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This month, it was reported that scientists at Harvard University have successfully made insulin-secreting beta cells from human pluripotent stem cells. This is an important milestone towards a “stem cell therapy” for diabetes, which will have huge effects on human medicine.

Diabetes is a group of diseases in which the blood glucose is too high. In type 1 diabetes, the patients have an autoimmune disease that causes destruction of their insulin-producing cells (the beta cells of the pancreas). Insulin is the hormone that enables glucose to enter the cells of the tissues and in its absence the glucose remains in the blood and cannot be used. In type 2 diabetes the beta cells are usually somewhat defective and cannot adapt to the increased demand often associated with age and/or obesity. Despite the availability of insulin for treating diabetes since the 1920s, the disease is still a huge problem. If the level of blood glucose is not perfectly controlled it will cause damage to blood vessels and this eventually leads to various unpleasant complications including heart failure, stroke, kidney failure, blindness, and gangrene of limbs. Apart from the considerable suffering of the affected patients, the costs of dealing with diabetes is a huge financial burden for all health services. The prevalence of type 2 diabetes in particular is rising in most parts of the world and the number of patients is now counted in the hundreds of millions.

To get perfect control of blood glucose, insulin injections will never be quite good enough. The beta cells of the pancreas are specialised to secrete exactly the correct amount of insulin depending on the level of glucose they detect in the blood. At present the only sources of beta cells for transplantation are the pancreases taken from deceased organ donors. However this has enabled a clinical procedure to the introduced called “islet transplantation”. Here, the pancreatic islets (which contain the beta cells) are isolated from one or more donor pancreases and are infused into the liver of the diabetic patient. The liver has a similar blood supply to the pancreas and the procedure to infuse the cells is surgically very simple. The experience of islet transplants has shown that the technique can cure diabetes, at least in the short term. But there are three problems. Firstly the grafts tend to lose activity over a few years and eventually the patients are back on injected insulin. Secondly the grafts require permanent immunosuppression with drugs to avoid rejection by the host, and this can lead to problems. Thirdly, and most importantly, the supply of donor pancreases is very limited and only a tiny fraction of what is really needed.

This background may explain why the production of human beta cells has been a principal objective of stem cell research for many years. If unlimited numbers of beta cells could be produced from somewhere then at least the problem of supply would be solved and transplants could be made available for many more people. Although there are other potential sources, most effort has gone into making beta cells from human pluripotent stem cells (hPSC). These resemble cells of the early embryo: they can be grown without limit in culture, and they can differentiate into most of the cell types found in the body. hPSC comprise embryonic stem cells, made by culturing cells directly from early human embryos; and also “induced pluripotent stem cells” (iPSC), made by introducing selected genes into other cell types to reprogram them to an embryonic state. The procedures for making hPSC into beta cells have been designed based on the knowledge obtained by developmental biologists about how the pancreas and the beta cells arise during normal development of the embryo. This has shown that there are several stages of cell commitment, each controlled by different extracellular signal substances. Mimicking this series of events in culture should, theoretically, yield beta cells in the dish. In reality some art as well as science is required to create useful differentiation protocols. Many labs have been involved in this work but until now the best protocols could only generate immature beta cells, which have a low insulin content and do not secrete insulin when exposed to glucose. The new study has developed a protocol yielding fully functional mature beta cells which have the same insulin content as normal beta cells and which secrete insulin in response to glucose in the same way. These are the critical properties that have so far eluded researchers in this area and are essential for the cells to be useful for transplantation. Also, unlike most previous procedures, the new Harvard method grows the cells as clumps in suspension, which means that it is capable of producing the large number of cells required for human transplants.

These cells can cure diabetes in diabetic mice, but when will they be tried in humans? This will depend on the Food and Drug Administration (FDA) of the USA. The FDA has so far been very cautious about stem cell therapies because they do not want to see cells implanted that will grow without control and become cancerous. One thing they will insist on is extremely good evidence that there are absolutely none of the original pluripotent cells left in the transplant, as they would probably develop into tumours. This highlights the fact that the treatment is not really “stem cell therapy” at all, it is actually “differentiated cell therapy” where the transplanted cells are made from stem cells instead of coming from organ donors. The FDA will also much prefer a delivery method which will enable the cells to be removed, something which is not the case with current islet transplants. One much discussed possibility is “encapsulation” whereby the cells are enclosed in a semipermeable membrane that can let nutrients in and insulin out but will not allow cells to escape. This might also enable the use of immunosuppressive drugs to be avoided, as encapsulation is also intended to provide a barrier against the immune cells of the host.

