Pieter Droppert | Biotech Strategy Blog

Innovation is seeing round the corners

By Pieter Droppert on July 12, 2011

Innovation involves insight that allows you to see around the corners. That’s the perspective according to Andrew Marks, Professor of Physiology & Cellular Biophysics at Columbia University Medical Center, who recently wrote a Commentary on Innovation in Science Translational Medicine.

Entitled “Repaving the Road to Biomedical Innovation Through Academia”, Professor Marks’ commentary captures the reader’s attention in the first sentence:

“The path to biomedical innovation requires a synthesis of seemingly unrelated observations.”

He goes on to say, “innovation requires joining the pieces to solve the puzzle.”

Innovation according to Marks is difficult to define, something I also noticed at BIO 2011 in the industry panel that I attended.

However, like pornography, “we know it when we see it” to paraphrase Justice Potter. Mark gives examples of innovation in the biological sciences: germ theory of disease by Lister, discovery of antibiotics exemplified by Fleming, Watson & Crick’s work on the structure of DNA.

I don’t disagree that these are examples of paradigm shifting scientific discovery fueled in some cases by serendipity. But are they the best examples of innovation in the biological sciences? Has nothing innovative happened in the past 50 years that is worth mentioning?

In his commentary, Marks goes on to outline the reasons he thinks biomedical research is threatened in the current environment. This includes the standard litany of woes expressed by many academics today:

increased costs
insufficient support
limited industry support
prolonged postdoctoral training
limited opportunities for research careers in academic medicine

Interestingly, however, he suggests that part of the fault for this lies with academia.

Academia and the National Institutes of Health (NIH) have failed to evolve with the times, he writes. They “have been guilty of a lack of innovation” in how they support science.

Today’s challenge according to Marks is the need to balance revolutionary research that is innovative with incremental research necessary to further knowledge.

Marks goes on to say that the NIH is not well equipped to judge innovative groundbreaking research. Moreover, “the unwritten rule, often said tongue in cheek, is that when applying for NIH funding one should only propose experiments that one has already done and for which one can show convincing preliminary data.”

The solution he proposes is to change the way federal funding of biomedical research takes place. The NIH should divert to industry the costs of clinical trials and establish distinct funding mechanisms for high-risk research. I am not sure I agree with this, as many clinical trials would not be funded by industry and translational research is not just about basic science, but is from bench to bedside.

The solution proposed by Marks also predisposes that you can properly assess and judge innovative research when you see it. This is not as easy as it seems. As Marks points out:

“NIH likely would not have funded proposals to test the germ-theory, antibiotic-action, or DNA double–helix hypotheses because these projects either would have been deemed too risky (that is, they have a low likelihood of success) or too speculative (lacking in sufficient “preliminary data”) or because the approach would have been criticized as being misguided.”

Instead of looking for new ways to fund basic science, Marks proposes a rework of the way NIH funds research. Cutting the same cake in a different way is unlikely to solve the fundamental problem: there is simply not enough government funding to go around. In the face of the US budget deficit, it is hard to imagine a significant increase in NIH funding to create new funding opportunities.

Would a more innovative approach be to ask academics to rethink how research is funded in their institutions? Focusing on the NIH and Federal Government funding is not the optimal solution in my opinion.

Marks is right in that Academia needs to innovate how science is supported. Incremental change of the way NIH funding takes place may fill in some potholes, but will not repave the road to biomedical innovation.

Marks, A. (2011). Repaving the Road to Biomedical Innovation Through Academia Science Translational Medicine, 3 (89), 89-89 DOI: 10.1126/scitranslmed.3002223

How we may be able to rebuild The Six Million Dollar Man

I grew up watching Lee Majors in the 1970’s TV show “The Six Million Dollar Man”, about an injured former astronaut whose bionic implants allowed him to do superhuman feats.

That was fiction, but it is becoming closer to reality as a result of new research into how artificial limbs can integrate with human tissues. This work on neural-electrical interfaces may ultimately allow someone to control a prosthesis as you would a normal limb, i.e. by nerve impulses that travel from the brain.

The promise of “functional integration” between the human nervous system and an electro-mechanical device is the greater control this would give amputees and potential for sensory feedback.

The laboratory of D. Kacy Cullen, Ph.D, assistant professor in the Department of Neurosurgery, Center for Brain Injury & Repair at the University of Pennsylvania, Perelman School of Medicine is actively working in this area. I had the pleasure to hear Dr Cullen talk about his research at Health Journalism 2011 earlier this year. I previously wrote on this blog about his research on nanomaterials that change color with blast impact.

