Pharmaceuticals From Breast Milk
Posted February 27, 2010
Creating New Medications Based on Human Breast Milk Components
Previously, I've written about the possibility of making therapeutics directly from donor breastmilk, such as Prolacta's HMF (the need for HMF has been discussed in the comments of another post about Prolacta). But what about individual breast milk components being recreated in a lab for use in medicinal products? In my first post on this topic I focused on the irreproducibility of breast milk, but what about the individual components that are reproducible - the ones that can be made in a lab?
This topic, though related to the question of how breast milk might be used by those who collect it (in this case, for research), spreads out into questions about biological patents and intellectual property (IP). True to being a bench scientist, I know little about patents, IP, business, money, etc. That's how they get us to work as postdocs to work for almost nothing.
What I do know is that if a biomolecule like the antimicrobial lactoferrin can be identified and characterized through the study of breast milk and used to prevent illness, I'm in (lactoferrin was brought up in a comment). If what we can learn from breast milk increases our understanding of human biology and allows us to develop effective medications and therapeutics, I support that.
Creating medicines based on the intricate, elegant molecules made by living organisms (as opposed to the relying on the random luck of screens or using sledgehammer drugs with global affects on the body) is tricky work. It's something we have been struggling to do this century because it is finally becoming possible through the sequencing of DNA (genomics) and study of it's gene products (proteomics).
As we move forward, we will be able to create more effective medications with fewer side effects than traditional drugs. Stories like this one about the drug PLX4032, which was created through research and understanding of the biomolecule B-RAF, show how the process works. Medications created like this are the future of treating cancer, cardiovascular disease, altzheimers, autism, HIV and other ailments that lead to human suffering.
If biomolecules discovered in human breast milk (and made in a lab) can be part of that and lead to therapies that improve outcomes for babies in the NICU or even adult patients suffering from something totally unrelated, I think that's great.
What inspires individuals and organizations to do the kind of difficult, expensive research it takes to develop these medications? Three things, really: a desire to help people, a desire for academic prestige and glory, and a desire for money. The individuals tend to focus on helping people and getting glory while the larger, more powerful organizations tend to focus on the money.
The current system for rewarding successful research with money is through patents. Patents allow those who generate new, useful ideas and information to limit anyone else from using them to make money for some period of time. Patents, especially biological patents can get very complicated in how they are issued and legally enforced. Of course, there's lots of controversy and deviousness that goes on around patents, like anything else that involves a lot of money. Valerie McClain, who has commented here, addresses more issues related to this in her blog. Incidentally, the academic glory reward system isn't perfect either, so to be a happy scientist you really have to work on something you believe will contribute to the common good.
In another life, I walked straight from the Cornell Chemistry Department over to the Law School the day after getting my Master's and became a patent lawyer instead of a PhD. In that life, I make way more money than I do now and know all about biological patents. As it is, I know only the basics, but I can still see that there are flaws in the system. Maybe we will find a better system someday. For now, we have patents, and to get them big companies spend about a billion dollars each bringing medications to market.
If some of those medications are designed based on therapeutic components of breast milk and created and delivered to the people who need them (a big "if" in the current US healthcare system), that's a good thing. However clumsily, we will have used our ingenuity to alleviate human suffering and to help or even (dare I say) cure the sick. That gives me hope, the only truly reliable reward for good biomedical research.
What About Formula?
Of course this all brings up another, much more breastfeeding-centric question: What about using this kind of research to make "better" formula? Is that a good thing or a bad thing? Although I don't see how any company could afford to use donor breast milk in the manufacture of formula, they could use what they learn from the research of breast milk to identify components (like DHA and ARA) that can be added to formula. Perhaps more important additives could be included to make formula a little less unhealthy. The question is, do we want unhealthy formula - to keep moms from seeing it as a suitable substitutre, or more healthy formula - to improve the health of those babies forced to drink it? What do you think?
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Pharm Woman Patent back in the year 1987
Heather,
You wrote about the "possibility" and the "if" of therapeutics from human milk. In 1987, three patent applications appeared in the USA, Europe, and Australian patent offices regarding making pharmaceuticals from human milk. Baylor College of Medicine of Texas was the assignee/owner. In Europe, the Green Party had the patent rejected because they were appalled by the concept. But in the US and Australia the patent applications became patents. The patent was on lactoferrin from human milk. This was the beginning of patenting human milk components for therapeutics. Although, there was a patent on HMEC (Human Milk Epithelial Cells) in 1980, a stem cell line used in research--given out freely to researchers by US government researcher Margaret Stampfer.