Stem cell therapy has been hyped for years but with the exception of the long established bone marrow transplant it has not yet delivered. An effective implant which is easy to insert and easy to replace would certainly revolutionize the treatment of diabetes, and given the importance of diabetes worldwide, this in itself can be expected to revolutionize healthcare.

Featured image credit: A colony of embryonic stem cell. Public Domain via Wikimedia Commons

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Every month OUP editor and author Jonathan Crowe answers your science questions in the monthly SciWhys column. Got a burning question about science that you’d like answered? Just email it to us, and Jonathan will answer what he can.

Today: how do organisms develop?

By Jonathan Crowe

Each of our bodies is a mass of cells of varying types — from the brain cells that give us the power of thought, to the cardiac cells that form our heart and keep our blood circulating; from the lung cells that take in oxygen from the air around us, to the skin cells that envelop the organs and tissues that lie within. Regardless of their ultimate function, however, each of these cells has come from a single source — the fertilised egg. But how can the complexity and intricacy of a fully-functioning organism stem from such humble beginnings?

At heart, the growth of any organism relies on the repeated growth and division of cells. A cell grows, then splits into two. Each of those cells grows, then splits into two… and so the cycle continues. Before long, we’ve gone from having one cell to two, from two to four, and then to eight, to sixteen, etc. In fact, after ten ‘cycles’ we already have over 1000 cells. (We still have some way to go to generate the millions of cells that form an embryo, but you get the idea.)

Initially, the egg divides to from a hollow ball of cells. However, living creatures aren’t hollow. Instead, they have a clear inside and outside, with the inside usually comprising some kind of gut, which passes the length of the body, from mouth to anus. So how do we go from a hollow ball to something with a clear internal structure? Well, imagine holding a sponge ball between the fingers of two hands, and then pushing in the bottom of the ball with your thumbs. The bottom of the ball folds up and in, almost forming a ‘tunnel’ into the ball. Our hollow ball of cells does the same thing: the cells at the bottom of the hollow ball move up and inside to form a tunnel. These cells will go on to form the digestive tract, which (as our experience tells us) runs right through the inside of our bodies.

Shortly after, a strip of cells along the back of the ball of cells roll up to form a furrow. The cells forming this furrow will go on to form the nervous system, with the furrow itself becoming our spinal cord. And, again, this fits with our experience: our spinal cord does indeed run up and along our back.

The previous paragraphs reveal an important feature of the development of a living organism. It’s not just a question of having lots of cells: to have a fully-functioning organism, we need different cells to do different things – to have different functions. After all, our bodies would be quite useless (not to mention odd-looking) if we were composed entirely of lung cells. Instead, as a population of cells grows, it also clusters into groups with common functions, forming different tissues and different organs.

So how does a cell know what kind of cell it should become? At the simplest level, it depends on the cell’s location – its position in the embryo. But how can cells tell where they are? Do they have some kind of cellular GPS system? Actually, in a way they do. Just as the GPS feature of a mobile phone can tell us our location by picking up a signal from a satellite, cells can also receive signals from their surroundings, which vary according to their location. And, because cells at different positions in the embryo — top or bottom, front or back, left or right — receive different signals, they behave in different ways.

Our everyday experience tells us that our behaviour is modified by signals in the world around us – the most obvious example being the traffic lights that tell us when to stop or go when driving. In a cellular world,

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By Dr Sesh Kamal Sunkara

In vitro fertilization (IVF) involves the retrieval of an egg and fertilization with sperm in the laboratory (in vitro) as opposed to the process happening within the human body (in vivo), with a natural conception. IVF was first introduced to overcome tubal factor infertility but has since been used to alleviate all types of infertility and nearly four million babies have been born worldwide as a result of assisted reproductive technology.

