Previously undetected mutations in bone marrow stem cells of young donors can be passed to recipients

Physicians use bone marrow stem cells from a donor, transplanted into a recipient, to treat patients with certain cancers or blood disorders. The donors for these procedures, whose blood or bone marrow is used for the procedures, are typically young, to optimize the quality of the donor stem cells.

Previous studies have found that error-corrected sequencing (ECS) of human blood samples, with a limit of detection of ≥0.0001, that nearly every healthy individual >50 years old harbors rare hematopoietic clones, i.e. genetically distinct subpopulations of blood cells caused by genetic mutations. Clonal hematopoiesis of indeterminate potential, or CHIP, is characterized by the presence of mutant hematopoietic stem cell clones in the bone marrow without overt signs of disease. However, emerging evidence suggests that this condition, which is more common in older patients, may not be as innocuous as previously thought, with recent studies connecting CHIP to a variety of medical problems (Xie et al, 2014). These mutations are below the detection limit of standard high-throughput sequencing used for screening. Screening procedures for bone marrow stem cells used for stem cell transplants are critical because even cancer cells have been transplanted from donor to recipient when standard screening procedures are used at hospitals (Maguire, 2019; Maguire, 2019A).

A new study by Wong et al (2020)has raised the possibility that young donors are also passing along mutations in stem cells that could lead to health problems for recipients. The study found that 44% of younger donors had mutations in the transplanted bone marrow stem cells that could raise the risk of conditions that are sometimes seen in recipients, a higher rate than previously suspected. The scientific team also reported that some of these mutations persisted and proliferated in the recipients’ bone marrow for at least a year.  Specifically, Wong et al (2020) performed ECS on 125 blood and marrow samples from 25 matched unrelated donors and recipients. Clonal mutations, with a median variant allele frequency of 0.00247, were found in 11 donors (44%; median, 36 years old). Of the mutated clones, 84.2% of mutations were predicted to be molecularly pathogenic and 100% engrafted in recipients. That is, in all of the patients who were recipients of the bone marrow stem cells (BMSCs), the BMSCs engrafted into the patient and remain alive. Further, 84% of the live BMSCs in the recipient were found to harbor possible pathogenic mutations.

Many questions remain, for example, are these  mutations present in the donor before the BMSCs are taken from the donor, or do the mutations occur during the BMSC collection process? If the mutations are present in the donor before the procedure begins, are the mutations causing problems in the 44% of donors with the CHIP? Because BMSC transplants can lead to many health issues in the recipients (Maguire, 2019A), understanding these mutations and their pathogenicity in both donor and recipient is important. Because BMSC transplants lead to implantation of the donor cells in a manner that is not consistent with a normal niche, that is, the extracellular matrix (ECM) and microenvironment of the implanted stem cells may be abnormal (Wood et al, 2016; Maguire, 2019A), implanted cells with mutations surviving in an abnormal ECM/microenvironment may lead to reprogramming of the implanted cells to a cancerous state (Bhat and Bissell, 2014). The combination of mutations along with an abnormal ECM/microenviornment is what is critical to the reprogramming, not one or the other alone.

References

Bhat R and Bissell MJ (2014) Of plasticity and specificity: dialectics of the microenvironment and macroenvironment and the organ phenotype. Wiley Interdiscip Rev Dev Biol. 3(2):147-63. doi: 10.1002/wdev.130. Epub 2013 Nov 18.

Maguire G. (2019) Transplanted stem cells survive a long time: do they make you sick? J R Soc Med. 2019 Oct;112(10):412-414.

Maguire G. (2019A) The Safe and Efficacious Use of Secretome From Fibroblasts and Adipose-derived (but not Bone Marrow-derived) Mesenchymal Stem Cells for Skin Therapeutics. J Clin Aesthet Dermatol. 2019 Aug;12(8):E57-E69.

Wong WH et al (2020) Engraftment of rare, pathogenic donor hematopoietic mutations in unrelated hematopoietic stem cell transplantation. Sciene Translational Medicine, 12, Issue 526, eaax6249.

