap! Holy crap!’ ”

While future circumgalactic studies will focus on gathering spectra from full CGMs, Tumlinson is hoping to squeeze more information out of Hubble while he still can. Hubble made CGM studies possible, but the telescope is 28 years old, and probably has less than a decade left. Hubble’s spectrograph is still the best at observing certain atoms in CGMs to help reveal the gaseous halos’ secrets. “It’s something we definitely want to do,” he says, “before Hubble ends up in the ocean.”

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This article appears in the July 21, 2018 issue of Science News with the headline, "A Galaxy's Ecosystem: The circumgalactic medium is an invisible cloak that controls how galaxies live and die."

The Invisible Brain

July 2, 2001 by Robert Wright
Original link:  http://www.kurzweilai.net/the-invisible-brain

How do societies evolve toward greater complexity in culture and technology? Robert Wright posits that there is an “invisible brain” at work.

Originally published January, 2001 as a chapter in Nonzero: The Logic of Human Destiny

All thought draws life from contacts and exchanges.

-Fernand Braudel

Explaining the affluence of the Northwest Coast Indians seems simple at first. They lived amid natural abundance. And abundance, after all, is affluence. Presumably that’s why so many of the affluent hunter-gatherer societies recently discerned by archaeologists lived near large bodies of water. If you want to be rich, settle on rich land.

But this explanation won’t wash. For starters, population tends to rapidly reach the “carrying capacity” of the environment. Although it’s true that an acre of Northwest territory offered more food than an acre of the Shoshone’s desert, it’s also true that an acre of Northwest territory had a lot more mouths to feed.

Granted, even on a per capita basis, a day’s work brought in more food for the Northwest Coast Indians than for the Shoshone. Bushels of fish were hauled in and packed away for winter dining. But this efficiency was due to high technologies–the massive salmon traps, the smokehouses, the storage cellars–as well as the social structures that governed them. And the technology and social structure are part of the Northwesterners’ advanced economic development-part of what we’re trying to explain when we seek the causes of affluence. To make them the cause as well as the effect would be cheating.

Besides, the Northwesterners’ affluence goes well beyond food, and thus can’t be merely the direct outgrowth of a fertile homeland. The designer robes, the spacious homes–these things don’t grow on trees.

Earlier this century, anthropologists thought it easy to explain such arduously crafted wealth as the indirect outgrowth of a fertile homeland. The key was “surplus.” (This scenario assumes that the “carrying capacity” of the environment wouldn’t quickly be reached–perhaps because there’s a limit to how many hunter-gatherers can peacefully coexist in a small space.) With tons of salmon just begging to be eaten, you could meet your daily food needs in an hour or two and have plenty of time left over to weave robes and build homes. After all, such industriousness comes naturally to people, no?

Apparently not. In 1960, the anthropologist Robert Carneiro published an influential paper about the Kuikuru, who inhabited the jungles of Amazonia and tended gardens of manioc, a staple food (once you remove the poison, which they did) and the source of tapioca. The Kuikuru could have doubled or tripled their manioc output, Carneiro calculated, but they preferred leisure time. Since then anthropologists have found various hunter-gatherer societies that, similarly, had time left over after their daily food gathering. And, as one scholar tartly put it, they “rarely spend this time designing cathedrals or in general ‘improving their lot.’”

So much for the theory that potential surplus always equals economic development. Indeed, against the backdrop of the Kuikuru and other apparently laid-back societies, it almost seems that the conventional wisdom about the Northwest Coast Indians might be right: they weren’t examples of a general trend in cultural evolution; they were just weirdly ambitious.

If surplus isn’t the ticket to wealth, what is? What did create all the specialization and trade found in “complex” hunter-gatherer societies? What did the Northwest Coast Indians have that the Shoshone didn’t have? What was the key to prehistoric economic development?

WORKING OVERTIME

Maybe we should direct these questions to a noted authority on economic development (and on non-zero-sumness, though he long predates such terminology): Adam Smith.