A company formed in Texas called Agennix that is now in either phase II or phase III (funded by US Government) on recombinant human lactoferrin to be used in wound treatment/diabetic foot ulcers. So this is not an "if" or a possibility, it is a done deal. Agennix has some 70 patents on recombinant human lactoferrin. This company has close ties to Baylor--in fact ex-president of Baylor is on board at Agennix--as well as a past FDA high-level employee. In Australia the company is called Agenix (one "n").
Human milk components can be made in a research lab by cell culture. But they are also made by transgenic cows and transgenic rice. Pharming in the Netherlands has patents on human lactoferrin made from what we call "cloned" cow's milk. (early 1990's). In the US cloned milk and meat are approved for use in the food industry. Ventria Bioscience uses rice to create human milk proteins. Green Peace has protested their fields in California and in other states. Human lactoferrin has been added to infant formula in Asia for quite some time. In fact the scandal of melamine in infant formula touched the company Fonterra in New Zealand (who has herds of transgenic cows) because their lactoferrin was contaminated.
Probiotics and prebiotics is used in supplements that is used as a therapeutic in hospitals. Antibiotics damage the gut of patients, and now it has become standard practice to give patients some form of probiotics to help these patients heal their intestines. Probiotics is often human milk components--sometimes the human milk sugars, sometimes the bacteria derived from the poop of the breastfed baby-cloned and part of the ATCC. The big guys own these patents--like Nestle.
DHA and ARA is whole different story. The basis for the belief that infant formula needs DHA and ARA was human milk research mostly funded by Mead Johnson, US Government, and Martek. Martek's DHA and ARA are fermented microbial oils with no relationship to human milk components. Martek was founded by scientists who were genetic engineers. This company was an offshoot of Martin Marietta's NASA space program. They deny these organisms are gmo.
I never included Martek's DHA and ARA oils in my count of human milk component patents (around 2000 patents and applications). I believe I was the first person to write about their patents back in 2000 or 2001 on Lactnet. It has been difficult to see that research plagarized by some organizations. Particularly, when one believes in what the organization is trying to do, but feels disheartened by the behavior of some people.
There are legal and ethical problems regarding patents that are not directly using human milk components (although some state that might be a possibility) but instead using the gene constructs of the components. The US FDA has continually stated that what is genetically engineered is identical to the natural component. This is an illusion, most scientists know that genetic engineering is not an exact science. Yet, by FDA ruling, we have gmo human milk components that are considered identical to the natural component. This can and will effect advertisments. How are we going to deal with the infant formula industry, when they can legally say that some part of their infant formula is identical to the human milk component? Want to be healthier? Take xyz, just like breastmilk. We are investing in a new science that essential changes the structure of DNA. The ramifications will impact human health and maybe our existence.
Genetic Engineering and Creating Medications
Hi Valerie,
My response got way too long, so I added some headers. Thanks for bringing up some important and interesting issues!
Important issues in the creation and distribution of medications
Thanks for all of this background into biological patents related to breast milk components. As noted in the post, there are certainly some suspicious things that go on around patents and biological patents are especially tricky. I linked to your site becuase I know you bring up a of lot the controversial issues that surround that process, and I thank you for bringing some of these up here as well. Any discussion of creating new medications to treat the sick, or any other significant scientific and technological advances, should acknowledge the financial interests that come into play as well as relevant ethical and legal questions.
Lactoferrin
I did intend to acknowledge that the process of creating therapeutics based on breast milk components, such as lactoferrin, is already underway. I think more such therapeutics are coming - not only based on breast milk components, but lots of other proteins, lipids, and molecules made by living organisms.
A complete rejection of drugs like lactoferrin?
Outside of the patent and disclosure questions, I am trying to ask whether we should object "whole-hog" to creating and using medications based on these molecules (certainly we have been doing that for some time already). Recombinant Lactoferrin is produced through expression of the lactoferrin gene in simple unicellular organisms, cultured cells, or (more rarely) plants or animals. If it's then used to prevent infection, treat wounds, or cure diabetic foot ulcers, I support that process. Of course, every situation needs to be evaluated individually, but I think the answer must always consider whether the medication can be used effectively to treat illness and abrogate human suffering.
Therapeutics made through genetic engineering and recombinant expression
I thank you for bringing up Lactoferrin and providing background on its manufacture since this is a great example of a large, complex biomolecule known primarily for its role in breast milk and used as medical treatment (even though it's also found in mucus, tears, and bile) . I can't think of any others like this yet, but maybe you know of some. I did see that Prolacta was looking at the viability of Immunoglobulin A from breast milk, though this would be an example of something pulled right out of breast milk (as discussed in the other posts) and not made elsewhere based on what's known about it and it's role in breast milk (as discussed in this post).