Wood WA, Krishnamurthy J, Mitin N et al. Chemotherapy and stem cell transplantation increase p16INK4a expression, a biomarker of T-cell aging. EBioMedicine. 2016;11:227–238.

Xie et al (2014) Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 2014 Dec;20(12):1472-8.

Hyping a New Drug that Treats Pancreatic Cancer

Headlines today are reading, “A study found a drug used to treat ovarian cancer doubled the lifespans of pancreatic cancer patients” (Guzman, 2020). Sounds great, right? A new drug study reports that a new drug called Lynparza from AstraZeneca, based in the UK, “nearly doubled the time patients lived without disease progression” (AstraZeneca website). Let’s look at what this actually means by analyzing the study (Golan et al, 2019) that led to the FDA approving the drug for pancreatic cancer. First, let’s assume the paper is a valid study, and all of the 19 physician-authors were actually involved in the study and acted without fraud. Those are big assumptions though, given that ghostwriting, i.e. someone other than the physician does the research and writes the medical paper, is rampant in medical centers where physicians are on the byline of a medical paper (Lacasse and Leo, 2010). Fraud among physicians on the byline of medical research papers is rampant too (Relman, 1983), and has been described by the former editor of the New England Journal of Medicine, Arnold Relman, M.D., as part of the “medical professionalism in the United States is facing a crisis” (Relman, 2007). Dr. Relman’s sentiment has been echoed by many others, including another former editor of the New England Journal of Medicine, Marcia Angel, M.D., who has written, “It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor of The New England Journal of Medicine” (Angell, 2009).

Now, assuming no fraud in the Golan et al (2019) paper, what are the results? The drug increased the length of life by 3.6 months compared to a placebo: “The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death).” That is about a 50% increase in survival. For the gain in 3 months survivability, one must consider the possible negative side effects: The most common side effects with Lynparza (which may affect more than 1 in 10 people) are tiredness, nausea (feeling sick), vomiting, diarrhea, dyspepsia (heartburn), cough, headache, dysgeusia (taste disturbances), decreased appetite, dizziness, upper abdominal pain (stomach ache), dyspnoea (difficulty breathing), anemia (low red blood cell counts), leucopenia (low white blood cell counts), neutropenia (low levels of neutrophils, a type of white blood cell that fights infection) and thrombocytopenia (low blood platelet counts) according to the European Medicines Agency. Further, given that this drug was just approved in December 2019, and that many drugs are not fully understood until used by a large number of people 4-7 years following approval and used in the market by a diverse group of patients, the negative side effects are likely not well understood (Downing et al, 2017).

Because pancreatic cancer involves the immune system, and those who live the longest with this cancer may have elevated T-cell activity in the tumor and in their blood (Balachandron et al, 2017), if the patient does things to better activate T cell function, such as eating fiber (Trompette et al, 2018), survivability may be improved. I have more to say about this in my new book: “Thinking and Eating for Two: The Science of Using Systems 1 and 2 Thinking to Nourish Self and Symbionts.”

References

Angell M (2009) Drug Companies & Doctors: A Story of Corruption. The New York Review of Books, Jan. 15, 2009.

Balachandron et al (2017) Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature, 551: 512–516.

Downing NS et al (2017) Postmarket Safety Events Among Novel Therapeutics Approved by the US Food and Drug Administration Between 2001 and 2010. JAMA. 317(18):1854-1863

Golan T et al (2019) Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med, 381:317-327

Guzman J (2020) FDA green-lights promising new pancreatic cancer drug treatment. A study found a drug used to treat ovarian cancer doubled the lifespans of pancreatic cancer patients. The Hill, Jan. 17, 2020.

Lacasse JR, Leo J (2010) Ghostwriting at Elite Academic Medical Centers in the United States. PLoS Med 7(2): e1000230. https://doi.org/10.1371/journal.pmed.1000230.

Relman AS (1983) Lessons from the Darsee Affair. N Engl J Med 1983; 308:1415-1417.

