Home › Blog › The Passion of Paul Knoepfler-A Review of the Niche Blog

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This is a blog a decade or more in the making. It’s about a university bench scientist and an out of control wild west stem cell space. Like all good stories, it’s protagonist is neither savior nor villain, as the truth is always somewhere in between. This blog post is written from the point of view of physicians and patients, so it could be the only look at this blogger through that lens. Let me explain.

Who is Paul Knoepfler?

I first met Paul a little more than a decade ago when we were embroiled in trying to establish what the FDA regulations should be around autologous stem cell use. Paul approached me a bit like a journalist with questions to answer about what was happening. Over the last decade, I’ve had countless interactions with Paul over email and have been featured in one way or another in his blog many times.

Paul is a university bench scientist who works at UC Davis in the Cell Biology department and who has a primary research interest in brain development and childhood cancers. I know that Paul is a prostate cancer survivor because he has written about this several times. Meaning, like the rest of us, he is very human.

As a scientist, you can see Paul is different just from reading the publication list on his lab’s website. Since about 2013, while the requisite publish or perish papers are there in his field of expertise, there is also a large chunk of the papers or opinion pieces he’s written about the out of control commercial stem cell space. In addition, for as long as I can remember, Paul has maintained a blog that is mostly about that one topic.

Understanding the History of the ISSCR Pushback Against Clinical Translation

You can’t understand Paul Knoepfler without understanding the history of this space and ISSCR. Most physicians using regenerative medicine procedures today really haven’t been around long enough to understand the full history of the bench scientist pushback and how that has shaped the landscape of regenerative medicine. In fact, few realize that ISSCR has been the main thrust behind the launching of countless news stories. So let’s dig in.

The ISSCR is the International Society for Stem Cell Research. It’s first real statements on the clinical translation of stem cells date back to the 2008/2009 time period. During that time, one of its first presidents, Irv Weissman launched a campaign to educate the public about stem cell clinics. It was shortly thereafter that a spate of negative news articles started appearing featuring quotes from ISSCR members. Hence, it was clear to me (after some online research), that ISSCR had hired a PR firm and had a strategy for getting the word out.

The ISSCR’s own history dates back to the Bush Embryonic stem cell research ban. In what was an unprecedented move at the time, embryonic stem cell researchers formed a society to protect their interests. Hence ISSCR really began as more of an activist organization than most scientific societies. Meaning, it has thrown its hat into the public debate since day one as at the time, the very existence of its members’ life work was being threatened.

The Paul Knoepfler Blog (aka The Niche)

The Paul Knoepfler blog really begins in about 2010, amidst the ISSCR push against stem cell clinics. Looking back at those simple days of a few clinics, most ex-US, it all looks positively tame and calm compared to what we have now. Back then, Paul’s blog topics were mostly focused on the emerging decisions around that existential crisis in embryonic stem cell research and the new Obama administration’s effort to try to right that ship. Then over the years, you see more and more stem cell clinic related stories. At some point, the name of the blog was changed to “The Niche” and most blog entries began to focus on stem cell clinics.

The Stem Cell and Exosome Wild West

On one hand, I have to applaud Paul for leading the charge against what has become an out of control wild west environment. I have tracked this for the last decade on this blog and I have to say that I now see things every day that astound me. Companies peddling fake stem cell products, selling illegal exosome concoctions, and altering third party lab reports. We see salespeople giving seminars to draw people in and then hiring barely trained nurses to provide injections of dead tissue after the patients are convinced in a high-pressure sales event that they are being injected with millions of young and vital stem cells. We even have physicians hiring RN’s to hook people up to dead umbilical cord products for anti-aging. This week I found an organization that sends a salesperson to your home to collect the answers to four simple questions and then will send a nurse back to inject you there at home to cure whatever ails you. So I recognize that having a voice out there like Knoepfler to fight that fraud is important.

Paul’s Logical Fallacies

Like all good stories, the moment you begin to believe that the protagonist is a saint, you dig deeper and it all becomes more nuanced. The same is true here. So while I applaud Paul for carrying the torch against the crazy stuff out there, at times, he struggles with logic. Let me explain.

You would think that bench scientists would be logical, as science is their life and logical arguments drive science. I’m sure many are, but many in the ISSCR camp seem to have thrown logic out the window in exchange for often irrational activism. Paul is no different and is guilty of illogic.

A logical fallacy is defined as “a flaw in the structure of a deductive argument which renders the argument invalid”. Paul’s biggest logical fallacy that he uses frequently is called a false dichotomy. He’s a master at convincing journalists that there are only two options in the adoption of new medical care: proven and unproven. In fact, let’s review Paul’s quotes in media stories:

LA Times: “…unproven fat stem cell product…”

Reuters: “Unproven stem cell injections…”

Spectrum” “…unproven stem cell treatments…”

I also reviewed Paul’s last 10 blogs on the topic of stem cell clinics. He uses the term “unproven” about an average of 4 times in each entry.