In his presentation to the Association of Health Care Journalists he described some of the neural tissue engineering work in his laboratory. This research has shown the ability to integrate axons in the peripheral nervous system (PNS) with an array of electrodes embedded in a living collagen matrix.

In essence this is the development of a nerve tissue/electrical interface that potentially allows the integration of man and machine.

Key to success has been the development of a living, 3-D scaffold where this integration between nerve and electrodes can take place. Nerve axons in the peripheral nervous system require a living target for innervation. This has involved designing and engineering a 3-D living cellular matrix/scaffold that will work within a living body (to date the research has been on animal models).

Not only is Cullen and his laboratory looking at machine/nerve interfaces, but they have also developed techniques that may allow nerves to be repaired. They have shown that nerves can be elongated or stretched using novel tissue engineering techniques.

The resulting axonal constructs via stretch-growth have been transplanted into rats and used to bridge an excised segment of sciatic nerve. What was subsequently seen was an interwining plexus of host and graft axons, suggesting axonal regeneration across the lesion.

While still early stage, and not yet tested in humans, this research has tremendous potential for those paralysed due to traumatic nerve damage in the future.

Moving forward, the Penn researchers aim to develop an application for CNS tissue repair that can be delivered to the brain or spinal cord via stereotactic microinjection. This is minimally invasive surgery that allows delivery of cells to a precise location using 3D co-ordinates.

According to research published in Critical Reviews™ in Biomedical Engineering they plan to use micro-engineered hydrogel conduits, several centimeters long and the width of three hairs. These hydrogels will contain living axonal tracts that will then hopefully reconnect damaged nerves, and provide a platform or path for regeneration.

Many challenges still remain to be worked out for the tissue engineered neural constructs such as issues relating to inflammation and immune tolerance.

The research also needs to move from animals to humans, and be shown to be safe. The long-term functional outcome is also unknown. It is far too early to think of this as a treatment option.

However, advances in neural tissue engineering, neuroregeneration and neuro-prosthetics do offer a lot of promise and hope to the many patients who suffer from spinal cord injuries or loss of a limb.

In a short blog post, I have not been able to do full justice to the innovative research or fully describe the techniques and methodology. More information on the fascinating work being done at Penn, along with details of the associated scientific publications, can be found on the web page of the Cullen Laboratory: Neural Engineering in Neurotrauma.

D. Kacy Cullen, John A. Wolf, Douglas H. Smith, & Bryan J. Pfister (2011). Neural Tissue Engineering for Neuroregeneration and Biohybridized Interface Microsystems In vivo (Part 2) Crit Rev Biomed Eng., 39 (3), 243-262

How does sunburn cause pain?

Everybody who has sat too long in the sun knows how painful sunburn can be, and how ineffective current treatments such as topical creams can be.

Research by John Dawes and colleagues at King’s College London & University College London has shed new light on how sunburn causes pain.

They investigated the inflammatory response associated with ultraviolet B radiation of the skin and found that the chemokine CXCL5 (also known as epithelial-derived neutrophil-activating peptide-78) mediates UVB irradiation-induced pain in the skin of rats.

The results, published in Science Translational Medicine (STM), suggest that CXCL5 mediates UVB irradiation-induced pain and may be a target for the development of new analgesics or pain killers.

The elegant series of experiments done by Dawes and colleagues attempted to overcome one of the main challenges of pain research – the results from animal models don’t always predict pain relief in humans.

They designed custom-made Taqman array cards to determine the expression of inflammatory mediators in UVB treated rat and human skin, and found chemokine CXCL5 expression to be up-regulated in both rat and humans 40 hours after UVB treatment.

They then tested the hypothesis that CXCL5 was the cause of the pain, and that neutralization of this reduced mechanical hypersensitivity in rats and decreased the number of infiltrating cells. The STM paper is well worth reading for the series of experiments they performed.

Inflammation and inflammatory mediators are poorly understood in many diseases such as osteoarthritis (OA), so generating a better understanding of the underlying biology and mediators of inflammation is key to drug development.

It is too early to tell whether CXCL5 will turn out to be a druggable target, but the work by Dawes and colleagues is a good example of translational medical research worth exploring further.

