Tag Archives: Chad Mirkin

A view to controversies about nanoparticle drug delivery, sticky-flares, and a PNAS surprise

Despite all the excitement and claims for nanoparticles as vehicles for drug delivery to ‘sick’ cells there is at least one substantive problem, the drug-laden nanoparticles don’t actually enter the interior of the cell. They are held in a kind of cellular ‘waiting room’.

Leonid Schneider in a Nov. 20, 2015 posting on his For Better Science blog describes the process in more detail,

A large body of scientific nanotechnology literature is dedicated to the biomedical aspect of nanoparticle delivery into cells and tissues. The functionalization of the nanoparticle surface is designed to insure their specificity at targeting only a certain type of cells, such as cancers cells. Other technological approaches aim at the cargo design, in order to ensure the targeted release of various biologically active agents: small pharmacological substances, peptides or entire enzymes, or nucleotides such as regulatory small RNAs or even genes. There is however a main limitation to this approach: though cells do readily take up nanoparticles through specific membrane-bound receptor interaction (endocytosis) or randomly (pinocytosis), these nanoparticles hardly ever truly reach the inside of the cell, namely its nucleocytoplasmic space. Solid nanoparticles are namely continuously surrounded by the very same membrane barrier they first interacted with when entering the cell. These outer-cell membrane compartments mature into endosomal and then lysosomal vesicles, where their cargo is subjected to low pH and enzymatic digestion. The nanoparticles, though seemingly inside the cell, remain actually outside. …

What follows is a stellar piece featuring counterclaims about and including Schneider’s own journalistic research into scientific claims that the problem of gaining entry to a cell’s true interior has been addressed by technologies developed in two different labs.

Having featured one of the technologies here in a July 24, 2015 posting titled: Sticky-flares nanotechnology to track and observe RNA (ribonucleic acid) regulation and having been contacted a couple of times by one of the scientists, Raphaël Lévy from the University of Liverpool (UK), challenging the claims made (Lévy’s responses can be found in the comments section of the July 2015 posting), I thought a followup of sorts was in order.

Scientific debates (then and now)

Scientific debates and controversies are part and parcel of the scientific process and what most outsiders, such as myself, don’t realize is how fraught it is. For a good example from the past, there’s Leviathan and the Air-Pump: Hobbes, Boyle, and the Experimental Life (from its Wikipedia entry), Note: Links have been removed),

Leviathan and the Air-Pump: Hobbes, Boyle, and the Experimental Life (published 1985) is a book by Steven Shapin and Simon Schaffer. It examines the debate between Robert Boyle and Thomas Hobbes over Boyle’s air-pump experiments in the 1660s.

The style seems more genteel than what a contemporary Canadian or US audience is accustomed to but Hobbes and Boyle (and proponents of both sides) engaged in bruising communication.

There was a lot at stake then and now. It’s not just the power, prestige, and money, as powerfully motivating as they are, it’s the research itself. Scientists work for years to achieve breakthroughs or to add more to our common store of knowledge. It’s painstaking and if you work at something for a long time, you tend to be invested in it. Saying you’ve wasted ten years of your life looking at the problem the wrong way or have misunderstood your data is not easy.

As for the current debate, Schneider’s description gives no indication that there is rancour between any of the parties but it does provide a fascinating view of two scientists challenging one of the US’s nanomedicine rockstars, Chad Mirkin. The following excerpt follows the latest technical breakthroughs to the interior portion of the cell through three phases of the naming conventions (Nano-Flares, also known by its trade name, SmartFlares, which is a precursor technology to Sticky-Flares), Note: Links have been removed,

The next family of allegedly nucleocytoplasmic nanoparticles which Lévy turned his attention to, was that of the so called “spherical nucleic acids”, developed in the lab of Chad Mirkin, multiple professor and director of the International Institute for Nanotechnology at the Northwestern University, USA. These so called “Nano-Flares” are gold nanoparticles, functionalized with fluorophore-coupled oligonucleotides matching the messenger RNA (mRNA) of interest (Prigodich et al., ACS Nano 3:2147-2152, 2009; Seferos et al., J Am. Chem.Soc. 129:15477-15479, 2007). The mRNA detection method is such that the fluorescence is initially quenched by the gold nanoparticle proximity. Yet when the oligonucleotide is displaced by the specific binding of the mRNA molecules present inside the cell, the fluorescence becomes detectable and serves thus as quantitative read-out for the intracellular mRNA abundance. Exactly this is where concerns arise. To find and bind mRNA, spherical nucleic acids must leave the endosomal compartments. Is there any evidence that Nano-Flares ever achieve this and reach intact the nucleocytoplasmatic space, where their target mRNA is?

Lévy’s lab has focused its research on the commercially available analogue of the Nano-Flares, based on the patent to Mirkin and Northwestern University and sold by Merck Millipore under the trade name of SmartFlares. These were described by Mirkin as “a powerful and prolific tool in biology and medical diagnostics, with ∼ 1,600 unique forms commercially available today”. The work, led by Lévy’s postdoctoral scientist David Mason, now available in post-publication process at ScienceOpen and on Figshare, found no experimental evidence for SmartFlares to be ever found outside the endosomal membrane vesicles. On the contrary, the analysis by several complementary approaches, i.e., electron, fluorescence and photothermal microscopy, revealed that the probes are retained exclusively within the endosomal compartments.

In fact, even Merck Millipore was apparently well aware of this problem when the product was developed for the market. As I learned, Merck performed a number of assays to address the specificity issue. Multiple hundred-fold induction of mRNA by biological cell stimulation (confirmed by quantitative RT-PCR) led to no significant changes in the corresponding SmartFlare signal. Similarly, biological gene downregulation or experimental siRNA knock-down had no effect on the corresponding SmartFlare fluorescence. Cell lines confirmed as negative for a certain biomarker proved highly positive in a SmartFlare assay.  Live cell imaging showed the SmartFlare signal to be almost entirely mitochondrial, inconsistent with reported patterns of the respective mRNA distributions.  Elsewhere however, cyanine dye-labelled oligonucleotides were found to unspecifically localise to mitochondria   (Orio et al., J. RNAi Gene Silencing 9:479-485, 2013), which might account to the often observed punctate Smart Flare signal.