Is Most of the Medical Care Being Delivered Today Proven?

Is the medical care we receive every day from our doctors’ binary and either proven or unproven? No, it never has been and Paul should know better. However, he has no medical training but is a Ph.D. who never attended a day of medical school and is not legally able to be responsible for patient care in any way. This is something that the public often forgets. As a speaker said at a recent medical conference when referring to bench scientists like Paul, “They sit on the bench, while the physicians are forced to play on the field”.

The Knoepfler False Dichotomy

A False dichotomy is defined as: “a type of informal fallacy in which something is falsely claimed to be an “either/or” situation, when in fact there is at least one additional option.” By fabricating a myth that medical care should only be categorized as proven or unproven, Knoepfler misleads journalists and the public. Why? There is a third option ignored by Paul. So let’s explore why this artificial narrative created by Paul is not reflected in the published medical literature.

What is the third option? In the real world of Evidence-Based Medicine, the third option is “Best Available Evidence” and it’s actually used more often than the other two. This means that oftentimes physicians and policymakers must use evidence to make clinical decisions which is less than perfect. This lack of a “proven/unproven” dichotomy in real-world medical evidence has been acknowledged for decades by expert panels creating medical treatment guidelines for insurers and governments (1).

Meaning in the real world of seeing patients, it’s a common occurrence that a patient presents to you with a problem for which there is no “proven” intervention. Put simply, your patient has a problem for which there is no “Level 1” treatment evidence. Hence, you look at the evidence that’s available and make a decision. There is no field in which this is truer than in orthopedic care. So let’s explore why Paul’s false dilemma is orthobiologics is so deceptive.

Orthobiologics

One of the most glaring areas of a false dichotomy that Paul is guilty of is writing about orthobiologics. These are things like platelet-rich-plasma or bone marrow concentrate used to treat problems like knee arthritis. Here Paul refers to it all as “unproven”. However, the problem is that there is often no “proven” traditional treatment available. Let’s dig in.

If you apply the false dichotomy used by Paul in the area of orthopedic surgery, it’s a hot mess. For example, a recent review article in the British Medical Journal found that 80% of orthopedic care was “unproven” (2). In fact, the mean level of evidence in the 1-5 evidence scale (1 is the best) for orthopedic surgical publications is 3. So the best you can do in orthopedic care is to frequently use that third option that Paul hides from the press, called “Best Available Evidence”.

A Knee Arthritis Example of Unproven

Every major university medical school in America offers two main non-surgical treatments for knee arthritis: corticosteroid and hyaluronic acid injections. So are these “proven” treatments? Nope, not even close.

We have evidence that corticosteroid injections used to treat knee arthritis are ineffective and that the injections can cause cartilage damage (3,22). The evidence base for whether hyaluronic acid (aka viscosupplementation or knee gel injection) is “proven” is all over the place. Meaning most large meta-analyses that have been published state that the benefits in knee arthritis are still unproven (4).

Now let’s compare that evidence against what Paul has called “unproven” on his blog, PRP used to treat knee arthritis. In fact, we can even compare PRP to these two traditional, but “unproven” therapies above. There are two randomized controlled trials in patients with knee arthritis where PRP was compared to a cortisone injection and the PRP was found to be more effective (5,6). There are also 15 randomized controlled trials where PRP was compared head to head to hyaluronic acid injection. In 13 of those high-level studies, PRP was found to be superior to HA  (7. 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 20, 21). Two of those RCTs demonstrated that PRP worked about the same as a hyaluronic acid injection (15, 19).

So Paul clearly has his facts backward. PRP is more “proven” than what’s commonly used for injections to treat knee arthritis. How’s that for a false dichotomy? Has this come out in a single news piece that Knoepfler has participated in? Not that I can find.

The Other Side of Campus

I lecture at several major medical conferences a year in this area. I see a parade of university professors who use orthobiologics in their daily practices lecture on the new and evolving research in this area. Why would these university professors who work on the other side of campus from Knoepfler and his colleagues use treatments like PRP or bone marrow concentrate or micro-fragmented fat in their own patients? Because as physicians who are forced to play on the field, they understand the concept of “Best Available Evidence” that seems to elude the scientists sitting on the bench.

I have written to Paul many times that he has an ethical duty to inform all of the reporters he speaks to that his beliefs and those of the bench scientists are often opposed by physicians at the medical schools across campus. That these physicians don’t use a “proven/unproven” false dichotomy pitched by the bench scientists, but instead they must consider that third “Best Available Evidence” option to be able to practice medicine.