Dawes, J., Calvo, M., Perkins, J., Paterson, K., Kiesewetter, H., Hobbs, C., Kaan, T., Orengo, C., Bennett, D., & McMahon, S. (2011). CXCL5 Mediates UVB Irradiation-Induced Pain Science Translational Medicine, 3 (90), 90-90 DOI: 10.1126/scitranslmed.3002193

Regenerative Medicine: Tissue Engineered Airway Transplant

Regenerative Medicine and the science behind replacing body parts with synthetic tissue engineered versions took another step forwards today after researchers announced they had transplanted a trachea made of a nanomaterial covered with the patient’s own cells.

Researchers from University College London led by Prof. Alexander Seifalian designed and built a polymer based nanocomposite tracheal scaffold, which was then seeded with the patient’s own stem cells.

After two days in a bioreactor (Harvard Bioscience), the cells and the synthetic trachea scaffold were transplanted last month at the Karolinska University Hospital in Stockholm by Prof. Paolo Macchiarini and colleagues, into a patient with late stage tracheal cancer.

As reported by BBC health, and the press releases of University College London (UCL), Karolinska Institute and Harvard Bioscience, the 36 year old man is doing well and because the cells on the trachea were his own, no immunosuppressive drugs were needed.

In the UCL press release, Professor Seifalian said:

“What makes this procedure different is it’s the first time that a wholly tissue engineered synthetic windpipe has been made and successfully transplanted, making it an important milestone for regenerative medicine. We expect there to be many more exciting applications for the novel polymers we have developed.”

While this is still experimental research that needs to be validated in a clinical trial with more subjects, there is the potential for Professor Seifalian’s nanomaterial based tissue scaffold to be used for commercial medical devices such as coronary stents and grafts.

In addition to the development of a nanomaterial that can be used as a tissue scaffold, key to success of the transplant was the ability to grow and cover the engineered material with the patient’s own stem cells. Harvard Bioscience have specifically designed a bioreactor to culture cells onto a graft for airway tissue reengineering.

As innovation in science drives new milestones in regenerative medicine, we can expect the market for tissue engineered products to grow as companies seek regulatory approval for commercial products.

Above all else, regenerative medicine offers major benefits for patients and the restoration of function and improved quality of life. Today’s news is yet another milestone that highlights the promise of regenerative medicine.

Science Translational Medicine on Innovation – part 1

With an image of Rodin’s bronze “The Thinker” on its cover suggesting deep thought and insight, Science Translational Medicine (STM) analyzes the state of innovation in its June 29 issue.

STM states (without any authority) that “A powerful perception that innovation has stagnated persists in the biomedical research community.” STM asks, “Why have remarkable advances in basic biological science been so slow to be translated to improvements in clinical medicine?”

Unfortunately there is no identification of any “remarkable advances” that have been slow in being translated into clinical practice.

That’s not to say they don’t exist, merely the fact that from a hard-hitting science driven journal, it’s hard to hang your hat on mere assertions.

The three Commentaries on innovation by thought leaders in the June 29 issue offer varying perspectives, but like all opinion pieces it’s hard to judge competing views. STM in their editorial notes the only common thread they could detect among the Commentaries on innovation is that “a new mindset must drive risk-benefit analysis.”

It is good to see a debate on innovation, but I think in the data driven world of science, I expected more from Science Translational Medicine and the American Association for the Advancement of Science (AAAS).

The first Commentary on Innovation published in the June 29 issue of STM is by Elazer Edelman, the Thomas D. and Virginia W. Cabot Professor of Health Sciences and Technology at MIT, and Martin Leon, Professor of Medicine at Columbia entitled “The Fiber of Modern Society.”

Why innovate? This is a good starting point for Edelman’s and Leon’s commentary. After all if innovation does not add value, then it’s a worthless exercise. The authors, surprisingly for distinguished academics loose the reader in the first few paragraphs through their verbosity and lack of clarity:

Now grafted onto this engrained philosophy is a drop-off in the metrics of novelty and the perception that creation has stagnated—at least in biomedical science. As we are well into the 21st century, it behooves scientists and policy-makers not only to assess the accuracy of this impression but also to validate the long-accepted mantra.

The above causes me pain to read and attempt to process. Does anyone really “behoove” anything in the 21^st century?

The authors touch on competing views about what innovation is, but having raised the question of how to define it, fail to offer their opinion. Instead they move straight on by saying “irrespective of the definition.”

Defining innovation is important – science is about preciseness. If you can’t define a theory how can you test it or measure it. While we may have different views of what innovation is, thought leaders on the topic should frame their perspective around some definition.