More recently, Mirkin lab has developed a novel version of spherical nucleic acids, named Sticky-Flares (Briley et al., PNAS 112:9591-9595, 2015), which has also been patented for commercial use. The claim is that “the Sticky-flare is capable of entering live cells without the need for transfection agents and recognizing target RNA transcripts in a sequence-specific manner”. To confirm this, Lévy used the same approach as for the striped nanoparticles [not excerpted here]: he approached Mirkin by email and in person, requesting the original microscopy data from this publication. As Mirkin appeared reluctant, Lévy invoked the rules for data sharing by the journal PNAS, the funder NSF as well as the Northwestern University. After finally receiving Mirkin’s thin-optical microscopy data by air mail, Lévy and Mason re-analyzed it and determined the absence of any evidence for endosomal escape, while all Sticky-Flare particles appeared to be localized exclusively inside vesicular membrane compartments, i.e., endosomes (Mason & Levy, bioRxiv 2015).

I encourage you to read Schneider’s Nov. 20, 2015 posting in its entirety as these excerpts can’t do justice to it.

The PNAS surprise

PNAS (Proceedings of the National Academy of Science) published one of Mirkin’s papers on ‘Sticky-flares’ and is where scientists, Raphaël Lévy and David Mason, submitted a letter outlining their concerns with the ‘Sticky-flares’ research. Here’s the response as reproduced in Lévy’s Nov. 16, 2015 posting on his Rapha-Z-Lab blog

Dear Dr. Levy,

I regret to inform you that the PNAS Editorial Board has declined to publish your Letter to the Editor. After careful consideration, the Board has decided that your letter does not contribute significantly to the discussion of this paper.

Thank you for submitting your comments to PNAS.

Sincerely yours,
Inder Verma
Editor-in-Chief

Judge for yourself, Lévy’s and Mason’s letter can be found here (pdf) and here.

Conclusions

My primary interest in this story is in the view it provides of the scientific process and the importance of and difficulty associated with the debates.

I can’t venture an opinion about the research or the counterarguments other than to say that Lévy’s and Mason’s thoughtful challenge bears more examination than PNAS is inclined to accord. If their conclusions or Chad Mirkin’s are wrong, let that be determined in an open process.

I’ll leave the very last comment to Schneider who is both writer and cartoonist, from his Nov. 20, 2015 posting,

LeonidSchneiderImagination

Insurance, nanotechnology, and risk

I’ve been meaning to do something on insurance and the nanotechnology industry for a while so I’m thankful to have stumbled across this July 15, 2013 article by Anya Khalamayzer, which concerns actuaries, for Property Casualty 360°,

“An emerging technology can leave insurers covering risks they never contemplated,” states the Casualty Actuarial Society (CAS) in a statement on this revolutionary occupation [nanotechnology].

Parr Schoolman, a CAS fellow and senior managing director at Aon Benfield, explains that despite the lack of definitive data on the nanotech industry, an actuary’s ability to analyze a situation can help insurers develop a product to cover a futuristic technology that has arrived on society’s doorstep.

“Working with limited data is exactly the area where actuaries add most value,” says Alex Krutov, president of Navigation Advisors, in an email to PC360. “In general, the ability to provide solid actuarial risk analysis can also help accelerate societal progress by making possible the development and introduction of new technologies and products that otherwise might be considered uninsurable and too risky.”

I find this bit from the article  interesting,

Krutov says, “Medical applications of nanotechnology are very promising.  At the same time, health and other risks of specific products based on nanotechnology have to be properly analyzed before any insurance underwriting decision is made.  While actuaries are not expected to be experts on nanotechnology or medicine, they provide the general framework for this risk analysis.”

It seems to me the only way a nonexpert could establish a general framework for risk analysis, as Krutov suggests, would be to read some of the literature and get reports from people who do have expertise. One has to wonder though, at what point a threshold, whatever it might be, is passed and something becomes insurable. For example, there’s Chad Mirkin’s therapeutic skin moisturizer breakthrough in July 2012, mentioned in my Penetrating the skin barrier posting,

Researchers at Northwestern University (Illinois, US) have found a way to deliver gene regulation technology using skin moisturizers. From the July 3, 2012 news item on Science Blog,

A team led by a physician-scientist and a chemist — from the fields of dermatology and nanotechnology — is the first to demonstrate the use of commercial moisturizers to deliver gene regulation technology that has great potential for life-saving therapies for skin cancers.

At what point, once the treatments have passed through clinical trials, does the treatment or the doctor giving the treatment become insurable? From the article,

Because nanotechnology has only been available since the 1984, and due to the cutting-edge speed at which it is being developed, reliable data describing its effects is often outdated. Furthermore, Kingdollar [Charlie Kingdollar, vice president and emerging issues officer of General Reinsurance Corporation] says more than 60 percent of firms and universities fail to conduct toxicity tests on nanomaterial.

According to the United States Environmental Protection Agency (EPA), nanomaterials are effective precisely because their size allows them to enter the body in ways not typically found in other chemicals: for example, through the blood-brain barrier or by crossing cell membranes.

Kingdollar appears to be suggesting uninsurability while at the same time noting possible future loopholes should companies insure some form of nanotechnology-enabled therapy or product.

A little digging unearthed this Dec. 17, 2012 news item on Nanowerk (Note: A link has been removed),

The article “Handling Nanotechnologies with foresight in the context of Liability insurance” (pdf), published by reinsurance company Gen Re, describes potential risks of nanotechnologies from the perspective of insurance companies and shows strategies for foresight handling.

The article concludes that “In summary it must be noted that our goal as an insurance industry should support highly profitable nanotechnologies from an underwriting perspective, but without losing sight of the considerable risk potential. This can only be achieved through risk identification, risk monitoring and risk analysis. Simply waiting until risk materialises could have significant consequences for the insurance industry.

… align both of those goals — support for nanotechnologies and justifiable limitation of the potential financial risks for the insurance industry. A step in the right direction could be to contain the problem of late claims, which are inherent with these technologies, by employing the claims made principle.”

While I find the jargon a little difficult, it does seem that another loophole is being developed in that last line about “employing the claims made principle.”

For further investigation, here’s a link to the 10 pp. article Handling Nanotechologies With Foresight in the Context of Liability Insurance by Richard Wieczorek for Gen Re.