The Bench Scientist vs. The Patient’s Point of View

Almost every major media story written about stem cell clinics has been written from the point of view of bench scientists. Why? The ISSCR is a bench science organization. I reached out to several patients to get quotes on what they think of Paul’s blog. None were at all positive, so I omitted them here as publishing them wouldn’t be productive.

The upshot? I have told Paul that I and many of my colleagues view him as a two-edged sword. On the one hand, he serves a positive public role in criticizing legitimately crazy things that are happening in regenerative medicine. On the other, he’s not been willing to update his views as the science of orthobiologics has evolved and spins a false dichotomy which is very unscientific. So as I said in the beginning, Paul is neither saint nor villain, but like all protagonists, just human with all of the same flaws we all share.

[It should be noted that I reached out to Dr. Knoepfler several times via email to get answers to questions for this piece or to have him comment. He ultimately did not respond.]

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References:

(1) Gavine, A., MacGillivray, S., Ross-Davie, M. et al. Maximising the availability and use of high-quality evidence for policymaking: collaborative, targeted and efficient evidence reviews. Palgrave Commun 4, 5 (2018) doi: 10.1057/s41599-017-0054-8

(2) Lohmander LS, Roos EM. The evidence base for orthopaedics and sports medicine: scandalously poor in parts. Br J Sports Med. 2016 May;50(9):564-5. doi: 10.1136/bjsports-2016-g7835rep.

(3) McAlindon TE, LaValley MP, Harvey WF, et al. Effect of Intra-articular Triamcinolone vs Saline on Knee Cartilage Volume and Pain in Patients With Knee Osteoarthritis: A Randomized Clinical Trial. JAMA.2017;317(19):1967–1975. doi: 10.1001/jama.2017.5283

(4) Ammar TY, Pereira TA, Mistura SL, Kuhn A, Saggin JI, Lopes Júnior OV. Viscosupplementation for treating knee osteoarthrosis: review of the literature. Rev Bras Ortop. 2015;50(5):489–494. Published 2015 Aug 5. doi: 10.1016/j.rboe.2015.07.007

(5) Uslu Güvendi E, Aşkin A, Güvendi G, Koçyiğit H. Comparison of Efficiency Between Corticosteroid and Platelet Rich Plasma Injection Therapies in Patients With Knee Osteoarthritis. Arch Rheumatol. 2017;33(3):273–281. Published 2017 Nov 2. doi: 10.5606/ArchRheumatol.2018.6608

(6) Joshi Jubert N, Rodríguez L, Reverté-Vinaixa MM, Navarro A. Platelet-Rich Plasma Injections for Advanced Knee Osteoarthritis: A Prospective, Randomized, Double-Blinded Clinical Trial. Orthop J Sports Med. 2017;5(2):2325967116689386. Published 2017 Feb 13. doi: 10.1177/2325967116689386

(7) Tavassoli M, Janmohammadi N, Hosseini A, Khafri S, Esmaeilnejad-Ganji SM. Single- and double-dose of platelet-rich plasma versus hyaluronic acid for treatment of knee osteoarthritis: A randomized controlled trial. World J Orthop. 2019;10(9):310–326. Published 2019 Sep 18. doi: 10.5312/wjo.v10.i9.310

(8) Raeissadat SA, Rayegani SM, Hassanabadi H, et al. Knee Osteoarthritis Injection Choices: Platelet- Rich Plasma (PRP) Versus Hyaluronic Acid (A one-year randomized clinical trial). Clin Med Insights Arthritis Musculoskelet Disord. 2015;8:1–8. Published 2015 Jan 7. doi: 10.4137/CMAMD.S17894

(9) Görmeli G, Görmeli CA, Ataoglu B, Çolak C, Aslantürk O, Ertem K. Multiple PRP injections are more effective than single injections and hyaluronic acid in knees with early osteoarthritis: a randomized, double-blind, placebo-controlled trial. Knee Surg Sports Traumatol Arthrosc. 2017 Mar;25(3):958-965. doi: 10.1007/s00167-015-3705-6.