Two factors, Smith noted in The Wealth of Nations, are especially conducive to the growing division of labor that characterizes economic advance. One is cheap transportation. Spending your afternoon making yarn for a Chilkat robe makes sense only if the finished product can be transported at a cost acceptable to its buyer. The second factor is cheap communication. The costs of finding out what buyers want–and the cost to buyers of finding out what’s available, and at what price–have to be bearable for transaction to ensue.

Note that the costs of transport and communication apply not just to the final “purchase” of the robe-at the “retail” level-but to the links in its creation, such as getting cedar bark from the south and copper from the north. At all levels, the movement of Smith’s “invisible hand” gets smoother as information and transportation costs drop. The lower these costs, the more highly non-zero-sum the relationship among the players-the more each can gain via interaction, the more productive, per capita, the web of exchange.

How to keep these costs low if your communications and transportation technologies are primitive? One way is to stay near your customers and suppliers. In other words: live in a society with high population density. This may be the key to the wealth of the American Northwest: not natural abundance per se–an abundance quickly diluted by thick population, anyway–but rather the thick population that does the diluting. Back before communications and transportation were sufficiently high tech to catalyze markets, the stimulus came instead from a habitat that would tolerate large, close populations. And, conveniently, such habitats were often near water, which could give both technologies an added boost. Goods and data sometimes travel better by boat than by foot.

Not only were patches of the Northwest thick with people, one of whom could make blankets while a next-door neighbor focused on woodcarving; larger stretches of the coast-hundreds of miles to the north and south-were thick with peoples, the various linguistic groups that constituted Northwestern culture. Their diversity of natural resources and of cultural heritage worked in synergy. Trading for cedar bark and copper was feasible, and the robes made by drawing on local tradition struck nearby peoples as enticingly foreign.

Maybe, then, what the ostensibly carefree manioc growers of South America lacked was not driving ambition but population density. In the rain forests of the Amazon basin, settlements were small and sparse. Had there been more nearby peoples–especially peoples with handicrafts and natural resources different from those on the local menu–farmers would have felt inspired to grow more manioc for exchange.

In fact, this speculation has been confirmed. Though many scholars have cited Carneiro’s 1960 paper in dismissing the surplus theory of economic development, few gave noted how Carneiro clinched his argument that manioc production in the rain forests was far below capacity: When Europeans showed up with lots of neat gadgets to trade, manioc production skyrocketed!

So, all along, the difference between native Americans of Amazonia and of the Northwest Coast hadn’t been their work ethic. The difference had been that the Amazonians weren’t getting paid to work overtime. Neither were the Shoshone. The arid Great Basin was even less conducive to thick population than were South American jungles.

ADAM SMITH AMENDED

Maybe we should amend Adam Smith’s trademark metaphor of the invisible hand. Smith’s point, of course, was that a bunch of far-flung people pursuing individual gain can, without really trying, collectively orchestrate a large-scale social process. The ingredients of a beautiful robe just seem to magically congregate, assemble themselves, and then find a buyer, as if guided from above.

It’s a nice image, and in some ways apt. After all, a “hand” can do more work if moving goods is easy-if transportation costs are low thanks to the proximity of the players. Still, this metaphor gives short shrift to the other kind of cost that Smith stressed: the cost of processing data and “deciding” where the various resources should go.

Hands aren’t very cerebral, after all; guiding any invisible hand there must be an “invisible brain.” Its neurons are people. The more neurons there are in regular and easy contact, the better the brain works-the more finely it can divide economic labor, the more diverse the resulting products. And, not incidentally, the more rapidly technological innovations take shape and spread. As economists who I espouse “new growth theory” have stressed, it takes only one person to invent something that the whole group can then adopt (since information is a “non-rival” good). So the more possible inventors–that is, the larger the group–the higher its collective rate of innovation. All told, then, the Northwest Coast Indians outproduced and outinvented the Shoshone not because they had better brains (the sort of conclusion Franz Boas worried about) but because they were a better brain.

The fact that population density and size lubricate economic and technological development has been largely ignored by archaeologists and cultural anthropologists. True, some of them, such as Marvin Harris, do stress population growth–indeed, some see it as the prime mover of cultural evolution. But they emphasize a different side of the growth: a downside, not an upside. “Irresistible reproductive pressures,” writes Harris, have “led recurrently to the intensification of production,” which in turn puts stress on the environment, leading to an ecological crisis that only new forms of technology and social organization can solve. In short: Innovate or die! Population density, in this view, drives technological and social development not by creating opportunities, but by creating problems.