 

Gloves, Québec’s (Canada) Institut de recherche Robert-Sauvé en santé et en sécurité du travail, and a workplace nanotoxicity methodology report

A new report on a workplace health and safety issue in regard to nanoparticles (Development of a Method of Measuring Nanoparticle Penetration through Protective Glove Materials under Conditions Simulating Workplace Use)  was released in June 2013 by Québec’s Institut de recherche Robert-Sauvé en santé et en sécurité du travail (IRSST). Little research has been done on exposure through skin (cutaneous exposure), most research has focused on exposure by inhalation according to the report (en français version here),

In the workplace, the main pathway to NP exposure is inhalation (Ostiguy et al., 2008a). Exposure by the cutaneous route has not been studied much, partly because of the widely held belief that skin offers an impermeable barrier to NPs (Truchon et al., 2008). Yet a growing number of studies have pointed to the possible percutaneous absorption of NPs, such as in the case of skin damaged by abrasion (Zhang et al., 2008), repeated flexion (Rouse et al., 2007) or even through intact skin (Ryman-Rasmussen et al., 2006). Pores, hair follicles and sweat glands may also play a role in facilitating absorption of NPs through the skin (Hervé-Bazin, 2007). The nanoparticles are then carried throughout the body by the lymphatic circulatory system (Papp et al., 2008). Induced direct toxic effects have also been reported for epidermal keratinocyte cells exposed to carbon nanotubes and other types of NPs (Shvedova, 2003). [p. 17 PDF version; p. 1 print version; Note: See report bibliography for citations]

The researchers examined gloves made of four different types of material: nitrile, latex, neoprene, and butyl rubber under a number of different conditions. One type of nanoparticle was used for the study, titanium dioxide in powder and liquid forms. The report summary provides a bit more detail about the decision to develop a methodology and the testing methods,

With the exponential growth in industrial applications of nanotechnologies and the increased risk of occupational exposure to nanomaterials, the precautionary principle has been recommended. To apply this principle, and even though personal protective equipment against nanoparticles must be considered only as a last resort in the risk control strategy, this equipment must be available. To respond to the current lack of tools and knowledge in this area, a method was developed for measuring the penetration of nanoparticles through protective glove materials under conditions simulating workplace use.

This method consists of an experimental device for exposing glove samples to nanoparticles in powder form or in colloidal solution, while at the same time subjecting them to static or dynamic mechanical stresses and conditions simulating the microclimate in the gloves. This device is connected to a data control and acquisition system. To complete the method, a sampling protocol was developed and a series of nanoparticle detection techniques was selected.

Preliminary tests were performed using this method to measure the resistance of four models of protective gloves of different thicknesses made of nitrile, latex, neoprene and butyl to the passage of commercial TiO2 nanoparticles in powder form or colloidal solution. The results seem to indicate possible penetration of the nanoparticles in some types of gloves, particularly when subjected to repeated mechanical deformation and when the nanoparticles are in the form of colloidal solutions. Additional work is necessary to confirm these results, and consideration should be given to the selection of the configurations and values of the parameters that best simulate the different possible workplace situations. Nevertheless, a recommendation can already be issued regarding the need for regular replacement of gloves that have been worn, particularly with the thinnest gloves and when there has been exposure to nanoparticles in colloidal solution.

For interested parties, here’s a citation for and a link to the report (PDF),

Development of a Method of Measuring Nanoparticle Penetration through Protective Glove Materials under Conditions Simulating Workplace Use by Dolez, Patricia; Vinches, Ludwig; Perron, Gérald; Vu-Khanh, Toan; Plamondon, Philippe; L’Espérance, Gilles; Wilkinson, Kevin; Cloutier, Yves; Dion, Chantal; Truchon, Ginette
Studies and Research Projects / Report  R-785, Montréal, IRSST, 2013, 124 pages.

I last wrote about gloves and toxicity in a June 11, 2013 posting about gloves with sensors (they turned blue when exposed to toxic levels of chemicals). It would be interesting if they could find a way to create gloves with sensors that warn you when you are reaching dangerous levels of exposure through your gloves. Of course, first they’d have to determine what constitute a dangerous level of exposure. The US National Institute of Occupational Health and Safety (NIOSH) recently released its recommendations for exposure to carbon nanofibers and carbon nanotubes (my April 26, 2013 posting). In layperson’s terms, the recommended exposure is close to zero exposure. Presumably, the decision was based on the principle of being ‘safe rather than sorry’.

One final comment about exposure to engineered nanoparticles through skin, to date there has been no proof that there has been any significant exposure via skin. In fact, the first significant breach of the skin barrier was achieved for medical research, Chad Mirkin and his team at Northwestern University trumpeted their research breakthrough (pun intended) last year, from my July 4, 2012 posting,

Researchers at Northwestern University (Illinois, US) have found a way to deliver gene regulation technology using skin moisturizers. From the July 3, 2012 news item on Science Blog,

A team led by a physician-scientist and a chemist — from the fields of dermatology and nanotechnology — is the first to demonstrate the use of commercial moisturizers to deliver gene regulation technology that has great potential for life-saving therapies for skin cancers.

The topical delivery of gene regulation technology to cells deep in the skin is extremely difficult because of the formidable defenses skin provides for the body. The Northwestern approach takes advantage of drugs consisting of novel spherical arrangements of nucleic acids. These structures, each about 1,000 times smaller than the diameter of a human hair, have the unique ability to recruit and bind to natural proteins that allow them to traverse the skin and enter cells.

This goes a long way to explaining why primary occupational health and safety research has focused on exposure via inhalation rather than skin.  That said, I think ensuring safety means minimizing exposure by all routes until more is known about the hazards.

DARPA (US Defense Advanced Research Projects Agency), nanoparticles, and your traumatized brain

According to the May 10, 2013 news item on Nanowerk,

DARPA, the U.S. Defense Advanced Research Projects Agency, has awarded $6 million to a team of researchers to develop nanotechnology therapies for the treatment of traumatic brain injury and associated infections.

Led by Professor Michael J. Sailor, Ph.D., from the University of California San Diego [UC San Diego], the award brings together a multi-disciplinary team of renowned experts in laboratory research, translational investigation and clinical medicine, including Erkki Ruoslahti, M.D., Ph.D. of Sanford-Burnham Medical Research Institute, Sangeeta N. Bhatia, M.D., Ph.D. of Massachusetts Institute of Technology and Clark C. Chen, M.D., Ph.D. of UC San Diego School of Medicine.

Ballistics injuries that penetrate the skull have amounted to 18 percent of battlefield wounds sustained by men and women who served in the campaigns in Iraq and Afghanistan, according to the most recent estimate from the Joint Theater Trauma Registry, a compilation of data collected during Operation Iraqi Freedom and Operation Enduring Freedom.