(10) Montañez-Heredia E, Irízar S, Huertas PJ, et al. Intra-Articular Injections of Platelet-Rich Plasma versus Hyaluronic Acid in the Treatment of Osteoarthritic Knee Pain: A Randomized Clinical Trial in the Context of the Spanish National Health Care System. Int J Mol Sci. 2016;17(7):1064. Published 2016 Jul 2. doi: 10.3390/ijms17071064

(11) Lana JF, Weglein A, Sampson SE, et al. Randomized controlled trial comparing hyaluronic acid, platelet-rich plasma and the combination of both in the treatment of mild and moderate osteoarthritis of the knee. J Stem Cells Regen Med. 2016;12(2):69–78.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5227106/

(12) Tavassoli M, Janmohammadi N, Hosseini A, Khafri S, Esmaeilnejad-Ganji SM. Single- and double-dose of platelet-rich plasma versus hyaluronic acid for treatment of knee osteoarthritis: A randomized controlled trial. World J Orthop. 2019;10(9):310–326. Published 2019 Sep 18. doi: 10.5312/wjo.v10.i9.310

(13) Huang Y, Liu X, Xu X, Liu J. Intra-articular injections of platelet-rich plasma, hyaluronic acid or corticosteroids for knee osteoarthritis : A prospective randomized controlled study. Orthopade. 2019 Mar;48(3):239-247. doi: 10.1007/s00132-018-03659-5.

(14) Lin KY, Yang CC, Hsu CJ, Yeh ML, Renn JH. Intra-articular Injection of Platelet-Rich Plasma Is Superior to Hyaluronic Acid or Saline Solution in the Treatment of Mild to Moderate Knee Osteoarthritis: A Randomized, Double-Blind, Triple-Parallel, Placebo-Controlled Clinical Trial. Arthroscopy. 2019 Jan;35(1):106-117. doi: 10.1016/j.arthro.2018.06.035.

(15) Di Martino A, Di Matteo B, Papio T, Tentoni F, Selleri F, Cenacchi A, Kon E, Filardo G. Platelet-Rich Plasma Versus Hyaluronic Acid Injections for the Treatment of Knee Osteoarthritis: Results at 5 Years of a Double-Blind, Randomized Controlled Trial. Am J Sports Med. 2019 Feb;47(2):347-354. doi: 10.1177/0363546518814532.

(16) Yu W, Xu P, Huang G, Liu L. Clinical therapy of hyaluronic acid combined with platelet-rich plasma for the treatment of knee osteoarthritis. Exp Ther Med. 2018;16(3):2119–2125. doi: 10.3892/etm.2018.6412

(17) Buendía-López D, Medina-Quirós M, Fernández-Villacañas Marín MÁ. Clinical and radiographic comparison of a single LP-PRP injection, a single hyaluronic acid injection and daily NSAID administration with a 52-week follow-up: a randomized controlled trial. J Orthop Traumatol. 2018;19(1):3. Published 2018 Aug 20. doi: 10.1186/s10195-018-0501-3

(18) Su K, Bai Y, Wang J, Zhang H, Liu H, Ma S. Comparison of hyaluronic acid and PRP intra-articular injection with combined intra-articular and intraosseous PRP injections to treat patients with knee osteoarthritis. Clin Rheumatol. 2018 May;37(5):1341-1350. doi: 10.1007/s10067-018-3985-6.

(19) Louis ML, Magalon J, Jouve E, Bornet CE, Mattei JC, Chagnaud C, Rochwerger A, Veran J3, Sabatier F. Growth Factors Levels Determine Efficacy of Platelets Rich Plasma Injection in Knee Osteoarthritis: A Randomized Double Blind Noninferiority Trial Compared With Viscosupplementation. Arthroscopy. 2018 May;34(5):1530-1540.e2. doi: 10.1016/j.arthro.2017.11.035.

(20) Lisi C, Perotti C, Scudeller L, Sammarchi L, Dametti F, Musella V, Di Natali G. Treatment of knee osteoarthritis: platelet-derived growth factors vs. hyaluronic acid. A randomized controlled trial. Clin Rehabil. 2018 Mar;32(3):330-339. doi: 10.1177/0269215517724193

(21) Cole BJ, Karas V, Hussey K, Pilz K, Fortier LA. Hyaluronic Acid Versus Platelet-Rich Plasma: A Prospective, Double-Blind Randomized Controlled Trial Comparing Clinical Outcomes and Effects on Intra-articular Biology for the Treatment of Knee Osteoarthritis. Am J Sports Med. 2017 Feb;45(2):339-346. doi: 10.1177/0363546516665809.

(22) Kompel AJ, Roemer FW, Murakami AM, Diaz LE, Crema MD, Guermazi A. Intra-articular Corticosteroid Injections in the Hip and Knee: Perhaps Not as Safe as We Thought? Radiology. 2019 Dec;293(3):656-663. doi: 10.1148/radiol.2019190341.

Chris Centeno, MD is a specialist in regenerative medicine and the new field of Interventional Orthopedics. Centeno pioneered orthopedic stem cell procedures in 2005 and is responsible for a large amount of the published research on stem cell use for orthopedic applications. View Profile