Relman AS (2007) Medical professionalism in a commercialized healthcare market. JAMA. 298(22):2668-2670. doi:10.1001/jama.298.22.2668.

Trompette A et al (2018) Dietary Fiber Confers Protection against Flu by Shaping Ly6c– Patrolling Monocyte Hematopoiesis and CD8+ T Cell Metabolism. Immunity. 48(5):992-1005.e8.

We Don’t Treat Disease With Our Drugs, We Treat Surrogates in the Quagmire of the Deregulated, Privatized Drug Approval Process.

Beginning in the 1980s during the Reagan administration, the approval and regulation processes for therapeutics have been deregulated and evolved into an increasingly complex and poorly working system with rampant fraud. Irrespective of the many other failures of the system, the use of surrogate measures has been encouraged and found to be of questionable value (Darrow et al, 2020). The use of surrogate measures means that a drug is not being tested for efficacy in treating the disease, rather the drug is being tested to modulate some measure that is associated with disease. For example, if a patient has gout, a disease with symptoms of inflammation, severe pain, redness, and swelling in joints, then a surrogate endpoint of serum uric acid (associated with the disease) can be used to determine efficacy of a drug instead of the disease itself. Remember, patients with gout don’t go to see their physician complaining of high serum uric acid levels. The FDA has increasingly accepted less data and more surrogate measures, and has shortened the review times for drug approvals. In our pro-business, deregulated environment, the process has become so corrupt that one drug was approved, despite the scientist at FDA who evaluated the drug disapproving the drug (Lowe, 2016), because the physician, Janet Woodcock, M.D., in charge of the review process, didn’t want the company to go out of business because the company’s drug wasn’t approved (Harper, 2016). I’ll repeat that: a drug was approved by a physician at the FDA for reasons of profit, even though the scientists evaluating the drug said the drug shouldn’t be approved. While increasing numbers of drug candidates are failing (DiMasi et al, 2016), and those approved and on the market are increasingly causing adverse events and deaths (Chen, 2018), the regulatory deregulation and short-cuts have not led to an increase in new drug approvals or to reduced total development times (Darrow et al, 2020). More than half of our drugs don’t work (Smith, 2003). For example, the FDA’s approval of bevacizumab for progressive glioblastoma, an aggressive brain cancer, “the confirmatory trial, with more than 400 patients, reported no improvement in terms of overall survival, quality-of-life end points, or neurocognitive functioning.” Furthermore, almost two-thirds of the patients on bevacizumab had severe to life-threatening side effects (DiMagno et al, 2019). Unfortunately, the only thing working in the drug development process is that the rich are becoming richer – Physicians are highly paid by pharma companies to put their names on ghostwritten medical journal publications (Wilson and Singer, 2009) or just steal the work of their Ph.D. colleagues and add their name (McCook, 2018), and billions are made by the drug companies (Herman, 2019), of which ownership is mostly by the wealthy (Cohen, 2018). When it comes to taking prescription drugs, do as Nancy Reagan told us about those other kinds of drugs: “just say no.” All of this is explained in greater detail, along with alternatives to prescription drugs in my upcoming book, “Thinking and Eating For Two: The Science of Using Systems 1 and 2 Thinking to Nourish Self and Symbionts”(Maguire, 2020).

 

References

Chen C (2018) FDA Repays Industry by Rushing Risky Drugs to Market. ProPublica, June 26, 2018.

Cohen P (2018) We All Have a Stake in the Stock Market, Right? Guess Again. NY Times, Feb. 8, 2018.

Darrow JD et al (2020) FDA Approval and Regulation of Pharmaceuticals, 1983-2018. Journal of the American Medical Association, 323(2):164-176. doi:10.1001/jama.2019.20288.

DiMagno S et al (2019) Accelerated Approval of Cancer Drugs—Righting the Ship of the US Food and Drug Administration. JAMA Intern Med. 179(7):922-923.

DiMasi JA et al (2016) Innovation in the pharmaceutical industry: New estimates of R&D costs. J. Health Econ., 47:20-33.

