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FDA Testing Artificial Liver
NIckGorton writes "Research is now underway in the US to seek FDA approval for an artificial liver. The Extracorporeal Liver Assist Device (ELAD) filters blood through a cartridge containing immortalized human liver cells with fiber tubes running through that allow the patients blood to interact with them. This allows the matrix of liver cells to perform both the metabolic (cleansing the blood of toxins/waste) and synthetic (producing albumin, clotting factors, etc) functions of the patient's failing liver. A small trial in China showed a statistically and clinically significant difference in 30 day survival with ELAD."
Obligatory: http://www.youtube.com/watch?v=aclS1pGHp8o
"Don't worry, there's nobody who's had their Liver taken out by Us who's survived."
I was feeling more like fava beans, and maybe a nice chianti.
Sorry, teleporters just kill you and then make a copy. A perfect, soul-less copy.
I'll drink to that!
A small trial in China showed a statistically and clinically significant difference in 30 day survival with ELAD.
So more people with this ELAD liver replacement were alive at 30 days than a control group, who presumably had their livers removed and replaced with nothing...
Ultimately, as we understand more, i believe the mechanisms of cancer will be more harnessed than eliminated.
That which does not kill us makes us... st
There's no information about the interface of this device to the patient. Blood flow to the liver is rather unique (http://biology.about.com/library/organs/bldigestliver.htm), with 3/4 of its bloodflow coming from the portal vein and 1/4 from the hepatic artery. The blood mixes before being processed by the liver.
Is the device similarly fed by both arterial and venous sources? How is the pressure compensated? Where is the output reintroduced? Does the device run in parallel to the natural liver or in series? If the latter, which receives the blood first? Does it attempt to handle any of the other numerous functions of the liver such as the creation of bile or lymph?
I think I'd just ask if they could immortalize all of my body's cells.
Some background on why an artificial liver is a really big deal, and why it has been really hard until now to produce one:
(Any doctors or biologists more knowledgeable can fill in the gaps and correct me)
The liver breaks down toxins in the blood by metabolizing them. That is, they get broken down into simpler compounds by chemical reactions that take place in and around living cells. Contrast this with dialysis - an artificial kidney - which is able to work by filtering out chemicals based on molecular weight. Dialysis uses bundles of membranes that allow relatively light molecules (such as water) to pass through, but block heavier ones. The stuff the liver breaks down are too unwieldy or complex to be filtered out based just on weight - there are lots of other, good things in the blood that are of similar weight or complexity. A simple filter can't distinguish them; hepatocytes (liver cell clusters) can.
The task of creating the filtering membrane of a dialysis machine is a relatively well understood materials and processing problem. An artificial liver, which usually has a mini dialysis unit on the front or back end, also requires you to have living clusters of cells, and keep them alive, nourished, and healthy long enough for them to do some effective and therapeutic blood filtering. That's a much trickier biological problem, and we are only now getting decent at it.
The uses for a bio-artificial liver is huge. It can help people with chronic liver failure live longer and healthier lives, true, but it has more uses than that. The liver, as it turns out, is one of the few organs that can regenerate itself. If it is damaged by disease or some toxic insult, it is possible for it to repair itself if given the chance (in normally healthy people - the liver can also be damaged beyond repair). The problem is that in lots of cases the patient will die before the liver gets a chance to heal, leaving two options: hope for a liver transplant on really short notice, or die. A device like this can be a bridge to transplant or, in some cases, take the burden off the liver long enough for it to heal itself.
Cell immortality is orthogonal to the abnormal replication present in cancerous cells. There are lots of cells in your body which are effectively immortal but do not undergo abnormal replication, and are therefore not cancerous. [Obvious examples are your spermatogonia and progenitor cells in your bone marrow.]
As far as immune cells go, so long as you've avoided including proliferative immune cells, you should be free from graft vs host issues. Growing the hepatocytes from cell lines that have been sorted pretty much guarantees this.
http://www.donarmstrong.com
Sure, but they don't have to be. (Car analogy: Ferrari's are often red, but they don't have to be.)
Not really. What you're talking about is a hybridoma, which is generally used in the formation of monoclonal antibodies. As far as what method is actually used to produce the line, it really depends on what you want a cell line for. (Cell lines are immortal by definition, by the way; they don't get immortalized.)