DHA, ARA, and probiotic bacterial strains
DHA and ARA are a little different - these simple, small molecules are not specific to breast milk (or even mammals). They are produced naturally by algae (DHA) and fungi (ARA), and don't require any genomic or proteomic information or techniques for their production. You also raised the good point that they are probably not that important as supplements for most people (who will get enough through diet), and as far as I know they are not used as medications. Probiotics, or helpful bacteria, may be easier to culture from baby poop or to feed with breast milk, but they are their own species and again, can be grown the old fashioned way, no genetic engineering necessary.
Genetic Engineering and Selective Breeding
So what about genetic engineering (clipping out and manipulating pieces of DNA) and recombinant purification (expressing DNA that will encode a desired protein or gene product in a living (though usually one-celled) organism)? Is it okay to manipulate DNA - either for research or for the production of useful biomolecules? It's certainly happening. Of course, selective breeding of domesticated animals and plants is a low-tech version of manipulating DNA and has basically allowed humans to develop "domesticated" species nothing like the ones we've crafted them from or that evolution intended (e.g., cows, pigs, dogs, chickens, corn, tomatoes, etc...).
The Limitations Imposed by Biology
Genetic engineering is different, of course, but still involves manipulating organisms into making what we want. Like selective breeding, it is also very limited by biology - only some biomolecules can actually be made this way. We will not be making any "Human-Animal Hybrids" (as evoked by George Bush) - no cows lumbering about with human heads growing out of their sides. This kind of thing is simply not allowed by biology (the animals would die or the added genes would be silenced and have no effect). One small change - the production of a single "foreign" biomolecule - will strain a biological system, and things like a centaur or a pig/goat hybrid (where a significant amount of DNA from each species is represented) are every bit as impossible through genetic engineering as they are through selective breeding. While the grafting of regenerative cells, a totally different process, may allow some things like the creepy ear-mouse we all remember, these processes and this mouse (which actaully had a synthetic mesh ear shape on it covered with bovine cartilage cells) are not examples of genetic engineering. Growing an actual human ear out of the back of a mouse thorough genetic engineering would be, I can say with confidence, biologically impossible.
The modifications we can make in living organisms through genetic engineering are much smaller than the changes we can and have already made through selective breeding and they are limited by the same biological principals. Genetic engineering is just a lot more specific and controlled. I'm not saying any of this gets an ethical free-pass, I'm just trying to put specific genetic modifications that rely on test tubes and a 21st century understanding of biology in the context of our human tendency to modify other species to our use and liking.
Using Animals
There is always the question of whether or not it's okay to use other creatures, even one-celled bacteria, to produce the things we want. Animals are used by humans to make all kinds of products - from food to medications to eyeliner. Many suffer and are killed in the process and some for unnecessary reasons (for me eyeliner would fall in this category). We have to choose how much of this we want to take part in, if any.
A cow expressing Lactoferrin is being used, though she may have a better deal than the one who has been selectively bred to be insanely meaty and produce way more babies than nature intended and is finally slaughtered for meat after lumbering around in a confined space for years. At least the Lactoferrin cow is making a medication to heal the sick instead of a bunch of hamburgers and other products of more dubious value to human health. The cow is highly unusual for recombinant expression, BTW, this is usually done in simple bacterial cells or some other type of cell culture (in flasks).
Informed Personal Choice
Each person should be allowed to make his own choice about whether or not to take part in manipulating the biology of animals to satisfy their own needs and to what extent they do. Some will choose not to consume animal products or any products with ingredients, including medications, developed through animal testing or produced recombinantly in animals. This is the right of any individual and why I promote transparency of process - from the earlier posts on Prolacta informing milk donors about what will happen to their milk to making patients aware of how their medications were made.
The Medications of Today and Tomorrow
Almost all medications available today were made using animals - either in the research leading to the drugs' discovery or in the testing of the drug. Many medications today, and many more in the future, will be made through genetic engineering (i.e. adding in the gene the encodes a desired product) of organisms from bacteria to rice to mice and even cows. Genetic engineering may also be part of the research leading to the discovery of medications produced using more traditional methods.
If It's Not About the Animals
If the problem with genetic engineering and recombinant expression for the development of medications is not about the animals, and you simply object to any type of any type of genetic engineering, than you should able to find out whether or not these methods were used in producing the drug you are being offered so that you can decline these medications based on your beliefs.