This is not the place to ponder the relative importance of the “upside” and “downside” of population growth (though it is the place to suggest that the downside has been overemphasized). The key point is that these two scenarios are compatible. Even if new ideas flow mainly from the synergy of a large, dense invisible brain, environmental stress could also spur innovations-and, in any event, could make people more receptive to them. If, for example, one village, for whatever reason, had developed a serviceable salmon trap, and a means of managing it, chronic food shortage would make nearby peoples acutely receptive to the idea. Also, peoples who lacked the technology might perish, freeing up real estate for those who did adopt it. So whether or not stress often triggers the birth of technologies and social structures, it could certainly hasten their spread. To borrow some terminology from biological evolution: stress raises the rate at which cultural “mutations” proliferate; it raises the “selective pressure.”

In both the upside and downside scenarios, non-zero-sumness looms large. Whether people are trying to add to their wealth or avert disaster, their rational pursuit of self-interest is leading to economic cooperation and social integration that make them better off than they otherwise would be. So either way, you expect population growth to foster upward cultural evolution. And since the human population has grown with few interruptions ever since it was human, the impetus behind cultural evolution would seem to be strong.

If this view is correct–that one way or another, more and denser population means more advanced technology and more complex social structure-then there should be a close connection between population size and density on the one hand and technological and social complexity on the other. And there is. Consider the indigenous societies that once flourished on the variously sized islands of Polynesia. The larger and more dense the island’s population, the greater its division of economic labor, the more advanced its technology, and the more complex its polity.

The story told by these and other such cultures on the ethnographic record–these “living fossils” of cultural evolution–is repeated by the archaeological record. During the Middle Paleolithic, as the human population grew slowly, the rate of technological innovation (not just the total number of technologies) also rose slowly. Then, around 40,000 years ago, both of these trends passed milestones. The human species was for the first time large enough to encompass the Old World, occupying virtually all inhabitable parts oil Africa and Eurasia; population growth would hereafter raise population density. Meanwhile, cultural evolution reached a level that warranted a new archaeological label–the Upper Paleolithic. During the Upper Paleolithic, the average rate of technological change would be one innovation per 1,400 years, compared to one per 20,000 years during the Middle Paleolithic. Then, after 10,000 B.C., during the Mesolithic, with population growing faster than ever, the rate of technological innovation reached one innovation per 200 years (including such gifts to posterity as combs and icepicks). Hunter-gatherer societies, as we’ve seen, reached a new level of social complexity.

Of course, correlations between population size and density, on the one hand, and cultural innovation, on the other, don’t prove that population growth is the driving force. Maybe things work the other way around. Maybe cultural advances are what allow population to rise. In fact, that is undoubtedly part of the story. Take away the Northwesterners’ salmon traps (and the Big Man’s guidance of their construction and use), or the Shoshone’s rabbit nets (and the rabbit boss’s leadership), and population would have to thin out.

But that, really, is the point: technological, economic, and political development spur population even as population spurs them. In this symbiotic growth lies the inexorable power of cultural complexification. Whether you stress the “negative” side of population growth or the “positive” side–whether you stress problems or opportunities–the link between that growth and cultural evolution is one of mutual positive feedback. The more people, the more culture; the more culture, the more people.

The “negative” side of population growth–environmental stress that makes subsistence precarious–may or may not be a big part of the story, but it is certainly not the whole story. The gadgets that pile up at an ever faster rate as population grows are not just subsistence technologies. Even back during the Middle Paleolithic, more than 50,000 years ago, people were intrigued by ochres (for painting) and pyrite crystals. And, as we’ve seen, during the Mesolithic, such “prestige technologies” as jewelry became an appreciable chunk of gross domestic product.

Great effort went into getting these status symbols. They seem to have been traded over hundreds of miles, back in a time when hundreds of miles was nothing to sneeze at. Even by 30,000 B.C., long before the Mesolithic, beads made of pierced seashells were migrating 400 miles from their point of origin. Later, regular networks of exchange blossomed, linking local invisible brains to distant invisible brains. The faint outlines of giant regional brains began to form. And the driving force wasn’t periodic environmental “stress” but a more constant force: human vanity, powered by the status competition that is part of all known societies and seems to be innate.