Harper M (2016) Approving A Muscular Dystrophy Drug Ignites A Civil War At The FDA. Forbes, Sept. 20, 2016.

Herman B (2019) Axios analysis: Drugmakers getting richer. May 13, 2019.

Lowe D (2016) Sarepta Gets An Approval – Unfortunately. Science Translational Medicine, Sept. 20, 2016.

Maguire G (2020) Thinking and Eating For Two: The Science of Using Systems 1 and 2 Thinking to Nourish Self and Symbionts. Smashwords, Los Gatos, CA.

McCook A (2018) Prominent health policy researcher plagiarized colleagues’ work, Dartmouth investigation finds. STAT, August 20, 2018.

Smith R (2003) The drugs don’t work. BMJ. 327(7428): 0.

Wilson D, Singer N. (2009) Ghostwriting is called rife in medical journals. New York Times. 2009 September 11; B5.

The Over-Medicalization of America Continues – Executive “Health” Programs for Profit, but Not Health

The premise of using Executive Health Programs with their associated cardiovascular diagnostic tests is that the results may help reduce mortality from cardiovascular disease through earlier disease detection, more precise risk assessment, and therefore better treatment. As is often the case in medicine, physicians have beliefs about what works despite the evidence against their cherished, money-making beliefs. Screening tests in general have not been found to reduce mortality in asymptomatic individuals (Sussman and Beyth, 2015; Smetana et al, 2016). Nevertheless, many physicians have an enduring belief in the benefit of using diagnostic tests to discover cardiovascular disease in its earliest stages. In a highly deregulated, capitalistic medical system here in the US where physicians and hospitals are incented to perform procedures in order to make more money, leveraging their beliefs in cardiovascular diagnostic testing is a platform for increased income. The money-making mentality among physicians and hospitals is particularly acute in some specialities and in some areas where their are too many competing physicians and hospitals per capita, and therefore physicians perform unnecessary procedures to protect their income. As an example, the U.S. has more than double the number of congenital heart surgery centers that it needs, and about 40 of those centers in the USA aren’t cooperating with authorities to report their medical statistics. Further, those non-cooperating centers have “unexpectedly high mortality rates,” according to Dr. Carl Backer, MD presenting at the 2019 Annual Meeting of the American Heart Association in Philadelphia, PA. In 2014, the Institute of Medicine released their analysis on graduate medical education, arguing there was no shortage of physicians, and that we have no need to invest more in increasing the number of new physicians who are trained annually (IOM, July 29, 2014). With an oversupply of physicians comes more procedures – unnecessary procedures; but money is made (Schroeder, 1992).

As Prof. Ralph Crawshaw, M.D. has said, “Clearly, a serious problem with an exaggerated and misanthropic human trait, greed, challenges the medical profession to move to higher moral ground in the care of the sick.” When asked why he robbed banks, Willie Sutton supposedly said “because that’s where the money is.” For the sake of  increased incomes, physicians and hospitals have created the demand for early diagnosis by leading people to believe that early diagnosis leads to better health. Establishing executive screening programs targeted to wealthy individuals who are able to pay directly for cardiovascular screening tests that are generally not covered by insurance is in vogue. Why? Because that’s where the money is.

In a new study published in the Journal of the American Medical Association Network, executive screening programs have been found to “run afoul of healthcare’s goal of evidence-based cost-effective equitable care” (Alan and Brown, 2020). Indiscriminate screening programs in healthy people can create a cascade effect and thus violate the principle of primum non nocere (first do no harm) wherein unnecessary medical tests may create a chain of adverse medical events resulting in additional ill-advised tests or treatments that may cause avoidable physical and psychological harm.

In a previous study, Prof. Ganguli, M.D. has found in a survey of practicing physicians that almost all (398 out of 400) respondents had experienced medical cascades after incidental findings that did not lead to clinically meaningful outcomes yet caused harm to patients and themselves (Ganguli et al, 2019). The problem is widespread and contributes greatly to the medicalization of America, leading to increased rates of sickness and, as described by Prof. Arnold S. Relman, M.D., former editor of the New England Journal of Medicine, the out of control industrial-medical complex (Relman, 1980; 1983; 2007). Learn how to take care of your own health because the medical-industrial complex won’t; read “Thinking And Eating For Two: The Science of Using Systems 1 and 2 Thinking to Nourish Self and Symbionts.”