The birth of Louise Brown in 1978, the world’s first IVF baby was from a natural menstrual cycle without the use of any stimulation drugs. As success rates were low with natural cycles in the early days of IVF, ovarian stimulation regimens were introduced into IVF to maximize success rates. The aim was to retrieve more eggs to overcome the attrition in numbers at fertilization, cleavage, and implantation. However, with the introduction of ovarian stimulation regimens the complication of ovarian hyperstimulation syndrome (OHSS) arose.

There have been several discussions among IVF clinicians on what the ideal number of eggs should be to optimize IVF outcome and minimize risk of OHSS. We analysed a large database of over 400, 000 cycles provided by the Human Fertilisation and Embryology Authority (HFEA) in order to establish the association between egg number and live birth rate in IVF.

We found that live birth rate increased with increasing number of eggs retrieved up to 15 eggs and plateaued from 15 to 20 eggs with a decline in live birth rate beyond 20. The analysis of the data suggested that around 15 eggs may be the optimal number to aim for in a fresh IVF cycle in order to maximize treatment success whilst minimizing the risk of OHSS. We also established a nomogram which is the first of its kind that allows prediction of live birth for a given egg number and female age group. This is potentially valuable for patients and clinicians in planning IVF treatment protocols and counselling regarding the prognosis for a live birth occurrence, especially in women with either predicted or a previous poor ovarian response.

The full paper and supplementary data has been made publicly available here, as published in Human Reproduction by Sesh Kamal Sunkara, Vivian Rittenberg, Nick Raine-Fenning, Siladitya Bhattacharya, Javier Zamora and Arri Coomarasamy. Above table appears with full permission from Human Reproduction and Oxford Journals.

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By Frederick Grinnell

On August 23, 2010, the United States District Court for the District of Columbia granted a preliminary injunction blocking NIH-funded research on human embryonic stem cells (hESC). According to Judge Lamberth’s ruling, NIH-funded research on hESC violates the Dickey-Wicker Amendment, originally passed by Congress in 1996, which prohibits use of federal funds for research in which human embryos are destroyed. The judge rejected the federal government’s claim that hESC research comes in separate pieces, i.e., human embryo destruction in the private domain on one hand vs. investigation of hESC by NIH-funded investigators on the other. Instead, he cited the holistic language of the Dickey-Wicker Amendment and the Random House Dictionary to conclude that the common definition of research includes development, testing and evaluation. According to Judge Lamberth’s ruling, destruction of human embryos and research on stem cells derived from human embryos are part of the same piece.

Destruction of human embryos occurs in the context of diverse research purposes. Some researchers aim to develop hESC-based therapeutic applications. However, others propose to improve the outcome of in vitro fertilization (IVF) procedures or to learn about early embryo development and disease progression. Currently, funding for research in which destruction of human embryos occurs is provided by non-Federal sources ranging from IVF clinics to biotechnology companies to state-sponsored biotechnology initiatives. Some of the research involving human embryo destruction has resulted in production of hESC lines. Some of the hESC lines that have been produced have been authorized to be used in NIH‑funded research, at least until the recent court order. Therefore, while one cannot deny that NIH-sponsored hESC research would be impossible without destruction of human embryos, destruction of human embryos is a research activity whose scope is much broader than and independent from the NIH‑funded work. From the point of view of research practice, the relationship between embryo destruction and hESC research is indirect.

In response to the judge’s preliminary injunction, the federal government has filed an appeal. The appeal challenges the judge’s understanding of the Dickey-Wicker Amendment regarding what constitutes the meaning of “research.” The appeal also challenges the judge’s conclusion that his decision would not seriously harm hESC researchers. On the contrary, if left in place, the injunction will have a potentially catastrophic effect because of its total disruption of NIH intramural and extramural hESC research.

One implication of Judge Lamberth’s ruling that has not been discussed but is of potential concern is whether the injunction against NIH-funding of hESC research might also apply to the FDA. The Dickey-Wicker Amendment concerns all of HHS not just the NIH. FDA is another major HHS agency that plays a role in hESC research. FDA develops guidelines and provides oversight for human clinical trials, including those involving hESC. As mentioned in the government’s appeal of the preliminary injunction, the FDA recently approved the enrollment of spinal cord injury patients in the first ever U.S. clinical trial of a hESC-based therapy. User fees from industry cover about half the costs of FDA drug review, but the remainder comes from federal f