“A major contributor to the mortality associated with a penetrating brain injury is the elevated risk of intracranial infection,” said Chen, a neurosurgeon with UC San Diego Health System, noting that projectiles drive contaminated foreign materials into neural tissue.

The May 9, 2013 UC San Diego news release by Susan Brown, which originated the news item, describes the reasons why DARPA wants to use nanoparticles in therapies for people suffering from traumatic brain injury,

Under normal conditions, the brain is protected from infection by a physiological system called the blood-brain barrier. “Unfortunately, those same natural defense mechanisms make it difficult to get antibiotics to the brain once an infection has taken hold,” said Chen, associate professor and vice-chair of research in the Division of Neurosurgery at UC San Diego School of Medicine.

DARPA hopes to meet these challenges with nanotechnology. The agency awarded this grant under its In Vivo Nanoplatforms for Therapeutics program to construct nanoparticles that can find and treat infections and other damage associated with traumatic brain injuries.

“Our approach is focused on porous nanoparticles that contain highly effective therapeutics on the inside and targeting molecules on the outside,” said Sailor, the UC San Diego materials chemist who leads the team. “When injected into the blood stream, we have found that these silicon-based particles can target certain tissues very effectively.”

Several types of nanoparticles have already been approved for clinical use in patients, but none for treatment of trauma or diseases in the brain. This is due in part to the inability of nanoparticle formulations to cross the blood-brain barrier and reach their intended targets.

“Poor penetration into tissues limits the application of nanoparticles to the treatment of many types of diseases,” said Ruoslahti, distinguished professor at Sanford-Burnham and partner in the research. “We are trying to overcome this limitation using targeting molecules that activate tissue-specific transport pathways to deliver nanoparticles.”

There is another major hurdle for treating brain injuries (from the news release),

Treating brain infections is becoming more difficult as drug-resistant strains of viruses and bacteria have emerged. Because drug-resistant strains mutate and evolve rapidly, researchers must constantly adjust their approach to treatment.

In an attempt to hit this moving target, the team is making their systems modular, so they can be reconfigured “on-the-fly” with the latest therapeutic advances.

Nanocomplexes that contain genetic material known as short interfering RNA, or siRNA, developed by Bhatia’s research group at MIT, will be key to this aspect of the team’s approach.

“The function of this type of RNA is that it specifically intereferes with processes in a diseased cell. The advantage of RNA therapies are that they can be quickly and easily modified when a new disease target emerges,” said Bhatia, a bioengineering professor at MIT and partner in the research.

But effective delivery of siRNA-based therapeutics in the body has proven to be a challenge because the negative charge and chemical structure of naked siRNA makes it very unstable in the body and it has difficulty crossing into diseased cells. To solve these problems, Bhatia has developed nanoparticles that form a protective coating around siRNA.

“The nanocomplexes we are developing shield the negative charge of RNA and protect it from nucleases that would normally destroy it. Adding Erkki’s tissue homing and cell-penetrating peptides allows the nanocomplex to transport deep into tissue and enter the diseased cells,” she said.

Bhatia has previously used the cell-penetrating nanocomplex to deliver siRNA to a tumor cell and shut down its protein production machinery. Although her group’s effort has focused on cancer, the team is now going after two other hard-to-treat cell types: drug-resistant bacteria and inflammatory cells in the brain.

“The work proposed by this multi-disciplinary team should provide new tools to mitigate the debilitating effects of penetrating brain injuries and offer our warfighters the best chance of meaningful recovery,” Chen said. [emphasis mine]

BTW, the term ‘warfighters’ is new to me; are we replacing the word ‘soldier’?

Returning to the matter at hand, I found DARPA’s In Vivo Nanoplatforms for Therapeutics program which is described this way on its home page,

Disease limits soldier readiness and creates healthcare costs and logistics burdens. Diagnosing and treating disease faster can help limit its impact. [emphasis mine] Current technologies and products for diagnosing disease are principally relegated to in vitro (in the lab) medical devices, which are often expensive, bulky and fragile.

DARPA’s In Vivo Nanoplatforms (IVN) program seeks to develop new classes of adaptable nanoparticles for persistent, distributed, unobtrusive physiologic and environmental sensing as well as the treatment of physiologic abnormalities, illness and infectious disease.

The IVN Diagnostics (IVN:Dx) program effort aims to develop a generalized in vivo platform that provides continuous physiological monitoring for the warfighter. [emphasis mine] Specifically, IVN:Dx will investigate technologies that may provide:

  • Implantable nanoplatforms using bio-compatible and nontoxic materials
  • In vivo sensing of small and large molecules of biological interest
  • Multiplexed detection of analytes at clinically relevant concentrations
  • External interrogation of the nanoplatform free from any implanted communications electronics
  • Complete system demonstration in a large animal

The IVN Therapeutics (IVN:Tx) program effort will seek unobtrusive nanoplatforms for rapidly treating disease in warfighters.

(I see DARPA is using both soldier and warfighter’.)

This team is not the only one wishing to deliver drug therapies in a targeted fashion to the brain. My Feb. 19, 2013 posting mentioned Chad Mirkin (Northwestern University) and his team’s efforts with spherical nucleic acids (SNAs), from the posting,

Potential applications include using SNAs to carry nucleic acid-based therapeutics to the brain for the treatment of glioblastoma, the most aggressive form of brain cancer, as well as other neurological disorders such as Alzheimer’s and Parkinson’s diseases. Mirkin is aggressively pursuing treatments for such diseases with Alexander H. Stegh, an assistant professor of neurology at Northwestern’s Feinberg School of Medicine. (originally excerpted from this the Feb. 15, 2013 news release on EurekAlert)

Coincidentally, Mirkin has just been named ‘Chemistry World Entrepreneur of the Year’ by the UK’s Royal Society of Chemistry, from the May 10, 2013 news item on Nanowerk,

Northwestern University scientist Chad A. Mirkin, a world-renowned leader in nanotechnology research and its application, has been named 2013 Chemistry World Entrepreneur of the Year by the Royal Society of Chemistry (RSC). The award recognizes an individual’s contribution to the commercialization of research.

The RSC is honoring Mirkin for his invention of spherical nucleic acids (SNAs), new globular forms of DNA and RNA. These structures form the basis for more than 300 products commercialized by licensees of the technology.

I’m never quite sure what to make of researchers who receive public funding then patent and license the results of that research.