The Ethical Costs and Benefits
Like I said, it's never an ethical free-pass. I believe people should consider all aspects of the situation when choosing whether to use (or eat) a product that comes from animals and/or genetic engineering. I don't believe, however, that we should should halt genomic and proteomic research because it seems sketchy for ineffable reasons, or due to an unfounded belief in our power to override the basic rules of biology and create the "human-animal hybrids" of Bush's dark prophecy or other sensationalized, impossible creatures of doom. I also don't think blatantly unethical or dangerous research projects should ever be funded, whether they involve genetic engineering or not. Additionally, all food and drugs, however they are made, should be carefully scrutinized for safety before they can be sold to the public, and should not be falsely marketed.
If your child or someone else you love is suffering or dying, and they can be cured using a medication created with the help of genetic engineering, you may decide that you want in. You may not. These medications, like all medications, come with their own costs and risks that must be considered. I do, however, think it's important to acknowledge the value of curing the sick and reducing human suffering and untimely death.
-Heather
Selective breeding, cloned cows, and values
Heather,
There is alot to consider regarding genetic engineering and you have brought up some issues that I think should be explored from a different perspective. You wrote at one point, "of course selective breeding of domesticated animals and plants is a low-tech version of manipulating DNA." There are some people, including myself, who believe that genetic engineering is fundamentally different from selective breeding. Selective breeding crosses only organisms closely related, genetic engineering crosses the species barrier.
In 1975 at the Asilomar Conference, scientists got together to discuss the risks, regulations, the concerns, the controversy regarding the technology of manipulating DNA. Quite a few well-known scientists (Paul Berg, David Baltimore, Herbert Boyer Stanley Cohen, etc) composed a letter to Science in which they discussed one potential hazard, "derives from the need to use bacterium like E. coli to clone the recombinant DNA molecules and to amplify their number....new DNA elements introduced into E. coli might possibly become widely disseminated among human, bacterial, plant, or animal populations with unpredictable effects."
In 1982 a very serious virulent strain of e.coli was recognized, O157:H7. E.coli had acquired the shiga toxin with deadly results. A natural happening in our bacterial world? Or is it possible that genetic engineering was responsible?
I am not sure what you meant that "the cow is highly unusal for recombinant expression."
In the Journal of Dairy Science in 1997 an article called, "Transgenic Dairy Cattle: Genetic Engineering on a Large Scale," R.J. Wall et al. state, "Commercial interests have fueled research on modifying the genetic control of mammary glands for the purpose of producing pharmaceutical proteins in milk. However, this technology also offers the opportunity to alter the composition of bovine milk destined for the dairy industry." and
"Sixteen years ago, transgenic technology was invented (article published 1997), and, since then, an industry has formed to exploit that technology. In the next 16 yr, products created by that technology will likely be in the hands of consumers."
http://jds.fass.org/cgi/reprint/80/9/2213.pdf
In 1997 the first transgenic cow, Rosie, produced milk with the human gene alpha-lactalabumin. Cloned dairy cows were first introducted at the 1999 World Dairy Expo. Pharming had plans in the year 2000 for huge herds of transgenic cows producing human lactoferrin by farmers in Finland. There are transgenic cows in New Zealand, USA, Canada, Finland, China. The FDA approved cloned milk and meat (unlabeled) for consumption. I wouldn't imagine they would do this unless the transgenic technology had grown to the point where they could no longer afford to throw out the cloned milk and meat.
Lastly, you wrote, about "the value of curing the sick and reducing human suffering and untimely death. I think most of us, value the healing of the sick and reducing suffering. In a "Open Letter to the Asilomar Conference on Hazards of Recominant DNA," scientists from Harvard Medical School, MIT, and Boston University state, "The public rationale for these rapid developments in genetic engineering generally involves positing hope for individuals suffering from rare genetic diseases.....However, the search for such dramatic cures often diverts attention from the massive health needs of the population as a whole and the need to prevent the epidemics of our time, such as environmental and industrial carcinogensis, maluntrition and coronary heart disease."
This letter also states, "Since the risks and danger of these technologies are borne by the society at large, and not just scientists, the general public must be directly involved in the decsion making process." The letter was written in 1975 and yet the public has not been allowed into the discussion. In fact, the reality is that most Americans do not realize that alot of their foods, some of their medicines and vaccines, supplements are genetically engineered. We do not have informed choice because we have not been informed about the changes to our food, medicines, supplements, vaccines. We don't even have labels. So how does the consumer make a choice, when he or she is completely left in the dark?