Is innovation really dead the authors go on to ask? They cite to the large number of publications in recent years that claim the death of innovation or express concern about it. However, while raising third-party concerns they also point out the progress that has been made in the reduction in mortality and morbidity over the past 40 years through advances in technology.

The authors again don’t answer the question they have asked on whether innovation is dead? Instead they move on to their next topic and suggest that “fear of risk stifles innovation” – spending cuts will lead to less creativity. The authors then launch into a diatribe on the pitfalls of a lower NIH budget. Evidence of the demise of innovation is the decline in the number of registered patents or FDA applications for new molecular entities (NME).

What are the authors conclusions and recommendations? They state:

“we must find ways to teach and support innovation without falling prey to conflicts of interest, without confusing innovation with greed-directed entrepreneurship.”

However, they don’t offer any specifics on how to do this, and what exactly is “greed-directed entrepreneurship” when it’s at home? Is it wrong to profit from innovation?

This Commentary by Edelman and Leon is not the deep insightful piece that Rodin’s Thinker suggests, instead it is a rambling piece that is disappointing in my opinion.

In future blog posts, I’ll be reviewing the other Commentaries on Innovation published by STM.

Edelman, E., & Leon, M. (2011). The Fiber of Modern Society Science Translational Medicine, 3 (89), 89-89 DOI: 10.1126/scitranslmed.3002190

BIO 2011 International Convention Video Review #BIO2011

Although I had to leave BIO 2011 early due to illness, I did shoot some video during the time I was at the meeting, and have now put this together into a short 2 minute video that you can watch below.

This post wraps up my coverage of the 2011 BIO international convention in Washington DC. Next week, I’ll be writing more about innovative science and new products in the pipeline that have caught my attention.

A happy holiday weekend to everyone in North America.

http://www.youtube.com/watch?v=hM_wmjaqDyc

Avastin for Breast Cancer is not Personalized Medicine

By Pieter Droppert on June 30, 2011

Bevacizumab (Avastin®) should be withdrawn for metastatic breast cancer. That is the unequivocal recommendation of the Oncology Drugs Advisory Committee (ODAC) yesterday.

Despite the passionate patient advocacy in favor of continued approval, withdrawal is the right decision and it is hard to see the FDA overruling ODAC, given the safety issues such as bowel perforations and relative lack of efficacy. The patient advocacy at this week’s public hearing was fundamentally biased, those who died early and who received no treatment benefit are not alive to stand up and share their experiences.

The bottom line is that Genentech were unable to identify the sub-set of patients who might benefit from the drug. They simply did not have the data, and the reality is that treating all potential HER2- patients in the hope of finding the few who might respond is not a rational drug development or marketing strategy, especially when those that don’t respond may do worse on the drug.

Personalized medicine requires a thorough understanding of the science and molecular biology of a disease. Pfizer recently showed an excellent example of this with crizotinib that targets ALK mutations in non small cell lung cancer (NSCLC).

It is disappointing that a scientifically orientated company such as Genentech would continue to try and push Avastin in Breast Cancer when the data is clearly unconvincing to ODAC. But, if we look at how Genentech approached the Lucentis v Off-label Avastin issue in AMD, with a 40x higher cost for using Lucentis, then what we see is that commercial decisions, and maximization of profit has become more important than doing what’s right for patients.

BIO 2011 Presentation Personalized Medicine Payment Sessions

This is a flawed long-term strategy in my opinion. Society cannot afford to pay for treatments that don’t work in many patients or pay for treatments that are excessively priced. We are already seeing “pay for results” being introduced in Europe, notably England and Italy where payors are reimbursing companies only for those patients that respond.

Personalized medicine is the future. This requires targeted therapies that are aimed at patients who we can predict will have a good chance of responding based on our understanding of mutations, molecular biology and biomarkers.

Avastin in metastatic breast cancer is not an example of personalized medicine and should be withdrawn from the market for this indication.

BIO 2011 What is the future for innovative medicines in our industry’s pipeline?

What is innovation? Like “strategy” and “leadership” it’s a term we frequently use, something we all seek in the biotech/pharma industry, yet it’s hard to define, even harder to develop or predict.

What is the future for innovative medicines in our industry’s pipeline? was the title of a session that I attended yesterday afternoon at BIO 2011, the annual meeting of the Biotechnology Industry Association (BIO) in Washington DC.