Getting back to soldiers/warfighters, I’m glad to see this research being pursued. Years ago, a physician mentioned to me that soldiers in Iraq were surviving injuries that would have killed them in previous conflicts. The problem is that the same protective gear which insulates soldiers against many injuries makes them vulnerable to abusive head trauma (same principle as ‘shaken baby syndrome’). For example, imagine having a high velocity bullet hit your helmet. You’re protected from the bullet but the impact shakes your head so violently, your brain is injured.

Chad Mirkin, spherical nucleic acids, and a new ‘periodic table’

There was a big splash in July 2012 with the announcement that Chad Mirkin’s team at Northwestern University (Chicago, Illinois) had devised a skin cream that penetrated the skin barrier to deliver medication (my July 4, 2012 posting),

A team led by a physician-scientist and a chemist — from the fields of dermatology and nanotechnology — is the first to demonstrate the use of commercial moisturizers to deliver gene regulation technology that has great potential for life-saving therapies for skin cancers.

The topical delivery of gene regulation technology to cells deep in the skin is extremely difficult because of the formidable defenses skin provides for the body. The Northwestern approach takes advantage of drugs consisting of novel spherical arrangements of nucleic acids. These structures, each about 1,000 times smaller than the diameter of a human hair, have the unique ability to recruit and bind to natural proteins that allow them to traverse the skin and enter cells.

Mirkin has just finished presenting (Feb. 15, 2013 and Feb. 17, 2013) more information about spherical nucleic acids and their implications at the AAAS  (American Association for the Advancement of Science) 2013 meeting in Boston, Massachusetts. From the Feb. 15, 2013 news release on EurekAlert,

Northwestern University’s Chad A. Mirkin, a world-renowned leader in nanotechnology research and its application, has invented and developed a powerful material that could revolutionize biomedicine: spherical nucleic acids (SNAs).

Potential applications include using SNAs to carry nucleic acid-based therapeutics to the brain for the treatment of glioblastoma, the most aggressive form of brain cancer, as well as other neurological disorders such as Alzheimer’s and Parkinson’s diseases. Mirkin is aggressively pursuing treatments for such diseases with Alexander H. Stegh, an assistant professor of neurology at Northwestern’s Feinberg School of Medicine.

“These structures are really quite spectacular and incredibly functional,” Mirkin said. “People don’t typically think about DNA in spherical form, but this novel arrangement of nucleic acids imparts interesting chemical and physical properties that are very different from conventional nucleic acids.”

Spherical nucleic acids consist of densely packed, highly oriented nucleic acids arranged on the surface of a nanoparticle, typically gold or silver.  [emphasis mine] The tiny non-toxic balls, each roughly 15 nanometers in diameter, can do things the familiar but more cumbersome double helix can’t do:

  • SNAs can naturally enter cells and effect gene knockdown, making SNAs a superior tool for treating genetic diseases using gene regulation technology.
  • SNAs can easily cross formidable barriers in the human body, including the blood-brain barrier and the layers that make up skin.
  • SNAs don’t elicit an immune response, and they resist degradation, resulting in longer lifetimes in the body.

“The field of medicine needs new constructs and strategies for treating disease,” Mirkin said. “Many of the ways we treat disease are based on old methods and materials. Nanotechnology offers the ability to rapidly create new structures with properties that are very different from conventional forms of matter.”

“We now can go after a whole new set of diseases,” Mirkin said. “Thanks to the Human Genome Project and all of the genomics research over the last two decades, we have an enormous number of known targets. And we can use the same tool for each, the spherical nucleic acid. We simply change the sequence to match the target gene. That’s the power of gene regulation technology.”

###

A member of President Obama’s Council of Advisors on Science and Technology, Mirkin is known for invention and development of biological and chemical diagnostic systems based upon nanomaterials. He is the inventor and chief developer of Dip-Pen Nanolithography, a groundbreaking nanoscale fabrication and analytical tool, and is the founder of four Chicago-based companies: AuraSense, AuraSense Therapeutics, Nanosphere and NanoInk.

Mirkin, in addition to his work with spherical nucleic acids, has been busy with other nanoparticles and possible dreams of a new ‘periodic table of elements’, from the Feb. 17, 2013 news release on EurekAlert,

Forging a new periodic table using nanostructures

Northwestern University’s Chad A. Mirkin, …, has developed a completely new set of building blocks that is based on nanoparticles and DNA. Using these tools, scientists will be able to build — from the bottom up, just as nature does — new and useful structures.

“We have a new set of building blocks,” Mirkin said. “Instead of taking what nature gives you, we can control every property of the new material we make. We’ve always had this vision of building matter and controlling architecture from the bottom up, and now we’ve shown it can be done.”

Using nanoparticles and DNA, Mirkin has built more than 200 different crystal structures with 17 different particle arrangements. Some of the lattice types can be found in nature, but he also has built new structures that have no naturally occurring mineral counterpart.

Mirkin can make new materials and arrangements of particles by controlling the size, shape, type and location of nanoparticles within a given particle lattice. He has developed a set of design rules that allow him to control almost every property of a material.

New materials developed using his method could help improve the efficiency of optics, electronics and energy storage technologies. “These same nanoparticle building blocks have already found wide-spread commercial utility in biology and medicine as diagnostic probes for markers of disease,” Mirkin added.

With this present advance, Mirkin uses nanoparticles as “atoms” and DNA as “bonds.” He starts with a nanoparticle, which could be gold, silver, platinum or a quantum dot, for example. The core material is selected depending on what physical properties the final structure should have.

He then attaches hundreds of strands of DNA (oligonucleotides) to the particle. The oligonucleotide’s DNA sequence and length determine how bonds form between nanoparticles and guide the formation of specific crystal lattices.

“This constitutes a completely new class of building blocks in materials science that gives you a type of programmability that is extraordinarily versatile and powerful,” Mirkin said. “It provides nanotechnologists for the first time the ability to tailor properties of materials in a highly programmable way from the bottom up.”

If I read these two news releases rightly, the process (nanoparticles as atoms and DNA as bonds), Mirkin uses to create new structures is the same process he has used to create spherical nucleic acids. Given Mirkin’s entrepreneurial inclinations, I am curious as to how many and what kind of patents might be ‘protecting’ this work.

Natural and engineered nanoparticles in an Orion magazine podcast & in a NanoBosc machinima piece

The Jan. 16, 2013 Orion magazine podcast discussion (more about that later) regarding safety and engineered and natural nanoparticles arose from an article (worth reading) by Heather Millar in the magazine’s January/February 2013 issue, Pandora’s Boxes.