The fitful but relentless tendency of invisible social brains to hook up with each other, and eventually submerge themselves into a larger brain, is a central theme of history. The culmination of that process–the construction of a single, planetary brain–is what we are witnessing today with all its disruptive yet ultimately integrative effects.

CONTINENTAL DIVIDES

Once you appreciate the importance of population size and density, the cultural gap between the Old and New Worlds starts to make sense. Twelve thousand years ago, as the occupation of the Americas was just picking up steam, population was larger and thicker back in the Eastern Hemisphere. Thereafter, so far as we can tell, the New World lagged behind the Old World in population by several millennia–which is roughly how far the New World lagged behind the Old World in reaching early technological thresholds, such as agriculture, and early political thresholds, such as the chiefdom. (Indeed, if anything, post-agricultural social evolution unfolded slightly faster in the New World.)

As the economist Michael Kremer has noted, a similar pattern appeared on the other side of the world at the same time. The melting polar ice caps that severed the Old and New Worlds also severed Tasmania and Australia. Tasmania’s small population promptly fell culturally behind the more numerous Australians. Modern explorers, on contacting the Tasmanians, found them to lack such Australian essentials as fire-making, bone needles, and boomerangs. Thus the four petri dishes created by the melted ice caps–Old World, New World, Australia, Tasmania–behaved in accordance with theory: larger and, denser populations equal faster technological advance.

Certainly, as we’ll see, social advance can be retarded by things other than scanty population. Still, population is vital. It helps explain why we can call a people “less advanced”–the Shoshone compared to the Northwest Coast Indians, native Americans in general compared to Europeans–without insulting them.

After all, an individual Shoshone’s brain could house as much information as a European brain. A hunter-gatherer is a vast and general data bank, featuring arcane knowledge about local flora and fauna and a basic grasp of all known technology. The average European in Columbus’ day knew much less about nature, and very little about most European technology. He or she used the cerebral space thus saved by specializing in one narrow economic task. It was the synergy of many such specialized European brains that created the technology with which Columbus and other such men intimidated Indians. Individual native Americans weren’t stupider than individual fifteenth-century Europeans–they just had the disadvantage of being Renaissance Men.

If the mutually positive feedback between culture and population were the whole story of cultural evolution, then we could end our narrative here with the words “and so on.” But it isn’t. As we’ve seen, there are forbidding thresholds that got crossed somewhere between the Shoshone and modern America. Among them are the “suprafamily” threshold, crossed by the Northwestern native Americans, and the “supravillage” or “chiefdom” threshold, which the Northwesterners flirted with but may have never quite crossed.

The reason these thresholds are so dicey is that, typically, along with all the benefits of affiliation comes a loss of autonomy-subordination to a political leader. And clusters of families, like individual families and for that matter individual people, prefer autonomy to subordination, all other things being equal.

To be sure, human nature in some ways lubricates these transitions. Our species is “naturally” hierarchical in the sense that people tend to sort themselves out by social status. And the resulting facility with which leaders lead, and followers follow, has no doubt eased the evolution of social complexity. But according to modern Darwinian theory, social hierarchies didn’t evolve for the “good of the group,” so followers don’t cheerfully submit to the leader for the sake of the public interest. People by nature like high status, and generally reconcile themselves to lower status only grudgingly (and temporarily, until a chance for advancement arises). Thus when any family, or any group, surrenders autonomy, submerging its identity in a larger body, subordinating itself to a central authority, some natural resistance has been overcome.

So far we’ve been talking as if economics alone can impel people across these barriers. The rational pursuit of wealth and economic security entails non-zero-sum interactions that–at least in societies which lack a currency–seem to call for political hierarchy. So political hierarchy materializes. But is the story really so simple? Can economics alone get people and groups to surrender their sovereignty? And if not, what else has helped to do that job?

From Nonzero: The Logic of Human Destiny, Copyright 2000 by Robert Wright. Used by permission of The Sagalyn Agency. www.nonzero.org .