Moderated by John Mendlein, the panel contained some R&D heavy weights:

Tom Daniel, President of Research & Early Development, Celgene
Charles Homcy, Venture Partner, Third Rock Ventures
Moncef Slaoui, Chairman R&D, GlaxoSmithKline
Doug Williams, Executive VP, R&D, Biogen Idec

Several people in the audience live tweeted the key messages of the speakers, and I encourage you to review them, if interested. The take homes that I took from this session were:

Innovation can be incremental or major breakthroughs

Many people think of innovation as a major breakthrough. Well worn clichés such as “ground breaking”, “game changing” come to mind. In pharma, I’d cite imatinib (Glivec®/Gleevec®) in CML as an example. In the consumer world, the Dyson vacuum cleaner jumps out to me. Something completely redesigned and made better = innovation.

However, incremental change can also be innovation if it has an impact. Take a new drug formulation that instead of daily dosing moves it to monthly doses and in the process improves patient compliance and adherence. That’s incremental innovation.

“Incremental versus major breakthrough” reminds me of scientific research. Most published papers are incremental, only rarely is there a major paradigm shift and landmark study. Only a few PhD students undertake truly novel research, instead the majority pursue incremental avenues associated with their supervisor’s interests. An oversimplification perhaps but there’s some truth to it.

Understanding science enables Innovation

Companies should focus their energies on disease mechanisms where the basic science has reached an inflection point of knowledge i.e. there is enough information for us to apply. This is why the work of research organizations such as the National Institutes of Health (NIH) is so important. In an area where there is the disease knowledge emerging, you can then put together a team of people who understand the science and biology of the disease. This does not guarantee innovation, but allows the identification of opportunities and in my view “enables innovation.”

Innovation will come from focus on molecular pathology of disease

Drug development is no longer focused on treating symptoms but on the underlying mechanism of a disease. Medicine itself is moving in this direction with personalized medicine and drugs that target specific mutations of genes e.g crizotinib in lung cancer. In a complex world of overlapping pathways (cancer and inflammation was the example cited), drug development innovation is going to come from understanding the molecular pathology of a disease. The terms “translational medicine” was not used in the session, but this is what comes to mind. Understanding science is key to success.

What is the future for innovative medicines in our industry’s pipeline? The panelists didn’t actually answer this question directly, but my view is that it is promising.

BIO 2011 Network till you drop #BIO2011

By Pieter Droppert on June 28, 2011

Everyone at BIO 2011, the annual international convention of the Biotechnology Industry Organization (BIO) is into networking. Sit next to someone on one of the shuttle buses, in a coffee line or in a meeting hall and a conversation will soon be struck up and business cards exchanged. Business development, partnering and making connections is what this meeting is really about.

With this in mind, there’s a series of receptions, parties and events that take place around BIO. Yesterday late afternoon, I attended a reception on the Kalmar Nyckel, AKA the Delaware Boat. It is a replica of the tall ship that sailed from Sweden to the New World in 1638, and landed 24 settlers in the Delaware Valley, in what is today Wilmington, DE. Today’s replica serves as Delaware’s goodwill ambassador. Hosting a reception on a boat made a change from the standard hotel ballroom.

In the evening the official BIO reception took place at the Newseum. Plenty of food, drinks and music, plus the opportunity to mix, mingle and explore the Newseum. I enjoyed it! You could even try your hand at being a newscaster at one of the interactive exhibits.

This evening I will be at the New Zealand and Italian Embassies for receptions. BIO 2011 – network till you drop!

BIO 2011 The face of Biotech Social Media #BIO2011

By Pieter Droppert on June 28, 2011

The most enjoyable part of Day 1 of BIO 2011 for me was the unofficial tweetup at the Old Dominion Brewhouse. Who are the people I have been interacting with on Twitter? Some have twitter handles close to their name, others like me are more cryptic. So at a tweetup it’s common to introduce yourself through the language of twitter, “I’m @3NT.”

Meeting up with someone you have had twitter conversations is like meeting up with a penpal (for those who can remember the days when we still wrote letters and didn’t have email, twitter or facebook). In many ways you already know each other and have common interests, so the conversation is easy. Putting a name to a face is fun.

At the BIO 2011 tweetup yesterday, it was great to meet up with @IAmBiotech, @LacertaBio, @ldtimmerman, @FierceBiotech, @JKureczka, @corytromblee, @christianetrue, @InVivoBlogChris, @lisamjarvis, @jacquimiller (apologies to anyone I missed who was at the tweetup but I didn’t manage to meet).

I look forward to following on Twitter what’s happening at BIO 2011 today, especially as there are several parallel sessions that I will not be able to attend.

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