References

  1. Alan AG and Brown DL (2020) Assessment of Cardiovascular Diagnostic Tests and Procedures Offered in Executive Screening Programs at Top-Ranked Cardiology Hospitals. JAMA Intern Med. Published online January 13, 2020. doi:10.1001/jamainternmed.2019.6607
  2. Crawshaw R (1993) Greed and the medical profession. BMJ, 3016: 151.
  3. Ganguli I et al (2019) Cascades of Care After Incidental Findings in a US National Survey of Physicians. JAMA Netw Open. 2019;2(10):e1913325.
  4. Relman AS (1980) The new medical-industrial complex. N Engl J Med. 303:963-970.
  5. Relman AS (1983) Lessons from the Darsee Affair. N Engl J Med 1983; 308:1415-1417.
  6. Relman AS (2007) Medical professionalism in a commercialized healthcare market. JAMA. 298(22):2668-2670. doi:10.1001/jama.298.22.2668.
  7. Schroeder SA (1992) Physician Supply And The U.S. Medical Marketplace. Health Affairs, https://doi.org/10.1377/hlthaff.11.1.235.
  8. Smetana GA et al (2016) Should We Screen for Coronary Heart Disease in Asymptomatic Persons?Grand Rounds Discussion From Beth Israel Deaconess Medical Center.  Ann Intern Med. 164(7):479-487.
  9. Sussman J and Beyth RJ (2015) Don’t perform routine general health checks for asymptomatic adults. Society of General Internal Medicine, https://www.sgim.org/File%20Library/JGIM/Web%20Only/Choosing%20Wisely/General-Health-Checks.pdf.

The Role of Fat Cells (Adipocytes) in Wound Healing

The study of dermal adipocytes in the skin is leading to a new understanding of skin phsyiology, how the skin maintains and heals itself, and in the development of new procedures and products for wound healing.  Dr. Valerie Horsley, Ph.D., professor of Molecular, Cellular and Developmental Biology and Dermatology at Yale University has pioneered the work of adipocytes in the skin. Her lab has revealed that adipocytes regenerate in the skin and are essential for regeneration of the hair follicle during its normal growth cycle and following injury (Festa et al., 2011; Schmidt and Horsley, 2013). Working with Dr. Matthew Rodeheffer, Ph.D., professor of comparative medicine at Yale University, has identified mesenchymal adipose progenitor cells in the skin and showed that these cells are necessary to induce hair follicle growth (Festa et al., 2011).  These studies showed that the progenitor cells were activated after injury and required for dermal fibroblast migration during wound healing (Schmidt and Horsley, 2013). Her lab has also shown that dermal adipocyte precursor cell self-renewal process decreases as we age and that this process is dependent on PDGF and IGF-1 signaling from macrophages (Gonzalez et al., 2016).  Further, her lab showed that CD301b marks a portion of midphase macrophages and that depletion of CD301b-expressing macrophages was sufficient to induce skin repair defects observed by depletion of myeloid cells more broadly. Transplanting CD301b+ macrophages was sufficient to enhance re-epithelialization, dermal proliferation, and fibroblast repopulation during the midstage wound repair. Additionally, they showed that CD301b-expressing macrophage gene expression was enriched for growth factors and cytokines involved in skin regeneration. Therefore, their results identify a subset of CD301b+ macrophages critical for activating skin repair during midstage wound healing.  CD301b+ macrophage–derived signaling selectively activated the proliferation of adipocyte progenitor cells and not other myofibroblasts.  PDGFC and IGF1 released from macrophages promoted myofibroblast heterogeneity and repair (Shook et al, 2016; Shook et al, 2018). These data are compatible with the function of macrophages in tissue fibrosis, the ability of exogenous PDGFC to rescue delayed skin wound healing in diabetic mice, and the promotion of fibroblast proliferation and repair by IGF1. Further, the importance of adipose derived mesenchymal stem cells in the skin to polarize macrophages from the M1 inflammatory to a M2 anti-inflammatory phenotype may be important in this adipocyte-mediated process of wound healing (Li et al, 2015).