For anyone familiar with the term ‘Pandora’s box’, Millar’s and the magazine’s bias is made clear immediately, nanoparticles are small and threatening. From the Pandora’s box Wikipedia essay,

Today, the phrase “to open Pandora’s box” means to perform an action that may seem small or innocuous, but that turns out to have severe and far-reaching consequences. [emphases mine]

Millar’s article is well written and offers some excellent explanations. For example, there’s this from Pandora’s Boxes,

So chemistry and physics work differently if you’re a nanoparticle. You’re not as small as an atom or a molecule, but you’re also not even as big as a cell, so you’re definitely not of the macro world either. You exist in an undiscovered country somewhere between the molecular and the macroscopic. Here, the laws of the very small (quantum mechanics) merge quirkily with the laws of the very large (classical physics). Some say nanomaterials bring a third dimension to chemistry’s periodic table, because at the nano scale, long-established rules and groupings don’t necessarily hold up.

Then, she has some dodgier material,

Yet size seems to be a double-edged sword in the nanoverse. Because nanoparticles are so small, they can slip past the body’s various barriers: skin, the blood-brain barrier, the lining of the gut and airways. Once inside, these tiny particles can bind to many things. They seem to build up over time, especially in the brain. Some cause inflammation and cell damage. Preliminary research shows this can harm the organs of lab animals, though the results of some of these studies are a matter of debate.

Some published research has shown that inhaled nanoparticles actually become more toxic as they get smaller. Nano–titanium dioxide, one of the most commonly used nanoparticles (Pop-Tarts, sunblock), has been shown to damage DNA in animals and prematurely corrode metals. Carbon nanotubes seem to penetrate lungs even more deeply than asbestos. [emphases mine]

I think it’s worth ‘unpacking’ these two paragraphs, so here goes.  Slipping past the body’s barriers is a lot more difficult than Millar suggests in the first paragraph. My July 4, 2012 posting on breakthough research  where they penetrated the skin barrier includes this comment from me,

After all the concerns  about nanosunscreens and nanoparticles penetrating the skin raised by civil society groups, the Friends of the Earth in particular, it’s interesting to note that doctors and scientists consider penetration of the skin barrier to be extremely difficult. Of course, they seem to have solved [as of July 2012] that problem which means the chorus of concerns may rise to new heights.

I had a followup in my Oct.3, 2012 posting titled, Can nanoparticles pass through the skin or not?, suggesting there’s still a lot of confusion about this topic even within the scientific community.

Moving on to the other ‘breaches’. As I recall, there was a recent  (Autumn 2012?) nanomedicine research announcement that the blood-brain barrier was breached by nanoparticles. I haven’t yet encountered any mention of breaching the gut and I mention lungs in my next paragraph where I discuss carbon nanotubes.

As for that second paragraph, it’s an example of scaremongering. ‘Inhaled nanoparticles become more toxic as their size decreases’—ok. Why mention nano-titanium oxide in pop tarts and sunblocks, which are not inhaled, in the followup sentence? As for the reference to DNA damage and corroded metals further on, this is straight out of the Friends of the Earth literature which often cites research in a misleading fashion including those two pieces.  There is research supporting part of Millar’s statement about carbon nanotubes—provided they are long and multiwalled. In fact, as they get shorter, the resemblance to asbestos fibers in the lungs or elsewhere seems to disappear as per my Aug 22, 2012 posting and my Jan. 16, 2013 posting.

You don’t need to read the article before listening to the fascinating Jan. 16, 2013 Orion magazine podcast with Millar (reading portions of her article) and expert guests, Mark Wiesner from Duke University and director of their Center for Environmental Implications of Nano Technology (CEINT was first mentioned in my April 15, 2011 posting), Ronald Sandler from Northeastern University and author of Nanotechnology: The Social And Ethical Issues, and Jaydee Hanson, policy director for the International Center for Technology Assessment.

The discussion between Wiesner, Sandler, and Hanson about engineered and natural nanoparticles is why I’ve called the podcast fascinating. Hearing these experts ‘fence’ with each other highlights the complexities and subtleties inherent in discussions about emerging technologies (nano or other) and risk. Millar did not participate in that aspect of the conversation and I imagine that’s due to the fact that she has only been researching this area for six months while the other speakers all have several years worth experience individually and, I suspect, may have debated each other previously.

At the risk of enthusing too much about naturally occurring nanoparticles, I’m mentioning, again (my Feb. 1, 2013 posting), the recently published book by Nanowiki, Nanoparticles Before Nanotechnology, in the context of the stunning visual images used to illustrate the book. I commented previously about them and Victor Puntes of the Inorganic Nanoparticles Group at the Catalan Institute of Nanotechnology (ICN) and one of the creators of this imagery, kindly directed me to a machinima piece (derived from the NanoBosc Second Life community) which is the source for the imagery. Here it is,

NanoBosc from Per4mance MetaLES ..O.. on Vimeo.

Happy Weekend!

Can nanoparticles pass through the skin or not?

Researchers at the University of Bath (England) have proved that nanoparticles do not penetrate the skin, according to the Oct. 1, 2012 news item on Nanowerk,

 Research by scientists at the University of Bath is challenging claims that nanoparticles in medicated and cosmetic creams are able to transport and deliver active ingredients deep inside the skin.
Nanoparticles, which are tiny particles that are less than one hundredth of the thickness of a human hair, are used in sunscreens and some cosmetic and pharmaceutical creams.
The Bath study (“Objective assessment of nanoparticle disposition in mammalian skin after topical exposure”) discovered that even the tiniest of nanoparticles did not penetrate the skin’s surface.
These findings have implications for pharmaceutical researchers and cosmetic companies that design skin creams with nanoparticles that are supposed to transport ingredients to the deeper layers of the skin. [emphasis mine]

Back in July 2012, a research team at Northwestern University claimed to have successfully delivered gene regulation technology using moisturizers to penetrate the skin barrier, excerpted from my July 4, 2012 posting,

The news item originated from a July 2, 2012 news release, by Marla Paul for Northwestern University, which provides more details about the researchers,

“The technology developed by my collaborator Chad Mirkin and his lab is incredibly exciting because it can break through the skin barrier,” said co-senior author Amy S. Paller, M.D., the Walter J. Hamlin Professor, chair of dermatology and professor of pediatrics at Northwestern University Feinberg School of Medicine. She also is director of Northwestern’s Skin Disease Research Center.