Most common cell lines are actually just isolated from various kinds of tumors, though.
http://www.donarmstrong.com
Side effects may include nausea, dizziness, dry mouth, and the tendency to transform into a zombie when exposed to the light of the full moon.
"You're right," Fisheye says. "I should have set it on 'whip' or 'chop.'"
It should be noted that the liver cells used in this device are most certainly cancer cells- the HepG2/C3A line was originally grown from a hepatocellular carcinoma cell taken out of a 15-year old boy. You can buy some here in fact.
Use of these cancer cells in an artificial liver does create the risk of transfer to the patient, but the cells in question will be suspended in a collagen matrix, and is kept separate from the blood by a dialysis-type semipermeable membrane. Contracting cancer from this device requires that the dialysis membrane fail, that cancer cells get out of the collagen and into the filtrate, that the cancer cells are not caught by the dual membrane cell filter, and that once in the body, a cancer cell from a line noted for low tumorigenic potential implants somewhere and begins to form a tumor. Not impossible, but it is unlikely.
"FDA staff reviewers expressed concern about the number of patients who were left out of the study because they died."
"we didn't want to worry about medical ethics"
http://twitter.com/OLDTELEGRAM
Also very important to note is that anyone who is getting this treatment is going to be seriously ill to begin with, and without it will be dying. I'm sure that they'll consider a chance of getting cancer is a small price to pay.
See also the comments above by rlseaman - this will address those as well.
The liver has multiple functions for both biochemical synthesis and detoxification. Unlike most organs and tissues, it has two circulatory inflows. The arterial circulation is the nutritive blood supply, just as the arterial circulation for any tissue. A portal circulation is one in which the venous effluent from a tissue does not return directly to the systemic circulation, but instead detours through another organ first. There are two portal circulations in most chordates - the hypothalamic-pituitary circulation, and the splanchnic portal system. The purpose of the splanchnic portal is to take raw digestate absorbed from the gut, and pass it through a chemical filter (the liver) which will detoxify or eliminate nasty exogenous compounds before they get back into the general circulation (via the hepatic veins). The hepatic artery supplies the liver; the portal vein is the business of the liver. Detoxified products that must be eliminated from the body are excreted into the bile, which is eliminated through the gut. Without a liver at all, death will occur within just a few days, about 3-7.
Renal failure is also lethal, but in the early 1950's, technologies were developed to keep renal failure patients alive - the dialysis machine. Dialysis is used as a bridge to organ transplantation, but for many people it is their permanent replacement kidney. It is an extraordinarily effective device. It could be "perfected" "back then" because the dialysis machine and the kidney are both relatively simple machines when it comes the elimination / detoxification aspects of its function. It depends simply on diffusion across semi-permeable membranes so that chemical concentrations can be equilibrated. No cells nor other active function is needed.
Compare this to heart function. We can transplant hearts quite successfully, but unlike the kidney, we cannot keep people alive without their native heart. Attempts in the past 10-20 years to develop mechanical bridge devices have all been technical, medical, and ethical failures, awaiting some future technologies to make the concept truly feasible.
The liver is in between. With regard to basic medical and ethical issues, an artificial liver should be comparable to the kidney. But technically and scientifically, making an artificial liver has been impossible until recently. Unlike the kidney, emulating liver function cannot be done by simple passive dialysis - the liver has MANY active chemical processes that must be actively metabolized. Attempts to run a patient's blood through a pig liver was the best available technology, and it doesn't work well at all, certainly not long term. What these researchers have done in this article is to mate living human cells to a dialysis device.
From the company's description of the product, it sounds like a fairly standard dialysis cartridge to start with. The key element, something that was NOT technically possible until the biotech revolution that we are now going through, is to put living cells in the device. I presume that the dialysis membranes are much more "porous" than renal dialysis membranes, allowing bigger molecules to get across, but hepatocytes remain sequestered on their side - there is no chance of "mixing and migration". All modern biotech "living cell" products go through ELABORATE testing and purification to get clean single cell lines. "Immortalized" means they have had their genome switched on so that they can mitose and replicate ad infinitum, without reaching the natural limits of mitosis that many differentiated cell lines have. Bile ducts, portal veins, and all that are not needed, because wastes come in through your normal arterio-venous dialysis shunt, and go out in the dialysis effluent. Because the device is not directly siphoning splanchnic blood, the clearance of potential dietary "toxins" is slower, but any patient with advanced liver disease has to make certain dietary adjustments anyway.