Another important aspect of adipocytes in the skin is to fight infection. Dr. Richard Gallo, MD, PhD, professor and chief of dermatology at UC San Diego School of Medicine, and colleagues have uncovered a previously unknown role for dermal adipocytes – they produce antimicrobial peptides (AMPs) that help fend off invading bacteria, viruses, and fungi.

So contrary to what many people have been told, Fat Isn’t All Bad, especially when considering adipocytes in the skin.

References

Festa, E et al (2011)Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cyclingCell 14676171 doi:10.1016/j.cell.2011.07.019pmid:21884937

Gonzalez GC et al (2016) Skin adipocyte stem cell self-renewal is regulated by a PDGFA/AKT-signaling axisCell Stem Cell19738751 pmid:27746098

Li Q et al (2015) Skin-Derived Mesenchymal Stem Cells Alleviate Atherosclerosis via Modulating Macrophage Function. Stem Cells Transl Med. 4(11): 1294–1301.

Schmidt and Horsley V (2013) Intradermal adipocytes mediate fibroblast recruitment during skin wound healing.Development 1401517–1527 (2013). doi:10.1242/dev.087593pmid:23482487

Shook,B et al (2016) CD301b+ macrophages are essential for effective skin wound healingJ. Invest. Dermatol. 13618851891 (2016).doi:10.1016/j.jid.2016.05.107pmid:27287183

Shook B et al (2018) Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair. Science, DOI: 10.1126/science.aar2971

Zhang LJ, Guerrero-Juarez CF, Hata T, Bapat SP, Ramos R, Plikus MV, Gallo RL. (2015) Innate immunity. Dermal adipocytes protect against invasive Staphylococcus aureus skin infection Science. 2015 Jan 2;347(6217):67-71

Transplanted Stem Cells Last A Long Time – Do They Make You Sick?

Careful You May Be Stuck with the Cell’s Phenotype and Genotype for a Very Long Time

Hematopoietic stem and progenitor cells (HSPCs) are responsible for generating and maintaining the extremely diverse pool of blood cells, everything from red blood cells to T-cells, for our lifetime. HSPC transplantation, also known as bone marrow transplantation, remains the only approved stem cell therapy, even though unapproved stem cell transplants for a variety of other indications continue to burgeon. The approved, clinical transplantation of human HSPCs from an allogeneic healthy donor can effectively replenish defective blood cell production caused by congenital or acquired disorders, but, as with most medical products or procedures, there are risks involved. Many case studies have reported the approved stem cell transplants to be associated with the later development of cancer (Cooley et al, 2000), and unapproved stem cell transplant procedures are notorious for side-effects, including development of cancer (Diouhy et al, 2014). Unfortunately, with most drugs and many medical procedures, the long term consequences to health are unknown. Often, when considering drugs, not until Phase IV, postmarket approval are the long term consequence of a drug discovered. Witness the many drugs pulled from market some three to four years after their approval (e.g. ProCon, 2014). Even more unfortunate, the problem is worse with medical procedures (Kumar and Nash, 2011). Such is the case with approved stem cell transplants. The effects of approved stem cell transplants in causing, or being involved, in cancer relapse are not well understood, but are thought to involve epigenetic factors in the stem cells used for the transplant (Christopher et al, 2018). In addition, any type of stem cell transplant may cause aging of the tissue as measured in T-cells using a p16 biomarker (Wood et al, 2016), indicating the increased level of cellular senescence in the surrounding tissue.