A co-senior author of the paper, Mirkin is the George B. Rathmann Professor of Chemistry in the Weinberg College of Arts and Sciences and professor of medicine, chemical and biological engineering, biomedical engineering and materials science and engineering. He also is the director of Northwestern’s International Institute for Nanotechnology.

Interdisciplinary research is a hallmark of Northwestern. Paller and Mirkin said their work highlights the power of physician-scientists and scientists and engineers from other fields coming together to address a difficult medical problem.

“This all happened because of our world-class presence in both cancer nanotechnology and skin disease research,” Paller said. “In putting together the Skin Disease Research Center proposal, I reached out to Chad to see if his nanostructures might be applied to skin disease. We initially worked together through a pilot project of the center, and now the rest is history.”

There’s more about how the nanoscale structures make their way through the skin but it seems the team from the University of Bath are prepared to contradict this claim, from the University of Bath’s Oct. 1,2012 news release (which originated the news item on Nanowerk),

Research by scientists at the University of Bath is challenging claims that nanoparticles in medicated and cosmetic creams are able to transport and deliver active ingredients deep inside the skin.

The Bath study discovered that even the tiniest of nanoparticles did not penetrate the skin’s surface.

These findings have implications for pharmaceutical researchers and cosmetic companies that design skin creams with nanoparticles that are supposed to transport ingredients to the deeper layers of the skin.

However the findings will also allay safety concerns that potentially harmful nanoparticles such as those used in sunscreens can be absorbed into the body.

The scientists used a technique called laser scanning confocal microscopy to examine whether fluorescently-tagged polystyrene beads, ranging in size from 20 to 200 nanometers, were absorbed into the skin. [emphasis mine]

They found that even when the skin sample had been partially compromised by stripping the outer layers with adhesive tape, the nanoparticles did not penetrate the skin’s outer layer, known as the stratum corneum.

I note they tested nanostructures larger than 20 nanometers so it’s possible that nanostructures that measure less than 20 nanometers could penetrate skin, non? However, it seems the structure used to ‘penetrate’ the skin by the team Northwestern University are considerably larger (excerpted from my July 4, 2012 posting),

The topical delivery of gene regulation technology to cells deep in the skin is extremely difficult because of the formidable defenses skin provides for the body. The Northwestern approach takes advantage of drugs consisting of novel spherical arrangements of nucleic acids. These structures, each about 1,000 times smaller than the diameter of a human hair, have the unique ability to recruit and bind to natural proteins that allow them to traverse the skin and enter cells.

(Side note: I believe a structure 1,000 times smaller than the diameter of a human hair would be measured in microns not nanometers.) I gather it’s the use of the nucleic acids in specialized formulations by the Northwestern team which make nanoparticle entry past the skin possible which contrasts with the work done by the University of Bath researchers who tested nanoparticles in standard cosmetic formulations.

Penetrating the skin barrier

Researchers at Northwestern University (Illinois, US) have found a way to deliver gene regulation technology using skin moisturizers. From the July 3, 2012 news item on Science Blog,

A team led by a physician-scientist and a chemist — from the fields of dermatology and nanotechnology — is the first to demonstrate the use of commercial moisturizers to deliver gene regulation technology that has great potential for life-saving therapies for skin cancers.

The topical delivery of gene regulation technology to cells deep in the skin is extremely difficult because of the formidable defenses skin provides for the body. The Northwestern approach takes advantage of drugs consisting of novel spherical arrangements of nucleic acids. These structures, each about 1,000 times smaller than the diameter of a human hair, have the unique ability to recruit and bind to natural proteins that allow them to traverse the skin and enter cells.

Applied directly to the skin, the drug penetrates all of the skin’s layers and can selectively target disease-causing genes while sparing normal genes. Once in cells, the drug simply flips the switch of the troublesome genes to “off.”

The news item originated from a July 2, 2012 news release, by Marla Paul for Northwestern University, which provides more details about the researchers,

“The technology developed by my collaborator Chad Mirkin and his lab is incredibly exciting because it can break through the skin barrier,” said co-senior author Amy S. Paller, M.D., the Walter J. Hamlin Professor, chair of dermatology and professor of pediatrics at Northwestern University Feinberg School of Medicine. She also is director of Northwestern’s Skin Disease Research Center.

A co-senior author of the paper, Mirkin is the George B. Rathmann Professor of Chemistry in the Weinberg College of Arts and Sciences and professor of medicine, chemical and biological engineering, biomedical engineering and materials science and engineering. He also is the director of Northwestern’s International Institute for Nanotechnology.

Interdisciplinary research is a hallmark of Northwestern. Paller and Mirkin said their work highlights the power of physician-scientists and scientists and engineers from other fields coming together to address a difficult medical problem.

“This all happened because of our world-class presence in both cancer nanotechnology and skin disease research,” Paller said. “In putting together the Skin Disease Research Center proposal, I reached out to Chad to see if his nanostructures might be applied to skin disease. We initially worked together through a pilot project of the center, and now the rest is history.”

As for the work itself, here are more details from Paul’s news release,

The key is the nanostructure’s spherical shape and nucleic acid density. Normal (linear) nucleic acids cannot get into cells, but these spherical nucleic acids can. Small interfering RNA (siRNA) surrounds a gold nanoparticle like a shell; the nucleic acids are highly oriented, densely packed and form a tiny sphere. The RNA’s sequence is programmed to target the disease-causing gene.

“We now can go after a whole new set of diseases,” Mirkin said. “Thanks to the Human Genome Project and all of the genomics research over the last two decades, we have an enormous number of known targets. And we can use the same tool for each, the spherical nucleic acid. We simply change the sequence to match the target gene. That’s the power of gene regulation technology.”

The nanostructures were developed in Mirkin’s lab on the Evanston campus and then combined with a commercial moisturizer. Next, down in Paller’s Chicago lab, the researchers applied the therapeutic ointment to the skin of mice and to human epidermis. The nanostructures were designed to target epidermal growth factor receptor (EGFR), a biomarker associated with a number of cancers.

In both cases, the drug broke through the epidermal layer and penetrated the skin very deeply, with cells taking up 100 percent of the nanostructures. They selectively knocked down the EGFR gene, decreasing the production of the problem proteins.

After a month of continued application of the ointment, there was no evidence of side effects, inappropriate triggering of the immune system or accumulation of the particles in organs. The treatment is skin specific and doesn’t interfere with other cells.

