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Human β-cell Precursors Mature Into Functional Insulin-producing Cells in and Immunoisolation Device: Implication for Diabetes Cell Therapies (Transplantation 87:983 (2009))
Ihave chosen to comment on this paper because it has good science and has attracted notice.
Unfortunately, however, it is difficult to see how this work could ever be construed to bring us any nearer at all to a cure.
“This study was designed to test the hypothesis that macroencapsulated human β-cell precursors transplanted into severe combined immunodeficiency (SCID) mice can survive and mature into functional β-cells in vivo.” Here is what these researchers at Burnham Institute in San Diego did. From human fetal pancreases they isolated islet-like cells clusters (ICCs), immature proto-islets. These ICCs were placed in a Theracyte macrocapsule (see figure below) and implanted under the skin of SCID (immune incompetent) mice. The SCID mice were made diabetic with the islet-killing drug alloxan. Similarly, neonatal mouse islets and adult human islets were put into Theracyte devices and implanted under the skin of NOD mice, a strain that becomes diabetic without drugs. The mice were studied in various ways including glucose, insulin and c-peptide, and microscopic examination of recovered tissues. Among the observations reported: The encapsulated human ICCs reduced, but did not normalize, blood sugar in SCID-alloxan mice. In NOD mice, the encapsulated ICCs delayed the onset of diabetes by about a month (Figure 5I in PDF), however nondiabetic blood sugar was defined as 300 mg/dl (I would call that a diabetic blood sugar!). In NOD mice encapsulated adult human islets did not normalize blood sugar.
What did they discover? Let’s consider their two final conclusions.
“Taken together, our data suggest that long-term protection of human β-cell cells in type 1 diabetic patients without immunosuppression is a realistic goal.”
The authors imply that implantation of Theracyte devices containing islets is a practical human cure (‘in type 1 diabetic patients’). How realistic is that? They estimate that an average of 216 adult human islets were placed in the Theracyte device (or only 70 human ICCs or 94 mouse ICCs). In standard human islet transplantation 5,000 to 10,000 islets are needed per kilogram of patient weight. For a 70-kg diabetic the number of Theracyte devices needed to achieve euglycemia without injected insulin is therefore at least 1,600. Each device is 2cm long; implanting 1,620 under the skin is obviously a practical impossibility.
Furthermore, scores of therapies prevent or cure diabetes in NOD mice, yet have never been shown to work in human beings. Mouse and man are very different metabolically (see my essay on this topic). A partial success in mice does not justify a claim about potential performance ‘in type 1 diabetic patients.’
And it is worth mentioning that the Theracyte device is old and very well studied. The company was founded in 1999 when it was spun out of Baxter (where the technology was invented). In the diagram found in my essay History of Diabetes Research you see the Baxter effort started in the 1980’s, a member of the large family of macrodevices developed by the companies shown in blue in the figure. The Baxter/Theracyte macrocapsule was studied in large animals at Neocrin in the 1990’s at great expense. The only published long term large animal studies use insulinoma cells, not primary islets; insulinomas are the cancerous form of β-cells. Implants of devices with parathyroid cells in humans show cell death and device fibrosis after a few weeks. In short, after years of study the Theracyte device has never been shown to work in a large mammal.
The length of time that the authors consider to be ‘long term’ in ‘long-term protection’ is not stated. Their longest result is five months. However, many islet encapsulation researchers have reported protection without immune suppression, in some cases for years. Some of these reports go back to the 1980’s. So we have known that this is a realistic goal for a long time. And it is unclear why five months in mice (and only 5 days of 200 mg/dl blood glucose; see Figure 2D in PDF) adds anything.
I believe that long-term protection without immunosuppression is realistic was not proven by their data, and in fact had been demonstrated by others decades ago.
“Further, encapsulation of β-cells precursers may be an ideal approach to enhance the success of β-cell replacement therapies.”
Having established that the β-cells precursors survive and multiply during several months in the Theracyte device, the authors suggest that this expansion can be exploited to enhance therapeutic success. It is difficult to imagine how this might work in the real world. As we have already seen, Theracyte devices cannot provide a functional cure of the disease. Are the authors suggesting that Theracyte devices in mice be used as incubators to expand β-cells precursors? In addition to the expense and complexity of such a scheme, it is difficult to imagine regulatory approval of mass animal islet culture. Alternatively, perhaps they envision allowing the cells to grow cancerously within the device after implantation into the human patient.
To the academic mind, taking a twenty-five year old device, already shown impractical, and introducing fetal cells, then publishing that such cells multiply more than adult islets, is sufficient. It is indeed an interesting piece of incremental knowledge of fetal islet behavior. And the histology is elegant and pretty. But it has no utility at all in the real world and gets us no closer to the cure. This type of work underscores the difference between academic research aimed at generating data for publication to add to the general fund, compared with the more product oriented research practised at companies like Cerco Medical (& LCT and others), which cannot satisfy their shareholders for long with a string of scientific papers.
Who paid for this research and why? On the JDRF web site the Director of Islet Replacement is quoted, “‘This approach may be an important step in our ability to translate the transplantation of human embryonic stem cell-derived progenitors into clinical testing,’ said Julia Greenstein, Ph.D.”
No Julia, it won’t. This is another waste of JDRF money. These JDRF funds were contributed by people expecting it to be used for finding the cure.
This reminds me of problems encountered during the research leading to the development of the atomic bomb. The most talented scientist in the research group, Dr. Edward Teller, refused to work on the atomic bomb — the only device which could be developed in time to help the war effort — because he did not find it as interesting as the more intellectually elegant problem of developing a hydrogen bomb. Only with someone like General Grove to discipline and focus the research efforts of many different scientists was progress possible.
But when you combine the impractical curiosity of research scientists with the artificial demand for scientific publications created by the ‘publish or perish’ practise in academia, with the need of junior researchers to earn a doctoral degree by getting at least something published of whatever quality, with the eagerness of corporations to pacify investors with apparent progress, and with the willingness of charitable funds to misspend their money to generate any results which will placate scientifically naive donors, you produce the present toxic mix that kills medical progress.