So what are some of the possible mechanisms for stem cells to cause these untoward and unpropitious side effects? First, a new study shows that transplanted stem cells (HSPCS) can survive a long time in human patients, such that they can be maintained independently of their continuous production from endogenous HSPCs (Scala et al, 2018). Second, we know that processed stem cells can carry an increasing number of genetic mutations as they are expanded, particularly the p53 mutation associated with many cancer phenotypes (Merkle et al, 2017). And, as I discussed in a previous blog, stem cells have memory, and change their phenotype, for at least many months, when they have experienced a wounding, inflammatory event (Naik et al, 2017). The new phenotype that Naik et al (2017) measured was one of an increased probability to proliferate, a cancer-like cellular behavior. An underlying mechanism for the increased probability of proliferation appeared to be epigenetic, where the DNA was less tightly bound around its histone protein. If we synthesize these data, stem cell transplants using cells that have genotypic, epigenotypic, and phenotypic changes conducive to proliferation, and given the cells ability to engraft, survive, and remain viable for long periods, means that the cells may be a cause of cancer. Coupled with the possible induction of aging in the surrounding tissue (Wood et al, 2016), another risk factor for cancer, stem cell transplants pose a significant risk for cancer, as well as other problems (Maguire, 2016). As such, the problems with stem cell transplants means they should only be used in life threatening conditions, or where their benefits clearly outweigh the risks. The problems with stem cell transplants also leads to the argument for the use of a “systems therapeutic” using stem cell released molecules (Maguire, 2014), instead of the cells (Maguire, 2013), for many indications, such as amytrophic lateral sclerosis and other neurodegenerative diseases (Maguire, 2018).

These issues will be further explored in my second book to be published in 2019.

References

Christopher MJ et al (2018) Immune Escape of Relapsed AML Cells after Allogeneic Transplantation. N. Eng. J. Med, DOI: 10.1056/NEJMoa1808777

Cooley LD et al (2000) Donor cell leukemia: report of a case occurring 11 years after allogeneic bone marrow transplantation and review of the literature. Am.J. Hematol. 63(1):46-53.

Diouhy BJ et al (2014) Autograft-derived spinal cord mass following olfactory mucosal cell transplantation in a spinal cord injury patient. J.  Neurosurgery,  DOI: https://doi.org/10.3171/2014.5.SPINE13992

Kumar S and Nash DB (2011) Health Care Myth Busters: Is There a High Degree of Scientific Certainty in Modern Medicine? Scientific American, March 25, 2011.

Maguire G (2013) Stem cell therapy without the cells. Commun Integr Biol. 6(6):e26631

Maguire G (2014) Systems biology approach to developing “systems therapeutics”. ACS Med. Chem. Lett. 5(5): 453–455

Maguire G (2016) Therapeutics from Adult Stem Cells and the Hype Curve. ACS Med. Che. Lett. 7(5):441-3

Maguire G (2018) Adult Stem Cell Released Molecules: A Paradigm Shift to Systems Therapeutics. Nova Science Publishers, New York.

Merkle FT et al (2017) Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations. Nature 545: 229–233

Naik S et al (2017) Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature 550: 475–480

ProCon (2014) 35 FDA-Approved Prescription Drugs Later Pulled from the Market. ProCon, Jan 30, 2014.

Scala S et al (2018) Dynamics of genetically engineered hematopoietic stem and progenitor cells after autologous transplantation in humans. Nature Medicine 24:1683–1690

Wood WA et al (2016) Chemotherapy and Stem Cell Transplantation Increase p16INK4aExpression, a Biomarker of T-cell Aging. EBioMedicine, 11: 227–238