After all the concerns  about nanosunscreens and nanoparticles penetrating the skin raised by civil society groups, the Friends of the Earth in particular, it’s interesting to note that doctors and scientists consider penetration of the skin barrier to be extremely difficult. Of course, they seem to have solved that problem which means the chorus of concerns may rise to new heights.

Nature of Things’ The Nano Revolution part 2: More than Human

More than Human (the episode can be seen here), part of 2 of a special Nature of Things series, The Nano Revolution, was aired by the Canadian Broadcasting Corporation on Oct. 20, 2011; one might be forgiven for thinking this episode concerned robots but that wasn’t the case.  The focus was on nanomedicine, specifically cancer and aging, along with a few scenarios hinting at social impacts of the ‘new’ medicine.

This episode, like the last one (Welcome to Nano City), presents the science in an understandable fashion without overexplaining basic concepts. A skill I much appreciate since watching a video of an engineer explain at length that the eye has a cornea and a retina to an audience of adults who were attending a talk about retinal implants.

More coherent than the first one, (Welcome to Nano City reviewed in my Oct. 17, 2011 posting), which featured three topics (one was totally unrelated to any city) both episodes,  convey excitement about the possibilities being suggested by nanotechnology.

As for this episode, More than human, it certainly told a compelling story of a future where there will be no cancer (or it will be easily treated if it does occur) and we won’t age as we can make perfect tissues to replace whatever has been broken. There were also hints of a few social issues as illustrated by future oriented vignettes interspersed through the programme.

I want to c0mmend the script writer for pulling together a story using disparate materials and videos (which I’m guessing are being repurposed, i.e., created for broadcast elsewhere and reused here). Given the broad range of nanomedicine research worldwide, this was a very difficult job.

Featured at some length was Dr. Chad Mirkin at Northwestern University. Here’s a description from Mirkin’s profile page on the Mirkin Group webspace,

Professor Mirkin is a chemist and a world renowned nanoscience expert, who is known for his development of nanoparticle-based biodetection schemes, the invention of Dip-Pen Nanolithography, and contributions to supramolecular chemistry, nanoelectronics, and nanooptics. [emphasis mine] He is the author of over 430 manuscripts and over 370 patents and applications, and the founder of three companies, Nanosphere, NanoInk, and Aurasense which are commercializing nanotechnology applications in the life science and semiconductor industries. Currently, he is listed as the most cited (based on total citations) chemist in the world with the second highest impact factor and the top most cited nanomedicine researcher in the world. At present, he is a member of President Obama’s Council of Advisors for Science and Technology.

Mirkin talked extensively about his work on biomarker sensing and its applications for diagnostic procedures that cut laboratory testing down from weeks to hours. This new equipment arising from Mirkin’s work is installed in some US hospital laboratories.

Dr. Silvano Dragonieri of Leiden University in The Netherlands discussed his e-nose technology which offers another approach to diagnostics. Here’s a description of Dragonieri’s (and another team’s) work in this area from an April 27, 2009 news item on physorg.com,

In 2006 researchers established that dogs could detect cancer by sniffing the exhaled breath of cancer patients. Now, using nanoscale arrays of detectors, two groups of investigators have shown that a compact mechanical device also can sniff out lung cancer in humans.

Hossam Haick, Ph.D., and his colleagues at the Israel Institute of Technology in Haifa, used a network of 10 sets of chemically modified carbon nanotubes to create a multicomponent sensor capable of discriminating between a healthy breath and one characteristic of lung cancer patients. This work appears in the journal Nano News. Meanwhile, Silvano Dragonieri, M.D., University of Bari, Italy, and his colleagues used a commercial nanoarray-based electronic “nose” to discriminate between the breath of patients with non-small cell lung cancer and chronic obstructive pulmonary disease (COPD). These results appear in the journal Lung Cancer. [emphasis mine]

Nanomedicine is fascinating, which is why it’s easy to lose perspective. Thankfully there was Dr. Philip Kantoff  (also very enthused and a major figure in this area) to provide the voice of reason. Here’s more are about Kantoff from the profile page on the WEBMD website,

Dr. Kantoff has published more than 100 research articles on a variety of topics, including the molecular basis of genitourinary cancers and improved treatments for patients afflicted with prostate cancer, kidney cancer, bladder cancer, and testicular cancer. His laboratory research involves understanding the genetics of prostate cancer. His clinical research involves clinical trials of novel therapeutic treatments for the genitourinary cancers. He teaches at Harvard Medical School, and lectures internationally to both medical and lay audiences. Dr. Kantoff has written nearly 100 reviews and monographs on cancer and has edited numerous books, including Prostate Cancer, A Multi-Disciplinary Guide published by Blackwell, and Prostate Cancer: Principles and Practice, a definitive text on prostate cancer, published in December 2001 by Lippincott Williams & Wilkins. He has also written a popular book, Prostate Cancer, a Family Consultation, published by Houghton Mifflin.

As Kantoff counsels against over-hyping he notes that much of the work in the area of nanomedicine is in the laboratory; there are still animal trials and human clinical trials to be convened for further testing.

Building on Kantoff’s observations: let’s consider the difference between research and clinical practice. Even after the human clinical trials have taken place, there’s still uncertainty about how this new procedure or medication, no matter how personalized, will affect an individual. Would aspirin be available over-the-counter today if we’d known all of the side effects which many people suffer from? No, not a chance. How long did it take to find out that aspirin was a problem? Several years.

The idea that this new ‘personalized’ medicine that Mirkin refers to will provide a perfect solution to any disease is based on the belief that we understand disease processes. We do not. Yes, we’ve catalogued any number of genomes, etc. but at least one question remains. Why do some people who have one or more biomarker for a disease never experience it while others with fewer biomarkers do?

While that question wasn’t raised in the episode I was impressed with the fact that they did mention patent issues (innovation and, in this care, care can be stifled by patents and this seems to be increasingly the case); some larger philosophical issues, just how long do you want to live?, and who gets to enjoy these new benefits (if  such they be)?

I do have a few quibbles, there was no Canadian content other than David Suzuki reading a script as narration for the episode (this was true of the first episode too). The title, More than human, suggests not just robots but human enhancement too and that topic was barely discussed.

In future, I’d like to suggest a little more humility in programmes about nanotechnology. I found the constant references to ‘controlling’ atoms, matter, disease, etc. to be disconcerting. As far as I’m concerned, we don’t control an atom, we try to understand it and based on that understanding find better ways to exist in this universe.