Adult Stem Cells Have Memory

Why Previously Injured Skin Heals Faster Than Normal

Tissues in our body contain small niches of quiescent adult stem cells that can, upon demand, multiply and differentiate into myriad somatic cell types as required and dictated by environmental demands. In the skin, stem cells can divide and transform into cell types that produce, for example, collagens, pigment, and keratin. Stem cells in the skin also create a secretome that includes signaling molecules and matrix proteins, used for many purposes including to help build the skin’s thick extracellular matrix. Serving as cellular factories for other cell types and a vast array of secreted molecules, the multiple stem cell types in the skin now appear to have another function as recently demonstrated in a collaboration between the laboratories of Dr. Shruti Naik, Ph.D. and Dr. Elaine Fuchs, Ph.D., both of whom are professors at The Rockefeller University (Naik et al, 2017).  Drs. Naik and Fuchs showed that if patches of skin in mice were wounded, causing inflammation, then allowed to heal, subsequent wounds in the same patch of skin would heal about 2.5 times more quickly than adjacent, previously unwounded skin. The effect in previously wounded skin could last up to six months given the conditions of the experiment. This functional adaptation was attributed to epithelial stem cells (EpSCs) and did not require an immune response because skin-resident macrophages and T cells were not involved. What the study showed was that EpSCs maintain chromosomal accessibility, where the DNA is less tightly packed and open to signals from the damaged tissue, at key stress response genes, activated by the inflammatory stimulus. This epigenetic change in the chromatin allowed, during a secondary inflammtory challenge to the same skin patch, genes in that patch of skin to be transcribed rapidly. While the secretome of skin stem cells has previously been shown to be altered by wounding, the exact nature of changes in the secretome was not reported in this study. However, underlying the memory of the stem cells in this study is Aim2, a portion of DNA that encodes an activator of the inflammasome, a conglomerate of proteins that contributes to the skin’s defence against bacteria and viruses. Although having the stem cells remember a wounding event so that future wounds may be more easily healed, like many things in biology where there can be positive effects coupled with potential negative consequences, the epigenetic memory in stem cells may lead to negative cellular behavior, namely overproliferation.  Tumors have often been described as wounds that do not heal.  As Dr. Mina Bissell, Ph.D. at UC Berkeley has taught us, normal tissue homeostasis and architecture inhibit progression of cancer, whereas changes in the microenvironment, such as continuous wounding, can shift the balance of these signals to the procancerous state (Bissell and Hines, 2011). Thus, the constant wounding may change the microenvironment in such a way as to epigenetically shift the stem cells into a very procancerous state, something they remember for a long period of time. An emerging area of research is quickly expanding as scientists continue to explore stem cell memory, and the field of immune-stem cell interactions, and stem cells as a part of the immune system. More about that later.

References

Bissell MJ and Hines WC (2011) Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nature Medicine,17:320-329.

Naik S et al (2017) Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature 550:475–480

 

Check Point Inhibitors for Cancer Delivered by Haematopoietic Stem Cells

Dr. James Allison’s Nobel Prize Winning Technology Delivered by Stem Cells

Scientists at UCLA reported this week in Nature Biomedical Engineering that they had constructed a stem cell conjugated to a platelet that had been decorated with anti-PD-1 antibodies. James Allison, Ph.D. developed “checkpoint inhibitors” while a professor at Berkeley beginning in the 1990s, for which he was awarded the 2018 Nobel Prize in Physiology or Medicine. Basically, this “checkpoint inhibitor” technology blocks the tumor cells from rendering T-cells ineffective, thus allowing a renormalization of the immune system to once again attack the tumor cells.

The UCLA scientist have now have used those inhibitors, anti-PD-1 antibodies, coupled to a stem cell using conjugation of a platelet loaded with the anti-PD-1 antibodies, to deliver the antibody to the bone marrow. In this manner, stem cell homing of haematopoietic stem cells to bone marrow serves as a targeting and delivery device for the checkpoint inhibitors. This cellular combination-mediated drug delivery strategy was shown to significantly augment the therapeutic efficacy of checkpoint blockade in a mouse model. This is the sort of out-of-the-box stem cell research that should be supported by agencies such as CIRM, but was, instead, supported by the Sloan Foundation, UCLA, UNC and NCSU, and the National Science Foundation of China.

Reference

Hu Q et al (2018) Conjugation of haematopoietic stem cells and platelets decorated with anti-PD-1 antibodies augments anti-leukaemia efficacy. Nature Biomedical Engineering, https://doi.org/10.6084/m9.figshare.7033481